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University of California, San Diego
       School of Medicine

 Pocket This!
 A Pocketbook of Essential
  Topics for the Medicine

         Compiled by
    Ken Antons, Class of 2002

Funding for this printing generously
           provided by:
           UCSD SOM
     Office of Student Affairs
April 2002

During my Medicine Clerkship I found that books like the "Washington
      Manual" were directed only at patient management with little
      information on pathophysiology. As its utility waned, it became
      heavier. I used "MD Consult," and spent countless hours searching
      for relevant articles. I found those articles useful to a point. They
      tended to be overly detailed and, more importantly, were impossible
      to review later. Using my 2nd year lecture notes as core material, I
      created a rudimentary pocketbook that served me well as a relevant
      portable reference and review book. The pocketbook was fully
      developed as an ISP project to provide medical students starting their
      core Medicine Clerkship with:
1) a handy portable concise relevant reference of essential topics and
      2) the greatest freedom in determining what they will carry in their
      already packed pockets.
I hope this pocketbook will help you read up on common topics and, more
      importantly, to review and review and review those topics so you can
      avoid hearing that dreaded phrase, "you should read more." Each of
      the topics covered has a clinical emphasis with all attempts made to
      make each one concise and relevant (to the best of my abilities.)
      Most topics are greatly redacted and reformatted lecture notes from
      the 2nd year, and summaries prepared for short talks on topics.
      Each chapter is formatted in a double sided printable format in a
      Microsoft Word document that can be printed, trimmed and then
      bound. A PDA version may be available in the near future.
I have tried my best to be accurate and up to date with each chapter. A
      great thanks goes out to student, fellow and faculty reviewers who
      gave constructive criticism on various chapters in the pocketbook:
      Colleen Bailey M.D., Harry Bluestein M.D., Richard Channick
      M.D., Quyen Dao, Timothy Dresselhaus M.D., Robert Engler M.D.,
      Ulrika Green M.D.., Alan Maisel M.D., Daniel O'Connor M.D., Truc
      Pham, Leland Rickman M.D., Thomas Savides M.D, Neil Sawhney
      M.D., Stephen Seagren M.D., and Paul Wolf M.D. Inevitably there
      will be some errors. Those are wholly my own. Feedback is greatly
      encouraged via the comments page and will allow those errors to be
      corrected in future versions.
I would also like to thank C. Brian Webb, Josh Breslow and Cathy
      SooHoo in the SOM Office of Educational Computing for helping to
      translate my idea into working source code.
Much thanks goes to Harry Bluestein M.D. , Timothy Dresselhaus M.D.,
      and Helene Hoffman PhD for all of their help and guidance in the
      evolution of this project.
Finally, I would like to thank the 2nd year faculty whose notes and wisdom
      inspired this book and form its genesis.
Good Luck on the Wards!!

Kenneth Antons
UCSD Class of 2002

                                                TABLE OF CONTENTS
TABLE OF CONTENTS ............................................ 3                    TREATMENT GOALS OF CARDIAC FAILURE ................ 33
                                                                                    DRUG TREATMENT OF HF ......................................... 33
                                                                                  CARDIOGENIC SHOCK ........................................ 34
      TABLE OF CONTENTS                                                             CLINICAL MANIFESTATIONS ..................................... 34
ADMIT ORDERS ....................................................... 7              INTERVENTIONS ....................................................... 35
PROCEDURE NOTE ................................................. 7                ARRHYTHMIAS ..................................................... 35
DISCHARGE NOTE .................................................. 7                 ATRIAL PREMATURE COMPLEXES (APCS) .................. 35
OFF SERVICE NOTE ................................................ 7                 VENTRICULAR PREMATURE COMPLEXES (PVCS) ....... 36
REVIEW OF SYSTEMS ............................................ 8                  TACHYCARDIAS .................................................... 36
ACUTE PHASE REACTANTS .................................. 8                          SINUS TACHYCARDIA ................................................ 36
SERUM PROTEINS ................................................... 8                ATRIAL FLUTTER ...................................................... 36
  PREALBUMIN ............................................................. 8      PAROXYSMAL SUPRAVENTRICULAR
  -1 GLOBULINS .......................................................... 8      TACHYCARDIAS .................................................... 36
  2-GLOBULINS .......................................................... 9         PAROXYSMAL ATRIAL TACHYCARDIA (PAT): ............ 36
  -GLOBULINS ............................................................ 9        AV NODAL REENTRANT TACHYCARDIA (AVNRT):... 37
  -GLOBULINS ............................................................. 9       PREEXITATION SYNDROME (WPW) ........................... 37
GI LAB TESTS ........................................................... 9        VENTRICULAR TACHYCARDIA (VT) ................ 37
URINALYSIS............................................................ 11           TORSADE DE POINTES .............................................. 38
  MACROSCOPIC ..........................................................11          VENTRICULAR FIBRILLATION AND VENTRICULAR
  MICROSCOPIC EXAMINATION .....................................11                   FLUTTER................................................................... 38
  OTHER URINE TESTS .................................................12             BRADYARRHYTHIMIAS ............................................. 38
RENAL LAB VALUES............................................. 12                  ANTIARRHYTHMICS ............................................ 39
CALCIUM ................................................................ 13         CLASS I AGENTS: ...................................................... 39
PHOSPHORUS ......................................................... 13             CLASS II AGENTS: BETA ANTAGONISTS. ..................... 39
MAGNESIUM........................................................... 13             CLASS III AGENTS:.................................................... 39
HOMOCYSTEINE ................................................... 14                 AMIODARONE, BRETYLIUM, SOTALOL, DOFETILIDE .... 39
TRACE MINERALS ................................................ 14                  CLASS IV AGENTS: ................................................... 39
PLEURAL EFFUSIONS ........................................... 14                    VERAPAMIL, DILTIAZEM ........................................... 39
CSF FLUID ............................................................... 15        CLASS V AGENTS: ADENOSINE .................................. 40
ACID BASE BASICS ................................................ 15              ATRIAL FIBRILLATION ....................................... 40
METABOLIC ACIDOSIS ........................................ 15                    INFECTIVE ENDOCARDITIS ............................... 41
  ETIOLOGY OF METABOLIC ACIDOSIS ...........................15                    VALVULAR HEART DZ......................................... 43
  ANION GAP ACIDOSIS ...............................................16              MITRAL STENOSIS .................................................... 43
  NONGAP ACIDOSIS ....................................................16            MITRAL REGURGITATION: ........................................ 44
  GAP: COMPLICATED VS. SIMPLE METABOLIC                                           MITRAL VALVE PROLAPSE ........................................ 44
  ACIDOSIS ..................................................................16     AORTIC STENOSIS ..................................................... 44
  CONSEQUENCES OF ACIDOSIS ....................................16                   AORTIC REGURGITATION .......................................... 45
  TREATMENT .............................................................17         TRICUSPID REGURGITATION ...................................... 45
METABOLIC ALKALOSIS .................................... 17                       CARDIOMYOPATHY ............................................. 46
  TREATMENT .............................................................17         ROLE OF MYOCARDIAL BIOPSY ................................. 47
RESPIRATORY ACIDOSIS .................................... 18                      MYOCARDITIS ....................................................... 47
RESPIRATORY ALKALOSIS ................................ 18                         CARDIAC TAMPONADE ....................................... 47
STEROID THERAPY .............................................. 18                 ACUTE PERICARDITIS ......................................... 48
                                                                                  CONGENITAL HEART DISEASE ......................... 49
                                                                                    LEFT TO RIGHT SHUNTS: ........................................... 49
 CARDIOLOGY                                               _Toc8027545               RIGHT TO LEFT SHUNTS ............................................ 50
                                                                                    OBSTRUCTIVE CONGENITAL ANOMALIES .................. 50
CARDIAC HX & PHYSICAL .................................. 21
  HISTORY-TECHNIQUES ..............................................21             ANEURYSM ............................................................. 50
  PHYSICAL EXAM .......................................................21         ARTERITIS .............................................................. 51
  CARDIAC AUSCULTATION: ........................................22                PHLEBITIS .............................................................. 52
  HEART SOUNDS ........................................................22         DIGITALIS............................................................... 52
  CARDIAC MURMUR ...................................................22            NITRATES ............................................................... 53
EKG READING ........................................................ 22           CALCIUM CHANNEL BLOCKERS ...................... 53
  (1) RATE:..................................................................23     CLINICAL USES OF CA CHANNEL BLOCKERS: .............. 54
  (2) RHYTHM: ............................................................23      -BLOCKERS .......................................................... 54
  (3) AXIS/R WAVE PROGRESSION ................................23                  DIURETICS.............................................................. 55
  (4) INTERVALS ..........................................................23
  (5) HYPERTROPHY/ENLARGEMENT ............................24
  (6) ISCHEMIA/INFARCTION: .......................................24
                                                                                  PULMONOLOGY .................................................... 57
  (7) OTHER ................................................................25    TESTS OF LUNG FUNCTION................................ 57
ATHEROSCLEROSIS ............................................. 25                    BASIC TESTS OF VENTILATORY LUNG FUNCTION ....... 57
ACUTE MYOCARDIAL INFARCT........................ 25                                 CLINICAL APPLICATIONS OF LUNG FUNCTION TESTS . 57
  CARDIAC ENZYMES ...................................................26             BASIC TESTS OF RESPIRATORY FUNCTION ................. 57
  MANAGEMENT ..........................................................26         READING A CHEST XRAY ................................... 58
PATHOPHYSIOLOGY OF AMI ............................. 27                             THE NORMAL LUNG ................................................. 58
ASA, HEPARIN, AND THROMBOLYTIC TX....... 29                                       PULMONARY EMBOLISM ................................... 59
  ANTIPLATELET THERAPY ..........................................29               PULMONARY INFARCTS ..................................... 60
  ANTITHROMBIN THERAPY .........................................29                COPD ........................................................................ 60
  THROMBOLYTIC THERAPY ........................................30                   DIAGNOSIS ............................................................... 60
  CLINICAL USES .........................................................30         TREATMENT: ............................................................ 61
CONGESTIVE HEART FAILURE ......................... 31                             ASTHMA .................................................................. 61
  FORMS OF HF ...........................................................32         BRONCHODILATOR AND ASTHMA THERAPY ............... 62
  PRECIPITATING CAUSES OF CHF................................32                   ACUTE BRONCHITIS ............................................ 63
  SYMPTOMS RELATED TO PULMONARY CONGESTION ....32                                 CHRONIC BRONCHITIS ....................................... 64
  CARDIAC MANIFESTATIONS OF HF ............................33                     LUNG ABSCESS ...................................................... 65
BRONCHIECTASIS ................................................ 65                ADDISON'S SYNDROME............................................103
INTERSTITIAL LUNG DISEASE .......................... 65 PHEOCHROMOCYTOMA ................................... 103
ALVEOLAR HEMORRHAGE SYNDROMES ...... 66 RENAL OSTEODYSTROPHY .............................. 104
BOOP........................................................................ 66   PREVENTION AND THERAPY ....................................104
RESPIRATORY FAILURE ..................................... 66
ARDS ........................................................................ 67
ENVIRONMENTAL LUNG DZ .............................. 68                               RHEUMATOLOGY
  PNEUMOCONIOSES .................................................... 68 OSTEOARTHRITIS ............................................... 107
                                                                                  MEDICAL MANAGEMENT: .......................................107
                                                                                 RHEUMATOID ARTHRITIS ................................ 108
     GASTROENTEROLOGY                                                             ADJUNCTIVE TREATMENT ...............................109
                                                                                  DISEASE MODIFYING TX ...................................109
GI BLEEDING ......................................................... 71
  UPPER GI BLEEDING: ............................................... 71          GOUT ...................................................................... 109
  LOWER GI BLEEDING: .............................................. 71            DRUG THERAPY .................................................110
ESOPHAGEAL DISORDERS ................................. 71 SYSTEMIC LUPUS ERYTHEMATOUS .............. 110
  ESOPHAGEAL MOTILITY DISORDERS: ......................... 71                    DERMATOMYOSITIS .......................................... 111
  ANATOMIC ABNORMALITIES: .................................... 72 FIBROMYALGIA .................................................. 112
GERD DISEASE ...................................................... 72 ANKYLOSING SPONDYLITIS............................. 112
GASTRIC & DUODENAL ULCERS ...................... 73
  DUODENAL ULCER ................................................... 73                            NEPHROLOGY
  GASTRIC ULCER ....................................................... 73       RENAL REGULATORS ........................................ 115
  ULCER TREATMENT .................................................. 74          ACUTE RENAL FAILURE.................................... 115
MALABSORPTION................................................. 75                CHRONIC RENAL FAILURE............................... 117
  TESTS OF MALABSORPTION ...................................... 75                 CLINICAL FEATURES................................................118
  DIFFERENTIAL DIAGNOSIS ........................................ 76               APPROACH TO PT WITH CRF ....................................118
DIARRHEA .............................................................. 77         TREATMENT OF CRF ...............................................119
  ACUTE DIARRHEA: ................................................... 77         POLYCYSTIC KIDNEY DISORDERS ................. 121
  CHRONIC DIARRHEA: ............................................... 77             ADULT POLYCYSTIC KIDNEY DISEASE (APCKD) .....121
  ANTIDIARRHEAL AGENTS ......................................... 77                INFANTILE POLYCYSTIC KIDNEY DISEASE ................121
IRRITABLE BOWEL SYNDROME ....................... 78                                ACQUIRED POLYCYSTIC KIDNEY DISEASE................121
INFLAMMATORY BOWEL DZ ............................ 78                            URINARY STONES ............................................... 121
ULCERATIVE COLITIS ........................................ 78                     MANAGEMENT ........................................................122
CROHN’S DISEASE ................................................ 80                PROPHYLAXIS .........................................................122
INTESTINAL OBSTRUCTION .............................. 81                         DISORDERS OF NA EXCRETION ...................... 122
DIVERTICULITIS ................................................... 81            HYPOVOLEMIA.................................................... 123
APPENDICITIS ....................................................... 82          EDEMA ................................................................... 123
VIRAL HEPATITS .................................................. 82               TREATMENT OF EDEMA ...........................................123
HEPATITIS A .......................................................... 83        SODIUM HOMEOSTASIS..................................... 124
HEPATITIS B .......................................................... 83          OVERVIEW OF WATER METABOLISM: .......................124
HEPATITIS C .......................................................... 84        HYPONATREMIA ................................................. 125
HEPATITIS D: DELTA AGENT ............................ 85                           TREATMENT ...........................................................125
HEPATITIS E: ......................................................... 85        HYPERNATREMIA ............................................... 125
FULMINANT HEPATITS ....................................... 85                    POTASSIUM........................................................... 126
ETOH INDUCED LIVER DZ.................................. 85                         HYPERKALEMIA ......................................................127
HEPATOTOXINS .................................................... 87               HYPOKALEMIA........................................................127
  INTRINSIC HEPATOTOXIN. ......................................... 87            HYPERTENSION ................................................... 128
  HOST-DEPENDENT HEPATOTOXIN .............................. 87                     ESSENTIAL HTN .....................................................128
CIRRHOSIS ............................................................. 88         EVALUATION OF A PT WITH HTN .............................129
PORTAL HTN.......................................................... 89            SECONDARY HTN ...................................................129
HEPATIC FAILURE (COMPLICATIONS) ........... 90                                     IS TREATMENT OF HTN BENEFICIAL? ......................130
BILIARY DISEASE ................................................. 91               NON DRUG TREATMENT OF HTN.............................131
  PATHOPHYSIOLOGY OF BILIRUBIN METABOLISM ....... 92                               DRUG TREATMENT OF HTN ....................................131
CHOLESTASIS ........................................................ 92            ANTI-HYPERTENSIVE MANAGEMENT: 1ST STEP .........133
  EXTRAHEPATIC CHOLESTASIS ................................... 93                  STEP CARE REGIMENS: SECOND STEP........................133
PANCREATIC TESTS ............................................ 93                   STEP CARE REGIMENS: THIRD STEP ..........................134
ACUTE PANCREATITIS: ...................................... 94                      HTN EMERGENCIES: ...............................................134
CHRONIC PANCREATITIS................................... 95
HEREDITARY PANCREATITIS ........................... 96
                                                                                                 INFECTIOUS DZ
            ENDOCRINOLOGY                                                        ANTIBIOTICS ........................................................ 135
                                                                                 BACTERIAL PNA .................................................. 137
DIABETES MELLITUS TYPE 2 ............................ 97                         ASPIRATION PNA................................................. 138
HYPERTHYROIDISM ............................................ 98                  LIPID PNA .............................................................. 139
  TREATMENT ......................................................... 98         VIRAL PNA ............................................................ 139
  PREGNANCY AND HYPERTHYROIDISM ....................... 99                       MYCOPLASMAL PNA .......................................... 139
  THYROID STORM ...................................................... 99        PNA IN THE IMMUNOCOMPROMISED HOST 139
HYPOTHYROIDISM .............................................. 99                 URINARY TRACT INFECTION........................... 139
  MYXEDEMA CRISIS ................................................ 100           INFECTIOUS DZ OF THE BOWEL ..................... 140
  CENTRAL HYPOTHYROIDISM................................... 100                    VIRAL INFECTIONS ..................................................140
  EUTHYROID SICK SYNDROME ................................. 100                    BACTERIAL INFECTIONS ..........................................140
THYROIDITIS ....................................................... 100            INTESTINAL PARASITES ...........................................141
ANTERIOR PITUITARY ...................................... 101                    TUBERCULOSIS ................................................... 141
  HYPERPITUITARISM ......................................... 101                 AIDS ........................................................................ 143
  HYPOPITUITARISM ........................................... 102                  STAGING/PROGNOSTIC MARKERS .............................143
  POSTERIOR PITUITARY .................................... 102                     PATHOGENESIS OF HIV INFECTION ..........................143
ADRENAL CORTEX HYPERFUNCTION .......... 102                                        MORBIDITY AND MORTALITY ..................................144
ADRENAL CORTEX HYPOFUNCTION ............ 103                                     HIV TESTING ........................................................ 144
  ACUTE PRIMARY HYPOFUNCTION ........................... 103                     INITIAL WORK-UP OF HIV PT .......................... 145
ANTIRETROVIRAL THERAPY .......................... 146                                     LOSS OF PLATELETS ............................................... 162
PULMONARY DISEASE IN HIV.......................... 146                                  VON WILLEBRAND DZ: ..................................... 162
  MALIGNANCIES ...................................................... 148               LIVER DZ & THE COAGULATION SYSTEM:.. 162
SYPHILIS ............................................................... 148            HEMOPHILIA ....................................................... 162
  CLINICAL MANIFESTATIONS AND STAGING .............. 148                                NATURAL ANTICOAGULANTS......................... 163
MALARIA .............................................................. 150              LUPUS LIKE ANTICOAGULANT....................... 163
PROSTATITIS........................................................ 151                 THROMBOCYTOSIS ............................................ 163
EPIDIDYMITIS ...................................................... 151                 TRANSFUSIONS ................................................... 163

                   HEMATOLOGY                                                                               ONCOLOGY
PERIPHERAL BLOOD SMEAR ........................... 153                                  GENERAL ONCOLOGY ...................................... 165
   RED BLOOD CELLS: ................................................ 153                  SURGICAL ONCOLOGY ............................................ 166
   LEUKOCYTES .......................................................... 153              RADIATION ONCOLOGY .......................................... 166
   MONOCYTES ........................................................... 153              MEDICAL ONCOLOGY ............................................. 166
   EOSINOPHILS .......................................................... 153           TUMOR MARKERS:............................................. 167
   LYMPHOCYTES ....................................................... 153              BREAST CANCER ................................................ 168
ANEMIA ................................................................. 153            PROSTATE CANCER ........................................... 169
   IRON STUDIES ......................................................... 154             METASTATIC PROSTATE CANCER ............................. 170
   RBC INDICES:......................................................... 154            LUNG CANCER..................................................... 170
HYPOCHROMIC MICROCYTIC ........................ 154                                       SMALL CELL CANCERS ........................................... 171
NORMOCHROMIC NORMOCYTIC ................... 155                                           NON-SMALL CELL CARCINOMA .............................. 172
MACROCYTIC ...................................................... 156                     BRONCHIOLARLOALVEOLAR CARCINOMA ............... 172
   NON-MEGALOBLASTIC ............................................ 156                     BENIGN LUNG TUMORS .......................................... 172
   MEGALOBLASTIC .................................................... 156               COLORECTAL CANCER..................................... 173
HEMOLYTIC ANEMIAS ...................................... 156                              THERAPEUTIC APPROACHES TO RECTAL CANCER: ... 173
   EXTRAVASCULAR HEMOLYSIS ................................. 156                          TUMORS OF LARGE INTESTINE ................................ 173
   INTRAVASCULAR HEMOLYSIS .................................. 157                       SCREENING AND SURVEILLANCE FOR COLON
PANCYTOPENIA .................................................. 157                     CANCER ................................................................ 174
ACUTE MYELOID LEUKEMIA .......................... 157                                     SCREENING FOR COLORECTAL NEOPLASIA .............. 174
CHRONIC MYELOID LEUKEMIA ..................... 158                                      LIVER CANCER ................................................... 175
ACUTE LYMPHOCYTIC LEUKEMIA................ 158                                          STOMACH CANCER ............................................ 175
CHRONIC LYMPHOCYTIC LEUKEMIA B-CELL                                                     ESOPHAGEAL CANCER ..................................... 176
................................................................................. 158     SQUAMOUS CELL CARCINOMA ................................. 176
MYELOFIBROSIS ................................................. 158                       ADENOCARCINOMA ................................................ 176
NEUTROPENIA ..................................................... 158                   HODGKIN’S LYMPHOMA .................................. 176
POLYCYTHEMIA VERA...................................... 158                             NON-HODGKIN’S LYMPHOMA......................... 176
MULTIPLE MYELOMA ....................................... 158                            AIDS RELATED LYMPHOMA:........................... 177
WALDENSTROM’S MACROGLOBINEMIA...... 159                                                 PANCREATIC CANCER ...................................... 177
INFECTIOUS MONO ............................................ 159                        THYROID CANCER ............................................. 177
SYSTEMATIC APPROACH TO BLEEDING                                                           ADENOMAS ............................................................ 177
DISORDER ............................................................. 159                CARCINOMA ........................................................... 177
CLINICAL APPROACH TO BLEEDING                                                           TESTICULAR CANCER:...................................... 178
DISORDERS ........................................................... 159                 GERM CELL TUMORS (GCT): ............................ 178
PLATELET DYSFUNCTION ................................ 160                                 NON GERM CELL TUMORS ............................... 179
THROMBOCYTOPENIA ...................................... 160                             RENAL CANCER .................................................. 179
   PRODUCTION DISORDERS ........................................ 160                    BLADDER CANCER ............................................. 179
   DISORDERS OF DISTRIBUTION .................................. 160                       TRANSITIONAL CELL CARCINOMA: .......................... 179
   DESTRUCTION DISORDERS ...................................... 160
                                                                                       ESSENTIAL BASICS--7

                                    ESSENTIAL BASICS
                                                                          Drug Levels: dig, aminoglycoside, theophylline,
                                                                           procainamide, acetaminophen, quinidine,
                ADMIT ORDERS                                               cyclosporin, lithium, vanco, serum tox, EtOH.
              A.D.C. VAAN DISSEL                                          Endocrine: -HCG, ICON, Ketones, osm, lactic acid,
1)       Admit: to ward, team, attending, resident, HO.                    fingersticks, HgA1C, C-fragement, TSH, T3, fT4,
2)       Diagnosis:                                                        AM cortisol, aldosterone, epi, Prolactin, PTH, FSH,
3)       Condition: stable/good/fair/poor/critical.                        LH, Cortrysin stim test.
4)       Vitals: unless pt is quite unstable q shift will suffice         ID: Blood Cx, MAI, CMV, Mycoplasma, Cold
5)       Activity: bed rest, ad lib, OOB to chair TID, OOB                 Agglutinins, legionella, Hgb A1C, IgM, Hep C, Hep
         walking with assistance, walker, bedside commode,                 B Core Ab, Surf Ag, ASO titers, RPR, VDRL, FTA,
         soft restraints.                                                  Monospot, Cyptococcus Ag, Toxoplasma Ab.
6)       Allergies                                                        GI: AST, ALT, GGT, Alk Ph, LDH, Amylase,
7)       Nursing: bed position, dressing changes, neuro                    Lipase, Ammonia
         checks, preps (enemas),showers, NT suctioning, daily             Pulmonary: Pulse Ox, ABG, Alpha-1 antitrypsin,
         weights. I/S to bedside, NG LCWS.                                 ACE
8)       Call HO for SBP > 160 or < 90, SBP >100 or <70,                  Tumor Ag: CEA (Colon. Also GI and Breast. Mild
         HR >120 or < 55, RR > 30 or < 10, T > 101.5*, UOP                 in tobacco, COPD, cirrhosis, hepatitis, IBD), -feta
         < 120cc q4*, Neuro checks q2*, FSG >300.                          protein (hepatoma, germ cell tumors, liver dx), CA
9)       Diet: NPO, regular, 2 gm Na, 4 gm Na soft,                        125 (ovarian CA. Non specific) PSA, Acid
         mechanical soft, puree, cardiac, renal, ADA 1200-                 phosphatase, CA 19-9 (pancreas) CA 15-3 ( Breast).
         1400 cal, no salt added, bland, low cholesterol/low
         fat, clear liquid, full liquid, low residue, high fiber,
         lactose restricted, gluten free.                                     PROCEDURE NOTE
10)      Ins & Outs:                                                1) Procedure: Diagnosis for which pt is getting
        I's & O's.                                                    procedure
         IV fluids:                                                 2) Consent: Procedure benefits and risks and
        Replacement: 75 to 100 cc/hr.                                 alternatives explained to pt who voiced
        Resusc:                                                       understanding of procedure and agreed to proceed
        Drains - NG to LCS, Foley to gravity.                         with ___. Consent signed and in chart.
11)      Specific drugs: antibiotics, antiarrhythmics,              3) Indication: Why procedure is necessary.
12)      Symptomatic drugs: Tylenol, Mylanta, MOM                   4) Physician: MD who performs procedure
                                                                    5) Description and findings: Area prepped/draped in a
        Ulcer Proph: Carafate 1 gm PO BID, Cimetidine, 400
                                                                       sterile fashion. Note anesthetics and medications
         mg po BID, Ranitidine 150 mg PO BID, Pepcid 2o
                                                                       used. Note body location, instruments used, and
         mg IV q12*, Protonix.
                                                                       technique. Note pertinent findings.
        DVT Proph: Heparin 5000 u SQ q12*, Venodyne
                                                                    6) Complications if any.
        Tylenol 650 mg PR q4-6* PRN T> 101.5*                      7) EBL if any
        Compazine 10 mg IV q6* PRN N/V                             8) Disposition: How pt tolerated procedure. Pt status
        Benedryl 25-50 mg IV QHS insomnia                             after procedure.
        MSO4 1-2 to 2-4 mg IV q2* PRN pain
        PCA for Pain
13)      Extras: x-rays, EKG's, Holter monitors, old chart to                  DISCHARGE NOTE
         floor, old EKG to floor.                                   1)     Name:
        Skin protect: MVI, Zn, Vit C, Egg crate, tape for IV       2)     Day of admission:
         only, heel protectors, turn q2*, OOB, duoderm, ¼           3)     Day of discharge:
         strength Dakins wet to dry dressing BID.                   4)     Admission diagnoses: 1*: reason for admit, 2*: other
        Nutrition: Aspiration precautions for all NG, keofeed,            active Dx
         and G-tube feedings, supplements  sustacal                5)     Discharge diagnoses: May state SAA (same as
         pudding, ensure shake, calorie counts, dietary                    above) if no change from admit
         consult, anergy panel.                                     6)     Service, attending, resident, and intern.
        Oxygen: ABG, pulse ox, peak flow, PFT, bedside             7)     Procedures: major procedures, or studies, performed
         PFT, Humidified NC, face mask, face mask non-                     during this hospital stay, date completed, and major
         rebreather, CPAP mask, chest PT, RT to induce                     findings ( e.g. cardiac echo 1/2/99: mild aortic
         sputum.                                                           regurgitation.
        Precautions: Seizure, Suicide, DT (Ativan 1-2 mg           8)     Consults: Services consulted and why. List person
         po/im q6* PRN, Ativan standing orders, call HO if                 seen.
         agitated), Aspiration precautions. Keep HOB                9)     HP: should be 1 liner. See admission H and P for
         elevated at all times. Pts with fistula  no blood                details.
         draws in arm with fistula.                                 10)    Hospital course: List systems or problems and go
        Vitamins: Calcitrol, MVI, Folate 1 mg, Thiamine 25                through them 1 by 1 and summarize the pertinent
         mg PO, Zn sulfate 220 mg PO, CaCO3 650 mg PO,                     aspects of the hospital course for each. Always at
         Vit K 1-2 mg sc/im, Vit C 500 mg PO, MgOx 400                     least these 4.
         mg PO.                                                             FEN: IV fluids switched to solids as tolerated.
14)      Labs:                                                              Resp: Breathing room air,
        Routine: CBC, Chem 7, Chem 12, Mg                                  CV:
        Blood: PT, PTT, bleeding time, Type and screen,                    ID.
         TIBC, Fe, ferritin, retic count, haptoglobin, folate,      11)    Disposition: where are you discharging the pt to?
         B12, fibrinogen, fibrin split prod, d-dimer,               12)    Condition: on discharge
         cryoglobins, G6PD, Sickle cell, Protein C.                 13)    Medications: out patient medications after discharge
        Cardiac: Cardiac enzymes, EKG, q8* x3, lipid               14)    Follow-up: List all follow-up appointments for the pt.
         profile.                                                   15)    Other instructions: special diet, activity restrictions.
        Connective Tissue: ESR, CRP, Rh factor,
         complement, ANA, anti-DS DNA, SSA, SSB, RNP,                        OFF SERVICE NOTE
         cANCA, pANCA, Cyrogloblins, SPEP, ACE,                     Chief complaint, DOA, Age, Sex, Race
         purkinje cell Ab.
Brief HPI (especially presenting symptoms)
Pertinent PMH (or "refer to H&P")
Initial assessment and plan                                                        ACUTE PHASE
Hospital course & work-up to date (list tests, dates,results,
and pending labs)
Medications currently taking                                  Erythrocyte Sedimentation Rate (ESR)
Current problems, plans, scheduled treatments                 Rate at which RBC  through plasma and depends largely
                                                                  on plasma concentration of fibrinogen. Is an indirect
     REVIEW OF SYSTEMS                                            measurement of plasma acute-phase protein
General: Wt gain/loss, appetite, night sweats, weakness,
     fatigue, fever/chills, sleep.                            Important proteins are fibrinogen, 2-globulins, and 1-
Skin: Rash, lesions, hair/nail changes                            globulin
Heme: Hx of anemia, bleeding, easy bruising,                  Changes slowly.
Eyes: vision, vision loss, blurring, discharge/tearing,               Variables in ESR: Size, shape and # of RBC, and
    diplopia                                                              Immunoglobulins.
Ears: Decreased hearing, tinnitus, pain/drainage                       Hct: inhibits fall   ESR
Nose/throat/sinus: sinus, epistaxis, rhinorhea,                        Hct: elevated ESR
    hoarseness, ansomia                                               Aging:  as get older. ♂ 65-79  0-38, ♀ 65-79  1-53
Mouth: sores, bleeding gums, dentures, hoarseness, taste              Estrogen:
    problems, dry mouth                                               Pregnancy: Hemodilution  elevated ESR
Lungs: dyspnea, wheezing, hemoptysis, cough, sputum
    production.                                                       Markedly Increased:
CV: Pedal edema, varicose veins, Hx of M, chest pain,                   Inflammation: infection or collagen dz.
    tachycardia, palpitations, claudication, orthopnea.                 Malignancy: Multiple myeloma, metastatic CA,
GI: Abd discomfort, Abd pain, N, V, hemataemesis,                        malignant lymphoma, leukemia
    consitpation, D, melena, hemorrhoids, hematochezia,                 Severe renal dz.
    dysphagia, heartburn.                                             Moderately Increased: Acute and chronic infectious dz,
Urinary: Dysuria, frequency, hesitancy, incontinence,                    RA, MI
    hematuria, discharge
Urology: Testicular pain, sores/discharge, libido, sexual
                                                                      C-Reactive Protein (CRP)              Normal Range <2
    dysfunction, sterility, contaception                              Choice for detection of acute inflammation and
Gyn: Gravida____ Parvida _____ abortion, last menstrual                    monitoring response to Tx of inflammatory dz.
    period ______ ago, regularity of periods ______                   Function: component of innate immune system. Helps to
Sexual Hx: active, men/women/both, satisfied with sex                      recognize foreign pathogens and damaged cells. Can
    life, libido changes                                                   active complement system.
Endocrine: polyuria, polydipsia, polyphagia, skin/hair                Changes rapidly w/pt‘s condition.
    changes, cold/heat intolerance                                    If > 100  80 to 85% have bacterial infections.
Bones, Joints, Muscles: Joint pain, sweating, arthritis,              Does not change with age.
    myalgia, joint swelling, ab ROM.                                  Most have normal <2. Some have up to 10. Thought to be
Neuro: Headache, vertigo, ansomia, diplopia, syncope,                      2/2 low-grade processes such as gingivitis, or trivial
    Hx of seizures, tremor, ataxia, dysethesia.                            injury. CRP values < 10 have been found in
Psychologic: Hx of anxiety, nervousness, depression,                       osteoarthritis pts.
    memory loss, mood disorder.                                       Slight  found to predict future coronary events.
                                                                      Exception: Pt‘s w/active SLE do not have  CRP, but do
Make Up of Daily Bodily Fluids                                             get  w/bacterial infections.
Fluid        Na       K Cl            HCO3          Volume
Biliary      145       5 100          35              50-800
Diarrheal     60      35  40          30              Varies                   SERUM PROTEINS
Gastric       60      10 130           0            100-4000
Ileal        130       5 100          50            100-9000                             Prealbumin
Pancreatic   140       5  75         115             100-800          Made in liver. T ½ of 2-3 days
Salivary      10      26  10          30            500-2000          Transport protein for Thyroxine and role w/Vit A
Make Up of Replacement Fluids                                          low protein intake and w/acute and chronic
Fluid Na       K ClHCO3             Ca    kcal/L      Glu                 inflammation.
1/2 NS 77      — 77 —               —     ——
NS    154      — 154 —              —     ——                                            -1 globulins
D5W —          — — —                —     17050
D10W —         — — —                —     340100                      1-Antitrypsin                   Normal Range 80-100
LR    130      4 109 28             3     9                           80% of 1 globulins.
                                                                      Protease inhibitor. Made by liver
Insulin Sliding Scale                                                   : Acute inflammation, malignant tumors.
If NPO, FS QID. If eating, check FS qam and qhs, after                  : Hereditary emphysema, hepatic damage (made in
    meals                                                                 liver), severe nephrotic synd., cachexia.
If FS <70,  1 amp D50 & call HO.    251-300  6 U Regular Insulin    HDL
70-150, give nothing                 301-350  8 U Regular Insulin
151-200  2 U Regular insulin        351-400  10 U Regular Insulin   Lipid transport
201-250  4 U Regular Insulin        > 400  12 U Regular Insulin,      :  risk of CHD
      call HO                                                           : Tangier dz
Insulin Basics                                                        -antichymotrypsin
Body needs 24 U insulin per day.                       Inhibits chymotrypsin
2 units Reg Insulin  Glu by 40
                                                         : Acute inflammation, surgical trauma.
                                                         : MI
If insulin dependent can start with
24 units NPH qam, and 12 U NPH qpm + sliding scale or Transcortin
30 units NPH qam, and 15 units NPH qpm + sliding scale Binds cortisol
                                                         : Pregnancy, OCP.
                                                                            ESSENTIAL BASICS--9
  : Afternoon                                                : Fe deficiency anemia, pregnancy, OCP, acute
Thyroxine-binding globulin
                                                              : Chronic dz (infections, renal insufficiency, collagen
Binds T4, T3.                                                   vascular dz, malignancy), nephrotic synd, hepatic dz ,
  : Pregnancy, OCP, hereditary                                 (-) acute phase response.
  : Hereditary                                             Fe deficiency anemia  attempt to  Fe stores by 
                                                                transferrin   Fe absorption from GI tract. May
                  2-Globulins                                  rise to 600.
Haptoglobin                       Normal Range 50-220       Hemopexin                        Normal Range 50-115
Binds Hgb. Helps to recycle Hgb w/hemolysis and             Binds free heme when Fe is in the ferric form. Complex
    conserve body-iron. Binds free Hgb and complex is           removed by liver w/start of bilirubin metabolism.
    removed by liver and destroyed.                             Plasma hemopexin  w/intravascular hemolysis and
Can get a mixed picture w/ due to inflammation and            is more sensitive than haptoglobin. Hemopexin is not
    due to hemolysis, so may get normal lab value               destroyed after being removed by liver.
    despite both processes.                                   : Acute inflammation. Not considered acute phase
: Acute inflammation                                           reactant.
: < 25. Acute hepatitis, liver damage, severe in vivo        : Hemolytic anemia, internal bleeding into body cavity
    hemolysis (need 7 days to restore serum levels after        & organs, necrosis of liver, nephrosis.
    hemolysis), severe nephrosis.                           LDL
Ceruloplasmin                     Normal Range 10-40        Lipid transport esp. cholesterol.
Binds Cu which is needed for oxidative mitochondrial          : Obstructive jaundice, hyperlipidemias
    function, and formation of Hgb.
                                                            C-3 Complement:
Also works as a ferroxoidase Fe2+  Fe3+ Fe2+ is
    absorbed from GI tract. Transferrin only binds Fe3+       : Acute inflammation, acute stress
: Malignancies esp. acute leukemia (Used as sensitive        : Acute GN, autoimmune dz.
    marker for relapse of Hodgkin‘s and Non-Hodgkin‘s       Fibrinogen
    lymphoma), pregnancy, OCP, acute inflammation
                                                            Coagulable protein.
: Wilson‘s dz , nephrotic syndrome, severe liver dz

    (impaired synthesis), malabsorption. Makes up only
    a small part of SPEP so will not distort 2 band.
                                                            Lysozyme: Bacterial wall lysis
Wilson’s Disease                                              : Monocytic leukemias, Sarcoidosis, regional enteritis
 serum Ceruloplasmin,  tissue copper,  urine copper,     C-Reactive Protein: Made by liver. Initiated by
    Kayser-Fleisher rings.                                      antigens.
Clinical presentation:                                        : Acute inflammation, trauma, bacteria.
Age of onset of symptoms variable. Most in adolescence.
    Up to 50‘s.                                             Immunoglobulins:
Kayser-Fleisher rings: Deposits of copper on cornea. Best   Only with liver dz will you get beta-gamma bridge
    viewed from above or front w/slit lamp exam. May        IgA: Surface immunity
    be reduced medially and laterally. More marked at       IgM: Early humoral immunity.
    superior and inferior aspects of cornea. Will fade      IgG:
    with penicillamine Tx.                                  Polyclonal Gammopathy:
Lenticular degeneration: rigidity, drooling, dysarthria,
                                                            Chronic liver dz, chronic infections, malignancy,
                                                                autoimmune dz, misc.
Psuedosclerosis: Flapping tremors of wrists and shoulders
Hepatosplenomegaly                                          Monoclonal Gammopathy:
Subacute to chronic or acute hepatitis.                     Multiple myeloma:
Renal: Diffuse and widespread. Hematuria, proteinuria,     Waldenstrom’s macroglobinemia:
    excretion of uric acid   serum uric acid.
Hemolytic anemia:
                                                                         GI LAB TESTS
Diagnosis:                                                  ALT                                Normal range 10-40
Serum Ceruloplasmin: < 20. 5-30% of pts will have
    Normal Ceruloplasmin. If clinically suspect continue    Highest concentration in liver. Only located in
    work up.                                                    microsomal portion of hepatic cell.
Urinary Copper: W/Wilson‘s dz > 100 mg/24 hrs. Nl is        Decreased:  Vit B-6. ♀ taking OCP, RF undergoing
    <30 mg                                                      dialysis
Kayser-Fleisher rings: 70% sensitivity, 100% specificity.   Increased:
Liver biopsy: Amount of dry copper per dry weight of        Hepatic injury: 20x > than normal.
    liver.                                                  Acute viral hepatitis: ALT > AST. Used as indicator for
                                                                HCV in donated blood. ALT rises early and returns
Treatment:                                                      to normal w/in a few weeks.
Early diagnosis                                             Chronic hepatitis: Elevations >6 mo. Minimal increase.
Penicillamine                                               AMI:  ~30%. 2/2 hepatic congestion.
Lipid transport, esp. TG
                                                            AST                                Normal range 10-40
   Hyperlipidemia                                          Located in microsomal and mitochondrial portions of
                                                                hepatic cell. Also present in heart, SkM, pancreas
C4 Complement:                                                  and kidneys.
  : Acute inflammation                                     Decreased:
                                                             Vit B-6: Poor nutrition.
                   -Globulins                              ♀ taking OCP
                                                            RF undergoing dialysis: B-6 inhibitor. Is a dialyzable
Transferrin                    Normal Range 250-400         Increased:
Binds iron.                                                 Viral hepatitis: 10-20x > upper range of nl, w/AST
                                                                >1,000, and ALT > AST.
Fulminant Acute Viral hepatitis: AST may rapidly  to nl
    or below Nl because of hepatic necrosis, and cellular    Elevated Unconjugated Bilirubin:
    exhaustion of AST.                                       Gilbert Syndrome: Genetic syndrome. Associated w/
EtOH Hepatitis: AST > ALT. AST ~300.                             during fasting.
AMI: . Not for diagnosis.                                   Crigler-Najjar Syndrome:
Other: infectious mono, hepatobiliary obstruction,           Hemolytic Anemia:
    cirrhosis, 1* and metastatic Ca of liver, hepatic        Resolving hematomas:
    granulomas, acute pancreatitis, hemolytic anemia,        Hemorrhagic pulmonary infarcts:
    and Pyelo.                                               Postoperative elevations
Alk Phos                          Normal range 25-100
                                                             Dissociation between AP and Bili: AP cannot be readily
Useful for diagnosing hepatobiliary and bone dz. There           re-excreted from non-obstructed areas of liver. Bili
    are multiple AP isozymes specific to various organs.         can   AP with Nl bili.
    This can be determined by heat treating sample.
Liver AP and bilirubin have separate routes of exit from     Albumin                          Normal range 3.1 – 4.3
    hepatic cells. AP exits directly to the lumen of the     Produced in liver. Sensitive, but non-specific for liver dz.
    biliary tree.                                                Carrier protein for calcium. Normal T ½ 17-26 days.
                                                             Physiologic functions: maintain osmotic pressure,
Decreased:                                                       transport protein.
Hypophosphatasia: Inborn error of metabolism.                Hypoalbuminemia:
Hypothyroidism: Thyroid hormone required for                 Liver dz:  synthesis, toxic effect of EtOH, malnutrition.
    osteoblastic function.                                   Renal dz: Proteinuria,  serum oncotic pressure
Pernicious anemia: B-12 required for osteoblastic                w/azotemia, edema.
    function.                                                Acute burns: Loss through transudation and skin loss.
 Zn and  Mg                                                GI dz: Malabsorption, malnutrition and pancreatitis.
 Phos.                                                      Skin: Exfolliative dermatitis
Anticoagulants in tube: fluorides, oxalate, EDTA.
                                                             Ammonia                             Normal range 12-48
Increased:                                                   Part of urea cycle. W/ESLD  inability of liver to
Liver:                                                            metabolize ammonia to urea. Most ammonia
 Cholestatic lesion: Results from  secretion of liver AP        produced from bacterial production in the intestine.
  into bile and regurg into circulation. Also with           Hyperammonia:
  Cholestasis get  synthesis of AP.                         Cirrhosis: Defective urea cycle.  ammonia associated
 Hepatic infiltrate: 1* or 2* metastatic Ca. Also seen           w/development of hepatic encephalopathy. Need to
  with amyloidosis, Tb and abscess. Have dissociation             restrict protein intake. Circumvention of portal
  between bilirubin and AP  bilirubin can be secreted            circulation.
  while AP is reabsorbed.                                    GI bleed:  production from bacteria acting on blood
Bone Osteolytic: hyperparathyroidism, Paget‘s dz, 1* and          protein
    2*bone cancer.                                           Drugs: Carbonic anhydrase inhibitors, Thiazides.
Hematologic: Hemolytic anemia, multiple myeloma,             Renal: ATN or hepatorenal syndrome   urea in GI
    thrombocytopenia, and thromboembolism.                        tract   ammonia production.
Reticuloendothelial: Gaucher‘s dz, Niemann-Pick dz,          Emphysema: Arterial hypoxia interferes w/liver‘s
    eosinophilic granuloma, histiocytic lymphoma, and             capacity to metabolize ammonia.
    Hodgkin‘s dz.                                            Obstructive Uropathy: BPH or uterine Ca   incidence
GI: malabsorption, peptic ulcer, UC                               of infection w/proteus   urea in urine  
Tissue necrosis: lung, kidney, spleen                             ammonia.
Cancer:                                                      Genetic
   Regan Isozyme: Ectopic Alk Phos production by            LDH                              Normal range 90-250
    lung, breast, colon, ovarian, & cervical Ca. A heat
    treated isoenzyme.                                     Insensitive to parenchymal hepatic damage.
                                                           Sensitive as measure of carcinoma
   Nagano Isozyme: Pancreatic and bile duct Ca.
                                                           Useful for discrimination between carcinoma of the liver
Dissociation between AP and Bili: AP cannot be readily          and intrinsic hepatic dz. Very  levels in EtOH pt
  re-excreted from non-obstructed areas of liver. Bili can      cannot be attributed solely to cirrhosis. Should
                                                                suggest complicating illness such as Megaloblastic
    AP with Nl bili.
                                                                anemia, EtOH myopathy, delirium tremens,
                                                                hemolytic anemia or pancreatitis.
2x : Acute  viral, toxic hepatitis, EtOH hepatitis.
5x : Infectious mono, and postnecrotic cirrhosis.         GGT                                   Normal range 1-94
10x : Drug Cholestatic hepatitis, Pancreatic head Ca,     Very specific for liver damage and esp to EtOH. May be
    Choledocholithiasis                                         elevated even w/out clinical evidence of liver
15-20x : 1* biliary cirrhosis, and Metastatic or 1* Ca.        damage.
Bilirubin                       Direct 0-0.4 Total 0-1.0   Sharp   obstructive process and hepatic mets
                                                            may indicate any acute hepatic dz, acute pancreatitis,
Unconjugated  Indirect              Conjugated  Direct        renal dz, EtOH ingestion, postop status, and prostatic
Heme  Unconjugated bili  transported w/Albumin to             mets.
    liver  Conjugated w/glucuronic acid  excreted
    into bile  into GI tract  bacteria cleave to         Antimitochondrial Ab
    Stercobilin                                            Found in ~95% of pts with PBS.
Low Total Bilirubin:
Women: reflects lesser quantities of Hgb.                  Ceruloplasmin                        Normal range 27-50
Anemia                                                     Made in liver.
Low Albumin                                                 in Wilson‘s dz. Serum copper , tissue copper .
                                                             Amylase                          Normal range 30-100
Elevated Conjugated Bilirubin:
Cholestasis: Intrahepatic and extrahepatic                   P isoenzymes: Pancreas
Post-Op intra and extra hepatic:                             S isoenzymes: Salivary glands, liver, small intestine,
Recurrent intrahepatic Cholestasis during pregnancy               kidney, fallopian tube.
Dubin-Johnson syndrome:
                                                                             ESSENTIAL BASICS--11
Hypertriglyceridemia can cause falsely  levels of             2) Hemastix or Labstix: Vit C can stop reaction. At
   amylase.                                                       urine pH < 6.0 RBC are not lysed  false (-) test
Absolute values are not important. Just an  .                    may result.
Causes of elevated amylase:                                    Myoglobinuria: toxic to renal tubule. More than Hgb.
1) Pancreatic leakage: Acute and chronic pancreatitis,         1) Trauma: Crushing injuries, beating, bullet
   pancreatic Ca, and ERCP. Sensitive for pancreatitis,        2) Electrocution
   but not specific. Serum amylase is usually  in acute       3) Infection: C. Perfringes infection, acute polymyositis.
   pancreatitis, especially when levels are > 3x Nl.           4) ―March‖ Myoglobinuria: unaccustomed strenuous
   Acute pancreatitis,  w/in 24 hours and remain                 exercise
   elevated for 1-5 days.  in lipase lags behind  in         5) Toxin: Fish poisoning, sea snake bite.
   amylase. Total rise is > w/lipase. If hyperlipemic          6) Paroxysmal: muscle cramps w/Myoglobinuria for
   and have pancreatitis will get normal amylase due to           72hrs sp.
   interference w/test.                                        Bile
2) Absorption of amylase from a peritoneal surface:            Direct or conjugated bilirubin reacts. NOT unconjugated.
   ruptured viscus (stomach, intestine), intestinal
                                                               Happens w/ levels of conjugated bilirubin. Kidney can
   perforation or infarction, ruptured ectopic pregnancy
                                                                   excrete. Need serum level > 0.5 then dump into urine.
3) Salivary gland lesions: mumps, sialadenitis,
                                                               1) Bili-Labstix
   alcoholism, bulimia
                                                               2) Ictotest tablets
4)  renal clearance: renal insufficiency,
   macroamylasemia Amylase complexes to either an Ig           Ketone Bodies
   or other large molecule, and therefore too large to be      Ketosis occurs w/starvation, frequent and persistent
   filtered by renal glomeruli.                                    vomiting, toxemia of pregnancy, thyrotoxicosis,
5) Pregnancy: placental amylase, ruptured ectopic                  Fanconi‘s syndrome, and Cushing‘s syndrome.
   pregnancy.                                                  1) -hydroxybutyrate Test: Only detects -
6) Tumor production: ovarian, lung, esophagus                      hydroxybutyrate which makes up 78% of ketones.
                                                               2) Acetest tablets: Detects acetone and acetoacetate.
                                                                   NOT -hydroxybutyrate.
Causes of decreased amylase:                                   3) Ketostix or Labstix: Detects acetone, and
Chronic pancreatitis: burned out pancreas.                         acetoacetate NOT -hydroxybutyrate.
Cystic Fibrosis:
In acute pancreatic amylase spills into the peritoneal         Need to have serum Glu > 150 to spill into urine.
     cavity  thoracic duct  jugular system  vascular        Benedicts Test: detects reducing sugars, ascorbic acid,
     circulation.                                                  salicylates, homogentisic acid
If there is a ruptured thoracic duct  pleural effusion        Clinitest test: Uses copper reagent that also reacts w/
     w/P-type amylase. Can also get amylase w/ruptured             reducing sugars  Glu, fructose, lactose, pentose,
     esophagus w/S-type amylase.                                   NOT sucrose. Vit C, salicylates, homogentisic acid
Lipase                              Normal range < 300             do not interact w/reaction. Is messier. W/test value
                                                                   goes up and then down so can miss.
More specific but less sensitive than amylase. Often           Labstix or combstix: Detects Glu w/Glu oxidase
   checked together with lipase with pancreatitis.                 reaction. Strong reducing agents (Vit C) can stop
 in lipase lags behind  in amylase. Total rise is >              reaction  false result.
   w/lipase.                                                   Causes:
                                                               Primary: IDDM, DM
                URINALYSIS                                     Dz of pancreas: Chronic pancreatitis, no pancreas,
                                                                   infiltration 2/2 hemochromatosis, tumor
                                                               Other endocrine dz: Acromegaly, Cushing‘s,
                   Macroscopic                                     Thyrotoxicosis, Pheo, aldo,  glucagon.
Color                                                          Drugs: Steroids, Thiazides, propranolol, Dilantin,
Turbidity: Bacterial infection or 1st am void.                     diazoxide.
Yellow: due to urochorme, also Vit B-6.                        Other dz states: CRF, CLF, infection
Red: Myoglobin, Hgb, RBC, Porphryins, drugs, foods             Misc: Pregnancy, insulin receptor Ab, abnormal insulin.
    (beets, red candy).                                        Protein                Normal Range < 100-125/24hrs
Green to Yellow-brown: bile. (Shake  white foam =             Can have some protein in urine. Also w/exercise. Not
    no bile,  yellow-brown = bile)                                pathologic.
Brown to black: Melanin, old blood, hemosiderin,               Abnormal is > 500, nephrotic is > 3 gm/24 hrs.
    myoglobin, rhubarb, alkapton bodies, laxatives             Sulfosalicylic Acid: Detects total proteins, some radio-
Specific Gravity                  Normal 1.010 to 1.025            opaque dyes, light chains. Does not pick up
Urine is normally tightly controlled                               everything. If get exposed to humidity then stops
    1.003                                                          working. 24 hrs out of bottle stops working.
                                                               Labstix or combstix: Screening test. Detects albumin
    1.018  sG in  mineralcorticoids,  effective
                                                                   only. 99% time ok. Does not pick up kappa or
                                                                   lambda light chains.
    1.030  SG in free water loss or  reabsorb                Bence-Jones protein: kappa or lambda light chains.
Urobilinogen                                                       Acid/heat precipitation at 56.
Formed by action of bacteria on bilirubin in gut. Partially
     reabsorbed and excreted by the liver and kidney.                  Microscopic examination
 in: Hemolytic anemia, early parenchymal liver dz.
 in: Obstruction of extrahepatic bile ducts (esp Ca of
     pancreas head) If stool is chalky white, no urobilin is   Either infection or chronic inflammatory process.
     present                                                   RBC                                         Nl < 2 HPF
Can also test for Acute Intermittent Porphyria  Will          Can get from bladder irritation from catheter.
     turn test strip red.                                      Dysmorphic RBC can come from glomerlular or tubular
Occult blood                                                       process.
Myoglobin also reacts                                          Casts
1) Guiac test modified
Precipitation of material w/in lumen of tubule usually            in the intestine, anabolism, catabolism, and capacity
    distal tubule or collecting duct.                             of liver to form urea.
EPITHELIAL CASTS: Tubular process. Formed by                  urea formation:
    precipitated protein from desquamated cells from         Catabolism: Steroids, fever and wasting
    epithelial lining of nephron. Has 2 rows of epithelial   Diet:  dietary protein
    cells. Once formed structure does not remain             Intestinal hemorrhage
    constant. The cells can disintegrate as move
    downward.                                                Urea excretion: depends on filtration with some
   Exposure to nephrotic agents and exposure to viruses.       reabsorption. Reabsorption is augmented with slow
   ATN                                                         urine flow rates. Active  ascending limb of loop of
Cellular Casts: Phase 1.                                        henle. Passive   diffusion in collecting duct.
Coarse Granular Casts: Phase 2. Nuclei and cytoplasm            Facilitated by ADH.
Fine Granular Casts: Phase 3.                                 BUN:
Waxy casts: Phase 4. Associated w/severe CRF and             Blood in GI tract: more likely a function of impaired renal
    amyloidosis.                                                 function from reduction in circulating blood volume.
BLOOD RBC CASTS: Glomerular damage. Severe                   Dehydration
    injury to GBM. Reddish orange color 2/2 Hgb              Acute GN
    pigmentation. RBC are packed in fibrin meshwork          Malignant Nephrosclerosis
    w/in cast matrix.                                        Muscle wasting diseases
                                                             Obstructive uropathy
   Acute GN, SLE nephritis, Goodpastures, and SBE.
                                                             Prerenal underperfusion
WBC CASTS: WBC are incorporated into protein                 Severe Tissue Trauma
    matrix. Enter urine stream by ameboid movement           Urinary-enteric fistula
    through and between tubular epithelial cells and
    sometimes they cross the glomerular capillary lumen.      BUN:
   leukocytic exudation and interstitial inflammation.      Chronic GN with protein deficiency
    Pyelo.                                                   Overhydration and rapid: Hemodilution of BUN.
HYALINE CASTS: Has mucoprotein that helps to                 Repeated hemodialysis  remove too much BUN
    entrap bacteria. Is transparent. Need to add red dye     Acute Liver failure:  urea synthesis.
    to see well. Made from Tamm-Horsfall protein. 0-2        EtOH abuse:
    casts/HPF is normal.
  benign essential HTN, & nephrotic syndrome.                Creatinine
                                                             Amino acid. Blood level depends on production vs.
FATTY CASTS: Leakage of lipoproteins. Characteristic
    of degenerative tubular dz.
                                                             Production: dependent on total muscle content.
   Nephrotic syndrome, DM, & damaged renal tubular
                                                             Excretion: Constant 1-2% per day. Depends on bulk
    epithelial cells.
                                                                  filtration w/out reabsorption.
Crystals (see section on Urinary Stones)                     Test: Jaffee reaction: this is a colorimetric reaction
Acid urine                                                        w/reading of the color red. Can get false  results
Envelops     Ca Oxalate                                           w/ bile in urine.
Diamonds     Ca Oxalate                                      If have  bili ask for non-Jaffee/Non-picrate creatinine
Needles      Tyrosine                                             test.
Spheres      Leucine                                         Estimated GFR
Sheaves      Sulfonamides
Hexagons     Cystine: 6 sided. Proximal tubule.              [(Ucr x Uvol) / SCr] x time = (140 –age) x wt in kg
                                                                                           (sCr x 72) If  x .85.
Alkaline urine:                                              Measured GFR
Coffin Lids      Triple phosphates
                                                             uCr mg/dl x uVol ml/day              = Urine Cr
Thorn apples     Ammonium biurates
                                                             (mg/24hrs) x 0.07
Amorphous debris Amorphous phosphates
                                                             Plasma Cr mg/dl x 1440 min/day                Plasma Cr
Mucous:                                                      mg/dl
Presence of any mucous  UTI. It is made to entrap
    E.Coli.                                                  Fractional Excreted Sodium
Nitrite and Leukocyte Esterase                               FeNa: (uNa x sCr) x 100
Nitrite: Have both nitrate and non-nitrite bacteria.               (sNa x uCr)
Leukocyte Esterase: Detects intact and lysed leukocytes.     FeNa < 1: Prerenal, Acute GN, rhabdo, contrast
    Can have w/UTI and w/trauma, kidney cancer, and          nephropathy
    bladder Ca.                                              FeNa >2: Intrinsic renal dz (i.e. ATN)
Can have (+) LE and (-) Nitrite and have a UTI.              Functional Kidney Tests
                                                                            Prerenal Azotemia         ATN
             Other Urine Tests                               BUN/Cr               >20               <20
Woods Lamp test: (+) ethylene glycol, porphyria              Urine Na             <20               >40
Urine PEP: Looks for papaprotein (myeloma)                   uCr/sCr              >40               <20
Endocrine:                                                   Uosm                 >500              <350
 5-HIAA  cushinoid                                          FeNa                 <1                >2
 Melanin  Melanoma                                          FeUrea               <30
 VMA/Catachols  Pheo.
 Ketosteroids  Cushing‘s                                    Urine anion gap (UAG).
                                                             UAG = u[cations] - u[anions]
                                                             UAG = u([Na] + [K]) - u[Cl].
      RENAL LAB VALUES                                       Normal range: 0 to -50 (that is, negative).
Blood Urea Nitrogen:                                         Urine Osmolal Gap: (UOG)
Formed in liver. Amount determined by equilibrium of         Urine osmolality = 2(u[Na + K]) + uGlucose/18 +
    amino acids produced by digestion of food or blood           UUN/2.8
                                                             Urine osmolal gap = (measured - calculated).
                                                                          ESSENTIAL BASICS--13
                                                            Thiazide inhibits Ca excretion.
Transtubular K Gradient
Calculate Transtubular K Gradient =                         Hypocalcemia:
Urine K x Plasma Osm                                        Symptoms:
Urine Osm x Plasma K                                        Tetany:
                                                               Paresthesias of lips, fingers, toes, and tongue
TTKG             Cause                                         Vague muscle cramps
>4         Mineralocorticoid excess, vomiting                  (+) Chvostek‘s sign (continued blinking of muscle
<2         Extrarenal loss                                      w/continued tapping.
                                                               (+) Trouseau‘s sign: Carpal spasm
                                                               Laryngospasm, bronchospasm
                   CALCIUM                                     Convulsions
Exists 50% ionized Ca and 50% bound to Albumin.             Skin: loss of hair
In normal serum PTH is inversely correlated to serum       CV: Prolonged QT interval and hypotension
    Ca. PTH values are controlled tightly. Secretion is :   Psych: Depression, anxiety
   suppressed by slight  serum Ca
   stimulated by slight  in serum Ca                      Causes:
Correction of Ca for Albumin                                Tumor lysis syndrome: Post chemotherapy.
                                                            Overhydration: dilution of total calcium
For every  in 1 below 4 of Albumin  of 0.8 in Ca.
                                                             Albumin
pH alters Ca binding. Shifts are usually small, but can be
    associated w/clinically important hypocalcemia.          Mg: Shuts down the parathyroids
Acidosis  protein binding   ionized Ca                    Phos: Chelates Ca
                                                            Resistance to PTH:
Alkalosis  protein binding   ionized Ca
                                                            Vit D disorder: Not eating.
Hypercalcemia:                                              Removal of Ca from blood
Clinical Manifestations:                                    Blood transfusion: citrate in transfusion chelates Ca.
Tip off: If try to draw blood will continue to clot. W/ Ca Replacement:
    not enough EDTA to chelate Ca. Need to use              Acute:
    heparinized tube                                        Correct Mg.
Renal: Nephrocalcinosis, nephrolithiasis,                   CaGluconate 2 amps 10% IV over 2 min then 0.5-2.0
    Polyuria/polydipsia                                          mg/kg/hr.
CV: Shortened QT,  sensitivity to dig, HTN, cardiac        Treat underlying condition.
    arrest                                                  If asymptomatic correct w/PO CaCO3 500 mg PO TID
GI: Anorexia, weight loss, constipation, abd pain, peptic
    ulcers, pancreatitis.                                   Chronic:
Neurologic: HA, lethargy, apathy, delirium                  PO Ca and Vit D supplement
Muscular: Myopathy, bone pain, spontaneous fractures.

Calcium supplementation                                     > 2.0  Neutraphos PO or Kphos 2 tabs PO TID x 1day
                                                            1.5-2.0  NaPhos or Kphos 0.08 mmol/kg IV over 6 hrs
    Cl/PO4 < 30: Primary. Ectopic PTH from tumor.           0 – 1.5  NaPhos or Kphos 0.16 mmol/kg IV over 6 hrs
    Cl/PO4 < 30:                                            After initial infusion, should recheck Phos level
          Secondary: After thyroid surgery. Removal of     Caution w/pts with Hypercalcemia because of metastatic
            parathyroids. Will get                               calcification.
          Tertiary: Renal dz   sPhos   Ca  
            PTH  over time  parathyroid hyperplasia       Hyperphosphatemia
             autonomous                                    Renal failure
Infections: Tb, Histoplasmosis, cocci, leprosy              Hypoparathyroidism
Meds: Thiazides (act on kidney to  Ca excretion),          Pseudohypoparathyroidism:
    diuretics, lithium, OCP, antiestrogens                  Diabetes Mellitus:
Paget‘s dz
Addison‘s dz                                                Treatment:
Neoplasm:                                                   Hypophosphatemia
  PTH-RP mediated: SCCA, renal, breast.
  OAF mediated: Multiple myeloma, leukemia              Common settings:
    Production of OAF                                    Inadequate intake
  Vit D: Lymphoma                                        1* and 2* hyperparathyroidism
Zollinger Ellison/VIPoma                                 Vit D deficiency
Endocrine non parathyroid: Thyrotoxicosis, Pheo, adrenal GI losses
    insuff                                               EtOH
Excess Vit D                                                                     Ca      Phos Alk Phos
Sarcoid                                                  Rickets                                
                                                         Dilantin rickets                       
Management:                                              Renal Osteodystrophy                   
Vigorous hydration to  urinary Ca excretion followed by Vit D Resistance          Nl            
     saline diuresis.                                    Hypophosphasia                         
Pamidronate 60-90 mg IV over 4 hrs. Onset days.
Plicamycin 25 microgm/kg IV over 4-6 hrs. Onset 2-4
     days Duration 5-15 days.                                              MAGNESIUM
Salmon Calcitonin 4-8 IU/kg IM/SQ q6-12 hrs. Onset hrs. Mg is bound to albumin. So  Albumin   Mg
     Duration days.                                      Mg replacement in pts w/ESRD can help with renal bone
Prednisone 20-50mg BID. Onset 5-10 days. Duration            dz.
     days.                                               Used to slow preterm labor and ♀ w/PIH.
PO Phos 0.5-1 gm PO TID. Onset days. Duration when in Hypermagnesemia:
Early signs  Paresthesias and peripheral vasodilation.
                                                            Selenium                     Daily Requirement 60 mcg
Nausea, vomiting, lethargy, hypotension, bradycardia and
    respiratory depression.                                 Lack  Cardiomyopathy
Concentrations >6 may have drowsiness.                      Clinical trials for pts w/prostate cancer as antioxidant
> 10  respiratory failure and heart block                  Chromium                  Daily Requirement 12 mcg
Etiology: CRF. Need GFR < 30 for  in Mg.                   Affects insulin receptor.
Hypomagnesemia:                                             Ingestion of Chromium   LDL levels
Mg is bound to albumin. If have  alb   Mg
Causes:                                                           PLEURAL EFFUSIONS
EtOH: EtOH  adrenal hyperplasia   cortisol                              Transudate                Exudate
    aldo   Mg excretion.                                  Protein          <3.0 g/dl     > 3.0g/dl
Malabsorption                                               LDH              Low           High
Hyperosmotic diuresis (DKA)                                 Pleural/ Serum
Diuretics.                                                  LDH ratio        <0.6          >0.6
                                                            RBC              < 10,000      >10,000
Hyperaldo   renal tubular excretion.                      WBC              <1,000        Usually < 1,000
Pancreatitis: Formation of insoluble soaps                  Diff             >50% L or M   >50% Lymphs  Tb, neoplasm
Hyperthyroidism:  cellular requirement for Mg.                                            > 50% PMN  acute inflammation
                                                            pH               >7.3          < 7.3
                                                            Glu              Same as blood Low  Infection
Clinical Manifestations:                                                                   Extremely low  RA, occ Ca.
Hypokalemia and hypocalcemia                                Amylase                        >500
Cardiac arrhythmias
                                                            Chylous Effusions
Anorexia and nausea.                                        Chylous Effusion: Damage or obstruction to thoracic
Treatment: If having Sz  IV Mg. Every 1 gm MgSO4           Psuedochylous Effusion: Chronic effusion of any cause
    IV   of 0.1.                                               cyst fluid, RA, Tb, or myxedema. Have 
Otherwise Mg Oxide PO.                                          cholesterol from RBC and other cell membrane.
                                                            Use Lipophilic dye test to discern: If the dye appears in
                                                                the fluid after 1 hr then have rupture of thoracic duct.
          HOMOCYSTEINE                                          If there is no dye then is a pseudochylous effusion.
Normal level is < 15 micromol/L.                        Causes of Pleural Effusions
By product from amino acid degradation. Metabolized by
    kidney.                                             Transudates: CHF, hepatic cirrhosis, and
Independent risk factor in CAD                              hypoprotinemia: nephrotic syndrome
Cause:                                                  Cancer: Broncogenic Ca, metastatic cancer, lymphoma,
Genetic: Cytathionine beta synthase (CBS) deficiency.       Mesothelioma (will have  hyaluronate 
    Autosomal recessive trait  1/344,000 births.       Infections: Tb, ( % of lymphocytes), bacterial, viral, or
    Variable deficiency. Minimal amount must be present     mycoplasma PNA.
    for successful Tx. CDNA probe for CBS has been      Trauma:
    cloned.                                             Pulmonary infarct:
Nongenetic: Nutritional deficiency of B6, B2, B12 and   RA dz:  pleural glucose.
    folate.                                             SLE: LE cells present
Renal Failure:  by 70% of Homocysteine clearance       Pancreatitis:  p-amylase level
Transplant pts: 50-100% develop hyperhomocystinemia. Ruptured esophagus:  s-amylase level
    Cyclosporine  may  uptake by kidney tubules  Chylous effusion: damage to thoracic duct from trauma,
     degradation.                                          lymphoma, carcinoma, or Tb.
Signs and Symptoms:                                         Causes of Pericardial Effusions
Dislocation of eye lens                                     Exudates:
Osteoporosis                                                Cancer: metastatic Ca, or lymphoma
Mental retardation                                          Infections: bacterial, Tb, fungal, viral, or mycoplasmal
Thromboembolism of arteries and veins.                          pericarditis.
Dementia                                                    Trauma:
Treatment:                                                  Hemorrhagic effusion: 2/2 anticoagulation Tx, leakage of
1 mg folic acid, 0.5 mg Vit B-12, and 10 Vit B-6                AAA.
                                                            Metabolic: uremia, myxedema
        TRACE MINERALS                                      RA dz:  pleural glucose.
                                                            SLE: LE cells present
Zinc                         Daily Requirement 3 mg
                                                            Causes of Peritoneal Effusions
                                                            Transudates: CHF, hepatic cirrhosis, and
 Zn   Cu  Reversible sideroblastic anemia.
Deficiency:                                                      hypoprotinemia: nephrotic syndrome
Zn needed for functioning of Alk Phos.                      Exudates:
Lack of growth, retardation of skeletal maturation, and     Cancer: Hematoma, metastatic Ca, lymphoma,
    hypogonadism.                                                Mesothelioma.
T-cells need Zn. May explain why may be useful in Tx of     Infections: Tb, ( % of lymphocytes), 1* or 2*
    cold.                                                        (appendicitis or intestinal infarct) peritoneal
Skin                                                             infection.
Taste and smell: can help w/distortion of taste and smell   Trauma:
    in pts that can happen w/ESLD and respiratory           Pancreatitis:  p-amylase level
    infections.                                             Bile peritonitis: 2/2 ruptured gallbladder or needle
Sexual function: Pts w/ESRD can get some improvement             perforation of bile duct.
    w/Zn                                                    Chylous effusion: damage to thoracic duct from trauma,
Vision: Required for various retinal enzymes.                    lymphoma, carcinoma, or Tb.
                                                                          ESSENTIAL BASICS--15
                                                            Metabolic acid production & renal acid
                 CSF FLUID                                  excretion
Protein: <15                                                H+ production: Oxidation/hydrolysis of foodstuffs  ~ 1
Glucose: 60% of blood glucose                                          +
                                                                mEq H /kg/day (phosphates and sulfates) In
Cell Count:                                                     particular sulfur containing compounds.
Causes of  CSF protein:
                                                            H+ chemical buffering:
Traumatic tap                                               Intracellular (-40%).
Diabetes:  up to 150. can be  if significant peripheral   Proteins, phosphates (organic, inorganic), hemoglobin (H,
    neuropathy is present.                                       Hb +~ HHb). Extracellular (-60%):
Brain tumor: 100-200. Marked  in meningiomas,              Primarily HCO3- (high concentration; varying pCO2
    acoustic neuromas, and tumors near ventricles.               changes pH).
Spinal cord tumor: Up to extreme levels 750-1000
MS: May have. Is usually mild. If > 80 diagnosis is           +
                                                            H excretion: renal "net acid excretion": NAE
    suspect.                                                NAE = titratable acidity + NH4+ + urinary HCO3-. More
 Synthesis of IgG + permeability: Meningitis, Guillain-       protons are leaving in urine than measuring urine pH.
    Barre, collagen dz (periarteritis, SLE)                    Also by attaching protons to buffers. Phosphates and
Neurosyphilis.                                                 creatinine. Also variability in urine is Ammonia.
Causes of  Neutrophils:                                    Must first reabsorb filtered HCO3- (-4000 mEq/day!).
Bacterial Meningitis                                                   +
                                                           Type of H excretion.
Early viral and Tb meningitis: later flips to lymphocytes. Free H+:  urine pH to 4.5-5.0; but <0.05 mEq H+/L.
Other infections: cerebral abscess, and subdural empyema        Even with urine pH of 5.0 do not excrete many
Following seizures                                              protons. Need a buffer system to excrete more
Following CNS infarct.                                          protons. Attachment of protons to these buffers. Not
Causes of  Lymphocytes                                         excretion of more buffer. These are at a steady state.
Viral, Tb, Fungal, syphilitic, leptospiral, parasitic           For Creatinine dependent on muscle mass. What
    meningitis                                                  varies is ammonium
Unusual bacterial organisms: Listeria monocytogenes.       Bound H+:
Degenerative disorders: MS, SSPE, Guillain-Barre           By Buffers: HPO4 2-, creatinine, uric acid; titratable
    syndrome.                                                   acidity.
Other: Sarcoidosis, polyneuritis, periarteritis of CNS.    By ammonia: proximal collecting tubule H ATPase 
                                                                H+ gradient. Generates by hydrolysis of glutatamine.
Causes of  Eosinophils                                         Then broken.
Parasitic infection                                        Sites in kidney: proximal tubule. Distal nephron: ???
Fungal infections
Rickettsial infection                                      Need to attach to buffer.
                                                           Phosphates and Creatinine. As acidify. Need these
       ACID BASE BASICS                                    % of phosphate to creatinine changes as change pH.  #
Definitions.                                                    of protons excreted w/out  pH of urine more.
1) Acidemia:  H =  pH                                    Ability to attach to Ammonium. Under basal only 1/2 of
2) Acidosis: A process that tends to produce  H =             protons attach to ammonium. During acid loading
    pH.                                                         with higher protons, greater and greater % attach to
3) Alkalemia:  H =  pH
                                                                ammonia and make ammonium cation.
4) Alkalosis: A process that tends to produce  H+ =  Proximal tubule: increases formation of ammonia. Now
    pH.                                                         have additional buffer source. Do not have to acidify
Review Henderson-Hasselbalch equation:                          the urine that much.
pH = pK + log10 [salt]/[acid]
pH = 6.1 + log10 [HCO3 ]/0.03 p CO2                        Time Sequence of response to an H+ load:
Review normal values and ranges (serum or plasma): Time                                    Response
pH = -log10 [H+] = 7.4                (7.35-7.45)          Immediate                 ECF buffering by HCO3-
[H+] =40                              (35-45 nM)           Minutes to hrs            Resp buffering by pCO2
[HCO3 ] = 25                          (23-27 mEq/L)        2-4 hrs                   ICF & bone buffering
                                                                                      renal H excretion
pCO2 =40                              (35-45 mmHg)         Hours to days

                                                            Where does proton secretion occur: Distal nephron in
    METABOLIC ACIDOSIS                                         cortical CD. ATPase. Take H+ and can secrete into
Pathophysiology                                                lumen vs. gradient. Distal nephron can get rid of
Primary  creation:                                            excess. Can secrete vs. gradient. pH inside 7.4 / pH
                                                               outside ~ 5.0.
Gain H+ (H+=  pH) with associated  HCO3-
pH ~ 6.1 + log10 (HCO3 /pCO2)   pH. Initial part

    is big fall in bicarbonate. Initial phase.                    Etiology of metabolic acidosis
                                                            Serum Anion Gap
Secondary  compensation, response:                         Definition and normal range:
1st phase is ventilatory. Impulse to lungs to               [sCations] - [sAnions] = Anion gap
     hyperventilate. Drop pCO2 and try to get back to                                -
                                                            [sNa] - ([sCl] + [s HCO3 ]) = -12±2 mEq/L
     normal. pH will not quite be as low
Pulmonary: ventilation  pCO2   pH.                     Meaning: Computational gap  [total cations] = [total
pH ~ 6.1 + + log10 (HCO3 / pCO2)   pH
                                                            Unmeasured anions in normal plasma:
Expected degree of compensation: normograms                      Albumin (pI ~ 4.5  anionic at physiologic pH)
s[HCO3-] by 1 mEq/L  pCO2 by 1.2 mmHg                         Phosphates, sulfates
Trick: Expect pCO2 to be ~ last two digits of the pH.
                                                            Can use anion gap to stratify pts by etiology:  chloride
    (if pH = 7.20, expect pCO2 = 20 mmHg.)
                                                                gap. No anion gap.  anion gap metabolic acidoses
                                                              Distal RTA (type 1, "classic").
           Anion Gap Acidosis                                 Aldosterone resistance (type 4 RTA).
                                                          Normal UAG: normal distal H and NH4+ excretion.
MUDPILES  Gap Metabolic Acidosis                            Make more ammonium and able to buffer that  acid
Methanol                                                     load. Preserved ability to produce ammonium.
Uremia                                                        Proceed to other cause  diarrhea.
Paraldehyde                                               Type 2 Proximal RTA
Iron, INH                                                 Failure to reabsorb HCO3 in proximal tubule.
Lactic acidosis: Uncontrolled DM, Leukemia, Alkalosis,    May be difficult to treat. If give NaHCO. Need to give a
         severe liver dz, hypoxia 2/2 circulatory or           lot. More than body generates per day.
         respiratory failure.                             Differential diagnosis:
Ethylene glycol or Ethanol  EtOH ketoacidosis           Congenital
         Retention acetoacetate                           Myeloma
Salicylates                                               Ifosfamide
Other: Toluene, rhabdomyolysis                            Hyperparathyroidism
Serum Osmolal Gap                                         Diamox
Use: Document ingestions.
Serum Osm: = 2Na + Glucose/18 + BUN/2.8                   Diagnosis:
Serum osmolal gap = (measured - calculated).              Fractional excretion of HCO3 >15% (calculate like FENa)
                                                           sK
 > 12:  LMW solute  Mannitol, ethanol, methanol,      Urine pH < 5.3
   ethylene glycol, other.
 < 12: Diarrhea, RTA, Cl acids.                         Type 1 Distal RTA
                                                          Inability to secrete H+ against gradient in CD. Cannot get
Urine Osmolal Gap                                             urine pH down to where want.
Use: Document ingestions. (+) UOG:  in unmeasured        Differential diagnosis: Sjogren‘s, and congential
    anion excretion is suspected like ketoacids in DKA,    sK
    hippurate after toluene. Excretion of measured        Urine pH > 5.3
    cations (Na + K) w/unmeasured anions  (+) UOG.
Calculate urine osmolality: 2(u[Na + K]) + uGlu/18 +      Type 4 Distal RTA
    UUN/2.8                                               Aldo resistance or  aldo
Urine osmolal gap = (measured - calculated).              Problems with mineralocorticoid production or response.
                                                          Found in elderly, diabetics, tubulointerstitial dz.
Negative or <40: Distal NH3/NH4+ production is            Diagnosis:
    impaired.                                              sK
Positive or >40: urinary NH3/ NH4+ is >20  distal        Urine pH usually < 5.3
    NH3/NH4+ production is intact & appropriate for
    metabolic acidosis.                                     Gap: Complicated vs. Simple
   Ethanol                    Methanol
   Ethylene glycol            Isopropanol                      Metabolic acidosis
   Sorbitol                   Mannitol                  Anion Gap/ HCO3- ratio Can apply & tease out
   Contrast Dye                                              causes of metabolic acidosis.
                                                          Principle: In pure  gap met acidosis,  in AG parallels 
              Nongap Acidosis                                 in HCO3-. But not exact relation.
                                                          Not all excess protons are buffered by HCO3. Chronic are
Normal Anion Gap < 12 -- Hyperchloremic                       buffered by intracellular buffers (Hb and Phosphate)
                                                               AG typically exceeds  HCO3 (typically ~ 1.6:1).
Category                             sK+
HCO3 loss/wastage:                                     
GI: diarrhea                                              AG = measured AG – normal AG (12)
Urinary: ureterosigmoidostomy, ileal conduit               HCO3- = Normal HCO3- (24) – measured HCO3-
                                                                          AG/ HCO3 ratio:
Type 2 proximal RTA.                                      Calculation:
Carbonic anhydrase inhibitors: acetazolamide              Example: AG = 54 HCO3- = 9
                                                           AG = 54 – 12 = 42
Administration of Cl containing acid:                   HCO3 = 24 – 9 = 15

NH4, C1, HCl, TPN (Arg HCI), Cholestyramine HC1              gap met acidosis & concomitant
                                                              metabolic alkalosis.
Impaired renal H secretion:
Type 1 Distal RTA                                      Interpretation:
Type 4 RTA: hypoaldosteronism                          <1:1. Combined hi and normal gap met acidosis.
Early renal insufficiency                              1:1 to 2:1 (avg ~ 1.6:1). Uncomplicated hi gap met
Urine Anion Gap                                           >2:1. Concurrent met alkalosis:  in HCO3 is < expected.
Use: Actually cation gap. Ddx of normal anion gap
    (hyperchloremic) metabolic acidosis. Kidney               Consequences of Acidosis
    problem or outside of kidney.
Why: Major unmeasured cation in urine is NH4+. Used to
                                                       Impairment of cardiac contractility
    dispose of acid loads. Unable to generate
                                                       Arteriolar dilatation, venoconstriction
    ammonium. Inability to excrete protons.
                                                        PVR
Definition: Normal range: 0 to -50                      CO, arterial pressure, hepatic, and renal blood flow
UAG = u[cations] - u[anions] = u([Na] + [K]) - u[Cl].   CV response to catecholamines

Abnormal UAG: impaired distal tubular H+ generation       Respiratory:
   & NH4+ excretion.                                      Hyperventilation
                                                           strength of respiratory muscles
                                                                       ESSENTIAL BASICS--17
Dyspnea                                                  3) Certain Na retentive states: Mechanoreceptors think
                                                            there is not enough arterial vol in system.
Metabolic:                                                   Heart failure:
 metabolic demands.                                         Hepatic cirrhosis:
Insulin resistance                                           Nephrotic syndrome
Inhibition of anaerobic glycolysis
Hyperkalemia                                             Differential Diagnosis
                                                         Profile by saline. Give NaCl treatment. Look at response.
Cerebral:                                                Chloride Responsive: Urine Chloride < 10-15. Corrects
Inhibition of metabolism.                                    if give saline.
Obtundation and coma.                                    Vomiting and NG suction: lose HCl (Gain HCO3 ) and
                                                             KCl, lose volume
                      Treatment                          Diuretics:  Na to distal tubule  lose K, lose H (gain
Emergent treatment                                           HCO3 ), lose vol
1. Severity. Emergently treat any s pH <7.2, s HCO3-     Post-hypercapnea
2. Especially if cause of acidosis not directly treatable. Chloride Resistant: Urine Chloride > 20
    If known cause then can treat that cause.              If HTN:
3. Timing: rapid (over several [4-8] hrs) for pH <7.2.        Excess mineralocorticoid: Hyperaldosteronism and
4. Goal. Raise pH to -7.2. [assuming normal resp                Cushing‘s syndrome  lose H and K, gain HCO3-
    function, raise sHCO3 to 10-12)                           Renal artery stenosis
5. Amount of alkali (Na HCO3 ) to administer: Compute         Licorice
    HCO3- deficit.                                         If normotensive:
Calculation of Bicarb deficit:                                Hypokalemic
      -               -                 -
HCO3 deficit = HCO3 space x s HCO3 deficit                    Bartter‘s
70 kg pt. s HCO - = 6. Desired HCO - is 12.                   NaHCO3 administration: too much base
                 3                   3
   HCO3- space = [0.7]x[kg body weight] = 0.7x70 =      Bartter's syndrome
    49L                                                  Unusual discrete "molecular" cause for metabolic
   HCO3- deficit =12 - actual s HCO3- = 12-6 = 6           alkalosis.
   49 x 6 = 294 mEq to be replaced over 4-8 hrs         Abnormality. 1°  NaCl reabsorption in loop of Henle or
                                                            distal tubule.
Long-term treatment.                                     Causes: inactivating mutations of either:
1) Type of acidosis.                                     1. Loop Na-K-2C1 co-transporter, or
     Treatment best established for diarrhea or         2. Distal tubule NaC1 co-transporter ("Gitelman' s
      ingestions.                                           variant" of Bartter' s syndrome).
     Lactate or ketoacids may metabolize to HCO3-.
2) H+ production. Body H+ production =1 mEq/kg/day. Electrolytes.
3) May use citrate ("bicitra" or "Shohl's solution", 1 Serum:  sK,  sCl,  spH (hypokalemic, hypochloremic
    mEq/ml)   eructation. Less CO2 production.           metabolic alkalosis),  renin,  aldosterone.
                                                       Urine:  uCl, diuretic screen negative.
  METABOLIC ALKALOSIS                                  History: No vomiting or diuretics.
                                                       Examination: Normal blood pressure.
Pathophysiology                                        Differential diagnostic: Can be exactly mimicked by
Primary: Lose H+ ( H+=  pH) w/associated  HCO3-         diuretic use (loop or thiazide; except for negative
    pH ~ 6.1 + log (HCO / pCO )   pH
                               -                           urine diuretic screen).
                     10       3          2
    Before compensation.                                 Sustaining factors
                                                         impaired renal HCO3 excretion
Secondary: Pulmonary:  ventilation   pCO2           Hypovolemia:
    pH.                                                  renal JG cells   renin   angiotensin II
pH ~ 6.1 + + log10 ( HCO3 / pCO2)   pH
                                                          aldosterone (2°).
Symptoms: 2° to                                          renal HCO3-
                                                          GFR   filtered HCO3 .
Volume depletion: weak, dizzy
Hypokalemia: polyuria, polydipsia, muscle weakness).
Impaired effect of ADH.                                  Cl depletion:
                                                          renin release   angiotensin II   aldosterone (2)
Role of Aldosterone                                       distal H secretion ( gradient for HCl secretion by H-
Aldosterone actions in the distal nephron (collecting        ATPase)
    tubule).                                              distal HCO3- secretion
 Aldosterone 
 distal Na channels   reabsorption of Na. As Na       Hypokalemia: If are hypokalemic do not have that K to
    comes in, voltage gradient is created.                  exchange for Na. Now will need to use H as
 Na  K exchange  K loss into urine   sK.               exchange cation   distal H secretion ( distal H
 Na  H exchange  H loss into urine   s[H],            exchange for Na).
    spH (alkalosis)
Primary mineralocorticoid: 1°  aldosteronism:
    adrenal cortical adenoma or hyperplasia. Unusual.    Non-specific Treatment (to SI s pH).
    Produce too much aldo.  renin in these pts.         Saline = NaCl (if likely to be saline responsive). Monitor:
                                                             upH (should rise from <5.5 to >7.0), uCl (should rise
Secondary  mineralocorticoid:  renin                     to >15 mEq/L).
    angiotensin II   aldosterone                       KC1: if saline resistant, hypokalemic, or edematous
1) Renovascular HTN.                                     Acetazolamide: if edematous. Carbonic anhydrase
2) Hypovolemia:  volume to renal JG cells   renin         inhibitor   renal HCO3- excretion.
      angiotensin II   Aldo.
HCl: 150 mM (isotonic) HC1 by central line over 8-24       1) Numerous congeners effective orally and absorbed
   hours. Only if intolerant of NaC1 and/or KC1 (e.g.,        from local sites
   renal failure, heart failure).                          2) >90% bound in plasma by transcortin (corticosteroid
                                                              binding globulin, [CBG] with high affinity, low
Specific Treatment:
                                                              capacity) and albumin (low affinity, high capacity).
1) Mineralocorticoid antagonist: spironolactone.              Analogues bound less well. Free form = active.
2) Underlying disease.
    Aldosteronoma: surgical excision.                     CHIPPEBOOGS
    Renovascular HTN: renal endarterectomy or             Cushingoid Habitus: humpty dumpty look. Waste protein
     angioplasty.                                                   to make glucose. Redistribute fat. Centripetal
3) H2 antagonist (Cimetidine):  continuing gastric H               obesity. Also acne. Muscle wasting.
   loss.                                                   Hyperglycemia: Prodiabetic.  Glu in blood and urine. 
                                                                    in propensity to get DM
                                                           Infection: Opportunistic infections that depend on
 RESPIRATORY ACIDOSIS                                               lymphocytes. TB follows the use of steroids like
Differential Diagnosis                                              a shadow. Can reactivate TB if have silent
                                                                    infection. Type IV Hypersensitivity
Respiratory depression                                     Peptic ulcers: Alteration in protection w/in gut. Acid
COPD                                                                production.
Neuromuscular weakness                                     Proximal muscle wasting: Protein breakdown of muscle
Pleural effusions                                                   as goes to glucose. Myopathy.
Pneumothorax                                               Electrolyte: All steroids have some mineralocorticoids.
                                                                    On distal tubule.  sK,  sNa, alkalosis.
Pulmonary edema
                                                           Behavior: Can make people feel good, but also
                                                                    emotionally labile, or depressed. Exacerbates
                                                                    emotions. Steroid psychosis.
            RESPIRATORY                                    Osteo: Important effect on bone. Loss of bone protein ~
                                                                    to muscle. Osteoporosis  Osteomalacia  
             ALKALOSIS                                              bone resorption. Can  Ca availability in gut.
Clinical Features                                                   Wasting of bone. Consequence.  risk of getting
                                                                    compression fractures. Spine and hip, dislocation
Diagnosis                                                           of femoral head. Very serious complications.
 Cl and  Bicarb.                                                  Also can get avascular necrosis of femoral head.
Causes                                                     Ocular: Cataract formation and  in intraoccular pressure.
                                                           Growth: Retard growth in young people. Perhaps
Vomiting and NG suction: Remove acid.
                                                                    alterations in growth factors.
Severe K depletion:
                                                           Skin: Thinning of skin. Less sensitive to damage. Will
                                                                    break down collagen in skin.
Pregnancy:  levels of progesterone                        Hypothalamic pituitary adrenal Suppression
GN sepsis:                                                 Normal cortisol output is 20-25 mg/day with diurnal
Cirrhosis: Liver metabolizes catecholamines. In liver          variation
    failure will have those neurotransmitters remain     Prolonged  dose steroids suppresses for prolonged
    respiratory drive  hyperventilation.                      period endogenous adrenal production of steroids by
Excess mechanical ventilation:                                 suppressing ACTH formation and secretion.
                                                           Large doses: (ie Prednisone 50 mg QD) suppress axis
       STEROID THERAPY                                         after 1-2 weeks
                                                           Slightly  than physiologic: (ie Prednisone 7.5-10 mg
Mechanism of Action                                            QD) suppression possible after 1 month
Binds to cytosolic receptors  translocated to nucleus    Low dose: (ie Prednisone 5 mg QD) no suppression.
    regulates transcription of specific genes by
    glucocorticoid responsive elements.                    Rate of recovery related to accumulated dose.
                                                           May take months to recover function. Pts have to have
Inflammation                                                   dose tapered when stop giving drug. Up to 9 months,
1) Inhibit arachidonic acid release from phospholipids         pts at risk of not having cortisol response. Can
    Inhibits Phospholipase inhibiting protein and             become adrenally deficient if there is some stress.
   inhibit induction of cytosolic PLA2 and COX2.           a. Duration and degree of HPA ~ anti-inflammatory
2) Alter Vascular tone and capillary permeability              potency
3) Inhibit collagen deposition and proliferation of        b. Adrenal atrophy may persist >9 months after
   fibroblasts, capillaries                                    stopping.
4)  PMN—Block functions                                   c. Acute withdrawal of steroid  acute adrenal
5)  Eosinophils                                               insufficiency. Must taper doses.
6)  Monos and  function                                  d. Time to recovery function of total dose.
7)  Lymphocytes: Deplete T cells   Type IV              Major Stress in pt w/HPA suppression:
   Hyper-sensitivity. Little effect on IgG and IgE         Minor stress: Viral illness. ??? Double replacement dose
8)  M antigen processing and  cytokines.  TNF             vs. no change in dose.
9) Anti-inflammatory potencies, parallel other             Minor surgical stress: inguinal hernia repair.
   glucocorticoid effects                                     Hydrocortisone 25 mg on op day.
                                                           Moderate surgical stress: total joint replacement, LE
No one effect explains anti-inflammatory action               vascularization. Hydrocortisone 50 mg IV intraop.
1) Therapy is palliative and symptomatic, not curative     Major stress: CP bypass. Cortisol 50 mg Q8hr for 48-72
2) Lose signs and symptoms but underlying condition           hrs.
    may worsen
Variation in receptor properties doesn't explain           Avoidance of HPA suppression:
    heterogeneous response of immunoreactive and           Normal output of cortisol is 25 mg /day. Prednisone is 4x
    inflammatory cells.                                       more potent.
Absorption, Distribution, and metabolism                   a. Minimize dose and duration
                                                           b. Single early morning dose if possible
                                                        ESSENTIAL BASICS--19
c. Alternate day therapy
d. Inhaled steroid for airway, or topical application
Variable requirements:
Individuals vary in sensitivity

                                                            Pain often more intense.
                                                            Often longer than 30 minutes.
 CARDIAC Hx & PHYSICAL                                      Associated symptoms: nausea, sweating, dizziness may
                                                                mimic indigestion.
            History-Techniques                              Dyspnea
Hx remains the richest source of information that helps
    establish a bond w/the pt and establish the impact of   Abnormal uncomfortable awareness of breathing.
    the dz on various aspects of the pt‘s life.             Associated with wide variety of diseases of heart and
Don't force Hx  You really didn't have chest pain did          lungs, chest wall, and respiratory muscles, as well as
    you? Use open ended questions: Tell me more about           with anxiety.
    it                                                      History is most valuable means to establish etiology.
Given the opportunity most pts will give you a pretty       Dyspnea From LV Failure
    good idea of what's going on.                           Exertional dyspnea
Risk Factors for Coronary Artery Disease                    Orthopnea
Family History:                                             Paroxysmal nocturnal dyspnea
                                                            Pulmonary edema
Misc:                                                       Wheezing
Smoking                       Obesity                       Syncope
HTN                           EtOH abuse                    Loss of consciousness resulting most commonly from
Lipids:                                                         reduced perfusion of the brain.
Genetic lipid disorders       Hypercholesterolemia          True syncope (bump on head to prove it) is always
 serum TG                     Lipoprotein Little a            considered cardiac until proven otherwise
 HDL                          APO A1 (HDL carrier)
 LDL                          APO AB (LDL carrier)        CV Causes of Syncope
Acute Phase reactants:                                      Arrhythmias
 Fibrinogen                   CRP                         Obstruction to blood flow (A.S., myxoma, HCM)
Other:                                                      Reflexes affecting heart rate and blood pressure:
 Homocysteine                 serum Fe                        vasodepressor syncope, orthostatic hypotension
                                                            Hypersensitive carotid sinus
Cardinal Symptoms of Heart DZ
Chest pain        Dyspnea             Syncope
                                                            To cover in Hx of Palpitations
Palpitation       Edema               Cyanosis, clubbing    Have Pt. mimic rhythm with hand.
Cough             Hemoptysis          Fatigue and other     Does palpitation occur with ……
    symptoms                                                   Isolated jumps or skips  Extrasystoles
                                                               Abrupt HR=120  Paroxysmal rapid heart
Character of pain                                              Conjunction w/drugs  Tobacco, coffee, EtOH,
(+) ischemic pain                  (-) ischemic pain                 ephedrine
constricting                     dull ache                     On standing  Postural Hypotension
squeezing                        knife-like", sharp,           When rate in known to be normal  Anxiety State
burning                          "jabs" change
     w/respiration                                          Symmetrical swelling with pitting in legs most
"heaviness"                                                     pronounced in PM.
"pressure"                                                  Minimal edema = to ~ 7-10 lb weight gain
                                                            Recumbency at night  diuresis
Location of pain                                            Later involves legs, thighs, & abdomen  bloating, RUQ
(+) ischemic pain                (-) ischemic pain              tenderness
substernal                       in left chest
mid-thorax, ant.                 in left hemithorax
in neck, cheeks, teeth, jaw                                 Central cyanosis
either or/both arms,                                         arterial oxygen saturation
     shoulders,                                             right-to-left shunting of blood
     forearms                                               impaired pulmonary function
                                                            Symptoms often worse during exertion
Factors provoking pain
Effects or induced by the 4 E’s:                            Peripheral cyanosis:
Exertion                                                    2* to cutaneous vasoconstriction
Eating                                                      Low CO
Emotion                                                     Exposure to cold, vasospasm
Extreme cold or heat
Episodic Chest Pain Resembling Angina                       From pulmonary venous hypertension:
Pectoris                                                       dry
Esophageal reflux         Esophageal spasm                     nocturnal, recumbency
Peptic ulcer              Biliary dz                           associated with exertion
PE                        Musculoskeletal                   Frothy pink-tinged sputum occurs in pulmonary edema
Hyperventilation          MVP                                   (rare)
Cervical disc             Aortic dissection                 Cough with hoarseness may be due to pressure of a giant
Unstable Angina                                                 left atrium
                                                                        Fatigue– Common but nonspecific
Change (more severe, prolonged, or frequent) in angina      Do you tire easy? What is the most vigorous thing you
   superimposed on stable angina.                               do?
New onset angina.                                           Relate to past events:
Angina at rest as well as minimal exertion.                 What was the most vigorous thing you could do last year?
Myocardial Infarction
                                                               Ventricle suddenly reaches its elastic limit and abruptly
                 Physical Exam                                     decelerates early diastolic blood flow.
1)   General appearance                                           Low- pitched sound
2)   JVP                                                          apex
3)   Arterial pulse                                               pt lying on the left side
4)   Cardiac inspection and palpitation                           stethoscope bell pressed lightly against the skin.
5)   Cardiac auscultation                                      S3 disappears with firm pressure of bell (split S-2 or O.S.
6)   Heart sounds                                                  does not) Dynamic interplay between force of
7)   Heart murmurs                                                 delivery of blood into ventricle and ability of
                                                                   ventricle to accept this flow
Angle D'Louis                                                  Always pathologic after age of 40. Physiologic in athletic
In most individuals, the center of the right atrium is about       heart (large stroke volume, slow HR), children, 
    5 cm from the attachment of the 2nd rib to the                 CO.
    sternomanubrial junction. This relation is maintained      Unlike a split S-2, you can dance to the S-3, gallop.
    in every position between supine and sitting upright.
                                                               Fourth Heart Sound
Arterial Pulses                                                ―Tennessee‖ ―Monica‖
Distinguishing Venous From Arterial Pulses                     Low frequency sound from atrial contraction into non-
Quality of the pulse                                               compliant ventricle:
Timing of the pulse                                               Hypertrophy
Effect of position of the patient                                 Coronary dz
Effect of respiration                                             MI
Effect of abdominal pressure                                      HF
Clinical Info from Arterial Pulse                                 outflow obstruction
Cardiac rate and rhythm                                        They are usually not present in normal individuals.
Differential pulsations (right-left, upper lower extremity     Heard best with bell with patient on left side.
Arterial thrills                                               Disappears with firm pressure of bell.
Wave form, contour (slow or rapid upstroke)
Palpation:                                                                   Cardiac Murmur
Info from Inspection and Palpation of Precordium               "A relatively prolonged series of audible vibrations of
Systolic movements caused by the ventricles, great                 varying intensity (loudness), frequency pitch),
    vessels, and the atria.                                        configuration (shape), quality, and duration."
Vibrations or movements caused by the heart sounds.            Production of Murmurs
Transmitted vibrations of murmurs, i.e. the thrills.           1) High flow rate through normal or abnormal orifices.
Apical Impulse (descriptors)                                   2) Forward flow through a constricted orifice.
Displaced left of MCL, size Diffuse                            3) Backward or regurgitant flow through an
Hyperkinetic                Hypokinetic                            incompetent orifice.
Dyskinetic                  Lift                               Grading Murmur Intensity
Heave                       Sustained  LVH                    Grade 1- barely audible
Sustained & Displaced  Dilated and hypertrophied              Grade 2- soft but readily detected.
Other Palpable Entities                                        Grade 3-prominent, loud. Not palpable.
Gallop Sounds: S-3, S-4                                        Grade 4- loud (palpable).
Palpable P-2: Pulmonary HTN                                    Grade 5-very loud (heard with just edge of stethoscope
Para-sternal Heave: RV enlargement                                 touching skin.
Thrill: Palpable murmur (4/6)  MR, and AS.                    Grade 6-audible without stethoscope.
                                                               Mid-systolic ejection:
          Cardiac Auscultation:                                   Innocent murmur
                 In each area, listen for:                        aortic or pulmonary stenosis
   S-1: Intensity, constancy, & variation                        atrial septal defect
   S-2                                                           left ventricular outflow obstruction.
                                                               Innocent Murmurs
   Extra Systole Sounds: Clicks, valve sounds, and rubs
                                                               Non-radiating systolic ejection in nature that is < grade 3
   Extra Diastole Sounds: Gallops, and O.S.                   May be seen in 30-50% of children that disappears
   Murmurs-Systole                                                w/puberty.
   Murmurs-Diastole                                           Adults, especially athletes may have innocent flow
Use bell & diaphragm in each position                              murmurs
Change positions.                                              Pansystolic Regurgitant Murmurs
                                                               Retrograde flow from a high pressure chamber to one of
                  Heart Sounds                                     lower pressure.
S-1 identifies the onset of ventricular systole.               Because of high pressure differential between two
S-2 identifies the onset of diastole.                              chambers throughout systole, murmurs are
These two auscultatory events establish the framework in           holosystolic, high pitched and blowing, with a
     which other heart sounds and murmurs can be timed.            plateau like configuration.
Wide splitting of S-2: delayed pulmonary closure               1) Mitral Valve Regurgitation
Delayed electrical activation of RV: RBBB                      2) Tricuspid Regurgitation
Prolonged RV mechanical systole:                               3) VSD
   Acute massive PE                                           Diastolic Murmurs: 2 mechanisms
   Pulmonic stenosis                                          Forward flow: MS "Rumbles" forward flow across AV
   Idiopathic dilation of PA                                      valves.
Reversed splitting of S-2: delay in aortic closure             Retrograde flow: AI. regurgitant murmurs across
Delayed electrical activation: LBBB                                incompetent semilunar valve.
Prolonged LV mechanical systole:                               Continuous Murmurs
   Outflow tract obstruction                                  Aorto-pulmonary connections: PDA
   HTN heart dz                                               AV connections: fistulas
Narrowly split S-2                                             Disturbances of flow patterns in arteries: ―mammary
   Pulmonary HTN w/right HF                                       souffle"
                                                               Disturbances in flow patterns of veins: cervical venous
Third Heart Sound                                                  hum
                                                                  next regular beat. Premature beats may occur in a
                                                                  pattern: bigeminy is every other beat, trigeminy is
             EKG READING                                          every 3rd beat, etc.
                                                             Premature Atrial Contraction (PAC): singular, paired,
                        (1) Rate:                                 atrial bigeminy (every other beat), or irregular
300/150/100/75/60/50/42/38                                   Premature Junctional Contraction (PJC):
                                                                  retrograde/inverted P; narrow QRS; R.P often <0.10
                      (2) Rhythm:                                 sec
Identify atrial rhythm by P waves (use Leads II and VI)      Premature Ventricular Contraction (PVC): wide QRS;
    and Ventricular rhythm by QRS complex.                        significant if runs or >6 per run.
                                                             QRS Aberration or Aberrant Ventricular Conduction or
                                                                  Sustained Aberrancy: PAC occurs after AV node‘s
Supraventricular Rhythms:                                         refractory period, but while bundle
Sinus: Impulse arises at the SA node. P wave for every            branch(es)/fascicles are still refractory. Timed like a
    QRS. Intervals regular. PR >0.12 sec. P                       PAC, but with a widened QRS in the classic pattern
    monomorphic and (+) in II (and usually I, and III). P         of a fascicular block, usually RBB. This Physiologic
    axis 0-90.                                                    IVCD may be sustained and must be distinguished
SVT: Non-specific term. Usually for tachyarrhythmias              from V-tach
    with discernable P waves and narrow QRS                  Fusion Beat: Impulses from supraventricular and
    complexes.                                                    ventricular foci activate ventricular contraction
                                                                  simultaneously Early characteristics of a sinus beat
Sinus Arrhythmia: Impulses arise at SA node at varying            and late characteristics of a PVC
    rate. Complexes are normal. Longest RR > shortest Escape Beat/Rhythm Impulse fails to initiate at SA node
    RR by > 0.16 sec; Etiologies  normal respiratory             and an alternate focus fires, often in the conduction
    variation, sick sinus syndrome, narcotics.                    system Pause terminated by ectopic atrial, junctional,
Ectopic atrial rhythm: Impulses originate low in atrium,          or ventricular beat
    traveling retrograde and distally. P inverted in II, but Junctional Rhythm Impulses originate in AV nodal region
    otherwise meets criteria for sinus rhythm.                    with retrograde and antegrade transmission. P waves
Wandering atrial pacemaker: Impulses originate from               inverted and retrograde (may be buried in or follow
    varying points in atria. Variations in P wave contour         QRS), narrow QRS; often 40-60 bpm
    (3+ waveforms), variations in PR/PP/RR intervals.        Ventricular Parasystole: Impulses arise regularly from a
Multifocal atrial tachycardia: Impulses originate                 single ectopic ventricular focus without reference to
    irregularly and rapidly at different points in atria.         sinus QRS PVC‘S at regular intervals from each
    Are often non-conducted. 100-180 bpm; variations              other
    in P wave contour, but is single and discernable.        Peripheral Conduction (Wolfe-Parkinson-White
    Variable PR/PP/RR intervals. Often due to COPD,                  Syndrome) Impulse originates at SA node & pre-
    CHF, and theophylline.                                           excites the peripheral conduction system and
AV nodal reentry tachycardia or paroxysmal Atrial                    ventricular muscle via accessory conduction
    tachycardia: Impulses recycle repeatedly in and near             pathway (bundle of Kent) without usual delay at
    AV node due to a slowing in the area of                          the AV node. Impulses also arrive at the ventricles
    unidirectional block. 160-220 bpm. P waves regular               via the normal route after normal delay at the AV
    and often inverted (esp in II) May be from excess                node. P immediately followed by a short Delta
    Digoxin with low K.                                              wave (slurred QRS upstroke), short/absent PR,
Atrial flutter: Impulses travel in circular course in atria          wide QRS. Risk of rapid direct or re-entry
    setting up regular rapid flutter waves. 220-350 bpm;             tachycardia, either orthodromic (antegrade thru
    ―Sawtooth‖ pattern; QRS rate regular (2:1 block is               AVN) or antidromic
    most common, ventricular rate ~150). 3:1 rare. 4:1
    in AV nodal disease; conduction may be variable;               (3) Axis/R wave progression
    sensitive to DC conversion.                              Right or Left Axis Deviation in Frontal Plane:
Atrial fibrillation: Impulses take chaotic random pathways Normal Axis (no deviation) -30°to 90°
    in atria. Atrial rate is undeterminable. (>300); P       Plot direction (+ or-) & net amplitude of QRS in I & aVF
    waves absent/fine/coarse; QRS rate is irregularly             e.g., if R = +5 and S -2, net amplitude- +3
    irregular.                                               Estimate angle of summation vector on imaginary grid
Ventricular Rhythms:                                              e.g,,3 mm (+) in I & 3mm (+) in aVF=45°axis
                                                                  frequently aVF areboth (+),giving axis of ooto900
Idioventricular Rhythm: Rate <40 bpm with wide QRS
                                                             Alternate Method: axis perpendicular to most isoelectric
Accelerated Idioventricular Rhythm: 40-120 bpm; usually
    short bursts of <20 sec often a few days after MI.
                                                             In RBBB, only use 1st 0.08 sec of QRS (ignore late
    Widely split S2
Ventricular Tachycardia: 120-200 bpm;
                                                             RAD: RVH, PE, post. fascicular block, lateral MI, tall
    rapid/bizarre/wide QRS; usually regular rhythm;
    often AV dissociation. Typical of coronary heart
                                                             LAD: LVH, ant. fascicular block, some LBBB, inf MI,
    disease, esp MI (2* to reentry and Ischemic block.
                                                                  short stature
Ventricular Fibrillation: 350-450 bpm;
    unidentifiable/erratic wave, coarse or fine; multifocal
    depolarization; no formed QRS.                                                (4) Intervals
Pulseless VT, polymorphic VT and Torsade de Pointes          PR Interval
    usually treated like VF in ACLS.
                                                             Normal <0.2 sec (3-Siren) from beginning of P to
Pacer Rhythm: transvenous pacemaker paces from apex
                                                                  beginning of QRS; <0.22 sec Wpt is >80 years old
    of RV, so QRS is wide and may look somewhat like
                                                             IACD: Intra-atrial Conduction Delay may be indicated by
    LBBB. Pacemaker spike may be small/absent and
                                                                  a widened P wave; P > 0.12 sec in II
    are easily missed. Spike intervals are often precisely
                                                             1° AV Block or Prolonged AV Conduction: fixed
    regular; LVH/Ischemic criteria are often unreliable.
                                                                  prolonged PR >01 sec (5mm)
    Pacer designation is 3 letters  Paced (A/V/D)
                                                             2° AV Block
    Sensed (A/V/D), Mode (Trigger/Inhibited/Dual)
                                                                  Mobitz I (Wenckebach): Progressive PR lengthening
Other Rhythms:                                                         intermittent dropped QRS (usually 3:2 or 43)
Premature Contractions: Impulse occurs before expected            Mobitz II (Non-Wenckebach): Sudden dropped QRS
    sinus beat, often with a compensatory pause before                 without poor PR lengthening
3° Complete AVB/Trifasicular: No relationship between        Early Transition (V1-V3): counterclockwise rotation,
    P & QRS; Junctional or Ventricular QRS                       RVH, RAD, posterior MI, incomplete RBBB (V1)
AV Dissociation: No relationship between P & QRS; P          Late Transition (V4-V6): clockwise rotation, LVH, LAD,
    rate slower than QRS rate; irritated ventricle               anterior/septal MI, breast attenuation, LBBB
Short PR~ <0.12 sec preexcitation syndrome (WPW);            R- Wave Regression: R is smaller than in preceding lead:
    AV-nodal rhythm (inverted P in aVF)                          classic for MI, lead misplacement
                                                             ―Poor R-Wave Progression‖: R should increase by 1+
QRS Interval:
                                                                 small box V1-V3; non-specific for septal/anterior MI
Normal < 0.10 sec (2.Snsn) from beginning of Q to end of
BBB: Incomplete/Partial (0.10-0.12 sac) or Complete
     BBB (0.12 - 0.20 sac)
                                                                        (6) Ischemia/Infarction:
RBBB: Terminal QRS is (+) V1 & (-) V6; RSR‘ In               Not reliable in LBBB; use ST segments in VI & V4-V6 in
     V1/V2 ―rabbit ears‖, deep S in V6-V5; ML axis                RBBB
RBBB: plus L anterior fascicular block gives LAD; plus              Site       Leads     Coronary
     L posterior fascicular block gives RAD                  Inferior        II/III/aVF  RCA> CX Q is very specific
                                                                                                         for MI; can
LBBB: Terminal QRS is (-)V1 & (+)V6; QRS peaks                                                           mask anterior
     slowly in V6, quickly in V1; narrow R (V2~V3)                                                       fascicular blocks
Complete: RR‘ in V5-V6/I/aVL LAD; ST depression; T           Anteroseptal    V1-V3       LAD          Q less specific for
     wave inversion                                                                                      MI; commonest
                                                                                                         Ml (inferior Ml
Anterior fascicle: 0.10-0.12 sac; LAD > -45 degrees;                                                     is 2nd)
     small Q (I/aVL), S(III); S>R (II/III/aVF)               Anterior        V2-V5       LAD          Q less specific
Posterior fascicle: 0.08-0.12 sec; RAD; S(1), Q(III); much                                              for MI
     rarer than anterior fascicle block.                     Anterolateral   V4-V6       LAD; CX      Q specific for
Intraventricular Conduction Defect (IVCD): QRS > 0.12                                                   MI
     sac; this is a non-specific term; BBB, atypical BBB,    High Lateral    I/aVL       CX           controversial;
     or fascicular block > 0.2 sec suggests slowed                                                      rarely isolated
     conduction in myocardium itself.                                                                   w/o inferior MI
Preexcitation Syndrome (WPW): prolonged from delta           Posterior       Vl-V2       RCA; CX        large
     wave (slurred QRS upstroke); short PR                                                              R=reciprocal Q;
                                                                                                        ST depression;
QT Interval:                                                                                            (+)T Q(V6)
Normal: Rate dependant Corrected QT, or QTc = QT             Q or QS Waves:
     /(RR)1/2 (use shortest RR). Variable reference range:   Q wave MI (55%), ―transmural‖; usually proceeded by
     mm <0.42, women <0.43, pads <0.44.
                                                                 acute ST
Estimate: Beginning of Q to end of T < 1/2 RR for HR of
                                                             Normal: isolated narrow Q usually normal in
     60-90 bpm measure longest segments                            l/aVL/V5/V6 if large R follows
Prolonged QT: can lead to R on T or Torsade de Pointes       Ignore: isolated narrow Q in Ifl/aVRJV1 if EKG is
Artificial: U waves may be confused with end of T; wide            otherwise nl
     QRS (subtract prolongation to correct)                  Sign: Q is > 1x1 mm wide & deep; more significant if>l/3
Congenital: Romano-Ward (dominant), Jervell/Lange-
                                                                   QRS height and 2+ leads
     Nielaen (recessive, associated with deafness)           Old: Q waves usually permanent; small R waves (<1mm
Acquired: CVA, Low K/Ca/Mg, drugs: anti-arrhythmics                taIl) may return & obscure
     (Ia/III), TCA‘s, Erythromycin.
Torsade de Pointes: long QT & polymorphic VT (VT), set       ST Elevation:
off by pause-related T/U augmentation Must distinguish    Acute change that usually returns to baseline (defined by
from VT, as Rx is different (eg. give beta agonist, remove     TP)
altiax ThythrnlCs Ia/UI)                                  Injury (Acute MI): ST ―tombstoning‖ ( (upward curve);
                                                                 often with Q waves and T wave inversion
    (5) Hypertrophy/Enlargement Vasospasm: usually lasts minutes (AKA Vasospastic/
Criteria for ventricular hypertrophy not reliable in RBBB        Prinzmetal‘s / Variant Angina)
                / LBBB                                    Ventricular aneurysm: usually post-MI; long-standing ST
RAE: P(V1) biphasic and the (+) component is> lx1 mm;             in Q wave leads
          tall P > 2.5-3.0 mm tall in II (& III/aVF).     Pericarditis: often ST convex  diffuse; young, non-CAD
          Clinical: ―P pulmonale‖: pulmonary HTN,                Pts
          COPD, PE                                        Pseudo MI: acute GI disturbance (cholecystitis,
LAE: P (Vl) biphasic and the (-) component is > 1x1mm;           pancreatitis); acute lyte changes; very rare
          P(II)>3.0 mm wide; PP‘; IACD. Clinical: ―P      Early repolarization: normal in youths; usually V2-V3;
          mitrale‖: systemic HTN, aortic insufficiency,          often J point notch; exercise normalizes may be
          mitral valve stenosis/insufficiency                    seen following large S waves (eg. in LVH) ignore
RVH: R>S (VI), R(V1) >5, & T (V1) inverted; deep                 if isolated in V2
          S(V6); RAD RAE; Severe RVH: Q in VI/V2.         J-Point Elevation:Early repol/LVH; distinguish from Ml
          Clinical: pulm HTN, COPD, mitral valve                 by notch, concave ST, WE on prior EKG
          stenosis/insufficiency, pulmonary stenosis, VSD
                                                          ST Depression
LVH: S (V1) + R (V5 or V6) >35 (or > 0 in children)
          R(I) + S(I1I) >25; R (aVL) >11-15. Associated    ignore aVR & V1; <1mm below baseline 2mm after J,
          with LAD and inverted/asymmetric T waves in          non-specific ST changes
          V5/V6; R peaks over >0.04 sec. Clinical:        Positive Stress Test: >1mm below baseline 2mm after J
          systemic HTN, aortic/mitral insufficiency            (―J+80msec‖), especially with slope reversal
RV strain: S (I), Q(III), ST  in RV leads                Injury (Ischemia/MI): non-Q wave MI (45%),
LV strain: LVH; Tall R(V4 - V6); ST  /convex up;              ―subendocardial‖; ST flat or convex up (slope
     inverted biphasic I                                       reversal)
                                                          Digitalis: concave down; many leads; often bradycardic,
                                                               PAT, PVC
R Wave Progression:                                       Ventricular Strain: convex up; wide angle between T &
Evaluates: rotation of axis in transverse plane                QRS axes (T opposite QRS)
Normal Progression: S>R (V1); R>S (V6);                   Secondary: IVCD, BBB, SVT, PVC, V-tech,
     transition/isoelectric lead is V3 (less commonly V4)      idioventricular rhythm.
T wave
Normally (+) in I/II/V3-V6, (-) in aVR others vary             1) Inflammation: currently very important. Activated
Inverted: LVII (asymmetric), ischemia (symmetric), MI,            monocytes  foam cells. Elevation of plasma
     pericarditis, low K/Ca, CVA                                  markers of inflammation such as C-reactive protein,
Flattened: non-specific T wave flattening (ischemia, DM,          predict an increased risk of coronary events in pts
     hypokalemia, drugs, etc)                                     w/stable and unstable angina. Role of these markers
Peaked: hyperacute MI (1st finding), hyperkalemia                 in clinical assessment remains under study.
     (narrow), LVH, early repolarization                       2 role of risk factors, especially hyperlipidemia
BBB: abnormal depolarization, abnormal repolarization;         3) focal nature of the lesions and their location in the
     T opposite terminal QRS                                      intima;
T Wave Memory: prolonged artificial pacing can make T          4) mechanisms of smooth muscle proliferation.
     inversion persist even after pacing stops
                                                               The response to injury theory  the lesions of
                      (7) Other                                   atherosclerosis are initiated as a
Ron T: R on the peak of T often precipitates VP (PVC on        1) response to some form of injury to the arterial
    T, long QTc, unsync. cardioversion)                            endothelium.
Low Voltage: QRS <5mm, all limb leads: COPD,                   2) Lipid is transported into the subintimal region.
    pericardial effusion; malnutrition; hypoendocrine          3) Smooth muscle cells migrate to this location to
PE: large S(I) large Q(III) ST depression in II; T inversion       engulf the foreign lipid material.
    in V1-V4; acute RBBB transient/incomplete RBBB;            4) Connective tissue matrix is formed and lipid
    Rt axis deviation; commonly, only sinus tach may be            accumulates.
    seen                                                       5) Repeat injury results in the development of an
Hyper-K: peaked I, flattened P. widened QRS;                       atheromatous plaque.
Hypo-K: flattened T; U appears
Hyper-Ca: shortens ST and thus QT                              Clinical Significance: occurs by 3 mechanisms
Hypo-Ca: lengthens ST and thus QT                              1) Plaque build up  gradual lumen obstruction  
Digitalis: gradual down-sloping of ST; ST concave down             blood flow to target organ (heart, kidney, brain, legs,
    & T wave ―scooped‖                                             etc)
Digitalis Excess: PAC/PJC; PAT with block sinus block;         2) Plaque rupture  induction of thrombosis/Plt
    AV block tachyarrhythmias most common                          activation  sudden cessation of blood to organ 
Pericarditis: ST  & concave  ; T off baseline; PR                death of target area (MI, stroke, renal infarct, etc)
    segment ;  voltage                                       3) Plaque weakening vessel wall  aneurysm or
IVCD: both R and S widened; RSR‘ complexes                         rupture.
Exercise: J point depression with up sloping ST (with
    injury~ ST stays depressed)
                                                                    ACUTE MYOCARDIAL
R-Sided EKG: Reversed EKG; lead R-V4 reflects the
    Right Ventricle; ST elevation with ischemia
                                                               Diagnosed on three criteria:
                                                               1) presence of typical clinical history
      ATHEROSCLEROSIS                                          2) ECG 
Most prevalent dz in the Western world, causes about             in cardiac enzymes.
   50% of all deaths in the United States.                     Clinical History of AMI
Most frequent vessels involved are the aorta, coronary
                                                               1) Severe CP lasting >20-30 min that is not easily
   arteries and cerebral arteries. Up to 50-60 yrs >  at
                                                                  resolved. Most common symptom.
    risk of developing. In menopause the ratio equals         2) Numbness or aching referred to the arm, neck or jaw.
   out.                                                        3) Occurs at rest or during sleep w/no precipitating
                                                                  cause: 50-60%. Precipitated by exertion or stress in a
Definition                                                        smaller number.
atherosclerosis is a disease of large and medium-size
                                                               4)  risk in AM hrs. There is an early AM  in plasma
Atheroma: a raised intimal plaque w/a core of lipid &             NE and EPI   platelet aggregability. Not
                                                                  counterbalanced by NO and PGI2 normally released
    covering fibrous cap.
Risk Factors –                                                    from a non-diseased vascular endothelium.
                                                               5) Clinically "silent" AMI: > 25%, diagnosed by ECG
Age: >55 if ♂ and 60 if ♀
Sex: ♂> ♀                                                         only (esp. with DM or HTN). 50% of these are truly
                                                                  silent, while the rest have atypical symptoms.
 LDL,  HDL
                                                               6) Indirect symptoms: Dizziness, palpitation, syncope,
Tobacco use
                                                                  nausea or vomiting. Occur when AMI is complicated
Under study: Homocysteine, Factor V Leiden,
                                                                  by acute HF.
    Fibrinogen, CRP, infection (Chlamydia pneumoniae,
    H. pylori, and CMV).                                       Electrocardiogram (ECG)
                                                               Presenting ECG is normal in 20%. diagnostic of AMI in
Morphology:                                                        65%. Serial ECG‘s  diagnostic sensitivity to 80-
Fatty streak: lipid deposition in the intima. Appear in the        90%.
    aortas of all individuals after 1 year of age regardless   During an AMI, the ECG typically evolves with
    of geography, race, sex or environment.  40‘s             1) ST segment elevation.
    where concern is and progression into atheroma and         2) Loss of QRS amplitude: Cell death progresses in a
    calicification                                                 wave front of necrosis from endocardium towards
Atheromatous plaque: localized to the intima of the vessel         epicardium. QRS voltage  as muscle mass  and
1) lipid-laden myointimal cells and macrophages;                   myocardium is replaced by scar tissue.
2) connective tissue including collagen, elastic fibers        3) Development of Q waves:
    and proteoglycans;                                         4) Normalization of ST segments
3) intracellular and extracellular lipid deposits.             5) Then T wave inversions that may persist or resolve.
As these lesions progress they become complicated
    plaques which have calcification, ulceration,              ST segment : Less severe ischemia. May indicate AMI,
    superimposed thrombosis or hemorrhage into the                 subendocardial ischemia, or reciprocal changes from
    plaque.                                                        a distal ischemic zone.
ST segment : Need >40-50% ischemia of wall thickness. 3) Retrospective diagnosis: Excellent for AMI. Troponin
      occurs in leads over those areas.                        remains elevated for 2-3 weeks.
                                                            4) Prognosis: Superior prognostic indicator for acute
Q-Wave Infarct: occurs when cell death involves >40%            coronary syndromes: Small  of troponin in pts
     of the wall thickness. Not synonymous with the             w/unstable angina & w/out of CK-MB are strong
     pathological term transmural wall infarct. Less severe     prognostic indicators for future cardiac events.
     damage causes non-Q wave infarcts. Q waves can
     resolve in about 10% (20-25% with inferior Q waves) Compared to CK-MB:
     due to hypertrophy in non-infarcted tissue and/or scar Clearly superior to CK-MB when confounding influence
     retraction.                                                of SkM disorders.
                                                            Better marker than CK-MB for high-normal patients:
                 Cardiac enzymes                               CK-MB has  specificity and sensitivity in detecting
                                                                micro infarcts. Diagnosis cut off values are set >
Ideal markers:                                                  upper limit of reference range
1) Cardiac specific and high concentration in myocardium       Minimally  CK-MB confounded by co-existing
2) Absent from serum of plasma of pts w/out AMI                 illness.
3) Rapidly released & diagnostically significant w/in 4 hrs
   of AMI                                                   Myoglobin
4) Marker should remain elevated for extended period s/p Initial rise is fast and decline is fast. Can use myoglobin
   AMI                                                          to follow after thrombolytic therapy.
5) Degree of injury should correlate to level in serum or   Clinical Uses:
   plasma                                                   For Pt presenting w/in 12 hrs of Chest Pain
6) Useful in detecting reinfarction & monitoring               When SkM damage not present  doubling of
   thrombolytic Tx                                              myoglobin in 2 hr time frame > 95% sensitive for
Cardiac Markers
                                                               Two (-) myoglobin 2 hrs apart rules out AMI in >
                 1st          Peak         Duration in        95% of pts
Myoglobin        2-3           6-9                   1                         Management
CK-MB            4-6          18-36                  3
Troponin T       4-6          24-36                14-20    Initial management
Troponin I       4-6          24-36                14-20    Specific interventions:
                                                            1) MSO4: Adequate relieve of ischemic pain  levels of
Reference Ranges:                                               circulating catechols and  myocardial O2
Myoglobin                                                       consumption
CK-MB                                                       2) Sublingual or IV nitro given in the absence of
Troponin I                                                      hypotension:
ANP                                                                a) dilates coronary collaterals
CK-MB                                                              b) prevents or reverses coronary spasm
3 CK isoenzymes:                                                   c)  pre-load to the heart   pulmonary
1. CK-BB: brain and kidney                                           congestion
2. CK-MM: skeletal muscle and heart                         3) Aspirin: Anti-platelet therapy w/ASA  mortality.
3. CK-MB: heart.                                            4) Heparin: Anticoagulation w/heparin in all patients.
                                                            5) Beta-blockers:  myocardial ischemia. May limit
Area under the time-activity curve directly related to          infarct size.
     infarct size, morbidity, mortality, arrhythmias, &     6) O2 therapy: indicated in most because hypoxemia
     ventricular function.                                      common
Will get a rise in CK-MB w/reperfusion. Can be used to 7) Admit to CCU.
     look at success of thrombolytic therapy.               General goals of immediate management:
                                                            1) ID candidates for reperfusion therapy. ~90% of pts
CK Index =[ (CK-MB mass (ng/ml) / Total CK activity ]           w/AMI and  ST segment have complete thrombotic
     x 100                                                      occlusion of the infarct related artery. Early
                                                                restoration of perfusion  infarct size, preserves LV
CK-MB          Index      Result                                function, and  mortality.
   <7          <2.5       Normal                            2) Recognize and treat potentially life-threatening
   >7          >2.5       Cardiac Damage                        complications such as hypotension, pulmonary
   >7          <2.5       SkM Damage                            edema and arrhythmias.
                                                           Acute coronary Reperfusion
Small intestine, tongue, diaphragm, uterus, and prostate
    contain small amounts of CK-MB.                        Prompt coronary reperfusion is indicated in all pts who:
Common causes of false positive  CK-MB:                   1) Present w/in 12 hrs of a prolonged ischemic episode
 Viral myocarditis            EtOH myopathy
 Duchenne‘s MD                Rhabdo                     2) New ST segment  of at least 0.l mV (>l mm) in at
                                                                least 2 contiguous leads.
 Polymyositis                 Malignant hyperthermia
                                                           Thrombolytic therapy.
 Dermatomyositis              Reye‘s syndrome            1st choice for restoring coronary perfusion.
 Viral myositis               Hypothyroid myopathy       Advantage: widespread availability and rapid
 Acromegalic myopathy  Therapeutic electric                   administration. Fibrinolytic agents will induce clot
  countershock                                                  lysis in 60-90% of patients by 90 minutes, depending
 Exercise                                                      on the agent used.
Troponin I and troponin T                                  Disadvantage: 1-3% incidence of life-threatening bleeds.
Regulatory proteins found in cardiac and SkM. Cardiac
                                                           Absolute contraindications include:
   specific forms w/unique AA sequences are readily
                                                           1) active bleeding
   detected in acute coronary syndromes.
                                                           2) prolonged CPR
1) Sensitivity: 100% for AMI diagnosis w/serial
                                                           3) recent major trauma
                                                           4) recent stroke
2) Specificity: 100% for Troponin I
                                                           5) unsuspected aortic dissection
6) active peptic ulcer disease                                   thrombus formation, ventricular arrhythmias, angina,
                                                                 and  mortality.
Marker of success of thrombolytic Tx: follow clinical         Mural thrombi: Most common within the 1st week of an
   markers for improvement in ST segment  and                   AMI. Form particularly with anterior wall infarcts,
   resolution of CP.                                             aneurysms or infarct expansion. Occur w/severe wall
                                                                 motion impairments. Mural thrombi may lead to
Coronary angioplasty (PICA): Mechanical reperfusion              systemic embolization.
    of a thrombotic coronary occlusion.                       Myocardial rupture:
Advantage: normal arterial flow can be achieved in at         Ventricular free wall rupture: fatal complication of AMI.
    least 90% of pts w/ST  and AMI.                             Accounts for 10% of in-hospital AMI deaths. Most
Disadvantage: 1 PICA takes longer to implement.                 occur within 3-6 days (up to 3 weeks). Usually
    Available in < than 20% of hospitals worldwide.              preceded by infarct expansion. Leads to
                                                                 hemopericardium, cardiac tamponade, right heart
Subacute Management:                                             failure, shock and death. Rupture more common in:
After 24-28 hours, pts who are free from recurrent            1) elderly women
    ischemia, hypotension, arrhythmias and heart failure,     2) pts w/HTN
    may be candidates for transfer to a step-down unit.       3) large transmural anterior wall infarctions
After 48 hours patients should progressively  activity
    levels.                                                   IV septum rupture:  ventricular sepal defects w/left to
ASA and -blockers should be continued indefinitely.              right shunts, biventricular failure, and shock.
ACE inhibitors   in short term mortality when initiated Papillary muscle rupture: usually incomplete. Produces
    w/in the 1st 24-48 hours.                                     acute mitral regurg. Many occur even with small
1) Pts receiving the greatest benefit are those with              infarcts. Typically, inferior wall infarcts cause rupture
    anterior infarctions or CHF.                                  of posteromedial papillary muscle.
2) Pts w/CHF or symptomatic LV dysfunction should
    receive ACE inhibitors indefinitely.                      Right ventricular infarction: Complicates about 1/3 of
                                                                  inferior-posterior wall AMI. Right sided heart failure
Complications of AMI:                                             
Arrhythmias:                                                  1. peripheral edema
Occur early (minutes to hours) and late (days) after an       2.  venous pressures
    AMI.                                                      3.  outflow casing inadequate left heart filling
1) Tachyarrhythmias: reflex or catecholamine-induced          4. hypotension while sparing the lungs from congestion.
    stimulation, particularly w/anterior wall AMI. Sinus The treatment is fluid expansion.
    tachycardia  myocardial 02 consumption                 Congestive heart failure: Complicates large infarcts,
    ischemic damage.                                              particularly if ventricular aneurysms form.
2) Bradyarrhythmias & heart block: occur 2 to reflex            Cardiogenic shock occurs when infarcts (old + new
    in vagal tone, particularly with inferior or posterior        involve >40% of the left ventricle).
    wall AMI.                                                 Pericardial effusions: Occurs 2-4 days (range is 1 day-6
3) Transient Mobitz 2 degree A-V block: can occur                 weeks) after transmural infarcts. Occur in 25% of
    w/inferior wall AMI. Rarely progresses to complete            AMI, particularly with anterior wall, large infarcts, or
    heart block.                                                  with CHF. Most effusions are not hemodynamically
4) Mobitz II 2 degree A-V block: can proceed to                   significant.
    complete heart block requiring temporary or               Dressler’s syndrome: Occurs 2-10 weeks after an AMI.
    permanent pacing.                                             Localized fibrinous pericarditis from an autoimmune
5) Ventricular arrhythmias: common. Caused by                     antibody response vs. pericardial and myocardial
    reentry,  automaticity, and altered action potential         antigens exposed during the AMI. Treated with ASA
    threshold with ischemia or pH changes. Ventricular            or steroids if severe.
    ectopy may precede ventricular tachycardia or             Compensatory Mechanisms:
    fibrillation and sudden death.                            Sympathetic stimulation   HR and  contractility  
Infarct Expansion:                                                myocardial O2 demand and exacerbates ischemia
After 5-7 days (may begin within 2 hours)  acute             Renal fluid retention   preload  pulmonary
    dilation and a thinning of the infarct area, particularly     congestion and hypoxia.
    with large, transmural and anterior wall infarcts. This Vasoconstriction to maintain BP   myocardial
    may be a precursor of aneurysms and cardiac rupture.          afterload  impairing cardiac performance and 
Over months, remodeling  may also involve dilatation of          myocardial O2 demand.  demand, in the face of
    non-ischemic regions with progressive ventricular             inadequate perfusion, worsens ischemia and begins a
    dilatation. The mortality  w/ heart size.                   vicious cycle that will end in death if uninterrupted.
Persistence of an occluded coronary artery,
    glucocorticosteroids and NSAIDS (impairs infarct              Pathophysiology of AMI
    healing), exercise and HTN can potentially                Atherosclerotic plaque and coronary thombosis in
    exacerbate remodeling effects.                                Ischemia
Remodeling  and ventricular dilatation can be prevented      AMI is usually precipitated by disruption of an
    by early reperfusion, maintaining a patent coronary           atherosclerotic plaque (e.g., intimal fissure, break,
    artery, or treatment with ACE inhibitors.                     tear, rent, erosion, or ulceration).
Prevention of chronic remodeling   the mortality from       Stable plaque: Relatively thick fibrous cap that separates
    AMI.                                                          arterial blood from the thrombogenic lipid core. Not
                                                                  easily ruptured.
Infarct extension: Acute, additional myocardial damage,       Vulnerable plaques: Well preserved lumen, substantial
    with a secondary  in CK-MB or troponin. Occurs in            lipid core and a thin friable fibrous cap that is subject
    10% w/in 1st 10 days of AMI and doubles mortality.            to rupture or disruption.
    Occurs more often w/non-transmural MI and pts
    w/prior MI.                                               Plaques may be disrupted by:
LV aneurysms: Develops w/in 3 mo (as early as 2-3             1. hemodynamic trauma from local shear forces
    days) post AMI. Esp. after anterior and/or the 1          2. normal mechanical bending and twisting of coronary
    AMI. Aneurysms  mechanical efficiency of                     arteries,
    ventricular ejection. Associated w/ CHF, mural            3. coronary artery spasm.
M activity may play a key role in rendering the plaque           the cardio inhibitory and vasodepressor Bezold-
    vulnerable to rupture through production of                   Jarisch reflex  inhibitory reflex responses 
    degradative enzymes that weaken the connective                bradycardia, hypotension, and nausea and vomiting
    tissue of the fibrous cap.                                    (due to vagal-induced gastric relaxation).
Total coronary artery occlusion is seen                      Reperfusion
1. Within 6 hrs post AMI: 85%                                Functional abnormalities reverse within a few hours if
2. 6-24 hrs: only 65%                                             coronary flow is reestablished after a few minutes of
3. 2 weeks to one year: 50%                                       ischemia. However, it may require weeks-months for
This is due to spontaneous thrombolysis of the occlusive          full recovery after one hour of ischemia. This
    thrombi. This partially restores vessel patency and           prolonged, but reversible impairment in function in
    coronary blood flow. Plaque disruptions and coronary          the absence of necrosis is termed myocardial
    thrombosis occur in other myocardial ischemic                 stunning. After 2 hours of ischemia, complete
    syndromes, but tend to be less severe. About 90% of           functional recovery may never occur, particularly
    unstable angina and 70% of SCO patients have plaque           with severe or extensive ischemia.
    disruption, but the coronary thrombus is occlusive in Functional recovery is greatest if reperfusion occurs
    only 30-50%.                                                  within 4-6 hours of an AMI. Some improvement still
                                                                  occurs with reperfusion after six hours due to salvage
Functional Consequences of AMI                                    of border regions, where the ischemia is less severe
Systolic alterations                                              than in the central ischemic zone. The presence of
Systolic shortening  (hypokinesis) in the ischemic zone          collateral blood flow limits infarct size.
    w/in secs of coronary artery occlusion so that the       Reperfusion causes sudden relief of symptoms,
    ischemic zone performs little or no effective work.      Reperfusion arrhythmias, reflex bradycardia (Reperfusion
Within 3-5 min, shortening in the ischemic zone ceases       of the inferior wall) and a rapid increase in cardiac
    (akinesis), then paradoxically lengthens or bulges       enzyme release.
    during systole (dyskinesis).Acutely the ischemic zone Pathogenesis of Coronary Heart Disease –
    retains residual contractile function and responds to    this is caused by an imbalance between the oxygen supply
    inotropic stimuli. The severity of functional                 and oxygen demand of the myocardium.
    impairments are related to                               1) atherosclerotic narrowing of the vessel
1. the severity of the coronary flow deficit,                2) Thrombosis in an atherosclerotic vessel
2. the transmural extent of ischemia, and                    3) hemorrhage into a plaque
3. ischemic zone size.                                       4) rupture of a plaque with thrombosis
The aneurysmal bulging of the ischemic zone is initially     Other factors which cause reduced coronary blood flow
    stable for 24 hours, and then healing occurs.                 include hypotension and aortic regurgitation with low
Ventricular function improves over days to weeks as scar          diastolic perfusion pressure
    forms and the ischemic zone becomes stiffer.             Factors which increase myocardial oxygen requirements
    Initially, the nonischemic area compensates for the           include hypermetabolic states, e.g. pregnancy,
    loss of function in the ischemic zone.                        hyperthyroidism and stress
    ―Hyperfunction‖ occurs in nonischemic areas due to
    increased catecholamines and recruitment of the          Categories of Coronary Heart Disease
    Frank-Starling mechanism (increased end-diastolic        Arteriosclerotic Heart Disease:
    pressures and volume). However, some of this energy atherosclerosis of the coronary arteries with atrophy and
    is wasted in paradoxically stretching the ischemic            fibrosis of the myocardium 2* to ischemia.
    zone. Chronically compensatory hypertrophy may           Morphology - the heart may be larger or smaller than
    develop in nonischemic areas.                                 normal. Coronary atherosclerosis is usually diffuse
Diastolic Alterations                                             and involves all 3 major vessels. Calcification is
The rate of LV pressure falls with AMI due to                     frequent. Occasionally all 3 major vessels have
1. asynchronous wall motion (between normal and                   regions of significant occlusion. Diffuse scarring of
    ischemic segments with impaired relaxation),                  the myocardium is the major microscopic finding.
2. incomplete ventricular relaxation                         Angina Pectoris transient attacks of precordial pain
3. altered loading conditions.                                    precipitated by exertion and relieved by rest. Patients
Myocardial stiffness increases, which increases diastolic         usually have severe coronary atherosclerosis without
    pressures.  HR  diastolic filling time. These factors       significant myocardial lesions.
    combine to impair diastolic filling and increase         Myocardial Infarction
    diastolic filling pressures. Mild  in filling pressures Pathogenesis
    improve ventricular function by the Frank-Starling       MI always occurs after complete occlusion of a major
    mechanism. However, marked   pulmonary                      coronary vessel. Occasionally no occlusion can be
    venous congestion, hypoxia, cardiogenic shock,                demonstrated in the major coronary vessels but small
    increased myocardial wall tension, and increased              vessel disease is present. Frequently thrombus
    mortality.                                                    formation superimposed on atherosclerotic plaques
The ―optimal‖ filling pressure for maximizing cardiac             causes occlusion of the vessels. Thrombosis ontop of
    output while minimizing deleterious effects is about          lesions may play additional role.
    15-20 mmHg. This can be measured by the                  Hypercoagulability of the blood may play a significant
    pulmonary capillary wedge pressure on Swan-Ganz               role. Occlusion usually occurs in the first 4 cm of the
    catheterization.                                              arteries. Frequency  right coronary = 40%; left
Size and site of infarction                                       anterior descendens = 40%; and left circumflex =
The ischemic zone size is a major determinant of early            10%
    and late mortality from an AMI. When the ischemic        Cardiac arrhythmias
    zone involves:                                           Occur within minutes of onset of ischemia. They are the
>10% of the left ventricle, ejection fraction decreases           most common cause of death in AMI. Pts need to be
>15%, end diastolic volume and pressure increases                 supported. Need to keep blood flowing. Most
>25%, congestive heart failure develops                           common cause of death in acute MI
>40% results in cardiogenic shock.                           1) Atrial Fibrillation: some pooling of blood. Thrombi
Anterior wall ischemia Early and late mortality are  1          forming in atrial appendage. Not efficient pumping.
    (but not entirely) due to large infarct size. Induces         Can go anywhere.
    excitatory reflex responses  tachycardia, HTN and       2) Ventricular Fibrillation: More serious. Ventricle not
    arrhythmia                                                    working at all. Challenge to reestablish heart beat.
Inferior wall Ischemia: Stimulate cardiac receptors in the CHF: Pulmonary congestion and edema  chronic
    inferior-posterior wall  vagal afferents that mediate        congestion of liver and viscera and  in perfusion of
   kidney  renal hypotension  perhaps to Cor                   Blocks adenosine uptake into blood, endothelial and
   Pulmonale.                                                    vascular cells → ↑ circulating adenosine (a
Cardiogenic shock                                                vasodilator and inhibitor of platelet activation and
1) Occurs in 10% of pts.                                         aggregation)
2) Signs of pump failure. Damage to enough of heart
                                                             Ticlopidine and clopidogrel:
   that left ventricle cannot keep up demands
3) Mortality is almost 100%. Poor                            Blocks ADP receptors on Plt to prevent ADP-induced
4) Pathogenesis:  blood volume  Inadequate                     platelet activation and aggregation. Both associated
   perfusion of tissues and cells. Multiple organ failure        w/TTP.
Rupture Early stages of MI, e.g. 5-10 days. Necrosis is      Ticlopidine effects require 2-3 days and are irreversible.
   most extensive and the structural integrity of the wall       A major side effect is neutropenia in 2%.
   is minimal. May occur in the wall, septum or              Clopidogrel: more rapid onset of action (6 hours) and
   papillary muscle resulting in tamponade, acute failure        lacks bone marrow toxicity.
   or sudden death.                                          GP IIb/IIIa inhibitors
Aneurysm Later stages of MI, e.g. 1-2 weeks. Aneurysm          (abciximab, eptifibatide, tirofiban)
   formation results in abnormal wall motion and the           Prevent fibrinogen binding to GP IIb/IIIa receptors in
   onset of heart failure. Some degree of healing.                 activated platelets. Blocks final step in platelet
   Enough integrity that does not break apart. Will see            aggregation. Inhibit ADP-induced platelet
   abnormal wall motion. May see onset of CHF.                     aggregation by 80%, compared with 10% for aspirin
                                                                   and 30% for ticlopidine and clopidogrel.
        ASA, HEPARIN, and                                      Abciximab: monoclonal Ab. Binds irreversibly to GP
                                                                   IIb/IIIa receptor.
        THROMBOLYTIC Tx                                        Eptifibatide and tirofiban: peptide & peptidomimetic
Platelet: small, non-nucleated cell, with lifespan of 7 to 10      competitive inhibitors.
     days. During laminar flow, plts concentrate in the
     periphery close to vascular endothelium.                            Antithrombin Therapy
TXA2: potent vasoconstrictor & promoter of Plt                 Activation of coagulation factors:
     aggregation.                                              Exposure of the subendothelium (e.g. with plaque
5-HT: Aggregating Plts release 5-HT. Also ADP and                  rupture)  thrombin generation with fibrin
     ATP.                                                          formation and deposition. Fibrin polymerizes and
NO: (endothelium-derived relaxing factors) released by             cross-links to stabilize platelet plugs.
   Mechanical: shear stress                                   1) Extrinsic or tissue factor dependent pathway:
   neurohumoral stimui: NE or a2-adrenoreceptors                 TF and tissue thromboplastin are exposed on cell
   local mediators: bradykinin or histamine                       surfaces of injured endothelial cells, SmM cells,
PGI2: promotes SmM relaxation & inhibit platelet                   fibroblasts, and activated monos.
aggregation.                                                      TF and factor VII activate factor X (and IX), + factor
PGI2 and TXA2: PGI2 and TXA2 are rapidly converted                 V converts prothrombin (factor II) to thrombin (Ila).
     into inert, but stable 6-ketoprostaglandin Fia (6-keto- 2) Intrinsic or contact activation pathway: Hageman
     PGF1a) and thromboxane B2 (TXB2), respectively.               factor (factor XII), high molecular weight kininogen
     These breakdown products are measured to infer the            (HMWK), and prekallikrein (PK) are circulating
     activity of PGI2 and TXA2.                                    plasma proteins that complex onto negatively
                                                                   charged surfaces (e.g. vascular subendothelium).
              Antiplatelet Therapy                                 Activates a cascade of factors (XII, XI, and IX)
Platelet response to arterial injury: Removal of                   activate factor X to convert prothrombin to thrombin.
     endothelial cells lining the blood vessel exposes         3) Thrombin: Thrombin cleaves fibrin monomers from
     subendothelial collagen. Platelets respond by:                fibrinogen. Fibrin monomers polymerize to form
1) Adhesion: Endothelial cells express vWF → binds to              fibrin polymers, which with factor Xffla forms cross-
     both subendothelial collagen and to the GP IIb/III            linked fibrin. Thrombin serves a positive feedback
     receptor on Plts. Plts then form a monolayer to cover         role (accelerating further thrombin formation) by
     the injury.                                                   activating factors V, Vifi, and XIII. Thrombin is a
2) Activation: Exposure to collagen, thrombin (from                potent stimulator of platelet activation, adhesion and
     concomitant activation of the clotting cascade), or           aggregation.
     high shear stress (e.g. stenotic vessels with plaque      Regulation of Coagulation
     rupture)  Activation  Plt release of 5-HT and
                                                               Heparan sulfate - antithrombin III (ATIII) system:
     ADP  binds and activate adjacent platelets.
                                                               Macromolecular proteoglycans binds to ATIII →
3) Aggregation: Conformational changes in activated
                                                                   conformational change that ↑ ATIII binding to
     Plts make glycoprotein receptor GP IIb/III available
                                                                   thrombin, factors XIIa, XIa, Xa, and IXa. Binding is
     to bind fibrinogen from plasma. Plt plugs form
                                                                   facilitated by heparin.
     w/fibrinogen interconnecting GP IIb/III receptors.
                                                               Deficiency in ATIII (autosomal dominant trait.
                                                                   prevalence of 1 in 2000) leads to recurrent venous
In dz states (e.g. atherosclerosis or hypercholesterolemia),
                                                                   thrombosis, & rarely arterial thrombosis.
     endothelial dysfunction impairs the release of NO and
     PGI2, → unopposed platelet effects of
                                                               Thrombomodulin / protein C / protein S system:
     vasoconstriction and platelet aggregation.
                                                               Thrombomodulin: endothelial membrane protein that
Aspirin:                                                           binds with protein C. Thrombin activates protein C,
Vascular endothelium: regenerates COX, restoring PGI2              which then inactivates factors Va and VIIIa.
     production within hours.                                      Inactivation is facilitated by protein S.
Plt are non-nucleated and cannot regenerate COX. 1 dose Deficiencies in protein C or S cause hypercoagulable
     of ASA irreversibly blocks TXA2 production for the            disorders with recurrent venous thrombosis.
     life of the platelet. As a result, aspirin preferentially
     inhibits TXA2> PGI2, thus favoring vasodilation and Fibrinolysis
     inhibiting platelet aggregation.                          Plasminogen binds to fibrin  tissue plasminogen
Aspirin prolongs bleeding time.                                    activator (tPA) and urokinase released from
                                                                   endothelial cells converts plasminogen to plasmin 
Dipyridamole (persantine):                                         plasmin cleaves peptide bonds in fibrin to form fibrin
Inhibits phosphodiesterase  slower breakdown of                   split products.
     cAMP → ↓ Plt responsiveness to activating stimuli.
Conversion is greatly facilitated if tPA and plasminogen  Paradoxical hypercoagulable state: Depletion of protein C
   are bound to fibrin.                                       (8-10 hour), a natural anticoagulant, causes an initial
Uncontrolled fibrinolysis is prevented by the short half-     hypercoagulable state, so often heparin is overlapped
   life of tPA and urokinase and due to irreversible          with warfarin Tx.
   inactivation by plasminogen activator inhibitors (PM)
   secreted from endothelial cells and platelets.                  Thrombolytic Therapy
Heparin Therapy:                                             Streptokinase
Binds to antithrombin III (ATIII) and induces a              Catalyze conversion of plasminogen to plasmin.
   conformational change causing ATIII to bind and               Enhanced in the presence of fibrin or fibrinogen.
   inactivate thrombin and Factor X.                             Plasmin cleaves fibrin in thrombus, and digests
Lower doses of heparin are required to prevent thrombus          fibrinogen, factors V and VIII.
   formation than prevent recurrence or extension of         Generation of free circulating plasmin creates a systemic
   active thrombus. In active thrombi, platelets bind            fibrinolytic state that causes minor bleeding
   factor X and fibrin binds thrombin, protecting them           complications (3-4%) in prior puncture sites, or major
   from the heparin-ATIII complex.                               bleeding problems (0.3%) such as hemorrhagic
Heparin is poorly absorbed in the G.I. tract so must be          stroke.
   given SQ (low dose) or IV.                                Produced from hemolytic streptococci. Antigenic causing
                                                                 mild allergic reactions and induces circulating
aPTT measures Heparin Tx: when factors XII, XI, LX,              antibodies that effectively neutralize subsequent
   and VII (intrinsic or contact activation pathway)  by        doses of streptokinase for 6-8 months, or cause more
   30-40%  aPTT  An APTT of 1.5-2.0 x control                  serious allergic reactions. Thus, avoid reusing
   values optimizes anticoagulant effects, while                 streptokinase for 2 years.
   minimizing bleeding.
                                                             Tissue plasminogen activator (tPA):
Standard (unfractionated) heparin:                           Secreted by endothelial cells. It is 300 times more
Non-linear dose-response relation that requires close            effective at activating plasminogen in the presence of
    monitoring.                                                  fibrin. tPA has a fibrin specific binding site allowing
Heparin induced thrombocytopenia: Some fractions                 preferential lysis of formed thrombus with less
    inhibit vascular smooth muscle proliferation  Plt           systemic plasminogen activation effects.
    agglutination.                                           tPA does not produce allergic reactions.
Resistance to Heparin: Several other proteins can bind to    In AMI, tPA is given frontloaded (15 mg bolus, then 0.75
    heparin.                                                     mg/kg over 30 min, then 0.5 mg/kg over 60 min) over
Heparin reversal: Heparin is (-) charged. This is required       90 min total. 2.5-3.5% absolute reduction in
    for binding to ATIII. Heparin can be rapidly reversed        mortality, and a relative reduction of ~25-30% in
    by (+) charged protamine sulfate.                            mortality (GUSTO, GISSI-2, ISIS-2, and ASSET
Low molecular weight heparin (LMWH):                         tPA costs more than streptokinase ($2200 vs. $290).
Inactivates Factor X, but because of its smaller size, it
    does not complex as well with thrombin.                                    Clinical Uses
1) More predictable anticoagulant response, allowing         Acute Myocardial Infarction:
    use of fixed doses.                                      Thrombolytic therapy restores coronary blood flow, 
2) Better bioavailability                                        infarct size, preserves ventricular function, and 
3) longer half-life (2-4 time that of standard heparin)          mortality if given within 12 hours of an AMI w/ST
4) less non-specific binding to plasma proteins,                 segment  or with a new LBBB.
    endothelial cells and macrophages.                       Early treatment: has > benefits. (esp. w/in 1 few hours)
Warfarin Therapy:                                            Late benefits: 6-12 hours after AMI may be related to
                                                                 maintaining an open coronary artery.
Prevents reduction of Vit K to its active form              Benefits anterior MI > inferior MI.
    inhibition of formation of six Vitamin K-dependent
                                                             Complications rates  elderly (>75 yo), but benefits may
    blood coagulation proteins
                                                                 be significant because of  mortality w/AMI.
1) prothrombin
                                                             Absolute Contraindications to thrombolytic Tx:
2) factors VII, IX, and X
                                                             Aortic dissection
3) protein C and protein S.
                                                             Previous hemorrhagic stroke at any time
                                                             Previous ischemic stroke w/in 1 yr.
Dose is adjusted to achieve an INR of 2.0-3.0.
                                                             Active internal bleeding (not menses)
For immediate anticoagulation  IV heparin for 3-5 days
                                                             Intracranial tumor
    until warfarin becomes fully effective.
Warfarin binds to serum albumin and is inactivated by
                                                             Relative Contraindications to thrombolytic Tx :
    liver microsomal enzymes.
                                                             Severe uncontrolled HTN > 180/110
Therapeutic doses vary markedly with liver disease,
                                                             Recent trauma or major surgery or internal bleeding (< 4
    alcohol, drugs interactions, Vitamin K in the diet or
    produced by gut bacteria (which are suppressed by
                                                             Bleeding diathesis
                                                             Active PUD
PT measures warfarin Tx: the extrinsic pathway, and
                                                             Prior exposure or allergic reaction to Streptokinase
    uniquely tests factor VII (factors X and V influence
                                                             Non-compressible vascular punctures
    both APTT and PT).
                                                             Current anticoagulation  INR >2-3
Warfarin depletes coagulation proteins at rates that
    depend on T ½
   Early depletion of factor VII (5 hrs)  PT to        1) ASA: should be given immediately with an AMI, and
    despite inadequate anticoagulation.                       continued indefinitely.
   Factors IX, X, and prothrombin are depleted over 1-3 2) Heparin:
                                                             used as an adjunct with tPA to maintain  rates of
   Antitbrombotic effects primarily related to depletion     infarct related vessel patency. Ass w/bleeding SE.
    of factor X over 5 days.
                                                              risk for systemic emboli in pts w/risk factors (large
                                                              or anterior wall infarcts, atrial fib, or prior embolus
3) tPA: Used in pts w/acute ST-segment elevation MI.           Prosthetic Heart valves: Tx w/chronic anticoagulation.
   Given in front loaded manner. Has significant                   Goal INR is higher @ 2.5-3.5 (not 2-3). Still at risk
   mortality benefits when given early.                            for systemic thromboembolism (1-5%/yr.).
Saphenous vein coronary artery bypass                          Tissue valves: risk is  w/tissue valves, anticoagulation is
                                                                   given for 3-6 mo after surgery, then stopped unless
surgery:                                                           there is atrial fib or prior systemic emboli.
5-15% risk of saphenous vein graft occlusion within the
    first month, 15-20% after one year, and 50% at 10          Venous thrombosis and PE:
    years.                                                     Prevented w/low dose heparin in pts undergoing:
Antiplatelet therapy:                                             elective surgery
   significant  acute & 1 yr incidence, esp if started          OR orthopedics procedures
    w/in hrs after surgery.                                       trauma
   ASA started before surgery  bleeding SE.                     hospitalized for AMI or HF
   little benefit of combining dipyridamole with ASA.         Full dose heparin followed by chronic oral warfarin is
   Late occlusions involve different mechanisms (graft            LMW heparin is safe, efficacious, and does not
    atherosclerosis).                                              require laboratory monitoring, making outpatient
                                                                   treatment possible. Acute thrombolytic therapy is
MI Prevention                                                      used for extensive venous thrombosis or severe cases
Primary prevention: ASA  incidence of AMI by 44%                  of pulmonary embolism with hemodynamic
    (from 0.4% to 0.2%/year) and overall vascular events           compromise.
    by 18%. Benefits were limited to men over 50 years.
Secondary prevention trials: ASA post-MI found
                                                             Atrial fibrillation (A. fib):
    significant  in nonfatal MI by 31%, vascular deaths The loss of atrial contractions predispose to blood stasis
    by 13% and strokes by 42%. Benefits are greater in           with activation of the coagulation system and fibrin
    the 1 2 yrs after MI, with little benefit after 3 years.     formation. Thrombi in the atrial appendage dislodge
    Benefits occur regardless of age, sex, diabetes or           causing systemic emboli, particularly when normal
    hypertension.                                                sinus rhythm is restored.
Chronic anticoagulation provides similar, but not superior Warfarin  the risk of ischemic stroke from 4.5% to 1.4%
    benefits. However, aspirin is cheaper and safer.             / year, but  risk of major hemorrhage from 1.0% to
                                                                 1.3% / year.
Unstable angina pectoris and NQWMI                           All pts w/Afib not at significant risk for bleeding should
 All pts w/UA or NQWMI should receive ASA as                   be Tx w/coumadin unless it is lone afib.
    mortality.                                               Prior systemic emboli within 2 years confer a 10-20% risk
 Addition of heparin  progression to AMI and                  for recurrent embolic events over the next 1-2 years.
    mortality at the cost of  bleeding over ASA alone.          Thromboembolic risk with A. fib & mitral stenosis
 Addition of IIb/IIIa inhibitors, esp. in  risk subsets        (Rheumatic Afib) (>6%/yr) is  25% by
    (+ cardiac enzymes,  ST, diabetics)  progression to        anticoagulation Tx. In non-rheumatic a. fib, the
    AMI.                                                         incidence of ischemic stroke is 3-7% / year.
                                                             Lone Afib as defined by 1) Age < 60 2) Nl Echo 3) No
Coronary angioplasty:                                            HTN 4) No Thyroid dz. Risk of thromboemboli is
Associated with acute occlusion in 7-15% and late                low (1%.yr). May forgo anticoagulation because risk
    occlusion in 25-40% by 3-6 months.  w/use of                of stroke is less than likelihood of significant bleed.
    coronary stents.                                         Elderly pts (>75 yrs):  risk for stroke. Derive greater
Acute closure is  by antiplatelet agents started before,        benefits from anticoagulation, but have more bleeding
    and IV heparin during and after the procedure.               complications. The risk of emboli is  w/new onset if
Following angioplasty the addition of GP IIb/IIIa                a.. fib (<48 hours).
    inhibitors to aspirin and heparin  35-60%  in the      Chronic a. fib, anticoagulate for 3-4 weeks before elective
    30 day incidence of death, MI, or urgent                      cardioversion to allow existing thrombi time to
    revascularization.                                            organize, while preventing new thrombus formation.
 bleeding complications can be controlled by  heparin           TEE may be useful to identify pts at  risk for
    dose.                                                         embolic complications w/cardioversion.
Late restenosis: Not  by long term antiplatelet agents
Cerebral vascular disease:                                           CONGESTIVE HEART
20% of CVA deaths due to cardiogenic emboli (e.g. atrial
    fibrillation, mural or valvular thrombi). Thrombosis                 FAILURE
    can occur without plaque ulceration.                       Causes of Heart Failure
Antiplatelet therapy:  the risk of nonfatal stroke by ¼ for
                                                               Predominant systolic failure
    3 yrs in pts w/prior stroke or TIA, but pts w/Afib
                                                               1. Coronary artery disease
    significantly benefit from Coumadin vs. ASA.
                                                               2. Hypertension
Anticoagulant therapy: indicated for cardiogenic emboli.
                                                               3. Dilated Cardiomyopathy (idiopathic, toxic,
Thrombolytic therapy: tPA has been approved for the
    treatment of strokes within <3 hours. Risk of cerebral
                                                               Predominant diastolic failure
Mural thrombi:                                                 1. Hypertension
Develops in 20% of patients post AMI, in 40% with              2. Hypertrophic cardiomyopathy
   anterior wall MI, and 60% with large infarcts.              3. Restrictive cardiomyopathy (amyloidosis, sarcoid)
   Systemic emboli occur in 2% of AMI (4-6% with               4. Constrictive pericarditis
   anterior wall MI) within 2-3 months. Anticoagulation        5. High output failure
   for ~3 months is indicated in anterior wall MI with         Ventricular Function
   large areas of akinesis. Patients with left ventricular
                                                               Heart failure (HF) is often associated with impaired
   aneurysms and dilated cardiomyopathy are at
                                                                  ventricular function. Muscle removed from patients
   increased risk for systemic embolism, but no
   randomized trials clearly demonstrate the benefits of          and animals with HF shows a  in the active length
   long-term anticoagulation.                                     tension relationship and icular function curve. In the
                                                                  presence of a disturbance in myocardial contraction
Heart valve replacement                                           or an excessive Lamic burden placed on the ventricle
                                                                  or both, the heart depends upon :
1. Frank-Starling mechanism: preload (i.e., lengthening            no upper limit value specific for LV failure. LVDP
     of sarcomeres provides an optimal overlap between             may  by other factors such as  compliance, severe
     thick and thin myofilaments) acts to sustain cardiac          volume overloading (mitral regurgitation), or cardiac
     performance                                                   tamponade.
2.  release of catecholamines by adrenergic nerves and        Forward Failure Hypothesis.
     the adrenal medulla   myocardial contractility
3. Myocardial hypertrophy: w/or w/out chamber                  Clinical manifestations of HF  inadequate delivery of
     dilatation in which the mass of contractile tissue is         blood into the arterial system manifestations due to
     augmented.                                                     CO   perfusion of vital organs, including:
Initially these 3 compensatory mechanisms may be               1. brain  mental obtundation
     adequate to maintain the overall pumping ability of       2. skeletal muscles  weakness
     the heart. However, these compensatory mechanisms         3. kidneys  Na and H2O retention
     have a limited potential, and if the disturbance in       Although CO is frequently  in HF, failure cannot be
     myocardial contraction and / or the excessive                 defined by a minimum value of CO. For instance, CO
     hemodynamic burden persists, the heart ultimately             at rest may be normal even when the heart is failing.
     fails.                                                     An enlarged heart may produce the same SV with 
                                                                   ejection fraction.
Alterations in the function of the                              A CO may be above normal, as in cardiac failure
Neurohumoral system                                                associated with sever anemia or severe
Adrenergic nervous system:                                         hyperthyroidism (high output failure).
Positive inotropic effect mediated by its interaction with
                                                               Right sided versus left sided failure
    the cardiac sarcolemmal -receptor which with the
    help of G proteins stimulate production of adenlylate      Fluid localizes behind the specific cardiac chamber that is
    cyclase  formation of cAMP.  intracellular cAMP              initially affected. Thus, symptoms secondary to
    activates cAMP-dependent protein kinases                     pulmonary congestion predominate in patients with
    catalyze transfer of phosphate groups to specific sites        myocardial infarction, hypertension, aortic and mitral
                                                                   valve disease (left heart failure). With time, fluid
    on other intracellular proteins   transcellular Ca
                                                                   accumulation becomes generalized and ankle edema,
    influx through slow channels in response to
                                                                   congestive hepatomegaly, and ascites occurs (right
    depolarization, as well as  release, faster                   heart failure).
    reaccumulation and  storage of Ca in the                  The most common cause of right heart failure is left heart
    sarcoplasmic reticulum.                                        failure.
While circulating catecholamines may help to maintain
    ventricular function for variable periods of time, there   Systolic versus diastolic
    is a price to be paid  worsened survival.                 Diastolic failure is impaired capacity to accept blood or
    Decompensation may be due to the ability of                    fill without a compensatory increase in LAP. It may
    catecholamines to:                                             be the sole cause of HF in 1/3 of pts. Unlike systolic
1. cause necrosis and/or apoptosis                                 dysfunction, in diastolic dysfunction, LV is usually
2.  regulate the -receptor-G protein-adenlylate                  small and thick, with a good overall ejection fraction.
    cyclase complex                                                Diastolic dysfunction may be seen in ischemic heart
3. cause arrhythmia.                                               disease, HTN, LVH, and infiltrative diseases. Some
Renin-angiotensin-aldosterone system:                              patients with systolic dysfunction also have a
                                                                   component of diastolic dysfunction
In low-output states  activation of the renin-
     angiotensin-aldosterone axis. While there are several
     signals for renin release, renin  conversion of
                                                                   Precipitating Causes of CHF
     angiotensin 1. Angiotensin II is then formed by ACE.      1. Inappropriate treatment reductions or additions, (salt,
Angiotensin II: potent vasoconstrictor. Contributes to             beta blockers, estrogens)
                                                               2. Arrhythmias:
     extreme  of systemic vascular resistance.
     Interruption of the renin angiotensin-aldosterone axis       Tachyarrhythmias:  time available for ventricular
     by means of an ACE inhibitor  SVR,  afterload              filling,  O2 consumption  ischemia
     cardiac output in HF.                                       Bradycardia: SV is max and cant  further   CO
ADH: released because the kidneys are now seeing an            3. Late complications from an MI: papillary muscle
     effective  in blood flow. Thus  H2O and salt
     retention occurs.                                         4. infections:  metabolic rate, fever, tachycardia
Endothelin: also released in HF  marked
     vasoconstriction.                                          Symptoms related to pulmonary
Atrial natiuretic peptide: counter regulatory protein that               congestion
     assist in combating the vasoconstriction.
                  Forms of HF                                1. Pulmonary congestion is associated with dyspnea
                                                                (difficult or labored breathing) only with exertion in
Backward heart failure                                          mild heart failure. W/worse HF progressively less
Inability of cardiac muscle to shorten against a load alters    exertion and finally even at rest.
    the relationship between ventricular end-systolic        2. Orthopnea: When a subject is supine, the fraction of
    pressure and volume. The following adaptations take         the blood volume contained in the lungs is .
    place:                                                   3. PND: In its worst form, it is accompanied by cough,
1.  ventricular end-systolic volume  ventricular end-         sometimes productive of white frothy sputum which
    systolic pressure                                           is occasionally blood stained. These attacks are
2.  volume and  pressure in the atrium behind the             termed pulmonary edema.
    failing ventricle.                                       4. Cough: 1 a respiratory symptom. However cough,
3. atrium contracts more vigorously                             on assuming the supine position or on performing
4. pressure in the venous and capillary beds behind (and        exercise, is an important symptom of cardiac disease
    upstream) to the failing ventricle .                       and is related to pulmonary congestion.
5. transudation of fluid from the capillary bed into the
    interstitial space leading to pulmonary congestion       Other Evidence of Pulmonary Congestion
    and/or peripheral edema and ascites.                     W/ pulmonary congestion  can hear on PE.
Although an  in LVEDP is associated with  ventricular Chest X-ray: Redistribution of the blood in the lungs 
    function,  pressure is not specific for HF and there is    engorgement of the pulmonary veins and to fluid in
    the interstitial spaces of the lungs or in the alveoli.     3. X descent: accompanies ventricular ejection
    Normal standing subject:                                    4. V wave: passive filling of the atrium from its
   upper lung zones are lucent (blood flow is least and           supplying veins
    the veins are almost collapsed)                             5. Y descent: opening of the tricuspid valve.
   blood lower lung zones flow is greatest.
In HF  normal distribution of blood flow from top             When the RV fails, JVP is . Rt ventricle dilation 
    bottom of the lungs is abolished and eventually even        1. large systolic v wave in the JVP
    reversed in cardiac failure   in appearance of lung       2. y wave, is precipitous
    fields on X-ray.                                            HR and Rhythm; BP
Enlarged heart: most forms of HF  cardiac enlargement.
    See an enlarged heart on X-ray. If a patient presents       Hypoperfusion  sympathetic stimulation  tachycardia
    with new onset severe CHF and a normal heart size,             which may partially correct  CO related to  SV.
    think of a recent AMI.                                      Sympathetically mediated vasoconstriction  mild HTN.
                                                                   LA HTN and stretching  to A. fib. Extensive
Systemic Congestion                                                myocardial dz  ventricular extrasystoles and
Pulmonary circulation: Normally  pressure,                       occasionally ventricular tachycardia.
     capacitance system. 5-10 mmHg suffices to drive            Regional Perfusion
     blood from the head of the pulmonary circulation (the
     pulmonary artery ) to its termination (the left atrium).   HF   CO (esp. during exercise). Major redistribution
If  LV diastolic pressure  pulmonary venous                     of regional perfusion occurs.
     pressure (from 10-30 mmHg), normal mean                    1.  in renal blood flow  retention of Na and H2O 
     pulmonary arterial pressure of approximately 11                blood volume  dilation of the heart,  of
     mmHg will not suffice to perfuse the pulmonary                ventricular diastolic pressures, and congestion of the
     vascular bed. Then obligatory pulmonary arterial              lungs and systemic tissues.
     HTN accompanies LVD HTN.                                   2.  capillary pressure (pulmonary and systemic) 
 systolic RVAP  hypertrophy and dilate and failure               moves fluid from the vascular compartment to the
      RVD pressure  transmitted throughout diastole             tissues.
     through the open tricuspid valve to RA  SVC and           Routine tests for heart failure.
     IVC (not separated by valves from the right atrium)        ECG: AMI, arrhythmias, heart block.
       in CVP  congestion of systemic tissues and            Chest x-ray: described above
     organ:                                                     Echo: allows us to see the size of the heart, the function,
1. liver becomes congested and eventually its function is          and the thickness and any vascular abnormalities.
     grossly impaired
2. subcutaneous fluid appears as edema
3. effusions in the peritoneum (ascites) and in the
                                                                     Treatment Goals of Cardiac
     pleural and pericardial cavities.                                        Failure
                                                                Improve symptoms
   Cardiac Manifestations of HF                                 Prevent deterioration of function
Heart Enlargement:  Manifested by clinical                      survival.
   examination, the chest radiograph, the                       Non-pharmacologic
   electrocardiogram, and the echocardiogram.
                                                                1. Removal or treatment of precipitating or aggravating
Cardiac Auscultation                                                causes:
S-1 is related to the closure of the mitral valve.              2. treating respiratory or other infections
S-2 to the closure of first the aortic. Then the pulmonary      3. management of arrhythmias
    valves.                                                     4. Treatment of HTN
Normally silent opening of the aortic and pulmonary             5. Treatment of MI.
    valves, and mitral and tricuspid valves is.                 6. Control risk factors for myocardial ischemia.
Abnormal Findings:                                              Diet. Restriction of Sodium Intake- a daily sodium intake
S-3 in adults w/enlargement and HF: In early diastole,              of 2 to 3 grams can be quite tolerable with food
    rapid ventricular filling takes place. In young adults,         additives to improve palatability. Salt binges are a
    this is signaled by an audible S-3. If in adults                major reason that patients decompensated.
    collaborates the diagnosis of HF. Associated with           Physical activities: because restricting exercise causes
    cardiac dilatation.                                             reconditioning and regular exercise can increase peak
Loud S-4: Sign of  ventricular diastolic compliance.               exercise capacity, encouraging patients to exercise
    Normally, blood flows rapidly from the atrium to                regularly and as strenuously as their symptoms
    ventricle in early diastole. Thereafter, occurs the             permit, or to enter into formal rehabilitation programs
    period of diastasis during which time little or no              can enhance their quality of life.
    blood flows from the atrium to ventricle. Atrial
    contraction causes a 2nd spurt of blood flow from           Cardiac transplantation:
    atrium to ventricle. When ventricular diastolic             1. Candidates should be < 60 y.o.
    compliance is  , atrial systole is accompanied by a        2. Advanced CHF
    loud S-4 sound which occurs in pre-systole.                 3. Strong psychosocial support system,
Pansystolic mumur: When the ventricles dilate, the AV           4. Exhausted all other therapeutic options,
    valves may become incompetent. This permits blood           5. Free of irreversible extra cardiac organ dysfunction
    to regurgitate from the ventricle to the atrium. A              that would limit functional recovery or predispose to
    pressure gradient from ventricle  atrium exists                post-transplant complications.
    throughout systole  pansystolic mumur.                     Survival is 90% at 1 year and 70% at Lye years.
The deep jugular veins are not separated from the superior
                                                                          Drug Treatment of HF
   vena cava by valves, so that the level of the central        Diuretics:
   venous pressure may be noted by observing the                 filling pressures of the heart but does not bring the
   jugular venous pulsations. Jugular venous pulsations              patient to a new Starling curve (no increase in cardiac
   ought not be visible above the level of the angle of              output).
   Louis in any posture supervened above 30 degrees.            Choice of appropriate diuretic agent:
1. A wave: generated by atrial systole                          1. Mild sodium retention-Thiazides.
2. C wave: Associated with isovolumic systole
2. Moderate to sever sodium retention--loop diuretics          Amlodipine and felodipine: 2nd generation drugs.
    (furosemide (lasix) bemetarnde (bumex).                       Vascular specific.  symptoms.
3. Persistent sodium retention--loop diuretics plus
    thiazides or metolazone.
                                                               Inotropic agents
4. K+ sparing diuretics (spironolactone) may also be           Digitalis
    added.                                                     The only approved oral inotropic drug.
Diuretic dose should be titrated to relieve congestive         Most useful with moderate CHF, esp. in the setting of A.
    symptoms and signs, normalize CVP, and stabilize               fib.
    weight. Side effects include intravascular volume          Least useful in cardiogenic shock with pulmonary edema.
    depletion, hyponatremia, hypokalemia, hyperkalemia,            Up to 25% of hospitalized patients get toxic. Toxicity
    metabolic alkalosis, hyperuricemia                             most often occurs in the setting of old age, renal
                                                                   failure, COPD, hypokalemia, hypocalcemia,
Pearls concerning diuretics:                                       hypothyroidism, and some drugs such as quinidine,
1. It's generally better to give HCTZ or lasix as a single         verapamil and amiodarone.
    daily dose. If inadequate, more diuresis will usually
    be obtained by doubling the dose rather than giving        Other inotropes have been tested, including beta agonists,
    the same dose twice.                                          dopamine like drugs and hospodiesterase inhibitors.
2. Avoid excessive diuresis that might prevent titrating          While short term improvement has been seen,
    ACE inhibitors to full therapeutic levels.                    tachyflaxis and long term side effects (including
3. Check serum K frequently during initiation and                 increased mortality) currently preclude their use.
    titration (about every 3 days)
4. Beware of combo of ACE inhibitor and K sparing              Parenteral inotropes have been used with much success
    agents.                                                        for decompensated patients. These drugs include:
5. If large doses of diuretics are used, Mg levels should      1. Dobutamine: -agonist.  CO,  wedge pressure at
    be checked.                                                    doses that don't  HR and BP.
6. Pt adjustment of dose: Since the need for diuretics         2. Milrinone: phosphodiesterase inhibitor. Both
    varies depending on the patient's diet and level of            inotropic and vasodilatory effects.
    activity, having patient adjust the dosage themselves
    is a useful approach. Pt can be advised to  or  their
    diuretic dose to maintain their weight-as measured         Some success in moderately severe CHF.
    each morning--titrate to a range in which they have        Start with  doses and titrate slowly in a compliant
    few symptoms of congestion.                                    patient.
                                                               Cavedilol: Newer -blockers may offer even better
Vasodilators                                                       results. Selective -blocker with -1 blocking effects.
Always used in patients w/CHF.                                     Also anti-oxidant effects.  function,  symptoms,
Most offer venodilation and/or arterial vasodilation. Most         and  survival in all but class IV patients with CHF.
    effective when pulmonary congestion is 2 to              Should be instituted (with a cardiologist) at 3.125 mg bid
    pulmonary wedge pressure rather than  CO.                     and doubled every 2 weeks up until 25-50 bid.
Afterload  and is therefore used for  SVR and HTN.
In combination w/nitrates   survival in patients with            CARDIOGENIC SHOCK
    CHF. Work well to  mitral regurgitation or aortic         Myocardial infarction (MI) is the 1* cause of cardiogenic
    insufficiency. More SE than ACE inhibitors.                    shock.
Nitrates                                                       7-20% of pt w/MI (10% on admit, 90% develop in
Mostly venodilation with some afterload .                         hospital)
                                                               Most pts have an anterior MI often with extension of
Complement diuretics in  right and left atrial pressures.
    Especially useful if coronary artery dz is present.            infarct in the hospital
    They are available orally or as a patch.                   Without interventions — mortality 70-80%
Tolerance to its effects have become an issue and to
    prevent this, a "nitrate free interval" should be          Pathology: Necrosis usually seen in 40% of LV. 2/3‘s
    instituted (3x/day vs. 4X/day).                               have 3 vessel dz (>70% obstructions. LAD almost
                                                                  always involved
ACE inhibitors
                                                               Mechanical cause of cardiogenic shock
Most important advance in therapeutics for HF in the past
    two decades.                                               Free wall rupture.
                                                               1. 15% of all deaths from AMI
Up to a 40%  in 1-year mortality in class IV pts.
                                                               2. Anti-inflammatory drugs or early exercise may
1. Slows remodeling (ventricular enlargement)
2.  hemodynamics and survival rates in patients with          3. Early use of thrombolytics may reduce incidence.
    LV dysfunction due MI.
3. Prevent clinical deterioration in asymptomatic
                                                               Rupture of the intraventricular septum
    patients with  ejection fractions.                        1. 2% of all MI patients
4. 1st line therapy for all patients with  LV function.       2. Occurs in first week
    Even mildly symptomatic patients who used to do            3. New heart failure and holosystolic murmur
    fine just on a diuretic should now also receive an         4. Diagnosis: on swan will have step-up in 02 sat, echo
    ACE inhibitor.                                                should diagnose VSD
ACE inhibitors should be instituted with caution if there      5. Treatment: surgery
    is renal dysfunction or hyperkalemia. While ACE
    inhibitors can cause a cough, many patients with CHF       Papillary muscle rupture
    also have cough.                                           Usually occurs with inferior MI‘s
Angiotensin II receptor antagonists: losarten, valsarten. In   Causes pulmonary edema and holosytolic murmur
    contrast to ACE inhibitors. No  bradykinin levels         Diagnosis: giant ―V‖ waves on swan-echocardiograph
     cough and  angioedema.                                 Treatment: urgent surgery
Calcium channel blockers
Verapamil, nifedapine, diltiazem: 1 generation drugs.              Clinical Manifestations
   Vasodilation counterbalanced by negative inotropic       1) Cool, clammy skin
   effects. Not well tolerated in congestive heart failure. 2) Mental confusion
                                                            3) Obtundation
                                                            4) Rapid and ‗thready‘ peripheral pulse
5) Arterial BP may be , or it may be maintained by             Helps reduce the high afterload—svr often greater than
   sympathetic stimulation.                                         2000
                                                                Increases stroke volume and may lessen ischemia
Blood pressure                                                  Great for acute mitral regurgitation and ventricular septal
important since it is a mistake to  levels too high                defect
    (impede left ventricular output and worsen tissue           Vasodilators used are nitroglycerin or nitroprusside
BP cannot be measured accurately with a                         Inotropic drugs
    sphygmomanometer in patients with shock. The cuff           May be tried in unresponsive pts in whom fluid challenge
    pressure often represents an underestimation of true            and after load reduction are of no avail. Digitalis is
    arterial pressure by an average of 15 mm Hg in                  not generally effective, unless atrial fibrillation
    patients in shock.                                              develops.
Thus, an intraarterial catheter provides the only reliable      Dopamine:
    measure.                                                    In doses which exceed 6 mg/kg/min  predominant
                                                                    alpha-1 effect   afterload.
Urine output is of paramount importance in                      May be used for transient vasopressor support in patients
shock.                                                              who have a marked  in arterial pressure that
1. It gives an indication of renal artery perfusion.                threatens immediate survival.
2. Fluid management constantly changes depending on             Should be used for only brief periods of time with the
   hemodynamics.                                                    understanding that  in CO and coronary blood flow
3.  UOP may be 1 indication that therapy has lead to
                                                                    are likely to be transient and that the risk of increased
   improvement.                                                     ischemic injury is present.
Central venous pressure (CVP).
Estimated by exam of the neck veins, or by placement of         Effective inotropic agent with predominant beta 1
    a catheter in the SVC.                                          inotropic effects
Often fails to reflect ventricular filling pressure reliably.   May not be able to be used in patients with low blood
   CVP may be normal in patients with acute MI who                 pressures.
    have LV failure; however, pulmonary congestion              Combination of an inotropic agent and a vasodilator (such
    may exist, and LV pressure may be elevated.                     as dobutamine and nitroprusside) sometimes gives an
   CVP may be elevated in pts w/acute PE, RV                       additive effect.
    infarction, or airway disease, and the LV pressure
    may be normal or low in these pts.                          Milrinone: a phosphodiesterase inhibitor, is both an
Wedge pressure                                                      inotropic and a vasodilating agent.
Because preload or LV filling pressure is a principle           Intraaortic balloon pump (IABP)
    determinant of cardiac output, measurement of PACP          effective option for temporary hemodynamic stabilization.
    or (PAWP) is mandatory in the diagnosis and                     Balloon is inserted in the thoracic aorta just distal to
    management of cardiac shock.                                    the left subclavian artery. It is immediately inflated
PAWP can easily be measured by inserting a balloon-                 after the closure of the aortic valve (onset of diastole)
    tipped catheter into the pulmonary artery via a large           so as to augment diastolic aortic pressure and hence
    vein. Inflation of the balloon occludes the proximal            coronary perfusion. It is deflated just before the onset
    blood flow; the resulting pressure gives an estimate of         of systole so that there is systolic unloading with
    pressure of the pulmonary venous system. This                   decreased aortic impedance of left ventricular
    closely approximates the left atrial or left ventricular        ejection.
    filling pressure.                                           This stabilizes patients, who may then be taken to the
Elevated pressures are associated with pulmonary edema.             invasive laboratory on an urgent basis for diagnosis,
Lower pressures indicate hypovolemia that may further               with view of surgical or other mechanical
    complicate the reduced cardiac output.                          intervention.
One can also estimate the cardiac output, using
    thermodilution technique or measuring the saturation        Complications are potentially fatal and include:
    in the pulmonary artery (mixed venous 02).                  1. injury to the lower extremities caused by critical
                                                                   reduction in femoral blood flow
Afterload                                                       2. embolism
Systemic vascular resistance                                    3. thrombocytopenia
(SVR) = MAP-RAP/CO x 80 normal = 800-1200                       4. hemolysis
    dynes/secbcm5                                               5. aortic dissection.

Pulmonary vascular resistance                                   Interventions once stable:
(PVR) = PAP (mean)-pcwpbCO x 80 normal = <250                   1. Angioplasty and stenting is preferred when possible.
   dynes/secbcm                                                    Patency rate is > 90%. A successful PTCA lowers
                                                                   mortality to 20-30%.
Complications                                                   2. Thrombolytic therapy: Opening an occluded artery
1)   Pneumothorax                                                  definitely improves change for survival (mortality
2)   Sepsis                                                        65% vs 80%). Unfortunately, reperfusion may only
3)   Endocarditis                                                  occur in 40-5-% of occluded arteries. A balloon pump
4)   PA rupture                                                    may help cardiac output enough to keep the artery
5)   Thrombosis                                                    open.
                                                                3. Bypass surgery may occasionally be used.
1) Pain relief
2) Rhythm stabilization
3) Fluid management
4) Judicious use of inotropes and vasodilators to                    Atrial premature complexes
   increase cardiac output
5) intraaortic balloon pump
                                                                Can be found in over 60 % of normal adults (including
Vasodilators                                                       worried medical students who drink too much coffee).
                                                                   They are usually asymptomatic and benign, although
                                                                   at times they may be associated with palpitations. In
    susceptible patients, they can initiate paroxysmal          movement away from treating symptomatic PVCs
    supraventricular tachycardias.                              with anything besides beta blockers. This is because
Mechanism:                                                      many of the antiarrhythmic drugs may have serious
Single irritable focus in the atria discharges an impulse       proarrhythmic effects.
    before the next regular SA node impulse is due to
    discharge  interrupts regularity of the underlying
    rhythm.                                                                 Tachycardias
   Abnormal shaped P wave: because these impulses       Arrhythmias with 3 or more complexes at rates exceeding
    arise from the atria, Abnl p wave before QRS              100 beats per minute; they occur more often in
    complex.                                                  structurally diseased hearts than in normal hearts.
   QRS complex: should be normal because the            In the hemodynamically stable patient, an attempt should
    depolarization of the ventricles takes place in the       be made to determine the mechanism and origin of
    normal way.                                               the tachycardia. Information from the ECG should
Very early APCs may reach the conduction system during   1) presence, frequency, morphology and regularity of
   the refractory period and either not be conducted or       the P waves and QRS complexes
   conducted with a delay manifested by a prolonged PR 2) relationship between atrial and ventricular activity
   interval. APCs, whether conducted or not, are usually 3) comparison of the QRS morphology during sinus
   followed by a pause before the return to sinus             rhythm and during the tachycardia
   activity.                                              4) response to vagal maneuvers
1) Reassurance                                                             Sinus tachycardia
2) Identifying precipitating factors such as                In the adult, sinus tachycardia occurs at heart rates> 100
   alcohol,tobacco, or adrenergic stimulants                     beats/minute; it rarely exceeds 200 beats per minute
3) Ruling out  MVP, ASD and pericarditis.                       and is not a 1* arrhythmia; instead,
4) Medical treatment is for bothersome palpitations or      It represents a physiologic response to a variety of
   when the APCs trigger other arrhythmias.                      stresses, such as fever, volume depletion, anxiety,
                                                                 exercise, thyrotoxicosis and congestive heart failure.
         Ventricular Premature                              Sinus tachycardia has
                                                            1) gradual onset and offset
          Complexes (PVCs)                                  2) ECG demonstrates P waves with sinus contour
PVCs occur when a single irritable focus in one of the           preceding each QRS complex.
   ventricles discharges an impulse before the next
   regular impulse is delivered from the sinus node. The                       Atrial flutter
   early discharge interrupts the regularity of the         Stimulation rate is about 300 per minute. Most commonly
   underlying rhythm. The QRS is usually wide (usually           the ventricular rate with atrial flutter is about 150,100,
   > O.12s) and not preceded by P waves. Usually they            or 75 beats per minute.
   are not conducted retrogradely to the atrium to reset    2:1 flutter  150 bpm  ratio of atrial rate (300) to
   the sinoatrial node. Thus, unlike APCs, PVCs                  ventricular rate (150).
   produce a fully compensatory pause; i.e., the interval   3:1 flutter  100 bpm
   between conducted sinus beats which bracket the          atrial flutter will  or  ventricular rate by stepwise
   PVC equals two basic RR intervals.                            fractions of the atrial rate.
Complete compensatory pauses most often follow              EKG: flutter waves are seen as regular sawtooth-like
   premature ventricular contractions, although this is          atrial activity, most prominent in the inferior leads.
   not a 100% reliable rule. Individual patterns may vary
                                                            Vagal maneuvers   in ventricular rate 2/2  in degree
   as to compensatory pauses.
                                                                 of AV block  flutter waves.
PVCs may occur singly or in patterns such as bigeminy,
   in which every sinus beat is followed by a PVC or as     Clinical significance:
   quadrigeminy, etc.                                       Rarely seen in people with normal hearts. It is usually less
Two successive PVCs are termed pairs or couplets, while         long-lived than is AF, although on occasion it may
   three or more consecutive PVCs are termed                    persist for months to years. One should always be
   ventricular tachycardia when the rate exceeds 100            suspicious with heart rates of 150 bpm.
   beats per minute. PVCs may have similar                  Can bring out flutter waves by transiently  AV nodal
   morphologies (unifocal) or different morphologies            block w/vagal maneuvers  valsalva, carotid
   (multifocal).                                                massage, or adenosine.
PVCs are common, occurring in >60% of adult males. In
   patients without heart disease, PVCs have not been       Management
   shown to be associated with increased risk. In the       Ibutilide IV works well for pharmacological control. Has
   setting of coronary artery disease (especially acute         ~60% likelihood of converting a-flutter to sinus
   myocardial infarction or with reduced left ventricular       rhythm. Small incidence of torsades-de-pointes. Can
   function) frequent (>10/hour) or multifocal PVCs are         consider long term drug Tx in pts who decline or fail
   associated with increased morality.                          RF ablation, and those at high risk of complications
Cardiac Arrhythmia Suppression Trial tested to see              w/ablation.
   whether suppression of complex PVCs after MI with        Radiofrequency (RF) ablation is excellent tx for typical a-
   antiarrhythmic drugs would improve long term                 flutter. Has led to an acute success rate of 100% and
   survival. The study was discontinued after 2 years           recurrence rates of 7%.
   because both sudden death and overall mortality rates    Quinidine should not be used.
   were significantly increased in patients receiving
   antiarrhythmic agents.
PVCs can cause palpitations or neck pulsations secondary
   to either occurrence of cannon a waves or to post
   extra systolic potentiation. Patients with frequent
   PVCs or bigeminy may rarely develop syncope or                        Tachycardias
   lightheadedness because PVCs do not result in an
   adequate stroke volume and cardiac output is reduced
   by ―halving‖ the heart rate.
                                                                Paroxysmal atrial tachycardia
In the absence of cardiac disease, asymptomatic PVCs do     Defined as 3 or more consecutive PACs.
     not need to be treated. Generally there has been a
Most episodes appear to be due to an ectopic (non-sinus)       Antidromic SVT: About 5% of tachycardias in patients
    pacemaker located in either the left or right atrium           with WPW will exhibit a reverse pattern with
    that fires off ―automatically‖ in a rapid way.                antegrade conduction through the bypass tract and
A sustained episode lasting 30 seconds or longer may              retrograde conduction through the normal AV system
    cause lightheadedness or even syncope.                     This produces
PAT has been observed in pt w/out apparent structural          1) Tachycardia w/wide QRS complex where the
    cardiac abnormality as well as in those with virtually         ventricles are totally activated by the bypass tract.
    any type of heart dz.                                      2) Atrial flutter and AF also occur commonly w/WPW
May initiate afib.                                                 syndrome.
Usual focus is in the pulmonic veins                           Since the bypass tract does not have the same decremental
Causes: electrolyte imbalances, acid-base disturbances,            conducting properties as the AV node, the ventricular
    drug toxicity, fever and hypoxia.                              response during AF or atrial flutter may be unusually
                                                                   rapid and may cause ventricular fibrillation and death.
AV Nodal Reentrant Tachycardia                                 Management:
          (AVNRT):                                             Aimed at altering refractoriness or conduction velocity of
Most common cause of supraventricular tachycardia.                one or more components of the reentrant circuit.
Usually presents as a narrow QRS complex with regular          1) Beta blockers or Ca blockers:  conduction and 
    rates ranging from 120-250 beats per minute.                  refractoriness of AV node
The reentrant circuit is localized to the AV node and          2) Quinidine:  conduction and  refractoriness
    adjacent atrial tissue. It spreads simultaneously up the      primarily in the bypass tract.
    atria and down the ventricles.
P waves: P waves are usually hidden in the QRS complex         Avoid digitalis or IV Verapamil:  refractory period of
    since the atria and ventricles are activated                   accessory pathway   ventricular rate   risk for
    simultaneously. P waves                                        V Fib
   may appear just before or just after the QRS and may       In patients with the WPW syndrome and Af:
    be difficult to see.                                        DC cardioversion if there is life-threatening, rapid
   will be negative in lead II because of this retrograde         ventricular response. Lidocaine (3-5 mg/kg) or
    (bottom-to-top) activation of the atria.                       procainamide (15 mg/kg) administered over 15-20
Episodes of AVNRT may cease spontaneously or may                   minutes will usually slow the ventricular response.
    require treatment.                                         RF Ablation: should always recommend. Have success
Clinical features:                                                 rate of >98%.
1) Palpitations                                                Chronic treatment:
2) Syncope                                                1) Beta blockers
3) Heart failure unlikely                                 2) Quinidine
Treatment:                                                3) Amiodarone.
                                                          Radiofrequency catheter ablation: high cure rate.
 vagal tone w/valsalva maneuver or carotid sinus             indicated in patients who:
    massage: The initial therapy attempts to increase        have sustained supraventricular arrhythmias
    vagal tone, since the vagus nerve slows conduction in     refractory to medical management
    the AV node. This ―braking effect‖ may interrupt the     are experiencing intolerable side effects to
    reentrant mechanism.
                                                              antiarrhythmic agents
1) RF ablation: first line Tx in symptomatic pts who
                                                             are at risk for sudden death due to atrial fibrillation
    require chronic Tx, and can cure AVNRT in >90% of
                                                              having a rapid ventricular response.
2) IV adenosine (6 or 12 mg) administered over 2
    seconds converts >90% of tachycardias to sinus                Ventricular Tachycardia
    rhythm. T 1/2 is only 8-10 seconds so SE like AV
    block and chest pain are only transient.                                (VT)
3) Verapamil can be given over several min may be         Sustained VT: VT that persists for > 30 sec or requires
    given if adenosine fails to work.                         termination because of hemodynamic collapse.
4) IV esmolol: beta-1 selective antagonist or dig may be VT generally accompanies:
    given.                                                1) Structural heart disease: chronic ischemic heart
No quinidine                                                  disease associated with a prior MI
                                                          2) Cardiomyopathy
  Preexitation Syndrome (WPW) 3) Metabolic disorders
AV bypass tracts: connections are composed of strands     4) Drug toxicity
    of atrial-like muscle which may occur almost          5) Can occur rarely in absence of heart dz (RV outflow
    anywhere around the AV rings.                             tract tachycardia)
Wolf-Parkinson-White (WPW) syndrome is applied to
    patients with both preexcitation on the ECG and       Always symptomatic and is often associated with:
    paroxysmal tachycardias.                              1) Marked hemodynamic embarrassment and/or the
AV bypass tracts that conduct in an antegrade direction       development of myocardial ischemia.
    produce a typical ECG pattern of                      2) Wide-complex QRS tachycardia at a rate exceeding
1) Short PR interval: (<0.12 s) because of ventricular        100 bpm.
    preexcitation,                                        3) Regular rhythm
2) Delta wave: slurred upstroke of the QRS                4) AV dissociation: Atrial activity may be dissociated
3) Widened QRS: Gives the superficial appearance of a         from ventricular activity, or the atria may be
    BBB pattern. Results from a fusion of activation of       depolarized retrogradely. Will see
    the ventricles over both the bypass tracts & the AV        fusion beats: since atrial pacemaker is still firing,
    nodal His-Purkinje system.                                   sometimes you see a ‗fusion‘ between atrial and
Orthodromic SVT: During PSVT in WPW appears                      ventricular complexes
    exactly as an AVNRT, the impulse is usually                capture beats: If VT is slow enough, sometimes a
    conducted                                                    well-timed atrial impulse will conduct through the
   antegrade over the normal AV system and                      AV node and depolarize the neck. Clinically,
   retrogradely through the bypass tract                        cannon A waves can often be seen in the neck.
Non sustained VT (less than 30 seconds) is also                  suppress TdP by maintaining the heart rate at 90-120
   associated with cardiac disease but occurs in its             bpm.
   absence more often than the sustained arrhythmia.
Non sustained VT usually does not produce symptoms.               Ventricular fibrillation and
Clinical features:                                                    Ventricular flutter
Symptoms depend on the rate, duration of the tachycardia,    Occur most often in
   and presence and extent of underlying cardiac             1) Ischemic heart disease
   disease.                                                  2) After dose of antiarrhythmic drugs esp. those which
1) Rapid tachycardia: associated with                           induce prolonged QT intervals and torsade de pointes
2) Severe myocardial dysfunction                             3) Pt‘s w/severe hypoxia or ischemia
3) Cerebrovascular disease                                   4) WPW pts who develop AF w/an extremely rapid
4) Hypotension                                                  ventricular rate.
5) Syncope                                                   5) Electrical accidents frequently cause cardiac arrest
However the presence of hemodynamic stability does not          due to development of VF.
   preclude the diagnosis of VT.                             Most pts who have 1* VF within the first 48 hours of an
Prognosis: Depends on the underlying dz state. If               MI have a good long-term prognosis. Ventricular
   sustained VT develops within the first 6 weeks               flutter usually appears as a sine wave with a rate
   following AMI, prognosis is poor, with a 75 %                between 150 and 300 beats per minute. These
   mortality rate at 1 yr.                                      oscillations make it impossible to assign a specific
Management:                                                     morphology to the arrhythmia and in some cases to
                                                                distinguish it from rapid VT.
Please review current ACLS standards for treatment
    algorithm.                                               Management:
Sustained VT:                                                Immediate defibrillation then
Immediate cardioversion: if sustained VT + hypotension,      Correction of underlying etiologic abnormalities:
    HF, dyspnea or angina.
                                                                 Hypokalemia
IV Amiodarone is the best drug. Procainamide is OK, but
                                                                 MI
    can  BP.
                                                                 hypoxia
Chronic treatment:                                           If they survive  ICD
ICD  Amiodarone
No other drugs should be used because they are                           Bradyarrhythimias
                                                             Sinus bradycardia or SA block:
Automatic implantable cardiac defibrillators (AICD):         A pathologic decrease in SA node automaticity or block
Effectively  mortality in selected pts w/life-threatening       of conduction from the SA node to the atrium may
    ventricular arrhythmias. Intended for pts who                occur as a result of sinus node ischemia, fibrosis,
1) have survived a cardiac arrest or                             hypoxia, hyperkalemia, acidosis, or the influence of
2) have recurrent, sustained VT not associated w/AMI             certain drugs such as beta blockers and calcium
3) in whom conventional medical Tx is ineffective.               antagonists. If profound SA node dysfunction or SA
                                                                 node arrest occurs, extreme bradycardia or asystole
Contraindicated for pts whose                                    (no heart beat) may occur unless a lower pacemaker
1) ventricular arrhythmias may be due to a reversible            emerges to maintain a slow heart beat. if asystole
    cause (e.g.; hypokalemia) or                                 occurs without a subsidiary pacemaker emerging,
2) in whom ventricular arrhythmias occur                         syncope (fainting) or cardiac arrest may ensue. SA
    w/unacceptable frequency                                     node dysfunction and bradycardia is often associated
Discharges are painful and may not prevent syncope               with paroxysmal tachyarrhythmias as well, and this
    before terminating the tachycardia. Implantation can         condition is called the sick sinus syndrome (SSS).
    now be performed via a transvenous approach.             AV block:
                                                             Similar disease processes that occur in the SA node may
            Torsade De Pointes                                   occur in the AV node and His-Purkinje system,
(‖twisting of the points‖) VT characterized by                   resulting in abnormalities in AV conduction.
    polymorphic QRS complexes that change in                 Mobitz II second and third degree AV block, particularly
    amplitude and cycle length, giving the appearance of         if associated with a wide QRS complex, are more
    oscillations around the baseline.                            commonly due to block below the AV node in the
This rhythm is, by definition, associated with QT                His-Purkinje system. Accordingly, they are more
    prolongation, may result from                                serious.
1) Electrolytes: mainly hypokalemia &                        Transient or prolonged AV block can lead to syncope
    hypomagnesemia                                               (Stokes-Adams attack), congestive heart failure, or
2) Antiarrhythmics: especially Quinidine                         cardiac arrest. AV block may also manifest as a very
3) Phenothiazines                                                slow ventricular response to atrial fibrillation or
4) TCA                                                           flutter.
5) Liquid protein diets
6) Intracranial events                                       First degree AV block:
7) There may also be idiopathic QT prolongation.             Prolongation of the PR interval above the normal of 200
                                                             No treatment needed if asymptomatic. If symptomatic (ie
Management:                                                      pts w/CHF exacerbation 2/2 loss of AV chronicity
Recurrent, non sustained arrhythmia; however, when it            caused by excessively prolonged PR interval  dual
    becomes sustained it can be fatal.                           chamber pacemaker.
   Withdrawal of the offending agent
                                                             2nd Degree AV Block:
   correction of the underlying electrolyte abnormality
   Active measures are required if torsade de pointes is    Mobitz I: PR interval gradually prolongs with each heart
    incessant or causes hemodynamic compromise.                 beat, culminating in a non-conducted beat.
Conversion:                                                  Caused by  vagal tone, antiarrhythmic drug effect,
   Magnesium sulfate IV.                                       electrolyte abnormalities, MI (typically posterior),
   Overdrive suppression: If necessary, temporary              and conduction defect.
    pacing or an isoproterenol infusion can be used to
Tx: is usually benign. Symptomatic Type I AV block can            shorten repolarization and do not have effects on
     be Tx w/atropine. If persistent  pacemaker.                 sinus, atrial or AV nodal tissue in therapeutic
Mobitz II: periodic non-conducted beats are not preceded          concentrations.
     by PR interval prolongation. Site of block is most       Lidocaine: no longer drug of choice for VT/VF.
     often His-Purkinje system.                               Lidocaine and phenytoin (dilantin) are used to treat
Caused by: conduction system dz, MI (typically anterior),         digitalis-induced arrhythmias.
     and  vagal tone.                                        Class Ic agents: Encainide, flecanide, and
Often antedates complete heart block. If
     hemodynamically unstable  temp. transvenous                propafenone
     pacemaker followed by permanent pacemaker.               Profoundly depress the maximum rate of rise of phase 0
Asymptomatic pts can also be Tx w/a permanent                     of the action potential and markedly slow conduction.
     pacemaker.                                                   Accordingly, these agents have pronounced effects
                                                                  on conduction in the His-Purkinje system and
3rd Degree AV Block Complete                                      ventricular myocardium. They also slow conduction
Complete heart block is characterized by independent              in the AV node.
     atrial (P) and ventricular (QRS) activity. The atrial    Encainide and flecanide have recently been shown to
     rate is always faster than the ventricular rate. The PR      increase mortality when given to patients for
     intervals are completely variable. Some P waves fall         ventricular arrhythmias after myocardial infarction
     on the T wave, distorting its shape. Others may fall in      and are no longer used. Flecanide still may have a
     the QRS complex and be ―lost.‖                               role in suppressing atrial fibrillation.
Etiologies: ischemia, drug toxicity, idiopathic, infiltrative Propafenone exerts modest beta antagonism. It has been
     dz (amyloidosis, sarcoidosis, metastatic dz),                effective both in atrial fibrillation and in ventricular
     rhematologic dz (polymyositis, scleroderma,                  arrhythmias.
     rheumatoid nodules), infectious dz (chagas dz, lyme
     dz), calcific aortic stenosis or endocarditis.
If no reversible cause  permanent pacemaker.
                                                               Class II agents: Beta antagonists.
                                                              Catecholamines  marked  in automaticity in isolated
                                                                  Purkinje and sinus node tissues and can  abnl
Treatment:                                                        automatic rhythms due to depolarizations.
2nd and 3rd degree AV block  atropine or isoproterenol. Beta-adrenergic stimulation enhances AV node
                                                                  conduction and shortens refractoriness. Beta blockers
                                                                  are effective in  automaticity and abolishing reentry
            Antiarrhythmics                                       arrhythmias involving AV node.
Vaughan-Williams classification based in part on the          Now frequently used in pts w/CHF even with low EF.
     ability of antiarrhythmic drugs to modify the cardiac Esmolol: beta 1 selective antagonist given IV. Very short
     cellular                                                     acting (recovery w/in 10 min of stopping) and can be
1) excitatory currents ( Na+ or Ca2+)                             used to control the rate of a-fib.
2) action potential duration
3) automaticity (phase 4 depolarization).                                      Class III agents:
These effects of the drugs on isolated cardiac cells are
     thought to account for some of the antiarrhythmic          Amiodarone, bretylium, sotalol,
     properties of the drugs. Thus depression of excitatory
     currents by Type I and type IV antiarrhythmics
                                                              Powerful drugs that markedly prolong action potential
     results in slowing of conduction velocity and may
     interrupt arrhythmias by blocking conduction in areas        duration and repolarization to a greater extent than
     of marginal excitability, where conduction velocity is       they depress conduction velocity. As a consequence,
     already slow. Type III antiarrhythmics allegedly exert       refractoriness is prolonged and the ability of the
     their action by increasing refractoriness through            membrane to undergo spontaneous diastolic
     prolongation of the action potential duration. Here is       depolarization is delayed.
     a run through of some clinically useful properties of    More research is going into this class of drugs than any
     the various drugs:                                           others. They may be the best group of drugs for
                                                                  suppression of life-threatening ventricular
                                                                  arrhythmias as well as the suppression and prevention
                   Class I agents:                                of atrial fibrillation and flutter.
Bind to Na+ channels and impede Na+ influx during             Amiodarone: great drug. It prevents the recurrence of
     phase 0 of the action potential.                             VT or VF in up to 60% of patients. It may take up to
Results in depression of conduction velocity.                     a month before full arrhythmia suppression is noted.
No Class I agents are really effective for VT.                    It has many side effects, including corneal
Ia agents: Quinidine, procainamide,                               microdeposits, photosensitivity , hypo or
disopyramide.                                                     hyperthyroidism, and pulmonary fibrosis. These side
                                                                  effects are usually reversible and occur less often
Increase QRS and QT intervals, reflecting progressive             when smaller doses are used (200-400 mg).
     slowing in conduction velocity and prolongation of       Dotetilide: New drug. Brand name Tikosyn. Renally
     cellular repolarization, respectively. Toxic doses may       excreted. Effective for therapy of a-fib, a-flutter, and
     lead to Torsade de pointes (1-3%).                           no evident negative inotropic effect.
 ventricular response to A-fib or flutter 2/2 vagolytic
     effect on AV node conduction.
Quinidine toxicity can lead to cinchonism (salivation,
                                                                               Class IV agents:
     tinnitus, vertigo, headache, visual disturbance). Pts                Verapamil, diltiazem
     often complain of GI upset while taking this drug.       These agents selectively block the slow inward current
Procainamide:  lupus like syndrome (fever, serositis,            carried primarily by calcium ions. The slow inward
     arthritis) may be seen in 33% of pts during chronic          current is responsible for normal depolarization of
     Tx. It usually spares the kidney and abates when the         sinus and AV nodal cells but may be pathologically
     drugs are stopped. ANA becomes positive in 75% of            induced in diseased atrial or ventricular muscle and
     patients.                                                    thereby plays an important role in mediating ischemic
Class lb agents: Lidocaine, phenytoin,                            and digitalis-induced arrhythmias.
                                                              Clinically, the major action of verapamil is to slow
     Mexiletine, tocainide
                                                                  conduction in the AV node. This effect is the
Effective in treating ventricular arrhythmias but not             principal mechanism by which the ventricular
     supraventricular arrhythmias. These drugs tend to            response in atrial fibrillation and flutter is controlled,
    as well as SVTs utilizing the AV node as all or part    Acute: Initial presentation, frequently highly
    of their reentrant circuit.                               symptomatic. Can result in hemodynamic compromise
                                                              that requires urgent intervention.
      Class V agents: Adenosine                             Paroxysmal: Short, repetitive, often self-limited episodes
An endogenous nucleoside which inhibits sinus node            of atrial fibrillation lasting from minutes up to 7 d.
    automaticity, depresses AV node conduction, and         Persistent: Still intermittent episodes of atrial fibrillation
    prolongs AV nodal refractoriness.                         but lasting over 2-7 d. Typically requires intervention
Adenosine is indicated for the treatment of reentrant         for termination.
    SVTs that can be terminated by blocking AV node         Chronic: Pt always remains in Afib. Restoration of sinus
    conduction.                                               rhythm not feasible.
The effects of adenosine wears off in about 10 seconds,     Postoperative: Extremely common after CABG (25-
    which makes complications unlikely.                       30%) and valvular surgery (up to 50%). Prognostic
The effects of adenosine are antagonized by                   impact is unknown and no one treatment strategy has
    methyixanthines such as caffeine or theophylline          proven much better than any other at prevention or
                                                            Lone Afib: occurring w/out overt evidence of structural
    ATRIAL FIBRILLATION                                       heart disease by PE, EKG, CXR, and Echo. Does not
Common sustained arrhythmic disorder seen in the              include toxic reactions. Can occur as an isolated event
  population at large. prevalence ~ 0.89%, and ~2.2           or may be paroxysmal, persistent, or chronic. frequent
  million pt with A fib. Incidence increases w/ (1) Age,      in younger patients, particularly those with paroxysmal
  (2) presence of structural heart disease, and (3) CHF.      Afib.
Uncommon in patients younger than age 60 years              Initial Rate Control
age-adjusted incidence has  since the 1960s, esp among
  men                                                       Pt with angina or hemodynamic compromise, urgent
                                                              cardioversion is usually indicated.
Clinical Assessment:                                        Stable but has a rapid HR, an initial goal is rate control.
Clinical history:                                           Pts with rates < 90 bpm may have intrinsic AV node
   history of heart failure                                  conduction disease.
   prior transient ischemic attacks                        Drug rate control almost invariably requires the use of a
   prior stroke                                              beta blocker or a calcium channel-blocking agent
   HTN: assessment of stroke risk, and comorbidity         Specific Rate Control Agents:
    (mainly the risk of bleeding on anticoagulation)        The most important drugs for rate control are Ca
   Valvular and structural heart dz: can often be ruled      Channels blockers and Beta-blockers.
    out by Hx, PE, and EKG.
                                                            Specific Drug Choices:
Lab: Thyroid function studies                               Stable pt w/out HF —>Diltiazem IV, verapamil,
Echo and stress testing may be appropriate for                metoprolol, propranolol, or atenolol.
  determining the presence or absence of structural or      Potentially unstable and in whom a drug with rapid onset
  ischemic substrates.                                        and offset of action is needed  esmolol.
Conditions Associated with or Causing Afib                  Thyrotoxicosis  B-blockers > response than Ca channel
Valvular heart disease                                      HF  digoxin. Usually inadequate as the sole drug. IV
Cardiomyopathy (dilated or hypertrophic)                      Amiodarone has also been used for acute rate control.
Coronary artery disease
Hypertension                                                Often, combo of meds are needed to slow HR. Whenever
Surgically repaired congenital heart disease                  rate control cannot be achieved or if a patient becomes
                                                              hemodynamically unstable, cardioversion is
Primary electrical
   Lone atrial fibrillation                                   appropriate.
   Wolff-Parkinson-White syndrome                           Calcium channel blockers:
                                                            Diltiazem: 0.25 mg/kg IV over 2 min. Repeat 0.35 mg/kg
   Reentrant arrhythmia degenerating to atrial fibrillation
                                                              in 15 min if desired heart rate response not achieved.
                                                              Continuous infusion can be started immediately after
                                                              bolus dose at a starting rate of 10 mg/h and increased as
                                                              necessary. Some patients may respond to lower bolus
Toxic-Alcohol                                                 and infusion rates.
Stimulant drugs                                             Verapamil (Isoptin): 5-10 mg IV over 2 min. Repeat with
Pulmonary disease                                             10 mg IV after 30 min if desired heart rate response not
Postoperative                                                 achieved.

Causes of Atrial Fib/Flutter                                -blockers:
Poor MISS ATRIAL Fib                                        Esmolol: 0.5 mg/kg/min IV over 1 min followed by a 4-
Pulmonary Embolus                                             min maintenance infusion of 0.05 mg/kg/ min. A
                                                              maintenance drip at 0.05 mg/kg/min can be infused if
Mitral Valve Prolapse                                         desired heart rate response is achieved. If the heart rate
Ischemia I Infarction                                         remains elevated, a loading dose can be repeated and
Sick sinus syndrome                                           the maintenance dose increased.
Sarcoid                                                     Propranolol: 1-3 mg IV at a rate of 1 mg/min. Repeat after
                                                              2 min if desired heart rate response not achieved. Drug
Atherosclerotic CAD                                           administration should not be repeated for 4 h.
Thyrotoxicosis                                              Metoprolol: 5 mg IV over 2 min. Repeat every 5 min to a
Rheumatic heart disease                                       total dose of 15 mg if desired heart rate response not
Inflammation (peri-/myocarditis)                              achieved.
Lone fibrillation                                           Other:
                                                             Digoxin: 0.25-0.50 mg IV followed by 0.25 mg IV every
Familial (autosomal dominant)                                 4-8 h not to exceed 1 mg in 24 h.
                                                             Amiodarone (Cordarone): 5 mg/kg IV over 30 min
Types of Atrial Fibrillation                                  followed by 1200 mg over 24 h
                                                                    TEE (-)  cardioversion  anticoagulation
Chronic Rate Control Therapy
                                                                    w/warfarin for several weeks or months.
Resting HR of 60 to 90 bpm should be maintained.                Electrical Cardioversion: cardioversion alone may not
Rate control is defined by an average rate of 80 bpm or           improve the clinical status, symptoms, or prognosis of
  less over 24 hrs on Holter or rates around 110 bpm              the patient with atrial fibrillation. Early recurrences
  w/light to moderate exercise, such as a 6-min treadmill         after cardioversion are possible, and often a short
  walk.                                                           course of antiarrhythmics is given in this event in hopes
Use meds above.                                                   that these changes will normalize as sinus rhythm is
Data do not support the use of sotalol (Betapace) or              maintained.
  amiodarone chronically for rate control.                      Antiarrhythmics: Also, many patients who have been in
Digoxin: provides reasonable rate control at rest and is          atrial fibrillation for more than 6 months to 1 year either
  useful in patients with HF. However, the increases in           fail to convert with antiarrhythmics or do not maintain
  sympathetic tone accompanying exercise typically                sinus rhythm after electrical cardioversion, despite the
  necessitate addition of either a calcium channel blocker        use of antiarrhythmics.
  or a beta-blocking drug. Care should be taken to avoid
  excessive heart rate blunting in very active patients.
Because of underlying heart disease and ventricular
  dysfunction, patients may not tolerate pharmacologic                      ENDOCARDITIS
  efforts at rate control or rate control may be difficult to   One of the most serious infections that can involve any of
  achieve.                                                          the heart valves. The vegetations occurring in
                                                                    infective endocarditis can be distinguished from
Clinical situations in which rate control can be difficult:         those occurring in other forms of valvular heart
1) Decompensated heart failure                                  Aggressive early treatment. It can prevent significant
2) Severe chronic obstructive lung disease                          potential complications. One always should have a
3) Thyrotoxicosis                                                   high degree of suspicion for this diagnosis when
4) Conditions with diastolic dysfunction, such as                   encountering a pt with FUO.
    hypertrophic cardiomyopathy                                 Infective endocarditis uncommon problem with incidence
Pts with bradycardia-tachycardia syndrome may require               of 4,000 to 8,000 cases per year.
  AVN ablation in conjuction w/permanent pacing early           Predisposing factors:
  in their course to gain control over both ends of their
                                                                Poor dental hygiene
  heart rate spectrum.
                                                                Long-term hemodialysis
Anticoagulation:                                                Diabetes Mellitus
All pt with 1 or > risk factors or echocardiographic risks      HIV infection
     should undergo anticoagulation if possible                 Mitral valve prolapse with  risk with presence of MR or
                                                                    thickened mitral leaflets.
Specific risk factors that must be sought are                   Rheumatic dz
1) age older than 65 years                                      Prosthetic valves.
2) history of hypertension                                      Bicuspid aortic valve
3) prior myocardial infarction                                  IV drug users
4) prior stroke                                                 Nosocomial bacteremia: usually after genitourinary or GI
5) mitral valve stenosis                                            tract procedures or surgical wound infection.
6) history of prior congestive heart failure                    Clinical:
7) Thyrotoxicosis
8) dilated or hypertrophic                                      Systemic Infection:
9) Cardiomyopathy                                               Fever +/- drenching night sweats
10) prior surgical repair of atrial septal defects              Anorexia
11) diabetes.                                                   Weight loss
Echocardiographic risk factors:                                 Arthralgias and myalgias
1) left ventricular dysfunction
2) left atrial enlargement.                                  Valvular Dysfunction:
                                                             Heart Murmur: 85%
In patients with atrial fibrillation who have clinical risk  CHF
   factors for stroke, the risk is around 7.2% per year, in
   comparison with 2.5% per year in those without clinical Systemic microemboli or immune complex vasculitis:
   risk factors. If no clinical or echocardiographic risk    Body recognizes bacteria as being foreign. Makes
   factors are present, the risk of stroke is ~ 1% per year.     antibodies to those organisms. Over time  IgG.
                                                                 Can get IgM and IgA formed. Get hyperIg and IgM
If warfarin is used  INR range is from 2 to 3.                  autoantibodies. Will have (+) rheumatoid factor.
At an INR < 2, the risk of stroke . Conversely, at an INR       Also cryoglobulins. With formation of IgG
                                                                 antigen complexes  immune complexes  GN,
   > 3,  risk of bleeding particularly in the elderly.
                                                                 myocarditis, anemia, PE, and skin manifestations.
Cardioversion:                                               Osler nodes: tender, palpable, purplish hemorrhagic
Acute Cardioversion first episode of atrial fibrillation        lesions in the pads of the fingers or toes, and the
      synchronous direct-current shock. IV amiodarone,           palms of the hand and soles of the feet. Result of
      procainamide hydrochloride, propafenone                    inflammation around the site of an infected arteriolar
      hydrochloride, ibutilide fumarate, digoxin, and other      embolus. 10-23%
      agents have been used to accomplish acute              Janeway lesions: raised, nontender hemorrhagic lesions in
      cardioversion. The earlier they are used in the course     the palms of hands and soles of the feet. From septic
      of A fib, the greater the likelihood of successful         emboli. <10%
      conversion.                                            Roth spots: oval retinal hemorrhages w/white or yellow
Anticoagulation: anticoagulate prior either electrical or        centers
     chemical cardioversion. INR of 2-3 for > 3 weeks        Glomerularnephritis
     before conversion.                                      Aseptic meningitis:
TEE used to ID atrial thrombi. This allows earlier           Petechiae: common. Occur in the conjunctiva, buccal
     cardioversion in pts w/A Fib of unknown duration. If        mucosa, and skin above the clavicle. Not specific.
Splinter hemorrhages: 15%                                             When BCx remain sterile after 48 to 72 hrs of incubation
                                                                          must notify lab of suspected diagnosis. If BCx
Macroemboli:                                                             remain negative after 5-7 days to intensify efforts to
Stroke                                                                   recover fastidious organisms and start serologic
Splenomegaly: 20-57%                                                     assessment.
MI: Emboli  block coronary artery. Rare
                                                                      Specific Test for Culture Negative Endocarditis:
                                                                      Abiotrophia  strep variant. Special growth medium.
UA: microscopic hematuria, proteinuria, or pyuria                     Bartonella: Serologic tests. PCR or valve or embolized
CBC: Elevated WBC                                                         vegetations. Special culture medium available. Slow
EKG: Evaluate for possible silent MI and get baseline.                    growing organism. Requires 1 mo or more for
Blood Cultures: Persistent bacteremia: > 75% of BCx                       isolation.
    drawn over 48 hrs are (+).                                        Coxiella Burnetti: Serologic tests, PCR, Giemsa stain or
   3 sets of BCx at least 1 hr apart over 24 hrs                         immunohistologic tests on operative specimens.
   At least 10 ml per draw.                                          HACEK organisms: BCx (+) by day 7. Occasionally
   Advise micro lab that endocarditis is suspected.                      prolonged incubation and subculturing.
   Incubated for at least 3 weeks.                                     Haemophillus Parainfluenzae, H. Aphrophilus, H.
   MIC of Penicillin necessary.                                          Paraphrophilus
                                                                        Actinobacillus Actinomycetemcomitans
                                                                        Cardiobacterium hominis
Duke Criteria for IE:                                                   Eikenella corrodens
Requires 2 major criteria or 1 major criteria and 3 minor               Kingella kingae
     criteria, or 5 minor criteria                                    Chlamydia: Serologic tests. Direct staining of tissue
Major criteria:                                                           with fluorescent monoclonal antibody.
(+) blood Cx (of typicial pathogens) from at least 2                  Tropheryma Whipplei: Surgical specimen  Silver and
     separate Cx.                                                         PAS stains, and PCR.
Evidence of endocardial involvement by echo                          Legionella: Serologic tests. Subculture from BCx. Lysis-
     endocardial vegetation, paravalvular abscess, new                    centrifugation pellet from BCx or operative specimen
     partial dehiscence of prosthetic valve, or new                       on special medium.
     valvular regurgitation                                           Brucella: Serologic tests. Prolonged incubation.
                                                                      Fungi: Regular BCx (+) for Candida species. Lysis-Cent
Minor criteria:                                                           with special medium can  yield. Urine 
Predisposition: Predisposing heart condition or IVDU.                     Histoplasma Ag and Cryptococcus capsular Ab.
Fever:  38*
Vascular phenomena: Arterial emboli, septic pulmonary                 Echocardiography:
    infarcts, mycotic aneurysm, conjunctival                          Helps to detect predisposing conditions, vegetations, and
    hemorrhages, or Janeway lesions.                                      complications. Cannot be used to assess a cure.
Immunologic: Osler;s nodes, Roth‘s spots, and (+) RF                  Timing for surgery: Sequential echos can help detect
Microbiologic: 1 (+) BCx (except for coag (-) staph or an                 complications about the need and timing of cardiac
    organism that does not cause endocarditis.                            surgery. Enlarging vegetation  potential of
Echo: Consistent w/endocarditis, but do not meet major                    embolic phenomena and may indicate the need for
    criteria.                                                             surgical intervention.
Species that cause Endocarditis:                                      Transthoracic Echo:
                                                                         98% specific and 60 to 75% sensitivity for detection
From Mylonakis E., Infective Endocarditis, NEJM Vol 345, No. 18, pg
    1319, Nov. 1, 2001.                                                   of valvular vegetations. Poor results in pts with
Prevalence of Common Species w/Native Valves:                             COPD, obesity, or chest wall deformities.
                 16-60 yo        >60 yo                                  Vegetations > 5 mm in diameter are seen by TTE.
Strep            45-65%          30-45%                                   Those < 3 mm are often missed.
Staph            30-40%          25-30%                                  Good-quality TTE w/no valvular vegetations or
Coag (-) Staph    4-8%            3-5%                                    pathologic regurgitation together with (-) BCx
Enterococcus      5-8%           14-17%                                   provides strong evidence against diagnosis of
GNR               4-10%            5%                                     endocarditis.
Fungi             1-3%            1-2%                                   Equivocal TTE  need TEE
Cx (-) & HACEK 3-10%               5%                                    Prosthetic valve: TTE and TEE
Diptheroids         <1              <1                                Transesophageal Echo: TEE.
Polymicrobial     1-2%            1-3%                                   75-95% sensitive and 85-98% specific for
                                                                          vegetations. Better visualization of posterior cardiac
Prevalence of Common Species w/Prosthetic Valves:                         structures like mitral valve
                Early Intermediate Late                                  Negative TEE has negative predictive value of >92%.
                 (<60 days from (60-120 days       (>12 mo               Greatest specificity w/mobile and oscillating lesions
                   procedure) after procedure) after procedure)           (freely moveable edge). Nonmobile echogenic
Strep            1                  7-10           30-33                  densities on the valves may be consistent
Staph          20-24                10-15          15-20                  w/vegetations, but not pathognomonic for infective
Coag (-) Staph 30-35                30-35          10-12                  endocarditis.
Enterococcus   5-10                 10-15          8-12               Prior probability of Endocarditis:
GNR            10-15                 2-4            4-7               Reliability of test depends on pre-test probability.
Fungi          5-10                 10-15            1                   Low Probability: < 4% probability  Initial TTE.
Cx (-) & HACEK 3-7                   3-7            3-8                  Intermediate probability: 4-60%. Pts with
Diptheroids     5-7                  2-5            2-3                   unexplained bacteremia with GPC, catheter
Polymicrobial   2-4                  4-7            3-7                   associated S. Aureus bacteremia, and pts admitted
                                                                          with fever or bacteremia with recent drug use 
Low virulence:                                                            Initial TEE
Coag negative Staph
Diphtheroids: Corynebacteria.                                         Complications:
HACEK                                                                 Cardiac:
Pseudomonas                                                           Valves have no WBC making it a zone of
                                                                          agranulocytosis. Always shedding organisms into the
Culture Negative Endocarditis                                             blood stream.
Most common cause is prior Abx use.
  Rheumatic dz: Mitral > Aortic > Tricuspid                 At the extremes, two options are available:
  Prosthetic Valve: Mostly on left. Mitral = Aortic.        1. normal flow (and thus Nl CO) may be maintained
Conduction abnormalities: AV block, fascicular block, or         across the valve   driving pressure in the left
   BBB.                                                          atrium. Or
Annular ring abscess                                         2. minimal  of LAP but flow is dramatically .
Myocardial abscess: Hard to eliminate by antibiotic          Many variations between these 2 extremes but what is
   treatment.                                                    certain is that  flow combined with  LAP is not
Mycotic aneurysm: Can cause pericarditis,                        possible in MS.
   hemopericardium  tamponade, or fistula to right or
   left ventricle.
                                                             Anatomical Consequences
                                                            1. LA becomes greatly enlarged being immediately
Neurologic:                                                     upstream to the obstruction,
Stroke                                                      2. LV is not enlarged and its end-diastolic pressure
Intracranial Mycotic Aneurysm: emboli to arterial vasa          remains normal in contrast to mitral regurgitation.
     vasorum or intraluminal space  invasion of intima 3. Pulmonary Arterial HTN:
     and vessel wall. Arterial branch points where emboli      LAP  pulmonary venous pressure is equally  
     hit. Variable presentation. Some produce HA, and           pulmonary arterial HTN w/degree required to
     mild meningeal irritation. Contrast CT, MRI, or            maintain a normal pressure head across the
     cerebral angiography to evaluate.                          pulmonary vascular bed (passive or obligatory
Systemic Emboli:                                                pulmonary hypertension).
Common sites: Spleen, kidney, iliac and mesenteric             vasoconstriction and/or spasm of the small
     arteries.                                                  pulmonary arteries  much more severe pulmonary
Splenic abscess: May cause prolonged fever. Also                HTN (reactive pulmonary HTN). Reactive
     diaphragmatic irritation  pleuritic or left shoulder      pulmonary HTN is itself reversible but 
     pain. Abd pain may be absent. Abd CT for evalution.        hypertrophy of the media of small vessels, a more
                                                                slowly reversible lesion.
                                                               Long standing pulmonary HTN  intimal thickening
Medical Treatment:                                              and thrombosis  obliterative changes. Pulmonary
Treatment based on organisms isolated. Treatment can be         HTN also gives rise to RVH, which may be severe.
     begun in the hospital and then continued as a
     outpatient.                                            Symptoms
In absence of clinical clues to specific cause, therapy for 1. Dyspnea:  LAP pulmonary venous and capillary
     culture negative native valve endocarditis should be       pressure  exertional dyspnea. Initial bout of
     individualized.                                            dyspnea is usually precipitated by exercise, emotional
   Penicillin, Ampicillin, Ceftriaxone, or Vanco in            stress, sexual intercourse, infection or arrhythmia, all
     combo with                                                 of which  the rate of blood flow across the mitral
   Aminogylcoside.                                             orifice, resulting in further  of LAP.
                                                            2. Hemoptysis: sudden hemorrhage from rupture of thin
Surgery:                                                        walled bronchial veins. Pink frothy sputum from
Pseudomonas, Brucella, Coxiella, Candida, other fungi,          pulmonary edema may occur 2 to rupture of
     and enterococci with no synergistic Abx combo. Abx         alveolar capillaries.
     treatment is usually not successful  common           3. Thromboembolism: Enlargement of LA combines
     indication for surgery.                                    with obstruction to its outflow to produce a degree of
Infection of prosthetic valve with early onset infection        stasis in LA   risk thromboembolism. Prior to
   Exceptions  Strep viridans, HACEK, or                      surgical treatment the incidence was as high as 20%.
     enterococci. No evidence of perivalvular extension.         CO and A.fib also contribute.
                                                             Physical Exam
     VALVULAR HEART DZ                                     1. Loud S1 if the mitral valve is still flexible due to wide
                                                               closure excursion of the valve leaflet.
                Mitral Stenosis                            2. Opening snap between S2 and diastolic murmur:
Almost all MS caused by childhood rheumatic fever.             Space between the S2 and the diastolic murmur, (the
25% of all rheumatic heart disease is pure mitral stenosis     opening of the mitral valve) is usually silent, but in
    (MS). 2/3 of all rheumatic MS in .                        mitral stenosis there is a sudden tensing of the valve
40% have combined MS and MR.                                   leaflets by the chordae leading to an opening snap.
Symptoms: Start in 30‘s to 40‘s but may occur sooner in        This is best heard at the apex with the diaphragm.
    underdeveloped areas.                                  3. A2-opening snap interval: (40-100 msec) important
                                                               indicator of dz severity. Tighter lesion   the LAP
Narrowing of the functional orifice of the mitral valve.        shortening of time into diastole before MV is
Cusps are fused at their edges                                 opened (short A2 o.s interval).
Fusion of the chordae results in thickening and shortening 4. Diastolic murmur: Begins after the opening snap and
    of these structures                                        parallels the shape of the pressure gradient. Loudest
Valve is funnel shaped, and the orifice is frequently          in early diastole where rapid filling occurs and trails
    shaped like a ―fish-mouth‖.                                off later in diastole. There may be some pre-systolic
                                                               accentuation. Murmur often heard best at the apex
Hemodynamics                                                   with the bell of the stethoscope (low pitched.) It may
During atrial systole should never have a significant          encompass only the circumference of about a quarter.
    measurable gradient between the LA and LV.  in            Must listen carefully.
    MV orifice 2/2 Rheumatic dz requires  gradient to
                                                           Other Tests:
    preserve blood flow to LV.
                                                           1. CXR: Vascular redistribution, enlarged LA and a ring
The normal valve area is 4-6 cm2 in cross-sectional area.      of Ca.
Mild MS: 2 cm blood flow left atrium  left ventricle      2. Echocardiography.
    flows only if propelled by a small pressure gradient.     2D echo shows a characteristic elbow or hockey stick
Critical MS: Defined as mitral valve area  1 cm because
                                                  2            appearance due to the tethering of the mitral valve
    here the LAP-LV gradient in usually unable to              leaflets (both).
    support the CO.                                           Doppler looks at the pressure half time (time interval
                                                               in msec required for the diastolic pressure gradient
                                                               across the MV to  to ½ initial value) to estimate
   severity of MS. Area of MV can be ~ by formula:             Even if asymptomatic  surgery appropriate if mild
   220/ pressure half time (msec).                              or more severe LF dysfunction (EF 50-60% and end-
Treatment                                                       systolic dimension 50 to 55 mm).
Medical: Many people can be managed medically for
   some time. Asymptomatic needs no treatment.
                                                             Acute Mitral Regurgitation
1) Heart rate control: for acute A Fib  IV dilt or          Occurs following rupture of a mitral leaflet in
   esmolol. Chronic A fib  beta-blocker or Ca               1. infected endocarditis
   Channel bocker.                                           2. malfunction of a prosthetic valve
2) Diuretics for dyspnea                                     3. rupture of a papillary muscle, as may occur early in
3) Anticoagulation for Afib: Target INR of 2.5 – 3.5.           the course of acute myocardial infarction
   This is higher than for non-rheumatic Afib.               Volume overload of the left side of the heart. The lesion
                                                                is so acute that the chambers have insufficient time to
Intervention: For refractory symptoms (SOB and/or               dilate.
    fatigue), difficult to control arrhythmias, or embolic   The normal sized LA can accommodate the regurgitant
    phenomena.                                                  flow only by enormous  in pressure. This high
1) valve replacement or                                         LAP  extreme pulmonary congestion. In fact
2) balloon mitral valvuloplasty.                                patients frequently present with pulmonary edema.
                                                             Treatment: stabilization with vasodilators and intraaortic
           Mitral Regurgitation:                                balloon pump, followed by valve repair or
Mitral regurgitation can occur because of
1. Chordae Rupture: may occur spontaneously or
    following infectious endocarditis.                                 Mitral Valve Prolapse
2. Changes in Chordae: chordae are congenitally too        Common (3-5%) but variable clinical syndrome. Results
    long, or the chordae and leaflets have degenerated 2      from diverse pathogenic mechanisms of one or more
    to a myxomatous lesion (MVP).                              portions of the mitral valve apparatus.
3. Infarcted papillary muscles: Pts w/CHD, papillary       Myxomatous  in leaflets 
    muscles may become infarcted or even rupture          1.  in surface area
    MR.                                                    2. thickening and redundancy of leaflets
4. Dilation of mitral valve ring: LV dilatation  dilation 3. elongation of the chordae
    of the mitral valve ring, as well as distortion of the 4. dilatation of the annulus.
    papillary muscles and chordae tendineae  MR.          There may also be inadequate production of type III
Hemodynamic fault: Mitral valve is incompetent            While usually a 1 condition unassociated with other
   systolic blood flow from ventricle to atrium               diseases, MVP may be associated with heritable
   volume overload  great dilation of LA (the chamber         disorders of connective tissue like Marfans or Ehlers-
   that receives the volume load) and of LV (the               Danlos syndrome.
   chamber that performs the volume work).                 Most patients are asymptomatic but people with MVP
When LA is highly compliant, LAP is not greatly .             may present with chest pain, palpitations, autonomic
When LA is less compliant, LA   pulmonary venous             dysfunction or anxiety neurosis.
   pressures are . In as much as pulmonary and arterial Physical Exam
   pressure must remain  than LAP, there is obligatory 1. Early to mid systolic click: caused by sudden tensing
   pulmonary HTN   in systolic and diastolic                 of the elongated chordae and prolapsing leaflets
   pressures of the pulmonary artery and systolic
                                                           2. Followed by a late systolic murmur: occurs when a 
   pressure of the RV. The RV diastolic pressure and the
                                                               of LV volume reaches a critical point at which the
   RAP remain normal, until eventually right heart
                                                               mitral leaflets no longer coapt. Maneuvers that 
   failure supervenes.
                                                               ventricular volume, such as standing or valsalva  to
Compliance of the left atrium                                  early prolapse  earlier click and louder murmur.
Important determinant of the hemodynamic and clinical      3. Rupture of chordae tendineae  intensification of
   picture. CO may remain normal. In cases of MR, CO           MR.
   means the forward output of LV. The total LV output Management
   is the combined forward output and the regurgitant
                                                           Reassurance is a mainstay of treatment.
   flow pumped by the LV. When forward CO remains
   normal, total output is very high. The LV then has a    -blockers: for chest pain or palpitations.
   large volume and a high EF. Ejection of blood into      Abx: If (+) murmur or significant redundancy on echo 
   the low impedance LA explains why mitral                    Abx before dental & surgical procedures.
   regurgitation is often well tolerated for a many years. Surgery: Mitral Valve repair preferred over replacement.
   A patient may not have many symptoms until the LV           Needing MV repair or replacement is dependent on
   begins to fail. When this occurs the damage is often        degree of MR and development of endocarditis.
   irreversible.                                           MVP most common cause for MV replacement in the
                                                               United States. This occurs in up to 15% of MVP
Physical Exam                                                  patients over a 10-15 year period. More prevalent in
1. Brisk, hyperdynamic arterial impulses.                      pts w/both a click and a murmur.
2. LV impulse is often displaced to the left (LV           . Other complications:
   enlargement)                                            1. Endocarditis
3. Blowing high pitched, holosystolic murmur, loudest      2. cerebral emboli  TIA, acute hemiplegia or
   at the apex with radiation to the axilla.                   cerebellar infarcts
Careful assessment of LV function should be performed.
                                                                             Aortic Stenosis
1. Vasodilators: ACE inhibitors or hydralazine              Symptoms:
    reduce the volume of blood regurgitating into the LA.    1. Angina: Occurs in 2/3 of pts w/critical AS, 50% of
2. Diuretics: for pulmonary congestion                          who have normal coronary arteries.
3. Digitalis: for systolic dysfunction.                      2. Syncope: relates to severe obstruction combined with
4. Criteria for surgery: (either valve replacement or           inappropriate vasodilatation.
    repair)                                                  3. CHF: may be due to valve obstruction which as a
   acute symptomatic mitral regurgitation                      very poor prognosis (50% survival at <2 yrs.)
   chronic severe mitral regurgitation and symptoms of
                                                             Physical Findings
    CHF even if there is normal LF function
1) Pulsus parves et tardus: Peripheral pulses  more         Valvuoplasty: 50% restenosis at 6 mo. Limited to pts that
    slowly than normal (esp carotid pulse) as blood is           are poor surgical candidates.
    slowly forced through the obstructing orifice of the
    aortic valve.  upstroke in AS vs.  upstroke with                  Aortic Regurgitation
2) Pulse pressure is  frequently.
3) Systolic thrill: Abnl flow into the aorta  thrill over   Two main groups of causes:
    the carotid arteries.                                    Abnormalities of the aortic leaflets:
4) Crescendo-decrescendo systolic ejection murmur:           bicuspid aortic valve, infective endocarditis, rheumatic
     Onset times w/beginning ejection period of systole         heart dz, and certain weight loss drugs.
      ~ 50 msec after S-1.                                   Aortic root abnormalities: marfans syndrome, aortic
     The more critical the AS, the later the peaking of         dissection, syphilis, ankylosis spondylitis, and
      the murmur.                                                psoriatic arthritis.
     murmur usually ends before the S-2
  intensity of S2 2/2 thickening & calcification of      Symptoms:
    cusps.                                                   Dyspnea on exertion
6) Left ventricular heave: palpated over apex.               Orthopnea
7) Prominent S-4: 2/2 hypertrophy  altered                  Fatigue
    compliance.                                              Acute AR   in CO  shock.
Pathophysiology                                              Angina: Multifactorial.
Critical narrowing of the orifice  regulation of outflow    Carotid artery pain
    by valve itself, not by the resistance of the systemic   Physical Exam:
    arterioles. Nl flow across valve can only be             Hyperactive apical impulse: displaced downward and to
    maintained by the development of a systolic pressure          the left
    gradient between LV and aorta. If LV can develop        Blowing diastolic murmur: > L sternal border w/pt
    enough systolic pressure, and  it when the demand            sitting upright. Early in dz, murmur only heard in
    for blood flow  , CO is maintained, though at the            beginning of diastole  As dz progresses persistent
    price of extreme LVH.                                         murmur through all of diastole.
Failure of this response  unsustainable normal flow         Mitral valve rumble: Austin Flint murmur. > L
    across valve   CO.                                          ventricular apex in severe aortic regurg.
Pressure overload  Concentric hypertrophy. Wall             Wide pulse pressure:
    becomes extremely thick and the cavity is greatly .     Hill’s sign:  in femoral systolic pressure of 40 or more
    Compliance of the chamber, expressed as its pressure          compared vs. systolic pressure in the brachial artery.
    volume relationship, is therefore severely . While
    hypertrophy  wall stress, LV requires much  filling
    pressures.                                               EKG: non-specific. Almost always demonstrates LVH.
Additionally, subendocardial blood supply may be             Chest X-ray: Enlarged heart.
    diminished. Hypertrophy will  wall stress.              Echo: Most important non-invasive tool for evaluation.
                                                                Can help to quantify the depth and width of the
Diagnosis:                                                      diastolic regurg jet into the L ventricle.
Echo: Accurate to demonstrate                                Treatment:
1. thickened, immobile valve
2. LVH                                                     Medical Tx:
3. overall systolic function                               Used for asymptomatic patients. If symptomatic or have
                                                                LV dysfunction then should undergo surgery.
Calculation of Aortic Valve Area (AVA):                    Mainstay is use of afterload reduction meds. Drugs that
The gradient across the AV can be estimated by                  are used are nifedipine, ACEI, and hydralazine.
    measuring the velocity of flow across the aortic valve If cause of AR is endocarditis, surgery may be delayed to
    and applying the following equation:                        allow for Tx of the endocarditis. Persistent severe AR
                                                                 surgery.
Gradient = 4 2
                                                           Surgical Tx:
Further calculations can estimate the AVA.
Usually a peak gradient of 50 torr or a mean gradient of   Repair a possibility, but most pts will require
    30 torr correlates w/significant AS.
                                                           Pt‘s should undergo replacement before symptoms impair
Severe AS: AVA < 1 cm2.
                             2                                  lifestyle.
Critical AS: AVA < 0.8 cm .
                                                           W/AR w/EF < 55% or ES dimensions > 55 mm, postop
Key is development of symptoms not a magic AVA.
                                                                outcomes decrease.
   When pt is asymptomatic there is no change in
                                                           Surgery should be done before deterioration to this point.
   survival by replacing AV no matter what the gradient
   calculates to.
Once the above symptoms develop, there is a precipitous              Tricuspid Regurgitation
    decline in mortality unless the valve is replaced.     Cause:
Management                                                   Usually 2/2 hemodynamic load on the R ventricle 
Abrupt  in preload or afterload can be catastrophic              dilation of R ventricle and of tricuspid annulus.
   because the heart cannot compensate with  SV 2/2         Causes:
   fixed aortic valve.                                       Left sided heart failure
  After exercise, diuretics, or vasodilators               Dzs that causes Pulmonary HTN like COPD  R
   hypotension.                                                   ventricle dilation  tricuspid regurgitation.
   in CP might occur after nitroglycerin.                  Infective endocarditis
                                                             Other: Carcinoid syndrome, rheumatic dz of the tricuspid
Surgery:                                                          valve, myxomatous degeneration, RV infarction, and
AS is surgical dz. Old age or severe LV dysfunction are           congenital heart dz.
    not contraindications to valve replacement.              Diagnosis:
Surgery is indicated for areas <0.75cm2 plus either:         Symptoms similar to those of rightsided heart failure
1) symptoms (angina, syncope, or heart failure)              Ascites
2) Progressive LV dysfunction                                Edema
3) abnormal response to exercise.                            JVD w/large v wave
Hepatic enlargement w/possible liver pulsation.               Genetic
Parasternal lift due to RV enlargement.                       Ethanol
S-3 originating from R ventricle that is accentuated by       S/P MI / ischemia
    inspiration (Carvallo‘s sign).                            Toxins (adriamycin, cobalt)
Echo: Gives the definitive diagnosis.                         Infection (HIV, chagas, coxsackie)
                                                              Endocrine (thyroid
TR w/out pulmonary HTN is well tolerated and may not
    need surgery.                                             Hypertrophic Cardiomyopathy
Moderate TR: cand get excellent results w/annuloplasty         Massive hypertrophy of septum that projects into LV
    of the posterior portion of the annulus.                       outflow tract  true mechanical obstruction to LV
Severe TR and 1* rheumatic tricuspid dz  valvotomy                ejection. Septum also hits the mitral valve as it moves
    and ring annuloplasty.                                         anteriorly (SAM).
                                                               Microscopically, there is myofibril disarray, and gross
                                                                   inspection of the heart reveals a small cavity with
       CARDIOMYOPATHY                                              significant hypertrophy of the myocardium.
Can help with prognosis. 1* a dz ruled out by exclusion. Abnl myocardium  abnormalities of diastolic filling of
      Rule out HTN, valvular heart disease, congenital             the heart   filling pressures and myocardial
      abnormalities and coronary heart disease are                 oxygen demand  supply mismatch.
      excluded. Often genetic basis. Dozens of genes           Genetic: Familial hypertrophic cardiomyopathy  1 of at
      identified so far, more to come.                             least 12 genetic defects, including troponin T,
 3 factors that limit interpretation and classification of the     troponin I, -tropomyosin, and -myosin heavy
      cardiomyopathies.                                            chain. Over 100 different mutations have been
1) the myocardium has a morphologically restricted                 identified on these genes.
      capacity for responding to different stimuli or          Symptoms.
      injurious agents
                                                               1. Dyspnea: due to  LVEDP.
2) light microscopy and histochemistry are limited
                                                               2. Angina
3) we lack a full understanding of how the many                3. Syncope
      variations and interrelations between genetic,           4. Sudden death is sometimes the first symptom.
      chemical, nutritional, hormonal, infective and
                                                               Physical Examination
      immunologic factors influence the structure and          Carotid pulse:
      function of the heart.
                                                                   briskly. Helps to differentiate HCM from AS
Genetic basis: Important to monitor other members of the
      family. Monitor for change. Can have early                  Bifid pulse. At mid systole pulse  as the gradient
      intervention.                                                develops, followed by a 2 rise (bifid pulse).
                                                               Harsh systolic ejection murmur: Heard best between left
Congestive Cardiomyopathy                                          sternal border and apex and radiates to the axilla but
Dilation and  in volume of both chambers.  in heart              not the neck.
      weight, and heart mass. Incidence of 2-8/l00,000         1. 2/2 outflow tract turbulence and concomitant MR.
Age at onset: any age                                          2. Labile in intensity and duration. HCM vs. MS.
Biopsy shows scattered scarring and  in pressure              HCM:  preload,  afterload, or contractility  
      w/atrophy of cells in that region.                           murmur intensity.
Early stages are variable in size.
Will go back and forth between small and large.                Echo: Standard for the diagnosis. Shows significant
It is useful to classify CHF into systolic (inadequate             hypertrophy of the myocardium in the absence of a
      ejection, low EF) and diastolic (stiff ventricle, normal     known cause. Although initially thought to be
      EF,  filling pressure needed to maintain SV                confined to the septum, the hypertrophy may be
      PVH) Echo, EF, BNP level are useful in Dx.                   located in any region of the left ventricle. Doppler
                                                                   echocardiography is useful in determining the
Clinical Features:                                                 presence and severity of LV outflow obstruction and
1) Biventricular heart failure: large heart size                   coexistent MR, obviating the need for catheterization
2) Syncope                                                         in most instances.
3) Arrhythmias: Unfortunately arrhythmias are poor             Natural History
      predictors of sudden death.                              Prognosis is variable. Overall the annual mortality of 3%
4) Embolization: always hard problem.  LV pressure                has been reported, but this  mortality may only
       LA stasis and clot. May embolize.                          pertain to referral centers that have a biased
Etiologies:                                                        population. Hypertrophic cardiomyopathy in the older
1) Idiopathic                                                      population may have a more benign prognosis.
2) Infections: Viral illness. Shows up weeks later.            Sudden death is a major cause of mortality: risk is  in
      Viral myocarditis. Difficult to prove. Narrow                young , esp those with a FH of sudden death,
      window. No specific landmarks.                               ventricular arrhythmias on Holter monitoring, and
3) Familial congestive                                             recurrent syncope.
4) Alcoholic                                                   HF, infective endocarditis, and AMI are less common.
5) Hyperkinetic cardiac failure: responds to thiamine          Treatment:
      (etiology is thiamine deficiency)                        Based on symptoms & presence of arrhythmias. These
6) Others:                                                         meds  contractility &  outflow gradient
    Multiple nutritional deficiencies: responds well.             w/improvement in symptomatology.
    Direct toxic effect                                       1. -blockers
    Peripartum: autoimmune reaction.                          2. Ca channel blockers (only verapamil)
    Fredrick‘s ataxia: spotty fibrosis                        3. Disopyramide.
    Storage: young pts. Glycogen storage                      Digitalis, diuretics and vasodilators may worsen
    Infiltrative: diffuse metastatic tumors.                      symptoms.
   Endocardial fibroelastosis
                                                              Surgical myectomy: may improve symptoms but has no
DDx Dilated Cardiomyopathy:                                       effect on mortality. Reserved for pts with severe
                                                                  symptoms unresponsive to medications. Recent
Collagen-Vascular                                                 research suggest a possible role for dual chamber
Obstetric                                                         pacing.
Nutrition: beriberi, carnitine
New, effective Rx is obliteration of septal artery w/EtOH
                                                            Myocarditis related to Autoimmune Dz
   causing septal infarction.
                                                            May occur as a component of all of the collagen dz. May
Restrictive Cardiomyopathy                                     be a transient phase or may be a significant
Amyloidosis  stiffening of ventricular cavity. Leads to       component of the entire clinical spectrum.
    diastolic HF and replacement of muscle w/amyloid.       1. Rheumatic Myocarditis - This occurs in the early
Also lymphoproliferative dz.                                   phase of rheumatic dz. Usually a pancarditis is
Some decrease in chamber size.                                 present. Aschoff nodules are present but after several
No way to remove deposits.                                     months the lesions are nonspecific.
Waxy appearance. Typical appearance on echo.                2. Systemic Lupus Erythematosus: In SLE flat, plaque-
                                                               like vegetations (Libman-Saks endocarditis) may
Restrictive Cardiomyopathy:                                    occur on the mitral valves. Focal fibrinoid necrosis is
HEALS                                                          present in the myocardium. The small arteries and
                                                               arterioles show similar changes to those occurring in
Endocardial fibroelastosis
Amyloidosis                                                    small vessels in other organs.
L                                                           3. Polyarteritis Nodosa: affects small and medium-sized
Sarcoid                                                        arteries. Granulomatous lesions are present w/in the
Ischemic Cardiomyopathy                                        involved vessel walls. These lesions may become
                                                               occlusive  ischemic heart dz. ~ 25% are associated
CHF occurring in pts with coronary artery disease w/or
                                                               w/asthma while others are associated with drug
    w/out co-existing HTN, 1* valvular disease,
    ventricular aneurysm formation or known causes of
                                                            4. Scleroderma - Arterioles are often involved. There
                                                               may be some interstitial thickening. Valvular
severe diffuse coronary artery disease accompanied by
                                                               involvement is rare although aortitis may occur.
1) multiple sites of infarct which lead to progressive
    dilation                                                Myocarditis due to Physical or Chemical
2) disproportionate wall thinning                           Agents
3) inadequate compensatory wall thickening                  Trauma: Direct myocardial trauma  myofibrillar
Obliterative Cardiomyopathy                                    degeneration occurs although coagulation necrosis
Common in Africa. Rare here. Young children.                   may occur if the trauma comprises high velocity
                                                               trauma or high temperatures.
                                                            Radiation Therapy: May cause myocarditis if the heart
        Role of Myocardial Biopsy                              is within the port. This appears as a diffuse interstitial
Rarely indicated for diagnosis except:                         fibrosis.
1) Cardiac transplant recipients: Permits early dz of       Catecholamine Injury: Shock, trauma, head injury or
    acute rejection.                                           pheochromocytoma  massive catecholamine release
2) Chemo Therapy: selected high risk patients taking            focal necrosis of cells may occur. These
    anthracycine therapy for cancer to prevent                 myocardial lesions are most frequent in the
    irreversible cardiotoxicity.                               subendocardial region. If the circumstances continue
3) Myocarditis: Useful for diagnosing viral type, but of       fibrosis may occur.
    no clinical or practical utility.
4) 1* and 2* cardiomyopathies & restrictive vs.             Idiopathic Myocarditis
    constrictive heart dz: Biopsy is not very useful for   Diffuse (Fiedler’s myocarditis): This is a diffuse
    ordinary restrictive/constrictive dz unless                 inflammatory process throughout the myocardium.
    eosinophilic endocardial fibroelastosis or amyloid is       The dominant cell type is the eosinophil. All cultures
    suspected. Even w/amyloid the heart biopsy is not           for infectious etiology are negative.
    very sensitive.                                        Granulomatous (Giant Cell Myocarditis): Occurs as a
                                                                primary myocarditis. The etiology is unknown.
                MYOCARDITIS                                     Grossly, the heart is enlarged and dilated.
                                                                Histologically there is an interstitial inflammation
Poorly characterized dz which may be viral or                   comprising edema, macrophages, eosinophils,
    autoimmune in nature. The clinical course is variable       lymphocytes and plasma cells. Occasionally the
    from mild pleuritis to sustained severe LV                  lesions are granulomatous resembling tuberculous
    dysfunction.                                                lesions but the cultures are negative.
Myocardial biopsy shows lymphocytic infiltrates and
    myocyte necrosis. Most often the histologic picture is
    non-specific so a detailed clinical history and other       CARDIAC TAMPONADE
    laboratory data are required to confirm the specific   Tamponade is defined as diastolic equilibration of all
    etiology.                                                   pressures.
Treatment is generally supportive. Trials of steroids and LAP = RAP = RVEDP = LVEDP.
    IVIG have failed to show significant benefit.          Initial suspicion is based on Hx (as any cause of
Immune mediated Reactions                                       pericarditis can cause effusion
                                                           Tamponade should be suspected w/the combination of
Drug hypersensitivity (e.g., methyldopa, sulfonamides)          unexplained hemodynamic abnormalities like
Transplant rejection
                                                              Pulus Paradoxus
Infectious Myocarditis                                         BP and  HR
Other laboratory findings usually required for specific        JVD
    diagnosis. Characteristic histologic features may         clear lungs
    confirm the dz on microscopic examination.             esp. when pericardial involvement is a reasonable
1) Viruses: coxsackievirus, ECHO, Influenza, HIV,               possibility.
    CMV                                                    Causes of Tamponade
2) Chlamydia
3) Rickettsia: R. typhi [typhus fever]                     TAMPONADE
4) Bacteria: Corynebacterium (diptheria), Neisseria        Trauma
    meningococcus, Borrella (Lyme disease)                 Anticoagulation
5) Fungi: Candida                                          Myocardial infarction/rupture
6) Protozoa: Trypanosoma (Chagas‘ disease),                Pericarditis
    toxoplasmosis                                          Operative
7) Helminths: trichinosis                                  Neoplastic involvement
Aortic Dissection                                            Severe volume depletion, sometimes a manifestation of
Effusion (e.g., chemo, uremia)                                   bleeding or excessive diuresis, may maintain the
                                                                 central venous pressure near normal, so-called low
Clinical Examination
                                                                 pressure cardiac tamponade.
Pulsus paradoxus:
Normally w/inspiration SBP  by < 10 torr. With
    tamponade this response is exaggerated.                       ACUTE PERICARDITIS
A positive pulus is defined as a >15 torr drop of SBP        History
                                                             1) Chest pain
Mild Tamponade:                                              2) Pleuritic  PNA or pulmonary infarction.
1) No distress. Any symptoms are those of the                3) Pericardial  Characteristic radiation of pericardial
    underlying condition.                                       pain is to the shoulder (the trapezius ridge.) Pt finds
2) No tachycardia unless the pt is febrile and acutely ill      relief by sitting up, and reports worsening of the pain
    from the underlying condition,                              with inspiration.
3) BP normal                                                 4) Dysphagia sometimes accompanies pericardial pain.
4) Pulsus paradoxus absent.                                  5) Fever
5) JVP is only modestly .                                   6) Pericardial friction rub (rub may come and go)
6) Normal inspiratory  in CVP is maintained                 Differential diagnosis
7) Y descent, the inward motion of the jugular pulse that    1)   AMI
    is asynchronous with the carotid pulse, is absent or     2)   dissecting aorta
    attenuated.                                              3)   pulmonary embolism
8) +/- Pericardial friction rub                              4)   number of thoracic and abdominal catastrophes
ECG: +/- signs of acute pericarditis.
Radiogram: enlarged heart.                                   Causes
Echo: Rt. atrial compression or rt. ventricular collapse     Any clue on history, PE or routine labs suggesting a
    during diastole.                                             systemic disorder as the cause of pericarditis must be
Mild tamponade does not necessarily call for early               followed up.
    pericardiocentesis. May resolve spontaneously, or in     1) Inflammatory illness  flu-like illness and fever.
    response to anti-inflammatory Tx depending on the            Sudden onset. Viral infection: Most common etiology
    cause.                                                       of acute pericarditis
Moderately severe tamponade:                                 2) Collagen vascular disorders
Atrial and pericardial pressures ~ 10-15 cm H2O.             3) Drugs such as procainamide
Hypotension is mild or absent. Pt may complain of some       4) Trauma or prior MI (Dressler‘s syndrome)
    dyspnea and chest discomfort, but not of dizziness.      5) Cardiac surgery (post-pericardiotomy syndrome)
    Clinical manifestations of  CO are likewise absent      6) Renal failure
 CVP is now much more obvious.                              7) Bacterial and other infections
Inspiratory  of venous pressure can still be observed and   8) Trauma and aortic dissection.
    the y descent is absent.                                 9) After radiation.
Echo: moderate or large pericardial effusion and             Lab evaluation: electrolytes, BUN, CBC (leukocytosis),
    unequivocal R atrial compression and RV diastolic            sed rate, CXR, and ECG.
    collapse                                                 Do further testing only to follow specific clues, or when
                                                                 the clinical course is atypical.
Severe Tamponade:                                            Echo: useful for confirming the diagnosis when it shows
Pericardial pressure reaches 15-20 cm H2O or higher.             even a small pericardial effusion, but absence of
    Frequently is, or will become decompensated                 effusion by no means excludes the diagnosis.
    serious  in CO and  systemic arterial pressure        Treatment
    pulsus paradoxus.
                                                          Bed rest, symptomatic treatment of pain, and careful
Tachycardia: almost always present w/severe tamponade
                                                              monitoring for development of hemodynamic
Echocardiogram:                                               compromise.
Most specific finding of hemodynamically significant      NSAIDS  indocin. Can use ibuprofen. In some pts
   tamponade by Echo is an exaggerated variation in the       cholchicine works well as monotherapy or as add on
   mitral inflow velocities with respiration.                 to NSAIDS.
Compression of the outflow portion of the right ventricle Steroids: Used only if required for a specific illness such
   during diastole is easily recognizable is highly           as a connective tissue dz or as the last resort
   suggestive of cardiac tamponade                        Recurrent Pericarditis
Atypical Cardiac Tamponade                                   One of the most difficult cardiac problems that internists
Underlying heart disease is the major reason causing             may have to face. What at first appeared to be a
   departure from the classic features.                          simple case of idiopathic or viral acute pericarditis
Absent Pulsus Paradoxus:                                         may, after apparent cure, recur on multiple occasions
1) Pre-existing high LV diastolic pressure may prevent           over a period of months or even years. The same
   equalization of diastolic pressure on the two sides of        phenomenon may follow acute effusive pericarditis,
   the heart and thus prevent pulsus paradoxus.                  Dressler‘s syndrome, post-traumatic pericarditis, and
2) Other cardiac causes of absent pulsus in tamponade            the post-pericardiotomy syndrome.
   are positive pressure respiration, AR and ASD.            Recurrences respond to prednisone, but because of its
3) Cor pulmonale or other causes of right heart                  unwanted effects and because some patients become
   hypertrophy or failure also prevent pulsus paradoxus          dependent on it, every effort should be made to avoid
   and furthermore do not allow the echo signs of                or minimize its use.
   tamponade to manifest.                                    Tuberculosis pericarditis:
                                                             Uncommon in the United States.
Renal failure is often associated w/pericardial effusion
                                                             Does not have a characteristic clinical course.
   (with or without tamponade), LV enlargement,  LV         5 % of pts w/apparent idiopathic pericarditis are
   diastolic pressure and the regional wall motion               subsequently found to have TB pericarditis
   disorders of coronary heart dz.                           TB must be considered a diagnostic possibility in all cases
Edema and  venous pressure can be due to tamponade,             of pericarditis, acute or chronic.
   HF or simple fluid overload, and CO may be 
   because of associated anemia.
If pericarditis resolves within a week, either                Also changes in pulmonary circulation as regards
     spontaneously or in response to simple anti-                 pulmonary circulation. Resistance is decreasing and
     inflammatory treatment, tuberculosis is very unlikely.       pulmonary pressure will decrease as well
TB pericarditis may be dry or effusive at presentation.
If pericarditis remains active for a week or more, a TB                  Left to Right Shunts:
     skin test is indicated and three samples of sputum or    40% of congenital heart cases
     gastric washings should be examined and cultured for     Acyanotic: No clinical features of cyanosis. Oxygen
     tuberculosis.                                                saturation is normal. Left to rt shunt.
TB pericarditis often progresses rapidly to effusive-          flow into rt heart.  rt heart output. Circulation that
     constrictive or constrictive pericarditis.
                                                                  goes through lungs is  . Over time can 
Diagnosis with PCR to identify TB in pericardial fluid,           pulmonary HTN.
     and adenosine deaminase activity helps indicate the      Compliance of connected chambers
     probability of TB.                                       Pressure gradient across stenotic region. Oxygen
Regrettably, a number of patients are treated on
                                                                  saturation of blood  the rt heart chamber. Can
     presumptive evidence such as a recent conversion of
                                                                  measure levels in heart to help diagnose.
     the skin test and known contact with the disease.
     AIDS presents a whole new subset of patients who         Atrial Septal Defect (ASD)
     may develop TB or other varieties of pericarditis        10% of congenital heart abnormalities. Isolated ASD
     because of their immunosuppression.                           usually does not become symptomatic until 30 years
Pericardiocentesis:                                                of age.
                                                              3 major types:
Effusions should be drained. Cardiac tamponade is an
     unequivocal indication for pericardiocentesis. If           secundum (90%): defect is located in fossa ovalis.
     pericarditis remains active or the effusion persists for      Left-to-right shunt  2-4 times normal pulmonary
                                                                   blood flow. EKG changes  R axis deviation, RVH,
     three or four weeks, pericardial biopsy should be
     done. Pericardiocentesis is frequently followed after         and rSR‘ in R precordial leads.
     several weeks by pericardiectomy because of the             Primus:
     likelihood that the patient has by that stage developed     sinus venosus: L axis deviation of P wave (ie (-) P
     effusive-constrictive pericarditis and to prevent             wave in lead III).
     chronic constrictive pericarditis. Whether adding        Irreversible pulmonary HTN develops in 10% of patients.
     prednisone to the treatment of acute tuberculosis             Surgical closure of the ASD  reversal of
     pericarditis prevents subsequent constriction.                hemodynamic abnormalities and prevents
                                                                   complications  HF, paradoxical embolization &
                                                                   irreversible hypertensive pulmonary vascular disease.
      CONGENITAL HEART                                        Treatment:
                                                              Decision to close ASD is based on the size of the shunt of
          DISEASE                                                  and presence or absence of symptoms.
Relative frequency of Cardiac malformations Significant asymptomatic shunt  closure indicated up to
                                                                   age 40. After age 40 closure indicated for
@ Birth                                                            symptomatic patient. Age >60 is not a
VSD                                            30.5%               contraindication for ASD closure.
ASD                                             9.8%          Small centrally located defects can be closed using a
PDA                                             9.7%               transcatheter technique.
Pulmonic stenosis                               6.9%
Coarctation of aorta                            6.8%          Ventricular Septal Defect (VSD)
Aortic stenosis                                 6.1%          33% of all congenital heart abnormalities. VSDs are
Tetralogy of Fallot                             5.8%               classified according to size and location. About 90%
Complete transposition of great arteries        4.2%               occur in the region of the membranous septum near
Persistent truncus arteriosus                   2.2%               the bundle of His. The functional significance of a
Tricuspid atresia                               1.3%               VSD depends on its size and whether pulmonary
All others                                     16.5%               stenosis is present or absent.
                                                              The most prominent physical sign of a VSD is a loud
Incidence of 1%. Has not changed. About 35,000 new                 pansystolic murmur, often associated with a thrill.
    cases appear each year. Now have more sophisticated            Some small VSDs may close completely as the child
    means of repair.                                               grows.
Etiologies                                                    In the absence of pulmonary stenosis severe pulmonary
1. Chromosomal abnormalities severe, multiple                     hypertension may occur. Correction of the defect is
    defects. Tend not to survive.                                  indicated before hypertensive pulmonary vascular
2. Other: Environmental, metabolic, viral (Measles),               disease develops.
    XRT, and drugs (thalidomide).                             All pts w/VSD of any size require endocarditis
3. Critical period during gestation. 1 trimester. When             prophylaxis.
    look at cardiac development. Many changes.                Patent Ductus Arteriosus (PDA)
    Happens in short period of time. 2 to 3 weeks.
Ductus venosus: oxygenated blood bypasses the liver.          90% of cases are isolated defects.
     Collapses when blood flow ceases after removal of        Normally when the smooth muscle in the wall of the
     the placenta. Later it becomes fibrotic                       ductus arteriosus is exposed to oxygenated blood after
Foramen ovale: oxygenated blood from the ductus                    the first breath, it actively constricts closing the
     venosus is diverted to the left heart and cerebral            ductus and in time fibrous tissue grows in to complete
     circulation while deoxygenated blood from the SVC             anatomic closure.
     is diverted to the systemic circulation and umbilical    Symptoms are proportional to the size of the left-to-right
     arteries. A flap valve closes it when LA pressure            shunt. A continuous ―machinery‖ murmur is
                                                                   characteristic and is loudest at the time of S-2. When
     2/2  transpulmonary blood flow at birth
                                                                   PDA is associated with another congenital heart
Ductus arteriosus: blood bypasses the high resistance
                                                                   malformation it may be life saving, e.g., in cases of
     pulmonary bed via the ductus arteriosus into the
                                                                   pulmonary or aortic valve atresia and transposition of
     systemic circulation. Actively constricts when blood
                                                                   the great arteries.
     oxygen saturation  at birth, later it becomes fibrotic Treatment:
Changes occurring at time of birth. When have 1 breath
                                                              Indications for closure: audible PDA by auscultation but
     fluid pushing out. Then air pulling in. Increased
                                                                   no Eisenmenger‘s dz. Closure leads avoidance of
    blood flow.
                                                                   endarteritis, heart failure, and late mortality.
After ligation of PDA in infancy or early childhood         Developmental failure of separation of the embryologic
    bacterial endocarditis prophylaxis is not required.          truncus arteriosus into the aorta and pulmonary artery.
Can be closed surgically or via transcatheter.                   There also is an underlying VSD.
                                                             Blood from the LV and RV mixes  early systemic
Atrioventricular Septal Defect (AV Canal)
                                                                 cyanosis and  pulmonary blood flow.
The embryologic AV canal fails to develop into the           Surgical correction at an early age is favored to prevent
   atrioventricular valves and close the lower portion of        the development of irreversible pulmonary HTN.
   the AV septum. There are variations that include a
   primum ASD, a VSD, cleft anterior mitral leaflet and      Tricuspid Atresia
   a widened anteroseptal commissure of the tricuspid        Complete occlusion of the tricuspid valve orifice. There is
   valve. More than one-third (33%) of patients with            hypoplasia of the right ventricle. To maintain life an
   complete AV septal defect have Down‘s syndrome.              ASD and a VSD are also present. Cyanosis is present
                                                                from birth.
            Right to Left Shunts                             Associated with  mortality unless reparative surgery
These comprise 20% of congenital heart cases.                   done.
    Characteristic features include:                         Total Anomalous Pulmonary Venous
1) Cyanotic: Look at mucous membranes and nail beds.
                                                             Connection (TAPVC)
2) Desaturated blood bypasses pulmonary circulation
    and enters directly into the systemic circulation.       Pulmonary veins do not drain into LA. The return to the
3) Two key anatomic features are:                               heart has a variety of different pathways that are
   communication between the pulmonary and systemic            usually to the right heart. Thus there is volume and
    circulations                                                pressure hypertrophy of the right atrium and right
   obstruction is present which  resistance in right          ventricle.
                                                                      Obstructive Congenital
Cyanotic Heart-Lesions:                                                    Anomalies
The The T’s
Tetralogy of Fallot                                          Coarctation of the Aorta
Transposition of great vessels                             Occurs in about 5% of all forms on congenital heart
Truncus arteriosus                                              disease.
Tricuspid atresia                                          3 to 4 x  frequent in  than in 
Total anomalous pulm return                                Preductal coarctation: Infantile. less common, leads to
Tetralogy of Fallot                                             signs and symptoms early in life and requires surgery.
1) VSD                                                          The narrowing is often severe and circulation to the
2) Obstruction of RV outflow tract (pulmonic stenosis           lower part of the body depends on a right-to-left shunt
     or subpulmonic stenosis)                                   through a PDA. Pulmonary artery pressure is  and
3) Aorta overriding VSD                                         RVH develops early in life. Early surgical treatment
4) RV hypertrophy.                                              is indicated.
Untreated pts often survive into adult life.               Postductal coarctation: Adult type. May be asymptomatic
Severity of obstruction to RV outflow determines the            and malformation may not be detected until well into
    direction of blood flow. As the obstruction  in            adult life.
                                                           1) BP differences between upper and lower extremities.
    severity   resistance to RV outflow. As it
                                                           2) Rib notching: Collateral circulation of intercostal
    approaches the level of systemic vascular resistance,
                                                                arteries may be seen on x-ray.
    right-to-left shunting predominates and also cyanosis.
Pulmonary stenosis restricts blood flow into the lungs. If 3)  Femoral pulses
    stenosis is severe, survival depends on patent PDA.    4) Systolic murmur: posterior chest at level of
With the hypoxia these patients become polycythemic and         coarctation.
    the hemoglobin concentration . Eventually right HF Pulmonic Stenosis
    develops and infective endocarditis frequently occurs. Obstruction at the level of the pulmonic valve. Depending
In childhood these pts often squat in an attempt to            on the severity there will be some degree of RVH. In
    venous return from the lower extremities to  flow          severe narrowing there may be jet flow through the
    either across the PDA or VSD to right side of the           valve orifice  injury to the pulmonary arterial wall.
    circulation.                                                Pulmonic stenosis may involve the infundibular
                                                                portion of the right ventricular outflow tract as well as
IHOP                                                            the valve cusps.
Intraventricular septal defect                             Usually associated with other malformations 
Hypertrophy of Right Ventricle                                  Tetralogy. .
Overriding aorta                                           Surgical resection of the infundibulum or enlarging the
Pulmonary Stenosis                                              valve orifice is the treatment of choice.
Transposition of Great Arteries (TGA)                        Bicuspid Aortic Valve
Abnormal formation of the truncal and aortopulmonary        Common and significant congenital malformation. Instead
    septa. The aorta arises from the right ventricle and        of the usual tricuspid valve the aortic valve has only
    lies anterior and to the right of the pulmonary artery.     two cusps that may be of equal size or
    The result is separation of the systemic and                disproportionate.
    pulmonary circulations, a condition incompatible with Vast majority of pts with bicuspid aortic valves at birth
    postnatal life unless a shunt exists for adequate           are asymptomatic and live normal lives. However,
    mixing of blood.                                            these individuals do have  incidence of infective
Other congenital heart defects exist in those patients with     endocarditis and calcific aortic stenosis (in men) in
    TGA that survive.                                           adult life compared to individuals with the typical
Prognosis depends on the degree of mixing that occurs.          tricuspid aortic valve.
    For longer survival surgical correction is necessary. A Also there is  incidence of dissecting aneurysms of the
    complete surgical correction is often possible, usually     aorta in these individuals in adult life. In both infants
    by ―switching‖ the pulmonary artery and aorta at their      and adults with coarctation of the aorta bicuspid
    origins from the heart.                                     aortic valves are present in 50%.
Truncus Arteriosus
Localized abnormal dilatation of any vessel. The most         Almost always occur in the thoracic aorta and aortic arch.
     common and significant ones occur in the aorta. They          When luetic aortitis involves the aortic valve ring, the
     produce serious clinical disease and often cause death        ring dilates causing aortic valvular insufficiency.
     by rupture.                                                   Since the organisms lodge in the vasa vasorum of the
                                                                   aorta, there is an obliterative endarteritis of these
                                                                   vessels rimmed by an infiltrate of lymphocytes and
Most common type of cerebral artery aneurysms.                     plasma cells. With the subsequent inflammation there
Account for 95% of aneurysms that rupture.                         is destruction of elastic fibers within the aortic wall
Occur at bifurcations of the major cerebral arteries.              and scar formation. As the scars contract, the aortic
 In 20-30% of cases, Berry aneurysms are multiple.                 intima is retracted leading to wrinkling or the "tree-
Although not present at birth, they develop because there          barking" change of the intima.
     is a discontinuity in the smooth muscle of the media
     at the branching points of the cerebral arteries.        Syphilitic aneurysms can attain immense size contributing
     Conditions associated with their presence include             to other clinical problems including
     polycystic kidney disease and the previous existence 1. respiratory difficulty due to encroachment on lungs
     of a cerebral AV malformation.                                and airways
Atherosclerotic                                               2. difficulty in swallowing due to compression of the
Most common form of aortic aneurysm.  > female.
                                                              3. persistent cough due to irritation of or pressure on the
     Occur after 50 yrs.
                                                                   recurrent laryngeal nerves
About 50% of the patients are hypertensive.
                                                              4. pain caused by erosion of bone, e.g. ribs and vertebral
They usually occur in the abdominal aorta and are
     saccular. There is usually a marked loss of elastic
     tissue and fibrosis of the media. These changes are
     due to ischemia of the smooth muscle of the aortic                          ARTERITIS
     media and release of macrophage enzymes causing
     fragmentation of elastic fibers. These changes are       Infectious
     secondary to the intimal atheroma and reflect the        Most caused by direct invasion of infectious agents, e.g.
     importance of inflammatory reactions in the                   bacteria or fungi, into the vessel walls. Also septic
     pathogenesis of atherosclerotic aortic aneurysms.             emboli.
They give rise to clinical symptoms by:                       The infection may weaken the vessel wall, causing a
1. rupture into surrounding tissues                                mycotic aneurysm, or result in rupture of the involved
2. compressing adjacent structures, e.g. ureter or                 vessel.
     vertebrae                                                Polyarteritis nodosa
3. occluding vessels supplying the spinal cord
4. embolism from mural thrombi                                inflammatory dz of unknown etiology affecting medium-
5. presenting as an abdominal mass simulating tumor.               sized arteries.
                                                              Symptoms and Signs:
Treatment:                                                    1. muscle and joint pain
Major concern is tendency to rupture.                         2. Fever
Abd aneurysms < 4 cm have 0-2% chance of rupture and 3. Ischemic lesions in many organs: kidneys (85%),
     expand slowly. > 5 cm have 22% risk of rupture w/in           heart (75%), liver (65%), and GI tract (50%).
     2 yrs w/significantly  rate of growth and rupture       4. Neuropathy
     when >6                                                  Most pts present w/non-specific signs of generalized
Medical Tx: beta-blockers help to reduce aortic pressure           illness  FUO, malaise and myalgia. Other non-
                                                                   specific signs include HTN and pericarditis
     and rapid rise during systole   force of blood vs.
     aortic wall. Should follow w/serial CT exams.            Early stages: arthralgia, abdominal pain, vomiting and
Size is major indication.                                     Pathology:
                                                              Acute lesions: fibrinoid necrosis of the arterial wall.
> 6.0 cm should be repaired. (If w/marfans  repair @
                                                                   Inflammatory cells infiltrate the involved vessels.
     5.5 cm.)
5.0 – 6.0 are good operative candidates.                           Necrosis of the involved vessel walls usually is
4.0 – 5.0 should be monitored every 6 mo.                          segmental in distribution.
                                                              Healing lesions: fibroblastic proliferation w/continuing
Mycotic                                                            necrosis. Vascular aneurysms occur in 50% of cases.
These are usually due to bacterial organisms. They            Rheumatoid aortitis
     commonly occur in patients who have overt or occult
     endocarditis and who have sepsis. In patients who        Pts w/rheumatoid dz, particularly the ankylosing
                                                                   spondylitis variant, inflammation of the aortic wall
     have occult endocarditis, mycotic aneurysms
     frequently present as catastrophic events. A common           may be a significant component. The aortic valve also
     organism isolated from these aneurysms is                     is involved.
                                                              Extension of the dz into the ascending aorta distinguishes
     salmonella. One should be highly suspicious of this
     possibility in a patient who has a fever of unexplained       this from rheumatic aortic valve disease. The
     origin.                                                       rheumatoid lesions also may extend into the bundle of
                                                                   His inducing some degree of conduction block in
Dissecting                                                         these individuals.
Most common catastrophic event involving the aorta.           Giant cell arteritis (Temporal Arteritis)
Uncommon dz w/< 2,000 cases/yr in US.
                                                              Most common of the vasculitides. Focal granulomatous
Occurs in 40-60 yo, 2-3x more common in ♂ vs. ♀.
HTN is present in 94% of cases.                                    inflammation of medium and small cranial arteries,
                                                                   esp. temporal arteries in older white individuals
Hemorrhage occurs between the middle and outer thirds
                                                              Symptoms: New onset of severe unilateral HA, partial
     of the media. An intimal tear, the origin of dissection,
     is found in the ascending portion of the arch in 90%          visual loss, cranial neuropathies and jaw claudication.
     of cases, usually within 10 cm of the aortic valve.      PE: Tenderness or loss of pulsation of temporal artery.
Without treatment, the mortality from dissecting              Labs:  ESR and anemia of chronic dz.
     aneurysm is 50% at 48 hours and 90% within one           Focal distribution of the lesions  (-) biopsies of the
     week.                                                         temporal arteries in 40% of cases.
                                                              Treatment: High dose corticosteroid therapy to prevent
Syphilitic (Luetic) aneurysms                                      stroke or blindness. Prednisone 1 mg/kg for at least 1
Occurs exclusively in late tertiary syphilis.
    mo. Can start Tx empirically before biopsy results             elsewhere. This curious disorder usually is
    return.                                                        encountered in patients having a deep-seated visceral
                                                                   cancer, including pancreas, lung and colon. It is one
Luetic aortitis
                                                                   of the paraneoplastic syndromes.
Inflammation of the aorta in patients with syphilis.
Clinical manifestations do not occur for many years. CV        Phlebothrombosis
     involvement in syphilis is not of clinical significance   This term implied that thrombosis was the initial event.
     until the 3 stage which may occur 3-4 decades after          The events are the same as occur in thrombophlebitis
     initial exposure.                                             described above.
Organisms originally layer out in the vasa vasorum of the      Varicose veins
     aorta. Since vasa vasorum are most dense in the
     ascending aorta and aortic arch, this is the region       Common clinical problem 
     most frequently involved.                                 occur in 50% of people > 50 yrs.
Slowly progressive inflammatory process                       > 30 yrs, 4-fold > in reflecting the venous stasis in the
     fragmentation of surrounding elastic fibers in the            lower legs caused by pregnancy.
     aortic wall and occlusive thrombosis of the involved      Abnormally dilated, tortuous veins produced by
     vasa vasorum. Eventually an aneurysm may form.                prolonged  intraluminal pressure. There is often
                                                                   associated ulceration, usually on the medial aspect of
Takayusu's arteritis                                               the ankle and lower leg.
Ocular disturbances and marked weakening of the pulses         Can develop persistent edema in the extremity and trophic
    in the upper extremities.                                      changes in the skin  stasis dermatitis and
Most pts are asian young or middle-aged . who present             ulcerations.
    w/HTN or ischemic symptoms in the arms. Renal
    arterial involvement can  HTN.
Lesions involve mainly the aortic arch. Also remainder of                        DIGITALIS
    the aorta and its branches, and occ descending          Used to treat HF 2 to chronically overworked heart 
    thoracic and abdominal aorta.                               hypertrophied.  CO   SNS output
Pathology: aortic arch shows fibrous thickening               Angiotensin II, renin produced by kidney to 
    w/narrowing or virtual obliteration of the origins of       circulatory volume
    the great vessels arising from the arch. Histologically   SNS response makes the heart problem even worse.
    vessels show mononuclear infiltrates, granuloma with        The heart is already over-worked and now it has to
    giant cells and extensive fibrosis.                         work even harder to accommodate  circulatory
Thromboangiitis obliterans (Breuger’s dz)                       volume  pulmonary and peripheral edema
                                                            Eventually heart gives up and stops trying to pump. Pt.
Young <35 yo heavy smoking . Evidence of genetic               goes into CHF.
Distinctive clinical picture:                               Cardiac glycosides are very effective drugs in
1. Peripheral gangrene in fingers and toes  changes        treating CHF
    are progressive  serial amputations.                   Direct Effect: Inhibit Na/K pump (ATPase)  less Na is
2. Segmental thrombosis and acute and chronic                   pumped out and less K is pumped into the cell
    inflammation of the intermediate and small arteries     Indirect: Na/Ca exchanger cannot work as well  Less
    and veins of the extremities characterize it.               Ca gets pumped out of the cell   IC Ca and in SR
3. When thrombi are present they frequently have small            Ca is available for contraction  + inotropic
    microabscesses.                                             effect
                                                               Results of Cardiac Glycosides
                  PHLEBITIS                                Potassium:  K gradient  resting membrane potential
Phlebitis: inflammatory condition of the veins.                (RMP) moves from –92  -80 (Closer to the
Although dz of veins are very common clinical problems,        threshold of depolarization)
    only a few entities occur. Inflammation is a key
                                                              Makes it more likely that cell wall depolarizes
    component of the process.
                                                               contractility but also  risk of arrhythmias
Phlebitis is clinically significant because it may
    predispose to intravascular thrombosis and potential   Calcium:  IC Ca. In cells that depend exclusively on Ca
    embolism and intravascular thrombosis of veins can         conductance for AP (SA and AV nodes)  rate of
    lead to venous stasis with its subsequent problems.        firing and conduction, and  refractory period. Cells
                                                               become more refractory because of the  RMP.
Thrombophlebitis                                               Since it does not get as negative anymore, cells, tend
Initial event was inflammation  to thrombosis w/in the        to stay in the refractory period instead of completely
     veins  further inflammatory changes w/in vein wall       repolarizing.
Veins of lower abdomen, pelvis and legs are most           Sodium: Inhibits the kidney Na/K pump   Na
     frequently affected.                                      reabsorption   Na to distal tubules   renin
Risk factors                                                   secretion.
1) Cardiac failure
2) Neoplasia                                               Indirect effects:  contractility   BP  activated
3) Pregnancy,                                                  baroreflex  activation of vagal tone  slowing of
4) The postoperative state                                     SA node
5) Estrogen therapy
6) Hematological disorders                                 Net Effects:
7) Prolonged bed rest or immobilization.                   SA node: direct and indirect effects both  rate of firing.
Deep leg veins are involved in 90% of cases. Periprostatic AV node: direct and indirect effects both  conduction
     veins in men and pelvic veins in women also are
                                                               velocity and  refractory period
     common sites.
1st manifestation of thrombophlebitis often is an embolic Arteries: direct effects  resistance and indirect effects 
                                                               resistance  cancel each other out so no net change
     episode, e.g. pulmonary embolism.
                                                               in arterioles
Thrombophlebitis migrans
                                                               Effects of digoxin on Failing Heart
Superficial venous thrombi form and resolve in different
   subcutaneous sites. This is a term given to the             Get changes within 30 min of IV administration.
   appearance of venous thrombi, often multiple, which,         SV by 50%,  HR,  Pulmonary arterial pressure, 
   classically disappear at one site only to reappear              RVEDP
 pulse pressure (indicates improved pump function)            3) Topical: Good for patients that cannot take oral
Allows pt to move on to an intermediate function curve to            medication. Also comes as patch.
     maintain adequate CO   less stress on the heart to
     maintain the same CO.                                     Hydralazine.
                                                               1. Action: Dilates vascular smooth muscle of resistance
Digoxin                                                              vessels (arterioles) directly  SVR  BP. Reflex  in
Good for people who tend to take one too many pills.                 HR, SV, CO, MVO2, renin, Na retention.
Water soluble. Mostly excreted by kidney in                    2. Disposition: Drug is metabolized by liver N-
     unmetabolized form. Limited Hepatic metabolism                  acetylation (enzyme activity genetically determined).
T ½ = 1.6 days. Before steady state is reached, plasma         3. SE: Reflex effects noted above, resulting in HA,
     levels of drug fluctuate. As the plasma concentration           palpitations. Also lupus (SLE)-like syndrome: 10%
     , the amount of drug excreted also . Once steady              AT > 400 MG/D, in genetic " slow acetylators" with
     state is reached, amount given is = to amount                   dosage.
     excreted. Steady state is reached after 5 half lives      4. Use in HTN: Almost always in combination with a B
     (general principle)  not reached for 7-8 days with             blocker or other sympatholytic (to blunt reflex
     digoxin                                                         tachycardia and hyperreninemia), and a diuretic (to
If you give a large loading dose, it still takes 7-8 days to         blunt Na+ retention).
     reach steady state, but theraputic concentrations are
     reached much more rapidly. Loading dose takes up ¾ Minoxidil (more potent vasodilator than hydralazine)
     of body compartment immediately.                          1. Action: Identical to hydralazine, but more potent
Digitoxin                                                      2. SE: Reflex effects as noted for hydralazine, results in
                                                                     palpitations. Also marked Na+ retention  edema.
Good for people who might forget to take their pills.                Hirsuitism (face and body) at higher dosages, not
     Since it has such a long T ½ it does not really matter          hormonal in origin.
     if they forget to take it one day.
                                                               3. Use in HTN: Always in combo with -blocker or
Greater metabolism by liver than digoxin
T ½ = 7 days. Takes 35 days to reach steady state. Must              other sympatholytic (block reflex  HR, renin) and a
                                                                     diuretic, often a loop diuretic (to block intense NA+
     use loading dose to fill up 75% of body compartment
     so that pt can be treated before steady state is reached.
     35 days is too long to wait, so must give loading dose. Parenteral (IV) Vasodilators
If rapid clearance needed  give Abx  drug binding  Diazoxide
      clearance.                                              1) Action: dilates smooth muscle of resistance vessels
Side Effects                                                         SVR BP. Reflex in Hr, CO, renin.
                                                               2) SE: Precipitous  in BP if given as a bolus dose.
Cardiac: Ectopic and reentrant rhythms, and heart block.
                                                                     Reflex HR, CO. HA, palpitations, flushing. Na+
GI: nausea, vomiting, anorexia, diarrhea, abdominal pain
                                                                     retention - edema. Suppression of insulin secretion -
Neurologic: Visual complaints, disorientation, and
                                                               3) Use in HTN: Useful only HTN crisis (diastolic BP>
Other: Fatigue, muscle weakness, psychic complaints,
                                                                     140 mmHg). Given either as an IV bolus (300 mg
     and HA
                                                                     over 10-30 seconds, because of 90% protein binding,
                                                                     BP fall may be precipitous) or by IV infusion (300
Toxic Index: Very narrow therapeutic window.
                                                                     mg over 15-30 minutes). Effect lasts several hrs.
Measure serum [dig] levels 6 hrs after last dose. Should
                                                                     Must be used with a loop diuretic. Do not use in
     be measured 3-4 times per year. Much individual
                                                                     presence of aortic dissection.
     variability. Serum level that is toxic in 1 pt may be
     non-toxic in another pt
Better to ask your pt how they feel to determine whether
                                                               Action: dilates vascular smooth muscle of both resistance
     their dose it too high. Rely on clinical symptoms.
                                                                     vessels (arterioles)  SVR   BP; and capacitance
Clinical Situations predisposing to Glycoside                        vessels (venules)  venous return.
toxicity                                                       Cyanide toxicity is very rare after nitroprusside. Toxicity
1) Dose too high for the pt                                    manifested by lactic acidosis (cyanide interferes with
2) Error in administration                                     cytochrome system and aerobic metabolism), "almond
3) Altered clearance                                           smell." Treatments include thiosulfate (S donor facilitates
     kidney function   digoxin metab   [digoxin] conversion of cyanide to thiocyanate), and
                                                               hydroxycobalamin (converts cyanide to cyanocobalamin).
     liver function   digitoxin metab   [digitoxin]
4) Hypothyroid
5) Hypokalemia: Diuretics  K depletion and  cardiac                CALCIUM CHANNEL
      sensitivity to dig.
6) Abnormalities in magnesium and calcium                               BLOCKERS
7) Quinidine  displaces digoxin from plasma binding Ca2+ causes everything   work and  rate  coronary
      sites and  concentration of effective drug in                vascular constriction.  heart uses more oxygen 
      circulation. Handle by  dose of qunidine and                 reflex cardiac vasodilation
      digoxin if pt take them both.                            Channels found in heart and peripheral SmM.
8) Other drug interactions: verapamil, spironolactone,          L-Type Ca channels: Slow channel. Prominent in
      flecainide, propafenone, and Amiodarone can lead to           different parts of the body. Open channels Ca2+ rushes
       serum dig levels.                                           in  release of Ca2+ from within muscle.
                                                               SA node: Almost entirely Ca2+. Misses Na component.
                                                                    Spontaneously depolarizes.
                  NITRATES                                     AV node: almost all Ca2+ current.
Oral Vasodilators                                              If block L-type Ca2+ then will affect SA and AV nodes. If
                                                                    block can bring those in balance with oxygen
1) Sublingual: Peak action in 2 min, with duration of
                                                               Peripheral: Vasodilation
      ~30 min. SE of HA, flushing and hypotension. Pt
                                                                                     Verapamil         Dilt Nifedipine
      should take on first indication of angina. Pt to get
      help if 3rd dose does not relieve angina.                Vasodilator                ++            ++        ++++
2) Long Acting: Indicated for therapy refractory to beta-      Reflex Sympathetic         +              +         +++
      antagonist therapy. Can develop tolerance.               (-) inotropy              +++            ++          ++
                                                               (-) chronotropy           +++           +++          +
(-) dromotropy        +++           ++           +          Impaired AV or SA (sick sinus) conduction
T ½ (hr)                5            5           5
Bioavailability (%)    20           25          40          due to dz or Beta-blockers:
Metabolism           Liver         Liver       Liver          Nifedipine and nicardipine: little effect on AV
Dose                120-480       120-360     20-120            conduction
                                                              Verapamil and dilt: may further compromise impaired
Verapamil (Calan and Isoptin)                                   AV conduction.
Works on nodal cells in the heart.  heart rate.  SmM      Stable angina:
    contraction. Also for treatment of SVT.
Slight negative inotropic effect on ventricular myocytes.   Effective as a monoagent or in combo with a beta-blocker
1) Does not  pressure too much. Slight baroreceptors           or nitrate.
    reflex.                                                    myocardial demand:  PSVR (All),  contractility
2) Prominent 1 pass effect.                                     (verapamil),  HR (Verapamil)
3) T ½ is 4 to 8 hrs. Can saturate                             oxygen delivery ( coronary blood flow)
4) Protein bound. Good depot in plasma                      Diltiazem is very effective for angina. Long acting
5) Secreted in urine as active metabolite. Kidney               Nifedipine preferred for chronic stable angina.
    excretion.                                              Contraindications for Verapamil: Sinus node dysfunction,
6) Dosing of 2 to 3 X day.                                      AV dysfunction, heart block, prolonged PR interval,
                                                                CHF, major  of EF, or  overall cardiac function.
Effect on Atrial Arrhythmias:                               Contraindications for Nifedipine: Rapid HR at rest or
Sinus Tach: Slowing                                             w/angina, peripheral edema, borderline  or
PSVT:                                                           hypotensive BP, dizziness, fainting spells, severe HA,
  Reentry: Conversion in 95% of pts                             or facial flushing.
  Ectopic: Conversion in 65% of pts                         HTN
  W/AV block: Conversion in 65% of pts.
Atrial Fib: Ventricular slowing and regularization. Rare    Because their SE profile is so good, drugs are well
    conversion to NSR.                                          tolerated, and have become 1st line antihypertensive
Atrial Flutter: Conversion to Afib then NSR.                    drugs.
WPW: Ineffective
Diltiazem (Cardizem)                                                      -BLOCKERS
1) Very good SE profile.                                    Actions of  receptors
2) Intermediate effect on coronary and peripheral
    vasculature. May enhance blood flow to stenosed         Ca2+ always a contractile signal. 
    vessels with flow limitations.                          SmM have same L type Ca Channel. Ca enters 
3) Little effect on His Purkinjee                               contraction. Also  agonists to GQ  contraction.
4) Prominent 1st pass. Metabolite also active.                   cAMP will relax.
Prolonged T ½                                               Cardiac   cAMP  enhance Ca2+ entry  more Ca2+
5) Effective anti-anginal agent.                                released. More Ca2+ taken up.
                                                            Also  interaction between troponin and myosin  more
Nifedipine (procardia)                                          rapid relaxation. cAMP (+) contractile signal.
1) Works on peripheral vasculature
2) Most potent. Good vasodilation at concentration that      receptors when activated.
    does not  HR too much. Pressure  quite a lot.         All important  receptors in the heart are -1. Some are
    Heart will initially pump easily. If reduce too much         in the JG complex. Most other in body are -2.
    then opposite.                                          Simulate -1  cAMP.  AV activity.  conduction
3) Light sensitive medication. Need to keep away from            velocity.  His Purkinjee.  ventricular myocytes.
    light.                                                  In JG -1 stimulation  renin secretion acts on
4) Well absorbed orally and from sublingual.                     Angiotensinogen  ACE 1  ACE 2 
5) Bypasses portal system. Can get in very well                  vasoconstrictor effect. Also stimulated aldosterone
    sublingual                                                    water retention.
6)` T ½ 3 to 4 hrs                                          SmM with -2 activation  relaxation.
Liver metabolism.
                                                            -3 on adipocytes
Narrow therapeutic range
                                                            Often in vasculature  receptors are on same cells as 
Side Effect Profiles:                                            receptors.   constrictor when stimulated.
                Diltiazem     Verapamil Nifedipine               Differential placement of receptors.
% occurrence      2-5%          8-10%    17-20%             Pancreas has -1 receptors. Activation  insulin
Hypotension         +             ++       +++                   secretion.
HA                   0            +        +++
Peripheral edema                 ++       +++               receptors when blocked.
Constipation         0            +         0               Efficacy depends on presence of stimulation.
AV block            +             ++        0                contraction
Cardiodepression    +            +++        0                rate
                                                             chronotropic and  inotropic effect
      Clinical uses of Ca channel                           Also  renin secretion from JG complex. Takes several
                                                                days. Will  angiotensin   BP   water and Na
               blockers:                                        retention.
LV Dysfunction:
                                                          Vascular SmM. Block -2  Constriction.
  Nifedipine and nicardipine: enhance LV contractility by Bronchial SmM constriction. Peripheral floating Epi is
    marked peripheral vasodilation  stimulates               keeping open
    sympathetic reaction accompanied by reflex
                                                          Also for DM pt  worry about blocking those insulin
    tachycardia. Angina by result when peripheral             receptors.
    arteriolar vasodilation is intense.
                                                          Also  activity in reticular activating system. May
  Verapamil and Dilt: both substantially  LV                 become obtunded.
    contractility that may precipitate CHF.
                                                            Inhibits the effects of sympathetic system.
1.    intotropy
2.    chronotropy   CO.                                       -antagonist with -antagonist
3.    cardiac oxygen consumption.                               Labetalol: Blocks both  and . Having  receptors 
4.   Also may act centrally. Some -blockers will get            orthostatic hypotension. Get venous pooling. Generally
     across blood-brain barrier  also have beneficial           steer clear of . Has same problem of fixed dose. Want
     effects.                                                    more flexibility. Available in Europe.
 antagonist   cAMP   Inhibition of contraction.                             DIURETICS
 CO by  HR and  contractility   pressure in
      system. If block -2 in peripheral   will take over
                                                                  filling pressures of the heart but does not bring the
      and counteract. Frequently will see in pts on
                                                                      patient to a new Starling curve (no increase in cardiac
      propranolol  not rapid . Then block of renin will             output).
      get  in BP. Effect can be variable. One side              Choice of appropriate diuretic agent:
      compensating for the other.                                1. Mild sodium retention-Thiazides.
Major Effects:                                                   2. Moderate to sever sodium retention--loop diuretics
 HR during stress. Protect from  HR. Heart does not                 (furosemide (lasix) bemetarnde (bumex).
      have to work as hard by almost a factor of 2. Will         3. Persistent sodium retention--loop diuretics plus
      make pt tired. Not getting O2 to right places.                  thiazides or metolazone.
No postural hypotension, but when try to exercise will be        4. K+ sparing diuretics (spironolactone) may also be
      tired. HR will not respond. Effect is quick.                    added.
Minor Effects:  contractility.  BP.                            Diuretic dose should be titrated to relieve congestive
Metabolism: Rapidly metabolized by liver on 1st pass.                 symptoms and signs, normalize CVP, and stabilize
      Liver takes out 1/3 just like that. Dosing takes this           weight. Side effects include intravascular volume
      into account. At  doses will saturate liver capacity to        depletion, hyponatremia, hypokalemia, hyperkalemia,
      remove. Then all of drug will go into simulation. Be            metabolic alkalosis, hyperuricemia
T ½ are 3 to 8 hrs. More water soluble  blockers are
                                                                 Pearls concerning diuretics:
      secreted by kidney.                                        1. It's generally better to give HCTZ or lasix as a single
  All well absorbed orally.                                         daily dose. If inadequate, more diuresis will usually
Side Effects:                                                       be obtained by doubling the dose rather than giving
1) Fatigue                                                          the same dose twice.
2) Impotence                                                     2. Avoid excessive diuresis that might prevent titrating
3) Vivid dreams                                                     ACE inhibitors to full therapeutic levels.
4) GI upset                                                      3. Check serum K frequently during initiation and
5) Bronchoconstriction                                              titration (about every 3 days)
6) Heart block, CHF do not want to  HR so much to              4. Beware of combo of ACE inhibitor and K sparing
      compromise. Can cause AV block.                               agents.
7) Withdrawal rebound: response of body to  blockade            5. If large doses of diuretics are used, Mg levels should
        synthesis of  receptors. Body does not very              be checked.
      effectively overcome blockade. Normally does not           6. Pt adjustment of dose: Since the need for diuretics
      matter. There are pts that are reactive and can more          varies depending on the patient's diet and level of
                                                                    activity, having patient adjust the dosage themselves
      sensitive to -simulation. With withdrawal now have
      excess of receptors getting EPI and NE  CV                   is a useful approach. Pt can be advised to  or  their
      collapse, arrhythmias in heart. To avoid withdrawal           diuretic dose to maintain their weight-as measured
      taper off over 1-2 weeks.                                     each morning--titrate to a range in which they have
                                                                    few symptoms of congestion.
Non-Specific  blockers                                          Thiazide Diuretics
Propranolol (Inderol)
                                                               Sulfonamide derivatives. More potent antihypertensive
1) non-selective -blocker.
                                                                   agents, though less potent natriuretic agents than loop
2) Need to take 4 to 6 hrs. Now timed release agents.
3) If block too much will get excessive slowing of heart.                       Daily dosage(mg)   Duration of action (hrs)
    Can get bradyarrhythmias.                                  Hydrochlorothiazide        25-100       12-18
  in libido  part of central effects                      Chlorthalidone             25-50        24-72
Nadolol and Timolol: longer half life
-1 specific antagonist:                                       Mechanism of action in HTN:
                                                               Acute (days-weeks):  Na reabsorption in cortical
Metopropol (Lopressor)
                                                                   diluting segment of the nephron  natriuresis  
1) Relatively specific for -1. Not absolute.
                                                                   plasma volume   CO   BP.
  renin,  in CO
                                                               Chronic (weeks-months):  SVR, perhaps by activating
3) Central sympathetic effect on brain  depression.
                                                                   endogenous vasodilator
4) Slight interaction with -2. Some
    bronchoconstriction. Some on insulin hypoglycemia. Loop diuretics
    If block sympathetic will block perspiring warning         Lasix. Shorter acting (4-6h) than Thiazides. More potent
    symptom in diabetics.                                          natriuretic, but a less potent antihypertensive.
5) More lipid soluble.                                         Useful in renal failure when:
                                                               1. thiazide efficacy  (at GFR < 30 ml/min, or sCr> 2.5
Atenolol (Tenormin)                                                mg/dL)
 -1 specific.                                              2. HTN complicated by edema, often after
2) Does not enter into brain.                                      sympatholytic or vasodilator therapy.
3) More water soluble. Need good kidney to get rid of.
4) Less SE.  depression.
                                                               K+ sparing diuretics
                                                               Spironolactone, Amiloride, triamterene.
Non-Specific -blockade with some  agonist. Useful when combined with thiazides to blunt/reverse 
Pindolol: Potent to block all  receptors. Has a little bit to K+. Fixed Thiazide/K+ sparing diuretic combo used in
    simulate -receptors. Can be useful in pts that            HTN Tx.
    standard -blockers are too strong. Pt faints. Has
    intrinsic sympathomimetic capacity.

                                                              to bottom. Bell over central airway and then do top
                                                              to bottom.
           TESTS OF LUNG                                      Normal: 3 sec, Moderate 6 sec.
             FUNCTION                                      Hyperinflation of static lung volumes (RV, FRC, and,
                                                              sometimes, TLC): barrel chests. Largely because
  Basic Tests of Ventilatory Lung                             residual vol increases. All measures will be elevated
             Function                                         esp FRC and RV. Easy to identify. Low flow, high
How does air flow?
1. Pressure gradient - mouth to alveolus                   VC may be normal or  .
2. Airway resistance - pressure/flow                       Restrictive lung diseases
3. Elastance (lung/chest wall compliance) -              PAINT:
   pressure/volume                                       Pleural: lung surrounded by fluid or pleural scarring.
Spirometry                                               Alveolar: no longer has air—Fluid/fibrosis
Used to measure VC (vital capacity. Focus on expiration) Interstitial: Space between air and blood. Dz that can
    and volume subcomponents (excluding RV) as well           affect the insterstisial. Fibrosis. Make balloon stiff.
    as maximum expiratory (and inspiratory) flow rates. Neuromuscular: to breath need activity of muscles. If you
    Air in and air out.                                       have weakness that will reduce vol.
Volume-Time.                                             Thoracic Cage: lung in cage. Scoliosis.
FVC: forced vital capacity.
FEV1: In 1 second. Corresponds with dz severity.           Characteristic lung function pattern
FEV1/FVC ratio: Assess severity of obstructive lung dz.    a. Reduction in VC (less from top to bottom) and TLC
FEF25-75%: Max mid expiratory flow rate. Average flow         (is a clear demarker for restricive).
    rate between 25 and 75% of vital capacity.             b. Flow rates affected variably
Flow-volume loops:                                         Pulmonary vascular diseases
Inspiratory and Expiratory Flow Rates: Peak Flow           Low DLCO2 with otherwise nl tests of ventilatory lung
    (Highest instantaneous) (PEFR, PIFR), FEF50%                  function
Lung Volumes
Volumes: RV, ERV, TV, IRV                                         Basic Tests of Respiratory
Capacities: VC, TLC, FRC, IC                                              Function
Important volumes                                          Arterial blood gases (PaO2, PaCO2)
TLC: maximum lung volume                                   Oxygen: Oxygen transport
FRC: resting, end-tidal lung volume. How much air in       1) O2 Uptake (lungs)
    lungs at end of breath.                                2) O2 Delivery = arterial O2
RV: obstructive lung dz might have volume at end of        3) O2 Consumption (tissues)
    maximum expiration.                                    4) O2 Return = venous O2
VC: maximum volume you can exhale (or inhale)
                                                           Determinants of arterial oxygen transport
Techniques to measure absolute lung volumes (include       Lungs: (PO2 - driving pressure to load hemoglobin):
       RV)                                                     Ventilation/Perfusion/Diffusion
1) Helium dilution/nitrogen washout: measure gas vol       Blood (hemoglobin): Affinity for O2. Oxyhemoglobin
   ―communicating‖ w/airways.                                  dissociation curve determines O2 saturation (SaO2).
2) Body plethysmography (―body-box‖): measures             Alveolar-arterial oxygen gradient [P(A-a) O2 or A-aDO2]
   ―compressible‖ thoracic gas vol.                        1) Important in assessing arterial hypoxemia: mixed
3) Radiographic: thoracic cage vol from standard CXR.          venous blood.
   Not as accurate.                                        2) Normal P(A-a)O2:  with age, <25 mmHg
                                                           3) Normal PaO2:  with age, and Rule of thumb -75
Comparability of techniques                                    mmHg at 75 years
Similar in normals, and may differ in disease
1) Communicating gas volume may underestimate true         Causes of Hypoxemia:
    lung volume in obstructive disease with                Normal P(A-a)02
    noncommunicating areas of lung                             F102: Altitude. Breathing  O2 content gas.
2) Thoracic volume may overestimate gas volume in
                                                              Alveolar hypoventilation:  PaCO2. drug OD.
    restrictive diseases with air-space filling.
                                                               Hypoventilate. Do not expire out CO2. Less oxygen
                                                               pressure to push out.
   Clinical Applications of Lung                           Elevated P(A-a)02
          Function Tests                                      Low V/Q: lung dz  obstructive, restrictive.
Obstructive:  in (expiratory) flow rate/  in airway          Responds to supplemental O2 (1%  in F102  7
    resistance                                                 mmHg in PaO2)
Restrictive: reduction in lung volume decreased               Right to left shunt: lung or heart dz: no response to
    compliance (increased elastance)                           supplemental O2
Pulmonary Vascular: little influence on lung mechanics         Diffusion: not important under usual clinical
Obstructive lung diseases
Asthma, emphysema, chronic bronchitis, ―COPD‖
Characteristic lung function pattern:                  PaCO2 = reflects adequacy of alveolar ventilation
Reduction in maximum expiratory flow rates: related to
    airway narrowing. What determines how fast can get Elimination of CO2 (VCO2)
    air out of lungs. May depend on size of tube.            VE=VA+VD
    Generally think relates to air way narrowing. Also       PaCO2  VCO2
    strength of abdominal muscles. Lungs may be stiff. Factors that lead to increase in PaCO2
    Flow obstruction. May be able to estimate. Forced      CO2 production (VCO2)
    expiratory flow volume. Can measure. Go from top       ventilation (VE)
    dead space (VD)                                         2. The visible portion of each normal hilum is the right or
Causes of hypercapnia:                                            left pulmonary artery. The pulmonary veins are
Normal lungs - reduced ventilation                                inferior and posterior to the arteries, behind the edges
   Depression of respiratory center: drug overdose, CNS          of the heart on the frontal view and overlapping many
     disease                                                      other structures on the lateral view. The major
   Neuromuscular disease involving respiratory                   bronchi are visible as lucencies. The lymph nodes are
     muscles: spinal cord transaction, Guillan Barre,             too small to be visible when normal.
     muscular dystrophy, myasthenia gravis                    3. The right and left pulmonary arteries are clearly visible
Lung disease                                                      on the lateral view, in the center of the image. The
   Increased ventilation (VD and VE): restrictive or             right pulmonary artery is just anterior the air column
     pulmonary vascular diseases leading to V/Q                   (trachea continuous with main bronchi) and the left
     maldistribution                                              pulmonary artery is just posterior.
    Decreased ventilatory reserve - limits ability to        Normal Lung Markings
     increase ventilation to excrete CO2                      1. The only normal densities within the lungs are the
Diffusing capacity (DLCO):                                        pulmonary vessels when filled with blood.
Noninvasive measure of gas transfer across                    2. The normal markings (vessels) can always be followed
     alveolar/capillary membrane. Not really a test of            from the hilum toward the lung periphery in all
     ―diffusion‖ Surface area that depends on alveolar-           directions. They branch at acute angles, taper and
     capillary surface area and thickness that CO2 is             diverge toward the periphery.
     exposed to. Test for lung dz. Anything that messes       3. Markings on end appear as small masses or nodules.
     up lungs.                                                    They are recognized as normal vessels by the fact
Affected by many factors                                          that they are superimposed upon vessels of the same
Age                                                               diameter branching in other directions.
Sex                                                           4. Abnormal pulmonary markings are all shadows in
Body surface area                                                 addition to the normal markings. Many such shadows
Smoking                                                           obscure the normal markings or displace them.
Membrane diffusion (DM)                                       The Airway
Hemoglobin                                                    1) The trachea is visible on both frontal and lateral
VA (lung volume)                                                 views because it satisfies Rule Number 1.
Q (blood volume and distribution)                             2) The main bronchi are visible within the mediastinum
Decrease in DLCO may be due to:                                  and the medial portion of the hilum.
Reduction in alveolar-capillary surface area                  3) Once a bronchus is surrounded by air-filled alveoli it
Pulmonary resection, fibrosis, emphysema, PNA.                   becomes invisible because nearly all normal
 in capillary-pulmonary vascular disease                        bronchial walls are too thin to be visible as lines.
Increase in DLCO may be due to:
Mild CHF, asthma, exercise, pulmonary hemorrhage.             Demystifying the Lateral View
                                                              The air column, which includes the trachea and largest
                                                                  bronchi, is visible because it satisfies Rule Number 1.
 READING A CHEST XRAY                                         1) The carina is not visible on the lateral view because
Density: Whiteness, or any area of whiteness, on an               the main bronchi continue in the same direction as
    image.                                                        the trachea.
Lucency: Blackness, or any area of blackness, on an           2) The round lucency in the center of the lateral view is
    image.                                                        the distal portion of the left main bronchus as it
Shadow: Anything visible on an image; hence, any                  becomes horizontal.
    specific density or lucency.                              The lateral view of the hila surrounds the left bronchial
Edge: Any visible demarcation between a density on one            lucency.
    side and a lucency on the other.
Line: A thin density with lucency on both sides or a thin     The heart shadow:
    lucency with density on both sides.                       1) The only margin of the heart that is visible as a
Stripe: Any edge or line.                                        distinct edge is the back of the left ventricle, which
Silhouette: Synonym for edge; the ability to see an edge         satisfies Rule Number 1 by bordering the left lower
    constitutes the "silhouette sign".                           lobe of the lung.
"The Rules of Visibility"                                     2) The top of the heart shadow is never a distinct edge
                                                                 because the pulmonary artery and aorta, rather than
"Rule Number 1"
The edge of any structure is only visible if it is bordered      lung, are directly above the heart.
    by a structure of a different fundamental density.        3) The relative lucency above the heart shadow is
1. On a chest radiograph, the only fundamental densities         caused by the relative thinness of the mediastinum in
    are air, soft tissues (including fat and blood) and          that region. It is thus an example of Rule Number 2
    calcium.                                                     and does not have distinct margins.
                                                              4) The thoracic spine always appears increasingly lucent
2. Rule Number 1 is not altered by patient position,
                                                                 from top to bottom, until it crosses the diaphragms.
    direction of x-ray beam, or by technique.
                                                                 This is another manifestation of Rule Number 2.
"Rule Number 2"                                               CHEST FILM SEARCH PATTERN
The lightness and darkness of any part of the image is the    Preliminaries:
     result of all structures through which the x-ray beam    Verify pt information and position of LEFT or RIGHT
     has passed.                                                  marker.
1. Lightness and darkness are easily changed by               Judge technical quality, especially adequacy of
     technique, but the whole film will be similarly              penetration.
     affected.                                                Look briefly at the entirety of both films for obvious
              The Normal Lung
The Hilum
                                                           1. Study the lungs, both up and down and side to side:
1. The hilum is the anatomic connection of the lung to the      include lung volumes and symmetry of markings
    mediastinum and therefore consists of a variety of     2. Check periphery of lungs for pneumothorax and
    vessels, bronchi, and lymph nodes.                          effusions.
                                                           3. Evaluate mediastinal contours, edges and shape.
4. Follow trachea to carina and main bronchi.                6) Stroke: in 1st or 2nd month ~ 50% chance of
5. Look at both hila for enlargement and abnormal bulges.        thrombosis
6. Beginning at the neck, review the periphery of the        7) Pregnancy and post-partum
    chest: include the shoulders, ribs, clavicles,           8) Advanced age after 45
    diaphragms. Check the upper abdomen for free air         9) Immobilized: bed rest > 1 or 2 days
    and abnormal air collections                             10) Nephrotic syndrome: Lose antithrombin III
                                                             11) Obesity
                                                             Initial evaluation:
1. Follow the airway from neck to hilum.
2. Note lung markings and look for fissures.                 Clinical assessment Signs and symptoms can be
3. Look down to the heart and up the anterior                    nonspecific.
     mediastinum to the neck.                                   Tachypnea
4. Follow the spine and posterior ribs to the costophrenic      Rales
     angles.                                                    Tachycardia
5. Judge the shape of the diaphragms and look at the            S4
     upper abdomen.                                             Increased P2
6. Check the anterior chest wall and sternum.                   Dyspnea
                                                                Chest pain often pleuritic
                                                                Cough and hemoptysis
                                                             ABG: Can have normal gas exchange in PE. May affect
  PULMONARY EMBOLISM                                             minute ventilation. Can  dead space ventilation.
                                                             ECG: Findings not specific or sensitive. T-wave
                                                                 changes, ST segment abnormalities and axis
   1% in the general population of hospital pts to
                                                                 deviation (R and L).
   30% in pts dying after severe burns, trauma or           CXR: Pleural effusion, atelectasis, pulmonary infiltrates,
    fractures.                                                   and mild elevation of a hemi-diaphragm.
Sole or a major contributing cause of death in 10% of        LE Doppler:
adults dying acutely in hospitals.
Small PE: Can be silent. May produce infarcts. Small         Many pts fall into intermediate category. Miss ~ 10% of
   emboli present at autopsy but not clinically. Far out                cases.
   in lung.                                                  Ventilation/Perfusion lung scan:
Large PE: Main pulmonary artery. (Saddle emboli) can         Albumin tagged. Want to microembolize the lung. Want
   cause sudden death. There are receptors that lead               to see normal flow in all areas of the lung. Needs to
   back to the respiratory center. Reflex arcs. Can build          be obtained from multiple angles.
   up over time and cause serious damage, but majority       Pt breaths in gas (Ventilation part)  specificity of the
   resolve.                                                        study. If pt has PNA then no ventilation and no
                                                                   blood flow matched defect. Want to look for a
Morality rate:                                                     mismatched defect.
Small embolism  low unless pt already compromised.          Mismatched defect. Do not get reflex
Saddle embolism  Very high                                        bronchoconstriction  high probability V/Q scan +
Surviving cases: clot lysis 2-3 weeks later. 60% of clots          high clinical suspicion  90% w/PE in PIOPED
    resolve within months.                                         study.
Fatal cases: 3/4 die within 1st 24 hrs.                      Majority of pts will fall into low and intermediate area.
                                                             Normal V/Q: rule out. Intermediate will need another
Origin of Acute venous thrombosis:                           test.
1) Peripheral vein: venous thrombosis. ~95% in deep
    veins of lower extremities. Can use diagnostic        Risk of exclusion: At 30% of dying from recurrent events.
    studies to look at those particular veins.            Risks of inclusion: Bleeding risks from anti-coagulation
2) Pelvic veins.                                              therapy—> in hospital for 1 week and outpt for 6
3) Upper extremity veins: indwelling catheters.               month. Short term costs. Establish preexisting
4) Cardiac chambers.                                          condition.
                                                          Pulmonary angiography: Gold standard. Invasive
Thromboemboli:                                                procedure. Expensive.
Most common cause.                                        Adjunctive Tests: These tests are done to limit the need
If Pul. circulation is otherwise intact and the bronchial     for angiography. If find DVT Tx is the same.
     arterial system is adequate, Pul. infarction rarely  D-Dimer test: Sensitive, but not specific. Will have Abnl
     occurs.                                                  result with wound healing and an inflammatory
Chronic thromboembolic occlusion of the main Pul. artery      response.
     or its 1* branches is a rare entity.                 Helical CT scan: Sensitive at lobar level. Not at segmental
Septic Pul. emboli can originate from:                        level.
1) Deep veins of the legs or pelvic veins                 Echocardiogram
2) Right-side endocarditis
Lung abscesses or infected infarcts are complications.    Heparin (LMWH):
                                                           Advantages: Longer half-life. 1x or 2x SQ injection.
                                                               Can be treated as outpt.  bioavailability. Dosing
―Virchow‘s Triad‖: stasis, intimal injury, alterations in      is standardized. More expensive, but provides
    coagulation:                                               simplicity. .
Major risk factors:                                        Disadvantages: Longer half life, no ability to monitor,
1) Prior thromboembolism                                       renally cleared  if pt has renal insufficiency can
2) Major surgery                                               give too much and cannot do dose adjustments.
3) Congenital and acquired hypercoagulable state: ~ 5 to Problems with Heparin Therapy
    10%. Antiphospholipid syndrome, Leiden Factor V         Delay in initiating therapy
    mutation (most common esp. during pregnancy),
                                                            Give too little
    Protein C and S deficiency, Antithrombin III
                                                            Delay in obtaining PTT
    deficiency and Hyperhomocystinemia
4) Malignancy
5) CHF
   Lower short term recurrence rates. Prolonged APTT        Elastic recoil:
    is not associated with increased bleeding risk.          Enlarged size of lung on x-ray. From reduction of elastic
    Bleeding occurs in pts with predisposing risk.             recoil.
   Subtheraputic APTT: is strongly associated with          Emphysema: Disorganization & loss of elastic tissue from
    emboli. Need to titrate. IV administration.                destruction of alveolar wall
Thrombolytic Therapy: In hemodynamically massive             Flow-volume loop is scooped and shifted to the left.
  event  produce more rapid resolution of abnormal
  V/Q scan or PA gram, but no proven effect on mortality                         Diagnosis
  or morbidity and bleeding major SE.                        Ventilatory Capacity and Mechanics:
IVC Filters: Traps clots.                                    FVC is . Airways close prematurely at an abnormally 
Indications                                                    lung vol   residual vol (RV).
  contraindication to anticoagulation (ie active bleeding)   1) FEV1: Greatly  .
  Failure of anticoagulation.                                2) VC:  or normal. Lung stops emptying at a earlier.
  Potential for fatal event: Fear of more breaking off.         Premature closure of airways.
Pulmonary Emboletomy: Indications 
                                                             3) FEV/FVC %: . Normal is about 80% - 120%.
    hemodynamically unstable not candidate for
                                                             4) FEF2575%: reduced.
Post Embolic Prophylaxis:
                                                             1) Cardiac silhouette usually narrow.
Standard pt target INR is 2 to 3 for standard. Treated for
                                                             2) Large hyperlucent lung fields in emphysema.
    min of 6 mo
                                                             3) Increased markings attributable to old infection.
Lupus anticoagulant (+)  INR of 3-4. Could be life
                                                             4) Parallel lines (―tram lines‖) may be seen, probably
    long dz.
                                                                caused by the thickened walls of inflamed bronchi.

  PULMONARY INFARCTS                                         No evidence to support CT, other lung volume
Sieve function of Lung                                        measurements, DL CO, and sputum exam in the routine
1) Schistomiasis                                              investigation. Staging of COPD based on FEV1.
2) Fat embolism: after liposuction.                           Prognosis is related to post-bronchodilator FEV1
3) Air embolism                                              Type A: ―pink puffers.‖
4) Amniotic fluid embolism: 2nd leading cause of death
                                                             Pt with pure emphysema does not have cough. Smoker.
    during birth.
                                                               Fighter. Trying to maintain ventilation. Very
5) Septic Embolism
                                                               dyspnenic. Keeps up ventilation well. Oxygen sat is
6) Tumor embolism
                                                               kept up well. Not really hypercapnic.
                                                             A typical presentation would be
Acute phase: Wedge shaped lesion. Over time infarct is
                                                             1) a man in his middle 50s
    replaced w/fibrous tissue. Infarct converts into
                                                             2) increasing SOB for the last 3 or 4 years
    contracted scar.
                                                             3) Cough may be absent or may produce little white
                      COPD                                   4) Physical examination reveals an asthenic build with
                                                                 evidence of recent weight loss.
Causes:                                                      5) Chest is over expanded with quiet breath sounds and
1) Cigarette smoking single most important factor.              no adventitious sounds.
   Accounts for 80 to 90% of the risk of developing          6) Cor Pulmonale is rare.
2) bronchial hyperreactivity                                 X-Ray:
3) passive smoking                                           1) confirms the over inflation with low, flat diaphragms,
4) air pollution/occupational exposure                          narrow mediastinum, and increased retrosternal
5) -1 antitrypsin deficiency: < than 1%                        translucency (between the sternum and the heart on
                                                                the lateral view)
Although bronchial mucous gland enlargement is               2) attenuation and narrowing of the peripheral
  characteristic of COPD, the airflow obstruction is due        pulmonary vessels.
  largely to structural abnormalities in the smaller         Type B: ―blue bloaters.‖
1) Inflammation                                              Cyanotic. Quitter. Arterial oxygen sat decreases, often 
2) Fibrosis                                                           PaCO2.
3) goblet cell metaplasia                                    A typical presentation would be a
4) smooth muscle hypertrophy in terminal bronchioles.        1) Man in his 50s
                                                             2) Hx of chronic cough w/expectoration
A major cause in emphysema is the loss of alveolar           3) SOB on exertion gradually worsening
  attachments to bronchioles. Part of the airflow                w/progressively limiting exercise tolerance.
  obstruction may also be due to bronchoconstriction.        4) Cigarette smoker of many years duration.
  Majority of COPD pts w/significant  in FEV, after         5) Stocky build with a plethoric complexion
  bronchodilator.                                                (polycythemia)
                                                             6) Some cyanosis.
Pathology                                                    7) Auscultation: scattered rales and rhonchi.
Airways collapse                                             8) Signs of fluid retention with a raised JVP and ankle
Dynamic compression: Leads to flow limitation.                   edema
  Determined by lung vol and compliance. Effort
  independent. Have collapse of airways w/small airways Ventilation-perfusion:
  tending to have higher resistance and are lost earlier.
Expiratory flow-volume loop: Scooped-out appearance.         dead space in COPD  hypoxemia w/or w/out CO2
  Flow is greatly  in relation to lung vol and ceases at           retention.
  lung vol because of premature airway closure.             Type A pt:
Inspiratory flow-volume curve: normal.                         only moderate hypoxemia (Po2 often in the high 60s
TLC, FRC, RV:  in emphysema.                                   or 70s)
RV/TLC % may > 40% (In young normal is < 30%).                 arterial Pco2 is normal.
                                                            Type B:
                                                                    severe hypoxemia (Po2 often in the SOs or 40s)
        w/increased Pco2, esp. in advanced disease.
A-a. :Always  , especially in pts w/severe bronchitis.
    Dead space is particularly  in emphysema, whereas       Now recognized that exacerbations are due to viral
                                                                 infections or URI or may be noninfective so Abx are
     shunt are more common in bronchitis.
                                                                 not always warranted.
Means to adapt to ventilation inequalities                   If Abx are to be used in acute exacerbation  broad
Hypoxic pulmonary vasoconstriction:                              spectrum ABX such as tetracycline, macrolide, and
Local response to a low alveolar P02 . Constriction of the       Pen w/beta-lactamase inhibitor. Help sputum to
    small arterioles.                                            become easier to spit up. Try to use QD or BID
 blood flow to poorly ventilated & unventilated regions,        dosing.
    minimizing the arterial hypoxemia.                       Oxygen: Should be given when PaO2 < 55 or O2 Sat <
                                                                 85%. Helps with symptoms. Does not improve
Arterial Pco2 Often normal in pts w/mild to moderate             survival in pts with less severe hypoxia. Beware of
    COPD despite V/Q inequality.  PaCO2 stimulates              CO2 retainers in whom too much oxygen will
    chemoreceptors, thus increasing ventilation to               remove respiratory drive.
    alveoli.                                                 Surgery:
W/severe dz, the arterial Pco2 may rise. Esp. Type B.        Lung Volume Reduction Therapy: Studies on going.
    Increased work of breathing is an important factor.      Lung Transplantation:
    Also, sensitivity of the respiratory center to CO2 is
    reduced in some pts.                                                        ASTHMA
  Respiratory acidosis: If arterial Pco2 rises, the pH      Type I reaction in the lung mediated by antigenic Ab,
    tends to fall.                                               usually of the IgE class. Vasoactive materials from
  Compensated respiratory acidosis by kidney                    sensitized mast cells after exposure to an antigen 
    compensation: In some pts, the Pco2 rises so slowly          vascular permeability and bronchoconstriction 
    that the kidney is able to compensate adequately by          eosinophils attraction.
    retaining bicarbonate, and the pH remains almost         Clinical:
    constant.                                                1) Wheezing
  Acute respiratory acidosis: PCO2  more suddenly          2) Hyperinflation
    and pH not compensate, perhaps as 2/2 acute chest        3) Status Asmaticus
                                                             Extrinsic asthma (classical) Allergic type reaction. Starts
Pulmonary HTN                                                    in infancy or childhood. An allergic history is
1) Capillary bed are destroyed  vascular resistance            present. Attacks are related to specific exposures.
   in emphysema.                                             Intrinsic asthma: Less common. Onset after 20 yo.
2) Hypoxic vasoconstriction  pulmonary arterial                 Allergies are more difficult to demonstrate. Often
   pressure.                                                     attacks are associated w/acute respiratory infections.
3) Exaggerated hypoxic vasoconstriction by acidosis.             Asthma may occur in patients with emphysema or
4) In advanced disease, histologic changes in the walls          chronic bronchitis. Nerve discharges beneath cells.
   of the small arteries occur.                                  Reflex arc and same response.
5) Polycythemia: more in pts w/severe bronchitis who         Status asthmaticus: Respiratory failure and even death.
   have lowest arterial Po2.                                     Release of His and SRS-A —> bronchoconstriction,
6) Fluid retention w/dependent edema and engorged                 vascular permeability and mucus hypersecretion.
   neck veins may occur, esp. in type B patients. Rt.            Eosinophil chemotactic factor of anaphylaxis (ECF-
   heart enlarges w/characteristic radiologic & EKG.             A) attracts numerous eosinophils to the bronchial
7)  CO: working high on the Starling curve.                     walls. PAF leads to the aggregation of platelets with
                                                                 the release 5-HT from their granules.
                   Treatment:                                1) over distension of the lungs
                                                             2) mucus plugs in the airways
Smoking Cessation:                                           3) thickened basement membranes
Only measure that will help loss of FEV. Will help with      4) eosinophilic infiltrates
    all symptoms. Bupropion as most effective                5) Charcot-Leyden crystals
    treatment. 9-week course of Bupropion   in             6)  size of mucus glands
    abstinence from 15% to 30% at 12 mo.                     7) bronchial SmM hyperplasia and hypertrophy.
Immunizations:                                               Atopic asthma:
Pneumovax vaccination every 5 years. Influenza vaccine. Triggered by a variety of environmental agents including
    Also proactive use of anti-influenza agents on first     dust, pollens, food and animal dander. There often is
    sign of influenza infection.                             a history of asthma, hay fever or atopic eczema..
Bronchodilators:                                         Clinical:
                                                         1. Episodic SOB and wheezing
Help w/symptoms, but not course of dz. Only cause small 2. Usually but not always separated by periods of
     in FEV.  symptoms by  hyperinflation and             normal function
    dyspnea.                                             3. marked by airways obstruction.
Need to instruct pt on proper use of inhaler.            4. variability in both clinical and physiological
1) Muscarinic blockers: Atrovent                             variables, both within a given patient over time, and
2) Short acting Beta-agonists: Albuterol                     amongst patients.
3) Long acting Beta-agonists Serevent                   Prevalence is about 1-5% w/strong genetic component
4) Combivent  combo Atrovent with Albuterol                 and considerable susceptibility to environmental
Corticosteroids:                                             conditions.
IV steroids for acute exacerbation. 2 week taper. Not    Affects all age groups and both sexes. It may not develop
    useful for longer term. SE profile high. Pts had         until adulthood, it may be present in childhood and
    improved clinical outcome and reduced length of          regress in adulthood, or may be lifelong.
    hospitalization.                                     Symptoms and function may or may not be readily
                                                             responsive to the usual therapies involving
Inhaled steroids:  exacerbations
                                                             bronchodilators and other agents.
PO Steroids: ~10% with stable COPD have some
                                                         Episodes are precipitated by:
    symptomatic and objective improvement. Most
                                                         1. Specific antigens
    likely that these pts also have asthma.
                                                         2. Viral/bacterial infections of the airways
3.   Exercise                                                7)   No role for alveolar-capillary diffusion limitation in
4.   Cold/dry air                                                 hypoxemia in asthma.
5.   Emotional crises                                        8)   Artrial PCO2 generally less than 40 torr (often 30-35
6.   Parasympathetic stimulation                                  torr).
7.   Unknown factors                                         9)   When PaCO2 equals/exceeds 40 torr, respiratory
                                                                  muscle fatigue imminent.
Allergic Bronchopulmonary Aspergillosis:
Usually superimposed on a background of chronic asthma
    or CF.
                                                                  Bronchodilator and Asthma
Clinical Presentation:                                                    Therapy
1) Wheezing                                                  Pathophysiological targets (asthma).
2) Fever                                                     Three primary factors:
3) Eosinophilia >1,000                                       1) smooth muscle spasm
4) mucous plugs w/grossly visible brown flecks               2) bronchial wall edema
5) More common in agricultural areas and in the winter.      3) hypersecretion and mucous plugs secondary to
                                                                 airway inflammation.
CXR: Fleeting infiltrates and parallel "tram-line" or ring   Cellular targets.
   markings on chest radiographs. Abnormalities upper        1) Mast cell and other inflammatory cells
   lobes > lower lobes.                                      2) Bronchial smooth muscle cells.
                                                             3) Mucous producing cells.
Diagnosis:                                                   Neural factors. Vagal reflexes, CNS contribution
Eosinophils > 1,000                                          Mediators: multiple, including leukotrienes, 5HT,
Immediate reaction to scratch test with Aspergillus Ag           histamine.
Hx of recurrent pulmonary infiltrates.                       Other: infection, IgE.
 total IgE                                                     catecholamines w/-2 activity  cAMP production;
Treatment:                                                      methyl xanthines (e.g., theophylline) cAMP
Steroids for acute exacerbations                                 degradation
Long term steroid use for prevention.
Follow up IgE levels and CXR at least 4x per year to         Other avenues of Meds:
     detect asymptomatic infection.                          1) -2 adrenergic agonists to  cAMP production
Use of antifungals in addition to steroids.                  2) Methyl xanthines to  cAMP breakdown.
PATHOLOGY                                                    3) Cromolyn sodium to prevent mast cell degranulation
There is a genetically determined hyperreactivity of the     4) Parasympathetic antagonists to prevent vagal
    airways to one or more of a variety of stimuli,              stimulation
    manifest most by SmM contraction and mucus               5) Antagonists of specific products of arachidonic acid
    hypersecretion. In addition, there is                        metabolism - experimental.
1) mucous gland hyperplasia
2) mucosal edema                                             Goals of therapy
3) SmM hypertrophy in the airway wall and                    1) Return patient to baseline - not just asymptomatic
    peribronchial inflammatory changes.                         status
4) Leukocytes, especially eosinophils, are prominent.            PFT‘s, Xrays, scans may offer quantitative
PHYSIOLOGY                                                       ―Baseline‖ may not equal ―normal‖
Lung Mechanics                                               2) Preventive medicine - prophylaxis is key
1) Obstruction of both large and small airways by            3) Pts exposed to allergens show both early & late
   bronchoconstriction, mucus, mucosal edema and                broncho spastic responses, which may show different
   hypertrophied muscle and glands.                             sensitivities to therapeutic maneuvers
2) Hyperinflation due to possibly  recoil and check-        Therapeutic strategies: Individualization
   valve obstruction.
3) Atelectasis (uncommon) if medium/large airways            Intermittent asthma: Acute attack
   completely obstructed.                                    1) Treat early: distinguish mild, moderate, severe
4) Respiratory muscle fatigue in severe, prolonged           2) Mild: inhaled B2-agonists as needed
   attacks.                                                  3) Moderate: -agonists first, then add ipratropium,
5) Pneumothorax/Pneumomediastinum in rare instances.             steroids; combined -agonist & theophylline may
                                                                 predispose to cardiac arrhythmias
Pulmonary Circulation                                        4) O2+ hydration
1) Vasoconstriction (uneven) due to regional alveolar
   hypoxia.                                                  Persistent asthma: anti-inflammatory therapy ± inhaled
2) Vasoconstriction (uneven) due to any of several                    -agonist
   mediators released.                                       1) Mild: -1 drug: inhaled steroids, cromolyn, sustained
3)  vascular resistance associated w/altered                    release theophylline, LT modified
   regional/total lung volumes, and also possibly            2) Moderate: inhaled steroid (+) long-acting -agonists,
   distortion of parenchyma.                                     and/ or theophylline, LT modifier (latter 2 may be
4)  CO due to sympathetic stimulation/anxiety.                  steroid-sparing)
5) Cor pulmonale from prolonged severe pulmonary             Status asthmaticus: will require systemic steroids and
   hypertension due to above (rare).                                  others
                                                             Exercise-induced asthma: -agonists, Cromolyn, LT
Gas Exchange                                                          modifiers prophylactically
1) Uneven distribution of ventilation due to uneven          COPD: inhaled -agonists, ipratroprium, theophylline,
   airway obstruction.                                           corticosteroids, 02
2) Uneven distribution of perfusion due to uneven
   vascular effects (as above).
                                                             Beta Agonists
3) Ventilation/perfusion inequality as a result.             1) Mechanism of action: activate cAMP
4) Hypoxemia from ventilation/perfusion inequality.          2) Inhaled agonists preferred  better effect, faster, less
5) Hypoxemia buffered by the elevated cardiac output.           loss, less SE: aerosolized particles should be l-5 um.
6) Virtual absence of right to left shunts, probably due        in diameter
   to collateral ventilatior                                 3) Predictable -adrenergic SE: cardiac, CNS, tremor, 
                                                                glucose,  K
Metaproterenol: Useful orally and inhaled but use
    supplanted now by other inhaled agents. Some -2
    selectivity. Non-catechol, so less susceptible to       Key anti-inflammatory agents especially via inhalational
    COMT                                                         route
Terbutaline: oral, subcutaneous forms and metered dose      Use in mild asthma becoming increasingly common
    inhaler 2x potent -2 vs. metaproterenol, less potent   Mechanism of action is probably multifaceted
    on heart, but still cardiac side effects Tremors and          alteration in prostaglandins/leukotrienes via  in
    muscle spasms                                                  phospholipase activity
Salbutamol (albuterol): activity resembles terbutaline            ―Permissive‖: Facilatory to -agonists; may
    (oral, inhaled); inhaled preferred                             reverse B-receptor desensitization
Salmeterol: long-acting (BID) inhalational -2selective     Acute situations: esp. when other measures fail, use
    agent with good efficacy, probably better then               enough to control symptoms and then taper rapidly
    salbutamol: especially good for nocturnal symptoms           (>10 days) to avoid HPA suppression (if given
    and for maintenance therapy but not acute therapy            systemically) and other steroid side-effects, esp.
    which requires use of short acting agents.                   osteoporosis
                                                            Chronic use: at least 70% can be maintained with
Muscarinic antagonists:                                          aerosolized forms [e.g., beclomethasone
inhalational treatment directed vs. vagal reflex large           dipropionate: flunosilide, triamcinolone, budesonide
     airways.                                                    (need fewer puffs)
Ipratropium bromide (quaternary NH4 cmpd like atropine) SE: Systemic SE much less common vs. p.o. steroid.
     airway restricted agent.                               1) Hoarseness commonest SE
Patients with COPD may do better than chronic               2) Moniliasis (―thrush‖) in pharynx is easily treatable
     asthmatics, but may be useful in acute asthma, esp. in      and occurs in about 5% patients; spacer device and
     elderly pts, and esp in combo w/B2-agonists. Well           mouth rinse help 
     tolerated. Treatment of choice for -blocker induced 3) Addisonian crisis  pts on systemic steroids are
     bronchospasm.                                               shifted too rapidly to aerosolized drug
SE: dry mouth & throat,  intraocular pressure in pts
     w/glaucoma                                             Fluticasone propionate may prove better because t active
                                                                      as anti-inflammatory and greater first pass
Theophylline                                                          metabolism (to eliminate systemic
Chronic airway disease: little improvement in controlled              bioavailability) vs. other inhaled steroids
1) Mechanism uncertain - besides PDE inhibition,            Leukotriene (LT) Modifiers:
     blocks adenosine receptors, ―direct‖ smooth muscle     Role as alts to inhaled steroids in mild asthma not yet
     effects, and releases adrenal catecholamines. ? Anti-            established
     inflammatory                                           1) Cysteinyl:  eosinophil migration, mucus
2) Multiple sites of action so multiple SE:                      production, airway wall edema, bronchoconstriction
      GI discomfort                                        2) Zileuton (LT synthesis inhibitor):
      insomnia and other CNS effects, HA, tremors,               for asthma maintenance therapy but requires 4xday
        seizures                                                   treatment.
      cardiac arrhythmia; hypotension; diuresis:                 Some pt. show liver toxicity: for aspirin-induced
      Low therapeutic index. Limited clinical use.                asthma together with steroids;
                                                                   hepatic clearance of theophylline, warfarin, and
Pharmacokinetics:                                                  propranolol
Important because one must have suitable blood level:       3) Zafirlukast (LT receptor antagonist):
      Optimal = 10-20 ug/ml;                                     maintenance treatment of mild-moderate asthma.
      side effects rare <13                                       less effective than inhaled steroids
      serious toxicity is preventable and predictable with       Food and other drugs (e.g. theophylline)  its
        plasma levels (esp> 20)                                    effect and zafirlukast (like zileuton)  serum
Absorption and metabolism highly variable, T½ =5± 1.5              theophylline and oral anticoagulants
          hr                                                       concentrations.
1) Microsomal oxidases w/induction by theophylline                SE: HA, GI intol.,aminotransferase, ? Churg-
     itself, or other drugs, incl. tobacco, marijuana.             Strauss vasculitis (perhaps .2°SI. steroid use)
     clearance in children <16. clearance in obesity, aged, 4) Montelukast (LTD4 receptor antagonist):
     liver disease, CHF, viral infections, hypoxia, fever         Similar activity to zafirlukast. May permit
     and with certain drugs, (erythromycin, cimetidine,            reduction in corticosteroid dosage (Churg-Strauss
     ciprofloxacin).                                               vasculitis noted in some pts).
2) For acutely ill patients, IV loading dose, maintenance         Effective with steroids for ASA-induced asthma.
     infusion. Plasma levels must be obtained                     Helpful in 75% w/exercise-induced asthma.
3) Commonly given as ethylene diamine salt,                       Only FDA-approved LT modifier for children ages
     aminophylline, only 80% of which is theophylline:             6-12; can give once daily
     must correct for this in dosing
                                                            Hydration and mucolytic agents:
Cromolyn sodium                                           1) Hydration is a useful adjunct to therapy, especially
Mechanism of action: unclear but inhibits degradation        when mucous plugging is evident.
    and release of mediators from mast cells; binds to    2) Mucolytic agents (acetylcysteine) are of dubious
    Ca~ channel                                              value;
Not absorbed PO; inhaled as a powder; also as nasal spray 3) DNAse approved for CF, ? also useful for chronic
Systemic effects but relatively selective for                bronchitis: data not convincing so far
    bronchopulmonary tree

Indications: prophylactic, for allergy-related and                ACUTE BRONCHITIS
    exercise-induced asthma but not for acute treatment.    Inflammatory dz of lower respiratory tract 2/2 acute
    Given in nasal form for allergic rhitinitis               infection.
Given as a particulate (in ―spinhaler‖), it will induce     Viral agents responsible for overwhelming majority of
    bronchospasm; may need bronchodilator first; also         cases.
    available in a nebulizer                                Mycoplasma pneumoniae and Chlamydia pneumoniae
Nedocromil is chemically unrelated drug with similar          found in up to 10%
Not all pts w/viral respiratory infections have acute          confused with acute bronchitis in an otherwise healthy
  bronchitis. Interaction between an infectious agent and      person.
  a susceptible host.
Pts w/pre-existing bronchial irritation from sources such
  as cigarettes or occupational exposures and those with a Patients with chronic bronchitis have:
  predisposition to reactive airways are more likely to         Daily productive cough for more than 3 months/yr
  exhibit symptoms consistent with acute bronchitis               for 2 consecutive years.
  during a viral respiratory infection.                         Experience irreversible bronchial wall thickening and
                                                                  hypertrophy of underlying mucous glands secondary
Pathophysiology                                                   to prolonged exposure to bronchial irritants such as
Excessive mucus production and airway narrowing                   cigarette smoke. Excessive mucus secretion results in
  associated with acute inflammation  Symptoms.                  the daily sputum production that typifies chronic
Spirometry  reversible airway obstruction ~ asthmatics.          bronchitis.
  As acute bronchitis episode resolves, spirometry revert Because of the excessive mucus production and poor
  to normal.                                                   mucociliary clearance, patients with chronic bronchitis
Clinical presentation                                          often experience superinfection with bacteria and are
                                                               more susceptible to respiratory viruses. Because the
often accompany those of URI                                   mucus present in the bronchial tree is an ideal culture
1) Low-grade fever                                             medium for bacteria, the bacteria found in sputum often
2) Productive cough that worsens with exercise or              do not represent an acute infection; rather, they are
     reclining. Generally lasts 1-2 weeks, although up to      colonizers. There is no simple way to differentiate
     25% of patients may cough for > 1 month                   colonization from superinfection, however.
3) Night cough
4) Occ. audible wheezing.                                    Diagnosis
5) Variable colored sputum: usually clear or white but Acute exacerbation of chronic bronchitis is defined as
     may be yellow, green, or blood-tinged. Color is not       changes in respiratory status and sputum appearance
     accurate predictor of whether bacteria are involved in    without evidence of underlying pneumonia.
     the infection.
6) Minor blood-streaking of sputum.               Caused by Symptoms:
     inflammatory changes in the bronchial tree. Large respiratory distress or
     amounts of bleeding or a cough producing blood worsened dyspnea in the presence of
     clots should prompt evaluation for other sources of change in the color or consistency of sputum, or severity
     bleeding.                                                 of cough usually are sufficient to make the diagnosis.
CXR: Should be limited to pts in whom PNA is strongly
  suspected. Not indicated if pt does not have a high fever Because of the compromised respiratory status of patients
  or signs of PNA on PE.                                       with chronic bronchitis, a chest radiograph may be
   May be useful if pt has hemoptysis and is at high risk     useful to exclude pneumonia as the cause of these
     for bronchogenic malignancies; however, in high-risk      symptoms.
     patients, cancer is not excluded by a normal chest      Causative Agents:
     film.                                                   Gram's stain of sputum is not useful in directing therapy
CBC and Gram's stain of the sputum: not useful in              because many organisms may colonize the respiratory
     making the diagnosis or guiding treatment.                tract in pts with chronic bronchitis,
Treatment:                                                   1) M. pneumonia
                                                             2) Haemophilus influenzae
Because > % of cases of acute bronchitis caused by a         3) Streptococcus pneumoniae
  virus, Abx not effective                                   4) Branhamella catarrhalis
Symptomatic treatment:                                       Many acute exacerbations actually may be viral in origin .
1) bronchodilators: pts treated with active drug were
     almost twice as likely to have stopped coughing in 1 Treatment
     week as those treated with antibiotics or placebo.      Due to underlying bacteria in respiratory tract of pts
2) cough suppressants: useful in patients w/cough that         w/chronic bronchitis & difficulty in deciding when a
     interferes with their ability to work or rest. Codeine-   bacterial infection is present, most acute exacerbations
     containing cough medications are effective agents.        of chronic bronchitis are treated with Abx.
Complications                                                Antibiotic selection:
                                                              Difficult  offending organism is not usually identified.
Nearly all pts w/acute bronchitis have resolution of their     Although multiple suggestions have been offered to
  symptoms within 2 weeks.                                     guide Abx selection, the original studies that
   small proportion continue to cough for 1 month or          demonstrated improvement all used either tetracycline
     longer. Chronic use of a bronchodilator may alleviate     analogues, amoxicillin, or sulfamethoxazole-
     their symptoms.                                           trimethoprim (SMZ-TMP).
   Possible Mycoplasma, Bortadella pertussis or             Because there is no evidence that cephalosporins,
     Chlamydia infection: Little evidence to substantiate      quinolones, or macrolides are superior to these drugs
     that bacterial infections are more likely in patients     and all are more expensive, treatment with
     with chronic cough. Nevertheless, empirical use of a      tetracycline/doxycycline or amoxicillin, or SMZ-TMP
     macrolide when coughing for a month may be more         Short courses of corticosteroids:
     cost effective than pursuing other laboratory or         Prednisone: may shorten the course and  severity of
     radiologic tests.                                         acute exacerbations of chronic bronchitis.
   Adult-onset asthma: large proportion have serologic Acute exacerbations may also afford another opportunity
     evidence of previous C. pneumoniae infection.             to counsel tobacco-using patients about the need to
     Hypothesized that asthma symptoms in these patients       discontinue smoking.
     actually represent a chronic Chlamydia bronchitis
     infection.                                              Complications
                                                             Respiratory failure & need for mechanical ventilation are
                                                               rare but can occur in pts w/very limited respiratory
    CHRONIC BRONCHITIS                                         reserve.
Pts experience  SOB along with  in the severity of
  cough or character of the sputum.                          Prevention
These types of episodes are categorized as an acute          Smoking cessation is the first key to reducing progression
  exacerbation of chronic bronchitis, which should not be      of chronic bronchitis and  risk of an exacerbation.
                                                             Annual influenza vaccination

           LUNG ABSCESS                                             INTERSTITIAL LUNG
Most frequent from aspiration.
  superior and basal segment of lower lobe                              DISEASE
  posterior segment of the upper lobe.                       Heterogeneous group of dzs characterized by
                                                                  inflammation and fibrosis w/in the lung parenchyma
Mechanism of Intro of agent:                                      or small airways.
1) aspiration of infective material: Most important           CXR: Bilateral symmetrical infiltrate, interstitial
   factor in the pathogenesis. Pt most likely to aspirate         reticulonodular, alveolar, or mixed patterns. Reduced
   are pts w/CNS dz or trauma, after anesthesia and               lung compliance  restrictive respiratory defect on
   alcoholics.                                                    pulmonary function tests.
2) Preceding primary bacterial infections: massive lobar      These features include
   pneumonia, as a complication of an infected infarct,       1)  TLC
   as a complication infection of cysts or bullae, after      2) reduced VC,
   penetrating chest trauma, distal to sites of obstruction   3) reduced FEV1,
   and after aspiration.                                      4) normal or  FEV1/FVC ratio
3) Septic embolism                                            5) relatively normal PEFR.
4) Neoplasia                                                  Idiopathic Pulmonary Fibrosis
5) Traumatic injury
                                                            Poorly understood pulmonary disorder characterized
6) Direct spread of infections in nearby organs
                                                                histologically by diffuse interstitial inflammation and
7) Hematogenous spread of other infections to the lung.
                                                                fibrosis that in the advanced case results in severe
                                                                hypoxemia and respiratory failure. It occurs in acute
Acute phase: cavity contains pus & is walled off by
                                                                and chronic forms.
    layers of fibrin and leukocytes & externally by
                                                            Chronic interstitial pneumonia has a clinical history
    developing granulation tissue. Although vessels may
                                                                lasting months or years with slowly increasing
    be disrupted by extensive necrosis they usually are
                                                                respiratory insufficiency, dyspnea, cough and finger
    sealed off by thrombosis. Rarely, fatal hemorrhages
    can occur.
                                                            There is interstitial fibrosis, infiltration with lymphocytes
Healing phase: granulation tissue is converted into scar.
                                                                and macrophages and microcyst formation. A
    Multiple fistulous tracts w/bronchi persist.
                                                                common form is fibrosing alveolitis that is a
                                                                progressive chronic pulmonary fibrosis of unknown
         BRONCHIECTASIS                                         etiology. This occurs mostly in patients who range
Permanent dilatation of bronchi and bronchioles. When it        from 45 to 65 years of age. They present with
    is not associated with obstruction, it usually involves     increasing dyspnea and a dry cough. This progresses
    the basal segments, the lingula or middle lobe, and         to respiratory failure with or without corpulmonale
    occasionally the anterior segments of the upper lobes.      within about 5 years. Fatigue and considerable
Primarily located in the second order branches of               weight loss may occur.
    segmental bronchi and beyond.                           Clinical:
Bronchi that do not have cartilage.                         1) Dyspnea
                                                            2) Tachypnea
Traction hypothesis as cause:                               3) cough
Bronchiectasis preceded by a necrotizing focal              4) finger and toe clubbing
    pneumonia.                                              5) dry crackles
The foci of bronchopneumonia involve bronchi,               6) right ventricular strain or failure may be present.
    bronchioles, and parenchyma distal to the bronchi       Men more than women
    that ultimately become bronchiectatic sacs.             Progressive dz is variable
As foci of necrosis become scarred and shrink, they exert Interstitial fibrosis on x-ray. Evenly distributed.
    on the intact proximal bronchi that then become         Honey comb lung in end stage dz.
Bronchi proximal to second order segmental bronchi have Pathology:
    cartilage within their walls that buttresses them       Diffuse alveolar damage with
    against the traction.                                   1) alveolar exudation
                                                            2) formation of hyaline membranes
Clinical features:                                          3) type II pneumocyte proliferation.
1) Chronic cough                                            4) patchy, heterogeneous distribution and temporal
2) Expectoration of large quantities of sputum,                 nonuniformity.
    sometimes flecked w/blood
3) Finger-clubbing (rare except w/CF)                       Etiologies:
4) Recurrent respiratory tract infections due to inability 1) living agents: viruses, mycoplasma
    of pt to clear pooled secretions. Infective processes   2) inhalants: oxygen (conditions where pts are
    may remain localized to the bronchi or spread.              administered for various reasons. If 100% oxygen
                                                                for 5 to 7 days or longer would lead to diffuse
Complications:                                                  damage) metal fumes
1) PNA                                                      3) Ingestants: kerosene, paraquat, drugs
2) Empyema                                                  4) immunologic factors
3) Septicemia                                               5) collagen diseases: 25% of patients with UIP have
4) Meningitis                                                   RA.
5) Metastatic abscesses                                     6) genetic factors: a few cases.
6) Amyloidosis                                              7) physical agents: UIP may occur after radiation
Depending on the extent of the disease, cor pulmonale           therapy. Careful to shield lung from radiation. Also
    may occur.                                                  pts undergoing chemo.
                                                            8) unknown (the largest category).
Pathologic:                                                 Drug and toxin reactions:
Due to obstruction or atelectasis
                                                            Cytotoxic drugs: busulphan and bleomycin  low-grade
                                                                alveolitis with healing by interstitial fibrosis and type
                                                                II pneumocyte proliferation. Many of the latter have
    atypical hyperchromatic nuclei with prominent             Anti-glomerular basement membrane Ab: (+) 95% of pts.
    nucleoli.                                                     This causes GN. It also acts on alveolar membranes
Paraquat: potent herbicide  releases hydrogen peroxide            pulmonary hemorrhage.
    and the superoxide free radical  diffuse alveolar        Treatment:
    damage. Pulmonary symptoms occur after about 5-6          Spontaneous remissions can occur but are rare.
    days because the drug remains highly concentrated in      Severity of the renal involvement best predicts the
    the lungs for several days after ingestion. Once              outcome.
    pulmonary symptoms develop, the condition is              Steroids,cytotoxic drugs, and plasmapheresis until
    rapidly progressive.                                          circulating anti-GBM Ab have been removed
Radiation pneumonitis: occurs after radiation to the lung.
                                                              Idiopathic pulmonary hemosiderosis:
    The clinical effects depend on the dose given, the
    volume of lung irradiated and the length of treatment.    Rare condition presenting most often in children.
    If heavily exposed a picture of diffuse alveolar          Clinical:
    damage is seen. if exposure is less severe and occurs     1) Recurrent episodes of intra-alveolar hemorrhage
    over a longer period, progressive pulmonary fibrosis          associated with hemoptysis, cough and dyspnea
    is seen with the typical restrictive defect of            2) Possibly insidious pulmonary fibrosis.
    pulmonary function.                                       The acute form shows evidence of diffuse alveolar
                                                                  damage with type II pneumocyte proliferation.
Desquamative Interstitial Pneumonia (DIP)
Prominent aggregation of alveolar macrophages w/in the        Prognosis: ~ 50% die w/in first few days despite
    alveoli and little or no fibrosis. Process is all             intensive therapy. Most survivors progress to full
    through lung. Bland infiltrates.                              recovery w/resolution of the inflammation and
                                                                  restoration of normal alveolar architecture. However,
Clinical:                                                         a small number of pts heal by organization  chronic
1) Slow development of cough and dyspnea  to                     pulmonary fibrosis.
    marked respiratory distress, cyanosis and clubbing of
    the fingers.
2) CXR: Ground glass infiltrates in bilateral lower lobe.                            BOOP
    Diffuse haziness.                                         BOOP
3) 90% are smokers.
                                                              Polypoid masses of granulation tissue form in distal
                                                                  airways, alveolar ducts and airspaces.
   Little interstitial infiltrate/primarily intra-alveolar   1) Infective agents: viral or mycoplasma
    components.                                               2) Idiopathic
   Minimal fibrosis                                          3) Connective tissue dz.
   Accumulation in airspaces of  # of macrophages           4) Hypersensitivity pneumonitis
    w/lipid and PAS (+) granules. Alveolar septa are          5) Drug and toxin exposure.
    thickened by sparse inflammatory cell infiltrates.        Result  obstructive or ―golden‖ PNA: accumulation of
   Walls of alveoli are still intact.                            fat filled phagocytes behind the site of bronchiolar
   Homogeneous pattern.                                          obstruction, their eventual disruption w/release of
                                                                  cholesterol and the resulting foreign-body reaction
Treatment:                                                        and fibrosis.
Stop smoking.
Good response to steroids but some may progress to            Bronchiolitis obliterans superimposed on
    interstitial fibrosis and honeycombing.                   lesions similar to UIP (BIP or BOOP).
Lymphoid Interstitial Pneumonia (LIP)                         Obstructive Dz added to restrictive lung disease clinically.
                                                                   Rapid clinical progression. X-ray features are highly
Precursors of a malignant lymphoproliferative disease.             variable.
CXR: Bilateral or reticulonodular infiltrates, dense          Interstitial infiltrate and nodular densities. See lacy
    infiltrates or focal nodules.                                  pattern on x-ray. Nodular densities. See that looks
Early phase changes are restricted to the lungs. However,          different. Still fragments of intestial. Plug
    on long-term follow-up, these pts develop diffuse         Etiology:
    lymphoproliferative disease.                              1) Mostly unknown.
                                                              2) Infections
Clinical features:                                            3) inhaled toxins
May have evidence of lymphoproliferative dz                   4) drugs
Immunocompromised pts esp. children w/HIV.                    5) collagen vascular disease
                                                              6) bronchial obstruction.
Pathologic lesions:                                            Major pathologic finding:
Lymphocytic infiltrate in interstitium                        1) Polypoid plugs of loose fibrous tissue filling
                                                                   bronchioles and alveoli.
               ALVEOLAR                                       2) A variable chronic inflammatory cell infiltrate is
             HEMORRHAGE                                       In most cases, patients improve gradually or with steroid
Goodpasture’s syndrome:                                         RESPIRATORY FAILURE
1* in young ♂ 18-35 yrs                                       Failure of the respiratory system to maintain normal gas
1) Hemoptysis: be modest. Can be massive and life-                exchange (pH, pCO2, P02). Substantial impairment
     threatening                                                  of the respiratory system can be present before gas
2) Hematuria: progressive GN                                      exchange is impaired.
3) Anemia: Hypochromic, microcytic                            Respiratory system extends from the brain (CNS, Nerves,
4) Pulmonary infiltrates: Bilateral symmetrical alveolar          NMJ) all the way to the chest wall. Therefore, failure
     or acinar infiltrates                                        of the system can be due to any or all of the
DDx: SLE, Wegener's, HSP, polyarteritis nodosa, and               following:
     cryoglobulinemia                                            Inadequate muscle (diaphragmatic) function.
                                                                 Failure, or depression of the respiratory control
Ventilation requirements: VD, CO2 production. How          As fatigue  may see normalization of PCO2. In pt w/Nl
    much do you have to breath to get rid of your CO2?          PCO2 means that are headed past normal on their way
    Infection, fever  Will produce more CO2                  to .
    respiratory rate to blow off.                          Late will develop hypercapnia.
 V/Q,  Dead space ventilation   respiration rate.      Signs:
                                                              Use of accessory muscles
Hypercapnic-Hypoxemic Respiratory Failure
                                                              Sitting up right
Hypercapnia indicates that alveolar ventilation (C02          Paradoxical breathing: sign that diaphragm is
    clearance) is inadequate                                    fatiguing. Pulls down.
                  PaCO2 = VCO2/VA                          Chronic Respiratory Failure: COPD
                  VA = VE - VD                             Have chronic respiratory failure  chronic respiratory
Therefore reduction in VA can be due to:                        muscle weakness.
1) Inadequate VE. (Total ventilation) Absolute alveolar
                                                           Chronic  PCO2  compensate w/metabolic alkalosis , 
                                                                bicarb to maintain normal pH.
2)  VD. (Dead space) Relative alveolar
                                                           Acute respiratory:  .08 in pH for every  10mmHg in
    hypoventilation because VE may be Nl or .                  PaCO2
                                                           Chronic:  .03 change in pH for every  10 mmHg in
Clinical contexts:
1) Absolute hypoventilation: CNS depression (drugs,
    brain injury) and neuromuscular disease
2) Relative hypoventilation: underlying lung dz:                                    ARDS
    emphysema, bronchitis, severe ARDS and/or thoracic Caused by diffuse alveolar capillary/endothelial cell
    deformities: kyphoscoliosis                                 damage and alveolar lining cell damage.
Common consequences of hypercapnic-respiratory             Clinically ARDS presents with:
    failure:                                               1) rapid onset of severe respiratory insufficiency: due to
Arterial hypercapnia dictates that arterial hypoxemia will      shock or post-surgery. 24-48 hrs.
    occur (partial pressures law):                         2) cyanosis
                  PAO2 = PI02 - PaCO2                      3) Severe arterial hypoxemia that is refractory to O2
                  PaO2 = PAO2 - (A-a DO2)                       therapy that frequently  extra-pulmonary
Hypercapnic respiratory failure w/out lung dz can be            multisystem organ failure.
         recognized by                                     4) White out of entire lung on X-Ray.
   Elevated PaCO2
   decreased PaO2 Proportionally decreased                1) PaO2/FIO2 ratio  200
   normal A-aDO2.                                         2) Diffuse pulmonary infiltrate
Calculate AA gradient and it is normal. Then what is the 3) Pulmonary wedge pressure < 18 mmHg or no clinical
    likely cause  hypoventilation (eg drug OD, CNS             evidence of CHF.
    event, NM drug) AA gradient is normal                  ARDS is a well recognized complication of numerous and
Pulmonary arterial vasoconstriction due to alveolar             diverse conditions including both direct injuries to
    hypoxia, alveolar hypercapnia, acidemia.                    the lungs and systemic disorders. Changes at
Cerebral vasodilation. May lead to cerebral edema               capillaries and lining cells of alveoli (epithelial cells
Eventual cardiovascular system dysfunction/collapse.            damage)
Principles of Management
Maintain adequate oxygenation and improve CO2              Direct lung injuries causing ARDS include
    clearance                                              1) Any type of severe infection.
   Oxygen supplementation                                 2) oxygen toxicity
   Assisted ventilation until woken up.                   3) inhalation of toxins and other irritants
   Keep PaCO2 the same as baseline. True for chronic 4) aspiration of gastric contents.
    COPD pt.
                                                           Systemic conditions causing ARDS include
Oxygen is a drug. Risks include lung injury, and depress 1) septic shock
         respiratory depression.                           2) traumatic shock
                                                           3) bums
Hypoxemic Respiratory Failure                              4) some hypersensitivity reactions
Basic defect: Alveolar-capillary ―block‖ (elevated A-      5) cardiac surgery involving extra-corporeal pumps.
    aDO2) leading to shunt and/or V/Q abnormalities
    and/or diffusion impairment. Lung dz. Isolated to      Pathogenesis:
    the lung.                                              Endothelial cell damage of capillaries.
PE; Hypocapnia and increased respiration. Pulmonary        Epithelial cell damage of Type I the main damage. Type
    embolism stimulates ventilation. Minute ventilation         II if intact are the ones that help to repair damage.
     and PCO2 .                                          Massive insult to alveolar-capillary walls  diffuse
Cause: Any pathologic process where no longer able to           alveolar damage.
         maintain the lung/airways.                        02 toxicity  damage caused by free radicals such as
1) PNA                                                          superoxides and peroxides.
2) ARDS                                                    PMN‘s release of enzymes and activation of complement.
3) Asthma
4) Aspiration                                              Morphologic Features:
5) Pulmonary embolism                                      Damages the alveolar endothelial and epithelial cells.
6) Late hypercapnia. May eventually lead to                An early acute or exudative stage is most prominent
    hypercapnia (respiratory muscle failure) as a 2*            within the 1 week of injury. Characterized by
    phenomenon.                                                 edema, exudation and hyaline membranes (5 days)
7) CHF  pulmonary edema.                                       Increase and will taper off.
ARDS: (see below)                                          A later proliferative or organizing stage in which fibrosis
Asthma;                                                         predominates occurs after 1 to 2 weeks. 9 days may
Can lead to respiratory failure.                                migration with neutrophils and have scar formation.
Early on see hypoxemia due to V/Q mismatch and             Morphologic changes occur primarily in the alveoli and
    hypocapnia due to simulation to respiration.                      interstitium.
                                                              Alveoli are filled with necrotic type I pneumocytes,
                                                                edema fluid and hyaline membranes.
   Interstitium has edema fluid and cellular infiltrates    3 forms of CWP that are anthracotic.
    which are mainly monos.                                  Anthracosis: presence of coal dust pigment. Main culprit
   In the healing or repair phase fibrosis may occur in          is silicosis.
    the interstitium while type II pneumocytes regenerate    Macular CWP: focal collections of walls of respiratory
    to reline the alveolar walls.                                 broncholioles, pulmonary arterio scarring is present.
Whatever the stimulus that causes injury. Damage to          Nodular CWP: progression from the macular stage seen
    endothelial and capillary. Become leaky. Plasma               in a background of more extensive macular CWP
    leaking —> interstitial edema. Also neutrophils               fibers. The upper lobes and upper segments of the lo
    migrating out to that region as well. Type I sloughed         nodules are located primarily adjacent to respiratory
    off. Combination of destroyed lining and plasma               bronchioles.
    form a hyaline membrane.                                 Progressive Massive Fibrosis (PMF)
50% of cases die within the first few days despite           May be a continuation or CWP. Is much more severe.
    intensive therapy. Most of the survivors progress to          Takes years to develop.
    full recovery w/resolution of the inflammation and       In addition to anthracotic pigment have silica —> fibrosis
    restoration of the normal alveolar architecture.              and thickening. Silica as contaminant. Also quartz.
    However, a small number heal by organization                  Immunologic factors. Infectious agents (poor areas.
    leading to interstitial pulmonary fibrosis.                   High prevalence of Tb.)
                                                             Nodes are black.
  ENVIRONMENTAL LUNG                                         Large, irregular nodules with scarring.
                                                             In some soft coal miners there is a central confluence of
          Dz                                                      the anthracotic pigmented lesions with massive
Inorganic                                                         scarring. This lesion is associated with severe
1. Pneumoconiosis                                                 infections with tuberculosis or histoplasmosis.
2. Neoplasia                                                 Large boli with destruction of lung tissue. May contract
3. Chronic bronchitis                                             leading to a nodules are usually mid-zonal or in the
Organic dusts                                                     upper lobes lesions consist of dense collagen and
1) Asthma: Substance gets down to airways —>                      pigment
    reactions. Asthmatic attack.                             Nodule: Coal particulate material on outside. Other slide:
2) Hypersensitivity pneumonitis: Constriction of small            more coal pigment.
    airways and also reaction to it. Can be vegetable        Coal nodules with coal within macrophages.
    matter or other organic. Reflect the environment of
    the pt. Slide: Lining heaped up. Some                    Caphan‘s syndrome is characterized by the presence of
    bronchoconstriction. Small granuloma. Muscle in             large pigmented necrobiotic nodules in patients with
    wall in small bronchous—> small Polypoid lesion.            CWP. This occurs in the presence of severe
    Similar to BOOP. Here has extensive lymphoid                seropositive rheumaatoid disease even though the
    infiltrate. Response to what the antigen is.                lung nodules may precede the development of
    Centered around terminal and respiratory                    systemic features. Like rheumatoid nodules, the
    bronchioles.                                                nodular lesions in Caplan‘s syndrome have central
3) Chronic bronchitis:                                          necrosis surrounded by fibroblasts, macrophages and
4) Usual interstitial pneumonia: Honey comb lung.               collagen. This syndrome can also occur in asbestosis
    Extensive interstitial fibrosis.                            and silicosis.
5) Neoplasia: Long exposure to these
Chemicals                                                    Major form of severe pneumoconiosis.
1. Pulmonary edema                                           Most prevalent chronic occupational dz in the world.
2. Asthma                                                    Nodules tend to form in the lungs after many years of
3. Acute and chronic bronchitis                                  exposure. With slow progressive fibrosis and
4. Pneumonitis                                                   increasing numbers of nodules, respiratory
                                                                 impairment increases. What do they work in and
Radiation                                                        what type of exposure do they have?
1) Pneumonitis                                               10 to 15% of workers with 30 yr exposure will get
2) Neoplasia                                                     silicosis.
                                                             Some pts develop reactivation of tuberculosis.
               Pneumoconioses                                Silicates are inorganic minerals abundant in stone and
Inhaled dusts that may be inorganic (mineral) or organic.
                                                                  sand. Industrial workers involved in the grinding of
Reaction: variable and includes inert (none), fibrous,
                                                                  stone or sand will be at risk for silicosis.
    allergic and neoplastic responses. At times co-
                                                             Small particles of silica less than 2 p~m in diameter enter
    existing disease may aggravate the reaction.
                                                                  the terminal respiratory units where they are ingested
The dust particles are phagocytosed by alveolar
                                                                  by alveolar macrophages.
    macrophages that then collect and drain to
                                                             In contrast to coal dust, silicates are toxic to macrophages
    peribronchiolar lymphatics and on to the hilar lymph
                                                                  leading to their death with release of proteolytic
                                                                  enzymes and the undigested silica particles. The
x-ray: related to degree of associated fibrosis & to the
                                                                  enzymes cause local tissue destruction and
    atomic number of the dust involved with same #
                                                                  subsequent fibrosis. The silica particles are ingested
    particles inhaled.
                                                                  by other macrophages and the cycle repeats itself.
Coal Worker’s Pneumoconiosis (CWP)
Region of respiratory bronchioles. Changes in pleural.       Pathology:
    Collection of coal dust. May give rise to                Nodules tend to form in the lungs after many years of
    emphysema. Coal dust macules —> focal                        exposure.
    emphysema —> coal nodules —> anthrancosis.               Progressive fibrosis and increasing numbers of nodules,
May get diagnosis of CWP w/little associated disabilities.       respiratory impairment increases.
    May qualify for extensive workers benefits.              Pulmonary function tests show a restrictive defect like
Other materials collect. Esp. silica. May be extensive.          any other chronic interstitial lung disease.
    May be within Nl limits. Some small foci with            No necrosis.
    emphysema. May stay steady over ind. life.
Dense fibrotic reactions in the pleura and in the                   fibrous fragments have a characteristic appearance,
     pulmonary parenchyma. Lesions comprise large                   namely the asbestos or ferruginous body, which is
     pleural plaques or fibrous adhesions and fibrotic              due to proteinaceous coats which give the fibers a
     nodules.                                                       nodular appearance. These fibers stain positively for
CXR:                                                                iron.
   Early  small discrete opacities in upper zones.
   Late  dz involving lower lobes.                            2 criteria must be met for the pathologic diagnosis of
Early stages: silicosis is characterized by tiny, discrete                asbestosis to be made:
     pale to black nodules in the lungs.                        1) interstitial pneumonia (interstitial fibrosis)
As dz progresses these nodules coalesce into hard               2) asbestosis bodies (ferruginous bodies).
     collagenous scars. Some nodules may undergo                Although other clinical criteria may support the diagnosis
     central softening & cavitation. May be due to                   of asbestosis, the pathologist can not make the
     superimposed tuberculosis or to ischemia.                       diagnosis in the absence of one of these criterion.
Silica particles present in the lesions are doubly refractile   Mesothelioma
     under polarized light.
                                                                Strongly associated with occupational exposure to
The mechanisms of tissue and cell injury by crystalline             asbestos.
    silica are thought to be based on the chemical              The incubation period is at least 20 years.
    reactivity of the particle surface. Although lung           Almost all who develop mesothelioma in this country are
    macrophages that ingest the silica particle may                 smokers.
    ultimately succumb to the toxic effects, silica causes      The occurrence of adenocarcinoma of the lung is greatly
    activation and release of mediators by viable                   increased in people having a history of asbestos
    macrophages. Thus these cells amplify the process.              exposure.

Occasionally with acute exposure to high levels of silica       Begins as nodules in the pleura that extend as a conluent
   dust the individual may develop alveolar proteinosis.            sheet to surround the lung and into the fissures.
   In this setting there is an accumulation of                  Chest wall is often invaded with infiltration of intercostal
   eosinophilic material within the alveoli with minimal            nerves leading to intractable pain.
   necrosis of alveolar lining cells. The patients have         Arc Welder’s Dz
   dyspnea and cough until the gelatinous material in           Not been regarded before as an important cause of
   the airspaces is removed                                              disability.
Talcosis                                                        Exposed to metallic oxides.
Surgical gloves. Different powders. May still have this         Minute particles of iron oxides and carbon are deposited
    occur. A variety of silicates can produce                       in the perilymphatic tissues of the broncho-arterial
    pneumoconiosis. Lesions and functional disability               rays and pulmonary septa of the lung.
    are less severe. Minute granuloma resulting from the        Some workers have developed severe dyspnea. Occ
    personal use of talc as a dusting powder are quite              developed lung cancer.
    common in the general population.                           Happens if workers are in confined spaces. What work
Occasionally these lesions may accumulate in sufficient             environment do they work in?
    numbers to produce pulmonary disability in people           Pathologic features:
    occupationally exposed.                                     Coarse macules
Pathologic Features:                                            Perivascular dust collection
1) Hyaline nodules. Not as extensive.                           Fe oxide does not stain
2) Interstitial fibrosis.                                       Positive staining of macrophages.
3) Bi-refringent particles. Each particulate matter has
    own structure. Can ID between silica and talc.              On x-ray will show dense areas. This is the Fe oxide.
                                                                    May have normal lung functions.
Common in ship building. Requires long exposure. Brief
    exposure is not dangerous. Long latent period of 20-        Indistinguishable from Sarcoidosis w/out history of
    40 yrs                                                          beryllium exposure.
Mesothelioma and adenocarcinoma. Smokers w/exposure             Exposure to beryllium known to be associated w/several
    to asbestos is 50x greater.                                     types of pulmonary dz. Acute and chronic types.
Pathologic:                                                         Work exposure. Fluorescent light bulbs.
1) Diffuse interstitial fibrosis                                1) DAD produced by exposure to  [beryllium]
2) pleural effusions                                            2) noncaseating granuloma
3) Fibrous pleural plaques.                                     3) pneumothroax.
4) Asbestos bodies: Brown staining. Asbestos particles          Chronic berylliosis caused by induction of cell-mediated
    get in. Fiber coated by macrophages. Breakup into               immunity. Only 2% of exposed workers develop the
    particulate matter. Transported into interstium. May            dz. Genetic susceptibility is necessary for initiation of
    extend out to pleura. Fe stain will bring them out              an immune response.
    clearly.                                                    Development of delayed hypersensitivity  formation of
                                                                    noncaseating granulomas in the lungs and hilar
1) bronchogenic carcinoma                                           nodes. The pulmonary granulomas become
2) Mesotheliomas                                                    progressively fibrotic. Direct analysis of the tissue is
3) laryngeal and perhaps other extrapulmonary                       necessary to detect the beryllium.
    neoplasms including colon carcinoma.                        Pathologic Features: Focal Granuloma. Large dense
Early symptoms:                                                          bodies: Shaman bodies. Asteroid bodies.and
1) Dyspnea                                                               giant cells.
2) Dry cough                                                    Others
3) Finger clubbing is common.                                   Siderosis: inhalation of oxides are inhaled with small
4) Inspiratory crackles: Typical late features. Indicate            quantities of silica and a diffuse lesion similar to arc
    significant diffuse pul fibrosis.                               welder‘s disease without carbon occurs. Silver
Lower lobes are more severely affected. Asbestos bodies             polishers. Hematite miners. Minimal fibrosis. Does
    in the sputum help to differentiate asbestosis from             not stain with prussian blue. Nice rusty red pigment.
    fibrosing alveolitis.                                           May go on to cause more extensive fibrosis.
Earliest lesions: in the pleura and in hilar lymph nodes        Fiberglass. Although fiberglass may cause sneezing and
    which become fibrotic. The responsible inhaled                  coughing, it rarely induces a pneumoconiosis.
―Polident.‖ Occasionally this substance has been
    identified in the lung in association with
    accumulations of phagocytes, foreign body reactions
    and interstitial fibrosis. Granuloma. Saw crystals.
    Have particulate matter. From polydent. Diffuse

                                                                 coordinated wave. Gravity also helps to pull bolus
                                                                 down. LES can stay open
                GI BLEEDING
Initial evaluation: orthostatic hypotension and               Dysphagia
     tachycardia. Start IV access.                            Symptoms predict the site.
Lab evaluation:                                               Oropharyngeal Dysphagia: Difficulty initiating
CBC                                                              swallow. Common causes:
Blood type and cross-match                                       Anatomical
Evaluation of coagulopathy, liver and renal dz.                  Neurological
                                                                 Muscular dx: Myasthenia gravis. Stroke—>
Clinical predictors of poor outcome: Advanced age, in-            complete loss of nervous function. Parkinson‘s,
    house pt, shock on presentation, recurrent bleeding           ALS, and cerebral palsy.
    or persistent severe bleeding, and major co-              Loss of coordination of muscles. Or actual loss of
    morbidity.                                                   muscle. Weak pharyngeal peristalysis  more
                                                                 common. Poorly relaxing LES is less
              Upper GI Bleeding:
Hematemesis, (+) NG aspirate  define upper GI bleed.         Esophageal Dysphagia: Food sticks once swallowing is
Melena: usually caused by UGI bleed, but a slow blood            initiated. Drink large amounts of water to get food
   loss from small bowel or right colon  melena.                down
                                                                 Solids only:
Diagnosis: Upper GI endoscopy.                                   Intermittent: Lower esophageal ring
Urgent scope: severe ongoing bleeding, recurrent                 Progressive: Mechanical. Strictures and/or cancer
    bleeding, bleeding in a hospitalized pt, and bleeding         esp in pt over 50.
    in pt w/liver dz.                                            Solids and or liquids.
No comorbidity, and low risk of recurrent bleeding can           Intermittent: Diffuse spasm
    get Tx on outpt basis.                                       Progressive: Achlasia or Scleroderma.
 Appearance of lesion and risk of recurrent bleeding:            Esophageal motility disorders:
                             Risk of
Endoscopic finding      Recurrent bleeding   Mortality rate   : Failed inhibition
Active bleeding               55%                11%
Nonbleeding visible vessel    43%                11%          Propulsive motion. Inhibitory area. Have relaxation at
Adherent clot                 22%                7%              level of LES until bolus comes right through. If have
Flat, pigmented spot          10%                3%              rise of LES pressure then cannot get food down while
Clean ulcer base              <5%                2%              bolus is still there. Cause spasm of esophagus without
                                                                 movement and lack of coordination.
Can use PPI. Improves outcome of upper GI bleed.              Cause: Achlasia. (Failure to relax) Loss of esophageal
Esophageal varices: If have pt w/Hx of liver dz or               inhibition. Normal sphincter tone is balance of
    possible portal HTN  octreotide. If at scope find           inhibitory and activating. Contractile are Muscarinic.
    varices  esophageal band ligation (associated w/           Inhibitory nerves are VIP and NO. Resting tone. Loss
    SE than Sclerotherapy)                                       of inhibitory tone have unopposed contractile forces.
                                                                 HTN or constantly contracting. Found by infection by
                                                                 Trypansoma Crusi.
              Lower GI Bleeding:
Most commonly occurs in elderly pts from colonic              Presenting symptoms:
     diverticula and angiodysplasias.                         1) Dysphagia: solid = liquids. 98% with some form.
Initial evaluation: colonoscopy after rapid colonic lavage.   2) Complain of regurg, but no regurg. Is breakdown of
If vigorous bleeding  visceral angiography may allow             food in esophagus.
     ID of lesion.                                            3) Chest pain
In lower vol bleeding  nuclear tagged RBC can help           4) Weight loss
     determine if there is sufficient bleeding to warrant
     angiography.                                             X-ray
Can use embolization or vasopressin infusion.                 Bird beak appearance. Does not empty as well. When see
                                                                  barium in stomach the esophagus should be empty.
               ESOPHAGEAL                                         Sigmoid esophagus.

                DISORDERS                                     Manometry: A contractile esophagus. Keeps expanding.
Esophagus: local and central control. 25 to 26 cm in             Results in large 4x normal with tight ends.
Simple stratified squamous. Papillae into basal layer.        [review the mano findings – i.e. simultaneous
   Only 15% of entire thickness of superficial layer.             contractions, hypertensive LES, failure of LES to
Two layers:                                                       relax]
Circular striated: alternations in innervation and
   polymyositis or autoimmune affect the upper 1/3.           Treatment:
Longitudinal smooth: Scleroderma affect this lower 2/3.       1) Nifedipine: Ca channel. Not very effective.
Depending on symptoms can look at underlying                  2) Bot Tox: Helps older pts. Blocks the cholinergic
   pathology.                                                    nerve ending. Help LES to stay relaxed. Very low
                                                                 risk, so useful in elderly.
Normal Physiology                                             3) Balloon dilatation: Most effective and least invasive.
Primary purpose: Oral phase. Need functioning palate.            Breaking the LES. Create incompetent sphincter.
Pharyngeal phase: protect from aspiration so food can            Can be done with laparpscopically. Now use gravity.
   pass down through into esophagus. Upon completion,            Food will move down. Slower, but better than
   the bolus is now in esophagus. Past                           before.
Esophageal phase. Peristaltic wave: behind bolus. In          4) Surgery. May provide best long term relief.
   front is the inhibitory wave to make sure that have           Especially useful in young patients.
Scleroderma: Failed contraction.                            usually begins in adults > 40 years
                                                            "Heartburn‖ or symptomatic reflux: Recurrent. 95-98%
Has normal inhibition. Now have esophagus that does not      have on endoscopy macroscopically normal tissue. No
   work as well. Low amplitude waves. Net decrease in        inflammatory changes. 7-10% of the U.S. population
   LES pressure. No barrier between esophagus and            have daily heartburn and 30-44% have it at least
   stomach —> Reflux. Strong predisposition for Reflux       monthly.
   and some dysphagia
                                                            Reflux Esophagitis: inflammation that is noted grossly
Cause: Scleroderma
                                                             and/or histologically; Progression from symptomatic
Simultaneous contractions. All of the contractions start at
                                                             reflux to reflux esophagitis is unclear. Small
   the same time. Diffuse spasm with the hour glass
                                                             retrospective study  ~ 15%.
   appearance suggestive of nutcracker esophagus.
Systemic Scleroderma:                                       Dysphagia
CREST syndrome: Raynaud‘s with esoph dysmotility.           Sore throat
Dysphagia is an early presentation with scerloderma.        Chronic hoarseness, burning
Develop a lead pipe esophagus. Lose LES tone. Prone         Chest pain: Pathologic reflux  recurrent CP w/out the
   for reflux and then for Barrett‘s esophagus.              characteristics of heartburn. Should respond to
Most common cause occur under setting of GERD and            appropriate anti-reflux Tx. Atypical recurrent CP
   idiopathic.                                               failing to respond to therapy  concern about the
                                                             diagnosis  both re-evaluation by the cardiologist and
                                                             consideration that symptoms reflect either a motor,
        Anatomic Abnormalities:                              emotional, or musculoskeletal disorder.
Esophageal web: overgrowth of mucosa. When occurs
                                                           Pathologic reflux  dz of oropharynx, larynx, and
   within 2 cm of. Frequently asymptomatic. Found on
   barium swallow. Sometimes. ***Plumber Vincent or          airways, but  prevalence
   Patterson Kelly Syndrome*** webs and anemia in          Esophageal Complications
   women.                                                  Complications   acid contact time than those with
Ring: hypertrophy muscle.                                     lesser disease. Unclear whether the greater acid
      Type A (muscular ring. 3 or 4 cm proximal to           exposure preceded and caused dz or whether it
       Schatzki‘s ring.) and                                  represents the consequence of prior severe dz. Pt‘s
      Type B (Schatzki‘s ring. Attached at squamo            w/reflux-induced strictures used NSAIDs more often
       columnar ring. Will have squamous on one side          than those with reflux dz w/out strictures
       and columnar) if have ring over 15 to 20 mm will    Ulceration and hemorrhage:
       not have symptoms. If over then will complain of Peptic strictures: Unable to eat certain foods. Occurring
       intermittent dysphagia. Can get down with water.       in 4-20%
       No other associated symptoms. These are the most Barrett's esophagus: non-keratinized, stratified
       common.                                                epithelium of the esophagus is partially replaced by
Zenker Diverticulum: Cricopharynx. Between the                foci of columnar epithelium which resembles that of
   pharyngeal muscles. Small herniation. Result of            the small intestine. The lower tubular esophagus
   increased pressure in pharynx. Pressure at the end and     becomes lined with intestinal-like columnar mucosa.
   pressure at the top. Cause this diverticulum.              10-15% of patients, respectively. Now have ability to
   Complain of bad breath due to stale food. Important        produce mucous. May be present in patients without
   for pts that complain of bad breath. Can become quite      prior signs or symptoms of reflux disease, supporting a
   large.                                                     possible congenital form, as well as reflux-induced
Esophageal Stenosis: Rings and webs. GERD, tumors,            form.
   caustic ingestions, Infections, Dermatologic                  Markedly  risk of developing an esophageal
   Iatrogenic: Pill induced esophagitis (ASA, K,                   adeno Ca, prompting regular endoscopic
   quinidine, Fosamax.. Can cause ulcer and sudden                 surveillance so that biopsies can identify dysplasia.
   onset of dynophagia) Radiation, Sclerotherapy,                Also  prevalence of both benign and malignant
   Nasogastric tubes.                                              colonic neoplasms  screening colonoscopy.

            GERD DISEASE                                Squamous cell carcinoma: Achlasia, Celiac Sprue,
                                                           minority. Plummer-Vinson syndrome. Head and neck
Healthy patient:                                           cancer. Narrowing of midesophagus. Shelf between
Spontaneous and transient lower esophageal sphincter       normal and abnormal mucosa. Hx of dysphagia for
  relaxation (TLESR) occurs normally numerous times        months. Only eat soft foods.
  each day most often after eating. Neurally-mediated   In African-American population incidence of squamous
  events whose signal originates in the upper stomach.      adeno. White  squamous  adeno. Do not know
  TLESR allows for venting swallowed air and               why there is change in the distribution. May be acid
  intragastrically produced gas. Similar mechanism used    secretion inhibitors. May have  reflux, dietary
  for belching. Rarely at night, do so without symptoms    changes, changes in drinking habits. Squamous
  or signs of tissue injury.                               associated w/drinking EtOH and smoking cigarettes
LES works well to prevent GERD.
                                                              Extra-Esophageal Complications
Pts with GERD:                                                GERD has been suggested as a causative factor in chronic
LEST occurs w/out stimulus and is > than normal.                 cough, sore throat, hoarse voice, laryngitis, laryngeal
   TLESR can last up to 30 sec.                                  polyposis, bronchitis, asthma, and aspiration PNA.
Also defects in mechanisms by which gastric acid is           Pts may have pulmonary and/or laryngeal symptoms in
   cleared from esophageal lumen  prolonged contact             absence of heartburn. Precise frequency of this
   of acid-pepsin w/epithelium, and/or impairment in             causative association not fully defined.
   defensive factors  normal tissue resistance vs. acid-     Children: Asthma  consider GERD.
   pepsin appear to be critical in the pathogenesis of        Middle-age and the elderly: recurrent laryngitis,
   reflux dz.                                                    aspiration PNA, laryngeal polyps  consider reflux.
Hiatal hernia: w/hernia will have a separation between        When reflux is the etiologic factor, effective Tx
   LES and crural diaphragm with a loss of ½ of the              frequently  resolution of the clinical manifestations.
                                                              Medical Management
Pts with mild reflux  eat fast food and food stays in        lifestyle modification
   stomach and delays.                                        Liquid antacids: PRN useful for rapid relief of occ.
                                                                  symptoms but, due to their transient effect and bowel-
   altering SE w/frequent ingestion are of little value        Associated with normal or low levels of gastric acid
   for chronic symptoms.                                        secretion
H2 blocker: (Ranitidine): Initial chronic Tx. Inhibit acid    Type II ulcers: body of the stomach and are associated
   secretion  refluxate less noxious to the esophageal         with a duodenal ulcer scar or active ulcer.
   epithelium. Does not work for all patients w/GERD,           Pathogenesis ~ to DU
   even at standard anti-reflux-therapy dosage (2x            Type III: located in the immediate prepyloric area.
   duodenal ulcer dosage). With cessation of acid-              Pathogenesis ~ to DU
   suppressive Tx  relapse symptoms and/or signs of
Proton pump inhibitor or PPI: (omeprazole,                    There is usually widespread superficial gastritis involving
   lansoprazole) Pt‘s w/erosive esophagitis often require       the area around the ulcer as well as the gastric antrum
   more complete inhibition of acid secretion than              (chronic active gastritis or atrophic gastritis). Antral
   provided by H2-antagonists. PPI of the benzimidazole         gastritis is prominent early in the history of gastric
   class are safe. Long term use  requirement for              ulcer disease, and it progresses proximally to involve
   esophageal dilatation in those w/strictures. Tx does not     the oxyntic gland mucosa, sometimes proceeding on to
    regression of Barrett's.                                   gastric atrophy. In fact, high lesser curvature ulcers,
Removal of acid-suppressive Tx  relapse of symptoms            which would be expected to reside in oxyntic gland
   and/or signs of dz.                                          mucosa, are instead located in antral gland mucosa that
Surgery: Surgery remains an option to long term medical         has undergone metaplasia from oxyntic to antral gland
   management. In skilled hands, has little operative           mucosa.
   mortality (<1%) and morbidity (2-8%), and in               The pathogenesis of antral gastritis in GU patients is
   comparative trials has proven superior to both antacid       likely secondary in large part to HP, but may also be
   or H2-antagonist regimens. Whether surgery is                due to diminished pyloric sphincter tone, with reflux
   superior in effectiveness or safety over long term           of noxious duodenal contents into the gastric antrum
   therapy with a PPI remains to be investigated. After 7        gastritis and in some cases ulcer. With the
   years, up to 60% of patients still taking PPI                observation that HP produces chronic active gastritis
   medications.                                                 due likely to its containing a number of potentially
Endoscopic: New techniques available to narrow the              cytotoxic agents (i.e. urease, lipase, phospholipase A,
   lower esophagus with either endoscopically-placed            vacuolating cytotoxin), it is likely that this
   sutures, radiofrequency ablation, or injection of            microorganism plays a pathogenetic role in the
   bulking substances.                                          development of GU in some patients.

Areas of Uncertainty                                          NSAIDS, H. Pylori and their interaction:
                                                              Prevalence of HP in patients with GU is 60 to 70%. Only
                                                                 approximately 10% of GU patients are neither
                                                                 ingesting NSAIDS nor HP-positive.
   GASTRIC & DUODENAL                                         NSAIDS are a major causative factor of GU. Although
                                                                 the risk of developing ulcer is related to NSAID dose,
         ULCERS                                                  age and prior history of ulcer disease, it is not possible
                                                                 to predict which patients will develop an NSAID ulcer
                Duodenal Ulcer                                   with high degree of accuracy. Patients predisposed to
Result from an imbalance between aggressive and                  develop NSAID-related ulcer disease include:
   defensive factors. DU disease is multifactorial            1. those with previous documented ulcers
                                                              2. those ingesting either excessive doses of a single
Major factors:                                                   NSAID or combining two NSAIDS
1. Gastric infection with Helicobacter pylori (H. Pylori)     3. those taking NSAIDS along with Corticosteroids
    inflammation of the gastric antrum (antral gastritis)    4. elderly patients above the age of 70.
2. gastric acid secretion that is normal or increased         Testing for H. Pylori
3.  duodenal bicarbonate secretion. bicarbonate
                                                            Should HP status be determined in all patients with DU?
   secretion (similar to serum gastrin and gastric acid
                                                            HP is present in at least 90% of patients. Prevalence may
   secretion) normalizes following eradication of H.
                                                               be somewhat less; this may be secondary to the lack of
                                                               accuracy of the methods of diagnosis or may be a real
No single pathophysiologic defect, even the presence of
                                                               phenomenon due to varying patient populations.
   H. Pylori, is present in all DU patients. For example,
                                                            HP status be determined in all DU patients.
   the Zollinger-Ellison syndrome (ZES) is caused by
                                                            1) Some would recommend empirically treating all DU
   marked acid hypersecretion due to a gastrinoma
                                                               patients to eradicate HP as the prevalence exceeds
   producing marked hypergastrinemia. The presence of
                                                               90%. However, drug costs plus the costs of untoward
   ulcer is not related to HP infection in these patients.
                                                               effects need to be balanced with the costs of
   However, about 10% of ZES patients do not have
                                                               determining HP status.
   ulcer disease despite markedly increased gastric acid
                                                            2) Breath tests: when readily available (e.g., '4C-urea,
   secretion. Increased defensive factors likely prevent
                                                               '3C-urea, 13C-bicarbonate) these should be substituted
   ulcer formation in this unique subset of ZES patients.
                                                               for the more costly endoscopic biopsies.
                                                            3) Serologic tests: are available and quite sensitive and
Precise mechanisms whereby H. Pylori, that resides in the
                                                               specific. However, they remain (+) for about 1 yr after
   gastric antrum, results in DU remains elusive.
                                                               HP eradication.
                                                            4) If conventional ulcer therapy is selected and ulcers
                  Gastric Ulcer                                recur, therapy could then be directed at HP. And, if
Most gastric ulcers (GU) are localized to an area of about     eradication of HP is chosen as initial therapy, it would
   2 cm in length on the antral side of the junction of the    be based upon the documentation of HP infection and
   antral and oxyntic gland mucosas along the lesser           the untoward effects of HP treatment would be
   curvature.                                                  acceptable.

Idiopathic GU: ulcer that develops in the absence of an       Should HP status be determined in all patients with GU?
   established exogenous cause such as NSAIDS or HP.          One could make an argument for determining HP status
   Account for only ~ 10 % of total GU. Most GU are             even though about one third of patients with GU are
   associated with either NSAIDS or HP.                         HP negative, and in whom GU is attributable to
GU Subtypes:                                                    NSAID intake or other causes. As most patients with
Type I: ulcers occurring in the body of the stomach and         GU undergo endoscopy, HP status can be determined
   not associated with other gastroduodenal disease.
   with biopsy tissue either with the Clo-test(r) or on      4. Limit to less than 200 mEq and less in elderly.
   histological examination of the tissue. Therapeutic
   decisions, as with DU, would then be based upon
   accurate diagnosis of the presence or absence of HP.      Used extensively in the past and has the highest
                                                                neutralizing potential.
                                                             Complications arising from chronic CaCO3 therapy
               Ulcer Treatment                                  indicate it not to be the antacid of choice:
Antibiotic Therapy:                                          1. Hypercalcemia, hypercalciuria and nephrolithiasis in
Clarithromycin 500 mg and amoxicillin 1 g both taken            patients impaired renal function.
    BID. Also with a PPI. Treatment should be for 2          2. An acid rebound due to a direct effect of Ca2~ and the
    weeks                                                       elevated pH in promoting gastrin release.
Other options:                                               3. Milk-alkalae syndrome, azotemia, hypercalcemia and
Flagyl 250 mg QID + tetracycline 500 mg QID                     renal calculi.
Flagyl 500 mg BID + Clarithromycin 500 mg BID                Milk of Magnesia
Flagyl 500 mg QID + Tetracycline 500 mg QID                  1. Mg(OH)2 + HC1  MgCl2 + H20 - Although MgCl2
Clarithromycin 500 mg BID. + Amoxicillin 1 gm BID               and carbonate are soluble, absorption is minimal.
                                                             2. Cathartic properties, but other side effects are minimal.
Resistance:                                                  3. Mg trisilicate - has less neutralizing potential than
Flagyl            43%                                           Mg(OH)2 and has been implicated in silica deposits in
Clarithromycin:   8%                                            the kidney.
Amoxicillin       3%
Tetracycline      <1%                                        Al(OH)3
                                                              Has a high neutralizing potential and minimal absorption
2nd treatment: should be treated using different Abx.            from the GI tract but only buffers to pH 3.5. Its
3rd treatment: endoscopy w/biopsy would be justified to          astringent action promotes constipation which enables
     culture H. pylori and conduct Abx sensitivity testing       it to be employed to balance laxative effects of
     in order to identify an appropriate Abx regimen.            Mg(OH)2.
Antacids                                                      Primarily retained in GI tract and will precipitate
                                                                 phosphate from the GI tract. Employed in phosphatic
Mode of action: Indirect suppressive action of acid peptic       nephrolithiasis treatment.
   activity by altering the pH of gastric juice. Irreversible SE:
   inhibition of pepsin occurs above pH 7, but this pH is Al toxicity
   difficult to achieve and not necessarily desirable.        Myopathy and encephalopathy if renal function is
   There is little evidence that the metal ions per se           compromised
   inhibit pepsin.
Secondary effects  output of gastric acid (gastrin           Other aluminum salts: dihydroxyaluminum carbonate,
   mediated),  motility, and  lower-esophageal                 dihydroxyaluminum aminoacetate and aluminum
   sphincter pressure                                            phosphate offer no advantages over AI(OH)3.

pH:  intragastric pH from 1.3 to 2.0 will relieve pain      H2-Antagonists
   (80%) neutralization). To inhibit pepsin requires a pH    Cimetidine:
   of 5.5 and this cannot be achieved with many of the       Mechanism:
   antacids.                                                      Dramatically  histamine and gastrin induced
Dose: Hypersecretors secrete 50 mEq of H+/hr. To effect             secretion (both volume and H+ ion) from parietal
   a complete and continuous neutralization would                   cells.
   require astronomical amounts of antacid. Thus,                  response to vagal stimulation. A single dose
   optimal use of antacids takes into account buffering             inhibits resting as well as the cephalic and vagal
   actions of foodstuffs, pancreatic secretions and a               phase promoted by foodstuffs.
   consideration of stomach emptying times. In acute         Use: Tx of Zollinger-Ellison syndrome, duodenal ulcer,
   ulcer, doses of 140 mEq of acid are given 7 times per        gastric ulcer and reflux esophagitis. Multiple reports
   day.                                                         for the effectiveness of the drug in pancreatic
Dose Intervals: Antacid disappear in 30-60 min on an            insufficiency and the prevention of gastrointestinal
   empty stomach but last for 2-4 hrs following a meal.         hemorrhage, aspiration pneumonitis and post surgical
1 hr after meals  takes into account buffering capacity        stress syndrome have appeared.
   of the meal, the delay in emptying after meals and        SE:
   controls post- prandial H+ secretion.                         hepatic blood flow  prolonged actions of drugs
For acute ulceration  frequent dosing intervals, q 1-2          efficiently extracted by the liver.
   hrs or continuously to manage acute ulceration.              Inhibition of microsomal oxidases  
General side effects of antacids                                 metabolization of certain drugs  prolonged effects
   Systemic alkalosis - absorption of cation                     of those drugs.
   Contribution to body Na~ loads                               Prolactin production stimulation.
   Constipation (A1++) versus diarrhea (Mg++)                   Antiandrogen effect: lowered sperm counts in ♂and
   Alkalosis and metal ion retention in renal failure            gynecomastia.
                                                                Antacids  cimetidine absorption thus more
Summary: Antacid therapy is best met with Mg(OH)2                consistent plasma levels are seen if the drugs are
     and AI(OH)3 in a ratio which does not lead to               given on independent schedules.
     diarrhea or constipation. The dose and its interval can
     be best judged in terms of whether the patient is a     Ranitidine and Famotidine: congeners of cimetidine of
     hypersecretor, the location and severity of the ulcer.    virtually identical efficacy but greater potency. They
     Dose should be adjusted in terms of antacid               can be given BID.
     equivalents rather than volume of suspension.           Chief advantage: drug interactions at the level of the
NaHCO3 (baking soda)                                           microsomal oxidases are 
1. High solubility limits its duration of action although it Absence of antiandrogenic activity
   is immediately effective in controlling an acute attack. Will  liver blood flow  prolonged actions of drugs
2. Chronic use is hazardous in individuals with renal          efficiently extracted by the liver.
   insufficiency, hypertension or congestive failure. Na+ Proton Pump Inhibitors
   load is significant.
3. Can precipitate the alkalae-milk syndrome.
Inhibitors of gastric H+/K+ ATPase in the apical                Several tests are available to pinpoint the specific defects
   membrane of the parietal cell.                                  responsible for malabsorption. Since fat absorption is
Reaches the parietal cell through the blood and becomes            vulnerable to defects in either intraluminal digestive
   entrapped there through protonation owing to the low            enzymes or defects at the mucosal absorptive surface,
   pH.                                                             the demonstration of steatorrhea by qualitative or
Efficacy parallels cimetidine, but they appear more                ultimately quantitative (72 hours) fecal fat
   efficacious in GERD.                                            measurement is the major criterion for establishing the
ZE: Beneficial to Z-E patients who are refractory to H2-           presence of fat malabsorption. From there, a logical
   blockers. Their blockade of H+ secretion is nearly              sequence of tests should lead to the establishment of a
   complete, but therapy may lead to gastrin-induced               specific cause.
                                                                Quantitative Fecal Fat Excretion
Misc Agents                                                     Anything that causes malabsorption will cause problems
Colloidal Bismuth Subcitrate (CBS) "cyto-protective' at            w/fat absorption first.
  ulcer site? Stimulates mucous secretion, antibacterial        Sudan staining: look for fat globules
  effects agonist H. pylori; black stools & tongue, some        Quantitative Fecal Fat excretion:
  diarrhea                                                      Pt placed on 100 gram/day fat diet for 3 total days. Nl 
Sucralfate: Polymer of Al(OH)3 and sucrose.                        excrete ~ 3-5 grams fat/day. > 15 grams excretion
  Nonsystemic drug that serves a protective function on            over the 3 days is (+) result  2 SD > normal mean.
  the ulcerated area. Sucralfate inhibits pepsin but has no     Can easily get false positive: Poor food intake,
  acid neutralizing capacity. It shows a  affinity for            constipation, forgot to collect stool. Eating nuts that
  ulcerated areas than normal mucosa.                              cause fat in stool.
Misoprostol synthetic PGE1  mucous secretion,                  D-Xylose Absorption-Excretion Test
  decreases acid secretion but enhances motility of
  smooth muscles (including uterine smooth muscle),             Dz that involves epithelium or mucosa itself.
  therefore has limiting side effects (diarrhea;                D-xylose is a water soluble, non-metabolized pentose that
  spontaneous abortion).                                           is absorbed mainly in the duodenum and jejunum. No
                                                                   intraluminal handling. No pancreatic enzymes needed.
                                                                   Will normally absorb across epithelium. Assimilation
         MALABSORPTION                                             of this sugar does not require the intraluminal
Intestinal tract optimized for absorption of nutrients.            pancreatic stage of digestion.
   Have high surface area. Cylinder  folds  villi               Abnormal test: SI mucosal disease  histological
   microvilli. Large surface area. Problems if                       examination of the mucosa by biopsy. Also with the
   compromise that surface area. If have decrease will               small intestinal bacterial overgrowth.
   take longer to absorb that nutrient. Mostly Ca and Fe           Normal test: deficiency of intraluminal (pancreatic)
Jejunum: Absorbed most nutrients.                                    digestive enzymes or bile acid deficiency.
Ileum: bile acid and Vit B-12. Restricted to ileum. Can         PABA Test to Evaluate Pancreatic function
   be passively absorbed. Active reabsorption is in
   ileum. If malabsorb bile bile acids in colon               Test is done w/PABA and an attached tripeptide. If have
   diarrhea. Vit B-12 anemic.                                       exocrine function then will cleave off tripeptide.
                                                                Normal function: Ingest PAPA-tripeptide  tripeptides
General Mechanisms                                                   cleaved  liberating PAPB which is absorbed 
Arise from disorders of intraluminal events (e.g.                    excreted in urine.
   deficiency of pancreatic digestive enzymes or bile           Abnormal: no cleavage of tripeptide. Is absorbed, but
   acids), disorders of events at the cell surface (e.g. lack        PABA is not excreted in urine.
   of specific cell-surface enzymes, oligosaccharide            Causes of pancreatic exocrine sufficiency:
   deficiencies, specific transport defects, glucose-           Chronic or hereditary pancreatitis
   galactose malabsorption and amino acid transport             Pancreatic cancer
   defects), abnormally of cellular events (e.g. mucosal        Operative resection
   injury in celiac sprue, defects in intracellular             Ductal stricture or fistula
   chylomicron synthesis in Abetalipoproteinemia) or            CF
   abnormalities in post-cellular events (e.g. intestinal       Protein-calorie malnutrition
   lymphangiectasia).                                           Isolated enzyme deficiency.
Pancreas: enzymes that breakdown fat. End up with               Small intestinal x-ray
   number of proteolytic enzymes. Also amylase to
   breakdown carbohydrate.                                      may reveal typical changes of mucosal pathology, internal
Bile Acids: Cannot absorb fat without bile acids. What            fistulae, blind loops, diverticulae or motility disorders
   can go wrong. Most easily is fat absorption. Needs             which might be associated with bacterial overgrowth.
   this extra stage. May not make if liver is dz, bile duct       It may also reveal ileal inflammatory disease (e.g.
   obstruction, breakdown of bile acids before secreted.          regional enteritis) responsible for bile acid and/or
Brush border in jejunum: enzyme dysfunction                      vitamin B12 malabsorption.
   dysfunction of lactase. Also inherited defects              Chronic pancreatitis: Output below normal. Low lipase --
   glucose, galactose malabsorption.                              . Low absorption of
Transport monosaccarides. Fat taken up by lymphatics.           Small bowel (jejunal) biopsy
   If have dz that affects lymphatics (radiation, TB with       Diagnosis of intestinal mucosal dz. Specific diagnostic
   blocked LN.) Do not deliver to blood.                           features include:
A- lipoproteinemia: fat will hang up within epithelial         1. changes in the architecture of villi and crypts: normal
   cell.                                                           ratio of 4 to 1 Physiologic inflamed (normal). See
Clinical Presentation                                              some intraepithelial lymphocytes and plasma cells
1. Diarrhea or steatorrhea                                         with occasional eosinophil and mast cell. Should see
2. Weight loss                                                     some CD4 cells. Celiac Dz.
3. Evidence of Vit deficiency                                   2. cellular changes in the epithelium
                                                                3. specific types of cellular infiltration in the lamina
    D: Osteomalacia, psuedofractures, tetany
    K: Bleeding tendency
                                                                4. as well as inclusions of bacteria or abnormalities of the
    B: Cheliosis, glossitis                                      lymphatics.
    Folate B-12: anemia, neuropathy.
                                                                B12 absorption test (Schilling test)
         Tests of Malabsorption
Oral dose of radioactive cobalt-labeled B12 w/or w/out              Observing a prompt clinical response and
   IF. Measures the % or orally ingested isotope excreted             improvement in mucosal histology upon
   in the urine.                                                      withdrawal of the offending proteins from the diet.
1. Abnormal B12 absorption alone: IF deficiency
   (classical pernicious anemia). Gastric atrophy
                                                                Whipple's Disease
2. Abnormal vitamin B12 and IF: bacterial overgrowth or         Occurs in 4th and 5th decades, w/ incidence in (:,
   with disease of the ileum. If bacterial overgrowth of           approximately 9:1).
   the small intestine is. responsible for the abnormal test,   Cause: Bacterial: Tropheryma Whippelii
   antibiotic therapy will return the test to normal.           Clinical Presentation:
                                                                    malabsorption
Other Tests for Malabsorption
                                                                    fever, increased skin pigmentation, anemia,
Pancreatic Function Tests. The secretin test is used to               lymphadenopathy, arthralgias and arthritis, as well
   measure secretory capacity of the exocrine pancreas.               as occasional central nervous system symptoms.
   After administration of secretin, bicarbonate                Histology:
   concentration is measured in the juice aspirated from            Villi are broad and flat
   the duodenum.                                                    Lamina propria contains dilated lymphatics: Do not
Measurements of serum iron, calcium, cholesterol,                     look quite right.
   folate and vitamin B12 often are used as screening
                                                                    Foamy macrophages which stain (+) with PAS
   tests for malabsorption, but are not specific.
                                                                      stain. Not much staining in normal pt.
Prothrombin Time. If prolonged, may reflect
                                                                      Glycoprotein in macrophages lights up. Want to
   malabsorption or liver disease. These possibilities can
                                                                      do this SI not colon. The PAS-positive material in
   be distinguished by measuring the response to
                                                                      the macrophages may, in fact, represent
   parenterally administered vitamin K.
                                                                      degenerating bacilli.
Serum Carotene. Carotene is a fat-soluble substance
   present in yellow vegetables and fruits, eggs, etc.              EM: rod-shaped bacilli can be demonstrated in the
                                                                      lamina propria beneath the absorptive cells.
   Serum carotene levels tend to be depressed in patients
                                                                Treatment: antibiotics.
   with fat malabsorption, but can be decreased also if the
   intake of dietary carotene is low.                       Abetalipoproteinemia
                                                            1. Rare disease which begins in childhood, often before
           Differential Diagnosis                              the age of one.
Abetalipoprotinemia:                                        2. Characterized:
Amyloidosis:                                                    fat malabsorption
Celiac sprue                                                    hypolipidemia
Crohn‘s dz                                                      acanthocytosis of the red blood cells
Eosinophilic gastroenteritis                                    cerebellar ataxia
Infection: Cryptosporidium, Isospora, Girardia, MAC.            "atypical" retinitis pigmentosa.
Lymphangiectasia                                            3. Patients have an inability to make the protein-
Lymphoma                                                       phospholipid-cholesterol coating of chylomicrons so
Mastocytosis                                                   the epithelial cells become laden with triglycerides.
Whipple‘s disease.                                          4. On histology
Celiac Disease (Gluten-Sensitive                                the villi are normal in shape
Enteropathy)                                                    abundance of lipid droplets in the mucosal cells at
                                                                   the tips of the villi.
1. Precipitated by the ingestion of wheat, rye, and barley.
   Activated by alcohol soluble proteins in wheat, rye,         No fat is found in the intracellular spaces and
                                                                   lacteals of the submucosa and lamina propria.
   and barley which are termed gliadins, secalins, and
   hordeins, respectively. Rich in glutamine and proline. 5. Malabsorption usually is confined to fat. The liver
   Results in malabsorption.                                   biopsy can also show infiltration of triglycerides.
2. Wide spectrum of dz manifestations.                          Intestinal Lymphangiectasia
3. HA associated dz: Dz susceptibility is associated with       Intestinal Lymphatic Obstruction
   the presence of HLA class II DQ sub-region alleles           1. Obstruction to the flow of lymph from SI  dilation
   DQA1 *0501, DQB 1*0201. These alleles can be                    of the intestinal lymphatic vessels in the villi,
   present in cis or trans and encode an HLA DQ2                   submucosa, serosa, and mesentery. The intestinal
   molecule which appears to be necessary, but not                 lymph that may leak from ruptured lacteals contains
   sufficient, for the phenotype expression of this disease        plasma proteins, chylomicrons and small lymphocytes.
   (i.e., these alleles are also present in approximately          Cells look normal.
   20% of healthy Caucasians). Peptide binding of               2. This disorder causes abnormalities in the delivery
   specific HLA. Peptide from glydins that bind to MHC             phase of absorption.
   II and activation of pathogenic T cells.                          Acquired: 2 to retroperitoneal disease, lymphoma,
4. Intestinal Histology: villous atrophy: loss of villi. Will          radiation enteritis, abdominal tuberculosis, etc.
   only see entrance to crypts. Increased crypt depth:               Congenital
   only crypt. Actively proliferating. Abnormal surface
                                                                     congenital and acquired forms cannot be
   epithelial cells. Lymphocyte and plasma cell infiltrate
                                                                       distinguished by small intestinal biopsy alone.
   of the lamina propria and an increased density of T
                                                                3. Findings:
   lymphocytes in the intraepithelial region.
5) The lesion is most severe in the duodenum and                     low albumin
   jejunum. Although the histological lesion is                      low Ig level due to gastrointestinal protein loss
   characteristic of this disease, it is not totally specific        low lymphocyte levels due to lymphocyte loss in
   since similar lesions can be seen in other diseases such            the gut.
   as tropical sprue, small intestinal lymphoma,                     Individuals do not absorb chylomicrons due to the
   Zollinger-Ellison syndrome and, in some instances,                  lymphatic obstruction.
   common variable immunodeficiency syndromes.                  Common Variable Immunodeficiency
6) Diagnosis: Can see similar picture in soy allergy. Gut
   can only respond in a few number ways to insult.
                                                                1. As many as 60% of patients with common variable
    Demonstrating malabsorption                                  immunodeficiency have diarrhea, and 20- 30% have
    Documenting the presence of the typical mucosal              mild to moderate malabsorption.
2. The biopsy can vary from normal to having partial            Inflammatory dz: UC & Crohn‘s. Mediators are being
   villous atrophy, similar to that of celiac disease, except      activated. Prostaglandins  enterocytes  
   for a lack of plasma cells in the lamina propria.               secretion.
3. Girardia Lamblia, often is found in the small intestinal
   aspirates of patients with this disorder. Treatment of                      Acute Diarrhea:
   Girardia infection usually reverses the malabsorption     Can be watched. Infectious. Viral, bacterial. Usually
   and villous abnormalities.                                   infectious in origin. May be toxins from food
4. Biopsy: lacks normal numbers of plasma cells.                poisoning. Usually self-limited.
5. Nodular lymphoid hyperplasia of the small intestine       Enteric pathogens can cause by several mechanisms:
   occurs in as many as 60% of patients, but does not
                                                             1. Simulation of  fluid excretion: Cholera (mucosa
   correlate with the presence of diarrhea or                   looks normal), E. Coli ST and LT. No impairment of
   malabsorption.                                               Na dependent solute reabsorption. Can give isotonic
Intestinal Lymphoma                                             solutions, the glucose coupled reabsorption is not
1. May be 1* or 2* to lymphoma arising elsewhere. 1*            affected. Can be treated with these glucose solutions.
   lymphoma can be localized to a short segment of the            Cholera A/B: B for binding to ganglioside and
   bowel, it can be multifocal or diffuse, and can cause a          inject A. Then A causes ADP ribosylation  
   disease in the delivery phase of absorption.                     cAMP  A-kinase  Cl secretion.
2. The ileum and jejunum are among the most frequent              C. Difficille: Antibiotic associated. Change in
   sites of involvement, the duodenum being less                    flora. Produces nasty toxins  colitis,
   involved.                                                        psuedomembranous. Make A and B toxin. One
3. 1* diffuse lymphoma involving the proximal small                 affects epithelium. The other marked inflammation
   intestine is found in individuals in the Middle East,             activation of immune response. Uses couple of
   particularly Arabs and non-European Sephardic Jews.              toxins and dz.
   They can present with malabsorption, but also have        2.  propulsion from stretch or toxins.
   abdominal pain, anorexia and fever. Early in the               Carcinoid
   disease, there may be partial villous atrophy and the          VIPoma: VIP and others.
   cellular infiltrate in the lamina propria consists of          Gastrinoma: gastrin
   benign appearing plasma cells. Later malignant            3.  permeability: rotavirus, Campylobacter.
   changes ensue with atypical plasma cells and              4. Nutrient malabsorption: Can damage microvilli so will
   reticulum cells. A number of these individuals have "-       not absorb lactose. Will contribute to the diarrhea.
   heavy chain" disease in which their serum and                Stop drinking milk products until microvillus structure
   intestinal secretions contain an excess quantity of free-    recovers.
   chains of the IgA molecule that frequently have a         5. Bile acid induced diarrhea: with bile acids  
   deletion in the normal amino acid sequence                   secretion. If not reabsorbed then bile acid are potent
                                                                simulators of diarrhea.
                  DIARRHEA                                      History
Worldwide problem. Causes much death and disability.            1) Rapid onset or short duration.
5 million deaths worldwide. Bulk are children under 1 yo.       2) Travel history:
Mean BM/day. Varies considerably in general                     3) Medications
   population. Wide norm. 3 per day to 1 per day.               4) Pt age
How do we define diarrhea: 200 g/day. Oral intake of 2 L        5) Diet
   of fluid. Add 7 liters from salivary glands from             Character: Frequency, Volume, blood: (IBD or infection),
   stomach, etc …. Present 9 L of fluid to intestine/day.          consistency
   Absorb 98%. Put out less than 200 ml/day. Body               Other: Fever, weight loss, anorexia, nausea, vomiting,
   taking up rest. Can  absorptive capacity up to 12 L            dehydration.
   day. Can take up max of 4 to 6 L/day.
Where is it taken up? Duodenum: 5.5 L, ileum: 2 L,              Clinical presentation
   Colon: 1.3 L Duodenum and jejunum are leaky.                 Clues about the patho.
   Farther down go the less leaky it is. Absorptive sites.      Blood or pus in the stool: implying infection.
   Fluid follows ion movement. Na, K and Cl are                 Persistent when pt fasts: Fast and does not stop then
   handled differently in the intestine.                           diet is not a factor. If  when pt stops  diarrhea,
                                                                   then osmotic.
Decreased Absorption of Fluid and
                                                                Fecal Leukocytes  bacterial.
1. Decreased absorption of fluid and electrolytes.                           Chronic Diarrhea:
2. Increase of osmotically active material in small             Mandates through evaluation
   intestine. End up with non absorbed carbohydrates.           Many causes.
   Lactase intolerance. Or colonoscopy  give
   GoLightly. Poorly absorbed cations. Cause marked
   osmotic diarrhea.
                                                                           Antidiarrheal Agents
3. Increased propulsive activity                                Principles: treatment of cause preferable to treatment of
Increased secretion of fluid                                    A. Fluid loss is disguised since H20 electrolytes become
Stimulated anion (Cl) secretion. Vili are the absorptive           sequestered in distended loops--circular muscle tone
   cells. Crypts are secretion.                                    may actually increase, while peristaltic waves
Osmotic:                                                           decrease.
Carbohydrates: lactose, Sorbitol                                B. Electrolyte and H20 reabsorption is still compromised
Minerals: NaSulfate Lavage solution, Mg Citrate                    in inflamed tissue.
                                                                C. In Shigella infections, antidiarrheal preparations
Stool should never be hyperosmolar. Will see osmolar               eliminate a natural defense mechanism.
   gap. (Na + K) x 2 Normal is gap of 50 to 100. If
   lower then there are other osmols leading to diarrhea.       Agents
Secretion induced diarrhea:                                     Antimuscarinic - atropine control of drug-induced
Cholera or water diarrhea ( VIP  cAMP  Cl                      hypermotility-gastrointestinal spasticity.
   secretion)                                                   Opiates (diphenoxylate and loperamide) - pass bbb poorly
Celiac dz (sprue): marked  in crypts   secretion.              but at higher doses CNS effec become evident.
Kaolin and Pectin - combine the constipating action of              Both UC and Crohn's: Caucasian > Jewish ancestry >
  Al~ salts in kaolin and absorbent demulcent action of                non-Jewish non-Caucasian.
  pectin.                                                           More In the United States and Western Europe,
                                                                    UC has an incidence of 6-8 cases per 100,000 and a
Miscellaneous:                                                         prevalence of 70-150 cases per 100,000 population.
1. Bismuth subsalicylate (Pepto Bismol) - can be                       Crohn's has an incidence of 2 cases per 100,000 and a
   effective in large doses - considerable Salicylate is               prevalence of 20-40 per 100,000 population.
   absorbed. These agents increase the efficacy of                  Peak age of occurrence for both dz is15-35 yo, although it
   antimicrobial agents in the) pylon infections.                      can occur at any age.
2. Enterovioform - banned in the U.S. since it causes an            There is a family history of IBD in 2-5% of patients with
   optic neuropathy but is still used other countries.                 UC or Crohn's.
                                                                    Etiology and Pathogenesis
         IRRITABLE BOWEL                                   Etiology unknown. Combination of genetic, infectious,
                                                              environmental, and immunologic factors.
             SYNDROME                                      Genetic predisposition: suggested by  incidence of both
Most common disorder seen by internists and                   Crohn's disease and UC in monozygotic, but not
     gastroenterologists.                                     dizygotic twins. There is also  frequency in people of
Present in up to 24% of ♀ and 19% of ♂.                       Ashkenazi Jewish ancestry, and some familial
Symptoms:                                                     clustering. There is active research to find a genetic
Abdominal pain relieved by defecation.                        marker for IBD. Predicts course and prognosis for dz.
Alternating diarrhea and constipation.                     Nod 2 gene for Crohn‘s found in 2002. Located on Ch 16
Bloating                                                      in IBD 1 region.
Symptoms are worse during periods of stress.               Infectious process might explain the chronic
No nocturnal diarrhea, weight loss, fever or rectal           inflammatory nature of the disease, but no infectious
     bleeding.                                                agent has been found to explain LBD.
                                                           Environmental factors:
Pts have a heightened response to noxious visceral stimuli     rate of IBD in urban vs. rural areas.
     such as balloon dilation of the rectum and sigmoid       More common in high socioeconomic classes.
                                                              Cigarette smokers:  risk of UC.  risk of CD.
Rome Diagnostic Criteria                                   Immune process: suggested by alterations in various
At least 3 months of abdominal pain                           cytokines and inflammatory agents, as well as the
1) Relieved w/defecation                                      clinical response to anti-inflammatory drugs. There are
2) Associated w/change in frequency of stool or,              also extraintestinal manifestations which could
3) Associated w/change in consistence of stool                represent an auto-immune phenomena. TNF is more
AND                                                           important. A role in therapy.
Two or more of the following for at least 25% of days: Colon Cancer
1) Disturbed defecation (3 or > BM QD or 3 or <
     BM/week)                                              Long-standing inflammation   risk for colon Ca
                                                                w/mutations in P53.
2) Altered stool form: lumpy/hard or loose/watery
3) Altered stool passage: Straining, urgency, or feeling      variation based on duration of disease. Longer
     of incomplete evacuation                                   duration  risk.
4) Passage of mucous                                          Extent of dz  if limited to rectum  risk If only
5) Bloating or feeling of abdominal distention.                 ulcerative proctitis (dz limited to rectum), have no 
                                                                risk of cancer. W/pancolitis risk of cancer is 10-40%
Treatment:                                                      after 25 yrs
Rule out other dz.                                         IBD pts do not have same polyps as other colon cancer.
Empiric trial of lactose free diet may relieve symptoms.        Will have to do 4 quadrant biopsies every 10 cm to
Reassurance.                                                    get more samples. Need at least 33 biopsies to rule
Stress reduction.                                               of dysplasia.
Fiber supplementation                                      UC: Because of the risk of colon Ca, after 8-10 years of
Antidepressants are frequently beneficial.                      dz pts w/UC usually undergo annual or biannual
Anticholinergic meds: may help relieve colon spasms.            screening colonoscopy to look for high grade
                                                                dysplasia or cancer. A finding of persistent high
  INFLAMMATORY BOWEL                                            grade dysplasia or cancer is an indication for total
IBD refers to idiopathic inflammation of the                             ULCERATIVE COLITIS
  gastrointestinal tract  Ulcerative Colitis (UC) and
  Crohn' s Dz.                                                      Pathology
                                                                    Ulcero-inflammatory disease limited to the colonic
.                           UC              Crohn's Disease (CD)       mucosa.
Extent of Inflammation *Limited to mucosa*Involves all layers       Always starts in the rectum and extends proximally
Intestine Involved        Colon only    Anywhere in GI tract           (retrograde) in the colon. The involvement can range
Rectal Involvement        Always        Sometimes - may spare          from only the rectum to anywhere more proximally in
                                        rectum                         the colon but is always continuous.
Pattern of spread         Contiguous    Skip lesions                Grossly, the mucosa appears red, friable, edematous, and
Granulomas                No            Yes
Fistula                   Rare          Common (40%patients)           ulcerated.
Strictures                Rare          Common                      Microscopic examination:
Abscess                   Rare          Common (20%patients)        1. loss of surface epithelium
Peri-anal disease         Rare          Common (30%patients)        2. crypt abscesses: infiltration of the crypts with
Bloody Diarrhea           Yes           No (unless affects distal
                                        colon)                         neutrophils. Eroded some of the crypt.
Ileal disease on xray     Rare          Common (75%patients)        3. branching, budding and distortion of the crypts.
High risk of colon cancer               Yes No (unless affects         Abnormal architecture. Hallmark of IBD. Alteration
                                        colon)                         of mucosa with crypts trying to grow back. Short and
Cure with surgery         Yes           No
% Who ever need surgery                 20% 70%                        may not make it to the muscularis.
Psuedopolyps: Islands of regenerating epithelium in              toxic dilation and perforation requiring emergency
   broad-based ulcers.                                           surgery.
Toxic megacolon: entire bowel wall may become thin,
   with transmural inflammation, and subsequent
   perforation. gangrenous necrosis. With longstanding        Made by flexible sigmoidoscopy or colonoscopy
   inflammation, there may be submucosal fibrosis.               w/biopsies abnormal mucosa beginning from rectum
Lead-Pipe colon: Long-standing UC can result with                with ulcerated, edematous, and friable tissue.
   fibrosis and shortening of the colon, giving a smooth,     Barium enema could also be used to show ulceration and
   "lead-pipe" appearance to the colon.                          loss of haustra in the colon, but does not allow biopsy.
Malignant change: After >10 yrs, mucosa epithelial cells      Main differential diagnosis:
   may become dysplastic and represent premalignant
                                                              Acute infectious diarrhea. This can include amoebic
   change. Severe dysplasia is associated with a  risk for      infection, C. Difficille pseudomembranous colitis, or
   co-existent colon Ca. Screening every 1 to 2 yrs              other bacterial infections.
   starting 7 to 10 yrs after onset of symptoms. If low       All pts w/suspected diagnosis of UC should have stool
   grade dysplasia  repeat colonoscopy in 3 to 6                sent for bacterial Cx, ova and parasite, and C. difficle
   months. May miss because can only take sample from            toxin determination to rule out an infectious etiology.
   one part of colon.
                                                              Main acute complication:
Clinical Features
                                                              Toxic megacolon: > 6 cm. air massively dilates the colon
1) Bloody diarrhea: Inflammation of mucous. Classic              and loses its tone. Can have perforation  colectomy.
   presentation. Low frequency of bowel movements                Loss of haustral markings on abdominal series. Use of
   (unless fulminant colitis)                                    high dose steroids and coverage of gut flora
2) Abd pain, fevers, and weight loss: in more severe             (Amp/Gent/Flagyl) If no response after 2-3 days then
   cases                                                         pt is steroid resistant. Need to start on cyclosporine.
3) Tenesmus: the sense of incomplete evacuation.
                                                               colon cancer,
   Associated with inflammation and swelling of the
   rectum                                                     Drug Therapy
4) Extraintestinal manifestations: immune response.        Sulfasalazine or 5-ASA: Sulfasalazine a sulfonamide
     joint pains: Monoarticular arthritis, arthralgias,      bound to a salicylate is cleaved by bacteria in the
       ankylosing Spondylitis (Central arthritis),             colon. Active portion is excreted in the stool and
       sacroiliitis. Joint pain in flares comes before GI      inhibits prostaglandin synthesis.. Sulfapyridine
       flare.                                                  portion is absorbed and is responsible for SE (rash,
     liver problems: Bile duct lesions  sclerosing          nausea, and headache).Time released (Pentasa) or
       cholangitis (seen in <5% of IBD pts) (can lead to       dissolve in the colon (Asacol) allow higher PO doses,
       liver dz)   risk of developing                        w/out SE from the sulfa component of the Azulfidine.
       cholangiocarcinoma.(beaded appearance).                 5-ASA products can also be given topically for rectal
     skin lesions: erythema nodosum (round sores over        or left colon disease. Long term 5-ASA does 
       the shin), pyoderma gangrenosum (sunburn                recurrence rate of symptomatic disease.
       looking lesion)                                     Prednisone PO or hydrocortisone IV: Pts w/moderate
     mouth lesions: oral apthous ulcers                      severity disease that does not respond to 5-ASA
     eye problems: iritis, uveitis, and episcleritis         treatment. Ideally used only for a few months at a
Physical exam findings are nonspecific.                        time, because of the long-term complications. Long
                                                               term steroids do not prevent recurrent disease. New
Laboratory studies:                                            non-absorbable steroids are being developed.
1) Fe studies  Fe deficiency anemia                       Immunosuppression: Pts with frequent relapses which
2) Thrombocytosis > 450,000                                    require steroids. 6-mercaptopurine or azothiaprine as
  WBC count                                                a steroid-sparing measure. 75% of previously steroid
  sedimentation rate                                       dependent patients can stop taking steroids with 6-
  albumin: from protein loss through the ulcerated         mercaptopurine. Cyclosporin can be used to treat
      mucosa.                                                  fulminant colitis in order to avoid emergency surgery.
6) Serum markers: p-ANCA (+) in 70% of pt‘s w/UC. NSAIDS: is the major cause of relapse in pts on other
      If (-) very unusual.                                     therapy. Can be difficult with other complications.
7) Stool bacterial Cx, stool O and P and C. Diff toxin (-) If well controlled and then condition worsens and after 2-
                                                               3 days on steroids no response should consider
Imaging:                                                       infectious cause  biopsy and widen differential.
Plain abd film: Initial assessment. Repeat only when
      information may change treatment. Not needed when Surgical therapy
      ordered as a Qam film to follow prognosis. Can use Required in ~ 20% of patients during their lifetime.
      serial exams to follow.                              Main indications: failure to respond to medical
Upright chest: rule out perforation. Look for                  management or evidence of dysplasia.
      pneumoperitoneum.                                    Emergency surgery: toxic megacolon or severe colitis
CT: If stable and ? of abscess  CT. Not to look for           not responsive to steroids.
      perforation. Can see 1 cc of air.                    Elective colectomy:
   Oral contrast: Most useful if looking for abscess. Used  chronic disease who frequently require steroids, and for
      to distinguish bowel from abscess.                      pts who on surveillance colonoscopic biopsies are
   IV: Least useful in abscess.                               found to have pre-cancerous high-grade dysplasia.
   Rectal: useful if looking at L colon.                    Complete removal of the colon (total colectomy) is
If any question of perforation should not use barium.         required, because any remaining colon can still have
      Barium peritonitis is fatal.                            disease and progress to cancer. Complete removal of
Clinical course:                                              the colon is generally curative of the disease, although
                                                              not all extraintestinal manifestations will go away.
Variable. Most pts will relapse w/in 1 yr of 1st attack,
    although some pts have prolonged remissions. Pt w/dz Prognosis
    limited to the rectum or rectosigmoid (left sided      Acute UC can be medically managed in 90% of cases.
    disease) generally have less severe disease. Disease   5% mortality with acute U.C.
    initially diagnosed as limited to the rectum can, over ~ 75% will experience a relapse at some point in their life
    time, extend more proximally. Approximately 15% of 20% will eventually have a colectomy.
    patients will develop a fulminant, pan-colitis, with
                                                                 67% and a Specificity of 86% for diagnosing Crohn's
        CROHN’S DISEASE                                          disease. Early onset CD are ASCA +.
Pathology                                                     1. Barium small bowel radiographs: show narrowing in
Gross Pathology                                                  the terminal ileum, and show fistula tracts
Transmural inflammation: all layers of the intestinal wall,   2. Colonoscopy: scattered areas of mucosal ulceration,
   and may involve the mesentery and regional lymph              edema, and friability. Early Crohn's will appear as
   nodes.                                                        apthous ulcers in the colon.
Any part of the intestinal tract can be involved. 30% of      3. CT scan: show thickened bowel and an inflammatory
   patients have small intestine involvement only (usually       mass around affected bowel.
   the terminal ileum), 30% have only colonic
   involvement, and 40% have terminal ileum and right         Differential diagnosis
   colon involvement.                                         RLQ abdominal discomfort w/inflammation in terminal
Skip lesions: The disease often involves different areas of     ileum and cecum
   the intestine, with normal intervening intestine. The      1) Appendicitis
   rectum is only involved in 50% of cases.                   2) infection with Yersinia or tuberculosis.
Cobblestone appearance:                                       Treatment
Creeping fat: wrapping of the mesenteric fat around the
   bowel wall.                                                Medical Treatment Strategies: Dependent on location
Fibrosis. Transmural inflammation  get fat sticking to           and on severity of dz.
   that inflammation  adhesion.                              Location: Stomach, Jejunum
                                                              Extent: Localized vs. diffuse
Microscopic Pathology:                                        Operative history
patchy transmural chronic inflammation and edema: if
   have 4 biopsies maybe only 1 will be inflammed. So         Mild to moderate dz of distal ileum or colon 
   even on microscopic will be a skip lesion.                      suflasalazine or mesalamine
Apthous ulcer                                                 Proximal small intestine dz mesalamine preparation
Granulomas are often present. Classic finding.                If intolerant to 5-ASA drugs  Flagyl
"skip" lesions, where linear ulcerated areas alternate with   If no response to 5-ASA or Abx  steroids.
   normal mucosa.                                             Major cause of relapse is use of NSAIDS. Smoking also
architectural distortion of the crypts: in common with UC          have poorer outcome

The transmural extent of the inflammation in Crohn's          Goal: induce remission, maintanence, low SE, steroid
    disease is responsible for its chronic sequelae.              sparing, and maintenance of QOL.
fibrosis  strictures:                                        Also evaluate for neuromuscular problems as found in
Fistula can form when the transmural inflammation                 IBS.
    involves adjacent structures. The fistulas can form
    between loops of bowel, or between the bowel and        First line:
    skin (enterocutaneous fistula), bladder (enterovesiculo 1) 5-aminosalicylate drugs: Sulfasalzine (5-ASA),
    fistula), or vagina.                                         Asacol (released in pH dependent fashion), Pentasa
Inflammatory mass: transmural inflammation involving             (microgranular preparation). Long-term 5-ASA
    the serosa and surrounding mesentery can also result         products may  relapse rates. 1* in pts w/colitis and
    in an inflammatory mass in                                   ileocolitis, and +/-ileitis. Addition of 5-ASA to
                                                                 prednisone does not improve remission rates in active
 Clinical Features                                               Crohn's dz in vs. prednisone alone.
1. RLQ abdominal pain                                       2) Flagyl: Perianal dz. Effective 1* therapy even in the
2. Non-bloody intermittent diarrhea: Intermittent is the         absence of bacterial overgrowth or complications
   classic finding. Bloody diarrhea is uncommon                  such as an intra-abdominal abscess. Best for pts
   (common w/UC) unless the rectosigmoid colon is                w/perineal dz and fistulas. Mechanism unknown.
   involved.                                                     ?action vs. enteric flora   inflammatory response.
3. Nausea and vomiting can occur if there is bowel               ?action s/p surgery   postsurgical recurrence.
   obstruction due to an inflammatory stricture.                 Benefit at 1 year, but less at 2 and 3. Cipro also
4. Fevers, weight loss, and fatigue.                             being studied.
5. Anorectal fistulas, fissures, and peri-rectal abscesses: Second Line:
   complications of the transmural inflammation. Can        1) Steroids: 2nd line. Effective for both small and large
   also occur between inflamed intestine and other bowel,        bowel dz. 60% had remission vs. 30% w/placebo.
   skin, bladder, or vagina.                                     Long-terms steroids do not prevent relapse. Steroids
6. Extraintestinal manifestations: immune response.              do not maintain remission. Tx until endoscopic
      joint pains: Monoarticular arthritis, arthralgias,       lesions recede does not provide better outcome vs. 
        ankylosing Spondylitis (Central arthritis),              steroids after clinical remission. Newer steroids
        sacroileitis                                             (Budesonide) being studied.
      liver problems: Bile duct lesions  sclerosing      2) Immunosuppression: 6-MP or azathioprine.
        cholangitis (can lead to liver dz)   risk of           Effective in treating active dz and maintaining
        developing cholangiocarcinoma.(beaded                    remissions. Need 3-6 mo to show optimal efficacy.
        appearance).                                             Main question is safety Allergic reactions w/fever,
      skin lesions: erythema nodosum (round sores over         rash, and joint pain, acute allergic pancreatitis,
        the shin), pyoderma gangrenosum (sunburn                 hepatitis.
        looking lesion)                                        Pts brought into remission w/azathioprine 1-yr
      mouth lesions: oral apthous ulcers                       relapse rate:
      eye problems: iritis, uveitis, and episcleritis          --5% relapsed if continued azathioprine
                                                                 --41%relapsed if stopped azathioprine.
Lab Studies                                                    Risk of relapse at 1 and 3 years:
Malabsorption: ileal involvement.  albumin                      --after stopping azathioprine 38% and 57%
Anemia due to blood loss.                                        --continued azathioprine 11% and 22%.
 sedimentation rate                                        3) Anti-TNF:
ASCA test: measures Ab to a yeast oligosaccharide              Chimeric antibodies: Useful in moderate to active
   isolated from Sacchromyces cerevisiae. Sensitivity of         luminal dz, fistulizing dz, and helps to heal mucosa.
                                                                 81% treated vs. 17% placebo had clinical response at
     4 weeks. If given every 8 weeks can maintain                1. Adhesions: Previous surgery/ Peritonitis
     remission. Also helped closure of fistulas 55% vs.          2. Hernia
     13% placebo. Symptoms recur ~8-12 weeks after               3. Neoplasm
     cessation of therapy.                                       4. Abscess
     SE: URI, abdominal pain, myalgias, fatigue. Can             5. Volvulus: A twisting of the bowel about the axis of its
       develop antichimeric Ab  lupus like reaction.               mesentery or around an abnormal fibrous band which
       Also can develop delayed hypersensitivity reaction.          usually results from previous peritonitis)
   Thalidomide: most potent anti-TNF drug. Use in              Large bowel cancer 67%. Small bowel  74%
     future for active intestinal and fistulizing dz.
6) Nutrition:                                                    Cause
   Adjunctive: maintaining adequate nutrition and              Small bowel: Adhesions 71.2% , Cancer 9.3 %, Hernia
     correcting specific nutritional deficiencies                   (external and internal) 3.7%, Crohn's Disease 3.7% ,
   1* therapy: elemental diet or liquid polymeric diets           and Other 7.7%
     may  dz activity acutely                                   Colon Cancer 67%, volvulus 9.0 %, diverticulitis 7.0%,
   Maintenance: managing intestinal failure or short              fecal impaction 4.6%, and Misc. 13.4%.
     bowel syndrome on a long-term basis                         Functional
   Growth-inducing: reversing growth failure in          Paralytic ileus.
     children and adolescents.                             1. Post-operative or post-traumatic.
                                                           2. Inflammatory (peritonitis).
Surgery:                                                   3. Ischemic.
70% of patients during their lifetime.                     4. Metabolic (hypokalemia).
Indications: persistent stricture or fistulas which do not Chronic motility disorders (pseudo-obstruction)
   improve with medical therapy. Surgery is not curative. 1) Hirschsprung's disease (congenital megacolon):
   Operation is preferable to continuing a fruitless           Failure of propulsive movement due to the absence of
   regimen of high-dosage steroids or                          ganglion cells in the myentenc plexus and in the
   immunosuppressive drugs.                                    submucosa. This results in (the) enlargement of the
Resection of involved bowel w/restoration of bowel             colon proximal to this defective segment. Lacks
   continuity.                                                 ganglions in meisners and auerbach plexus.
75% recurrent rate of disease within a few years. There is 2) Achalasia: Failure of the lower esophageal sphincter
   hope that medical treatment after surgery will diminish     to relax
   this recurrence rate.                                   3) Others.
Complications                                                    Characteristic of Proximal and Distal
When patients relapse, they tend to have the same type of        Obstruction
    complication as they had previously (i.e. people with
                                                                                   Proximal                    Distal
    strictures get recurrent strictures, rather than fistula).
If well controlled and then condition worsens and after 2-            Onset         Acute                    Acute
    3 days on steroids w/no response should widen                     Pain          At frequent intervals    frequent
    differential  biopsy                                             Vomiting      Prominent                Prominent
1) Small bowel obstruction: due to strictures                                       Non feculent            Feculent
2) Fistulas: can  intra-abdominal abscess, and                       Distention    Minimal or absent       Noticeable
      drainage of intestinal continents from the skin,
      bladder, or vagina.
3) Colon Ca: Long-standing inflammation   risk for                          DIVERTICULITIS
      colon cancer.                                              Acquired saccular herniation of mucosa and submucosa
    Duration of >8 years or limited L sided dz >15 yrs.           through muscular layers of the colonic wall. At point
    Extent of dz  if limited to rectum  risk. Limited           of weakness.
      well controlled L sided involvement  can screen at        Pathogenesis:
      15 yrs.                                                    1.  intramural pressure gradient between the colonic
Prognosis                                                           lumen and serosa
CD is a chronic, intermittent dz. Most pts require surgery       2. Areas of relative weakness in the colonic wall.
  and will continue to have intermittent relapses                Environmental factors: Consumption of  residue diets
  throughout their life.                                            which produce a  amount of sticky stools with 
                                                                    transit time is correlated with  incidence of this dz.
                                                                    Diverticulosis is rare or absent among people who eat
              INTESTINAL                                             residue diets which produce bulky stools of short
             OBSTRUCTION                                            transit time.

Mechanical                                                       Clinical features: Older patient
Obstructive obstruction                                          1) Occurs most often in sigmoid colon.
1. Polypoid tumors: lipoma. Can obstruct. Could also be          2) Abd pain: Starts as vague discomfort in the
   leimyoma or cancer.                                              midabdomen  LLQ or suprapubic area.
2. Gallstones: large stone impacted in small bowel.              3) Anorexia
   Image was of pt with Crohn‘s dz. Lumen size was               4) Changes in bowel habits: either  defecation or
   decreased.                                                       constipation
3. Fecal impaction:                                              5) Dysuria 2/2 bladder inflammation
4. Foreign bodies: bezoar.                                       6) Fever
5. Intussusception (Telescoping of one segment of bowel          7) Often a mass is palpated
   into another). Peristaltitc mov‘t loses its coordination.     8) Leukocytosis
   One segment gets too active. Telescopes itself into
   next segment. Then distal area squeezes and causes            Radiology:
   cutting off of blood flow.                                    CT: inflammation of pericolic fat, peridiverticular
Intrinsic bowel lesions                                             abscess, thickening of bowel wall > 4 mm, and
1. Atresia:                                                         presence of diverticula
2. Stenosis/Strictures: Neoplastic, Inflammatory                 Barium enema: replaced by CT scan.
3. Vascular disorders: Arterial or Venous Occlusion              Complications: bleeding, diverticulitis, abscess, fistula
Extrinsic bowel lesions                                             and obstruction.
                                                                 Medical Treatment:
Close observation w/bowel rest, hydration                       5. Fulminant viral hepatitis.
IVAbx: trimethoprim-sulfamethoxazole or cipro, plus
                                                                Acute viral hepatitis
   flagyl for 3 to 5 days after resolution of fever
Narcotics should be avoided as they  motility.                 Tissue injuries vary little among different subtypes of
Emergent Surgery:                                                  acute viral hepatitis. They are characterized by the
~25% require surgery  if general or progressing                   following changes:
   peritonitis or evidence of systemic sepsis.                  1) Diffuse liver cell injury: cellular swelling  results in
Most pts improve in 2 to 3 days. If persistent pain, fever,        disarray of liver cell cords
   leukocytosis, or peritonitis after 3 to 4 days of medical    2) Apoptosis: acidophilic bodies / Councilman bodies of
   therapy  surgery                                               random, isolated liver cells, or small cell clusters.
Elective Surgery: After resolution of acute episode               This represents a programmed cell death accentuated
   possible surgery because of high possibilities of               by viral hepatitis. Not to be confused with Mallory
   complications in future. Controversial.                         bodies. Nature of tissue injury is different
                                                                3) Inflammatory cellular infiltrates mainly lymphocytic
                                                                   (Lymphocytic infiltrates tend to be more prominent in
              APPENDICITIS                                         hepatitis C than in other types) in portal tracts and
Most common causes for abdominal surgical                          focally within parenchyma
  emergencies.                                                  4) Prominence of hepatic macrophages: due to reactive
                                                                   changes Kupffer cells and sinusoid-lining cells
1. Obstructive lesion: facalith, calculi, foreign body,         Clinical Picture:
   parasite.                                                     levels of aminotransferases. In EtOH hepatitis are only
2. Accumulation of secreted fluid in the lumen                   raised to mid 300. Hep  mainly parenchamyl dz:
   intraluminal pressure. When the intraluminal pressure           AST , ALT 
   > venous pressure                                            Bilirubin 
3. Hypoxic injury with mucosal ulceration and bacterial         ALPase  (only modest)
   invasion.                                                    Impaired synthetic formation.
                                                                PT: Prolonged with near normal serum albumin. PT has a
Infection is 2 and accentuates the tissue injury.                 shorter half-life than albumin
Eventually, gangrene and perforation may occur
                                                                Interpretation of Serologic Tests In Diag of
This concept is compatible with the majority of cases of        Acute Hepatitis
   appendicitis, but does not explain about one third of                 IgM Anti-          IgM             HCV   IgM
                                                                           HAV HBsAg      Anti-HBc Anti-HCV RNA Anti-HDV
   cases in which no obstructing lesion is found in the
   lumen. The pathogenesis of these latter cases is             Acute HA (+)       (-)      (-)         (-)    (-)     (-)
   unknown.                                                     Acute HB (-)       (+)      (+)         (-)    (-)     (-)
                                                                Acute HC (-)       (-)      (-)    seroconversion(+)   (-)
Clinical manifestations:                                        Acute HD (-)       (-)      (-)         (-)    (-)     (+)
1) Pain, nausea, vomiting and fever                             Acute HA
2) Abdominal tenderness (rebound tenderness)                    Chronic HB
3) Leukocytosis with left shift.                                Prior exposure
                                                                To Hep C (+)       (+)       (-)        (+)    (-)     (-)
           VIRAL HEPATITS                                       Acute HB
Infections and EtOH are dominant causes of hepatitis.           Chronic HC(-)      (-)      (+)         (+)    (+)     (-)
Wide variety of infections involve the liver, viral             Chronic viral hepatitis
   infections, especially those by a small group of viruses
                                                              Subjective symptoms
   with a particular affinity for the liver are the principal Early: Myalgia, flu-like symptoms, nausea, anorexia,
   cause of hepatitis.                                           fatigue, occasionally arthralgia
Term viral hepatitis disorder caused by their infection
                                                              Later: Continued fatigue, anorexia
   with Hep A, B, and C.
                                                              Chronic: Fatigue, weight loss
Other viral infections, CMV and EBV, involve the liver
                                                              Objective signs
   less often, and only as a part of systemic involvement.    1. Fever
Clinico Pathologic Syndromes                                  2. Jaundice, dark urine
Hepatitis viruses may cause one or some of the following 3. Large tender liver, often splenomegaly (often with
   clinical syndromes:                                           onset of cirrhosis with portal HTN)
1) Asymptomatic infection: Infection resolves without         4. Rarely, arthritis, lymphadenopathy, nephrotic
   giving rise to a clinical illness.                            syndrome (Ag-Ab complex dz/almost exclusively
2) Carrier state: Infection persists without clinically          hepatitis B)
   apparent disease or with mild chronic hepatitis.           5. Chronic: Often edema. With onset of cirrhosis, all of
   Individual with this condition constitute reservoirs of       the signs of cirrhosis.
   infection.                                                 Laboratory abnormalities
3) Acute viral hepatitis: Clinical manifestations < 6         Albumin: chronically low
   months. Biopsy not normally done. Only with Hep C. PT: prolonged
   Have diffuse cellular injury. Distorted. Inflammation "Hepatocellular" enzymes: continuously (though at low
   here and there. Within and around portal tract. A             levels) out of proportion to Alk Phos
4) Chronic viral hepatitis: The duration of the disease is    Hyperbilirubinemia: tends to occur late
   determined by clinical history , not by biopsy (tissue     Classification:
   pathology).                                                Chronic hepatitis has been classified according to the
     Clinical manifestations > 6 months in the absence         extent of tissue injury and inflammation:
       of reexposure.                                         1. Chronic persistent hepatitis Inflammation is confined
     Hepatitis B, C , D and G have potential to become         to portal tracts
       chronic. Clinical experience has been that if          2. Chronic active hepatitis
       laboratory and / or clinical manifestations of viral   Portal tract inflammation spills into parenchyma and
       hepatitis are present continuously for 6 or more          surrounds apoptotic hepatocytes.
       months, the process tends to continue a long time      Primary determinant of dz progression is the type of
       and is unlikely to resolve spontaneously (although        etiologic virus. Classification of chronic hepatitis
       occasionally it does). It may progress into cirrhosis.    strictly by histologic criteria is obsolete. Information
   on tissue injury is still useful to assess the severity and   Confirmed by IgM Ab to HAV.
   progression of the dz.                                        Seroconvert to IgM then IgG
Histologic hallmarks include:
                                                                 Control Measures:
1) Piecemeal necrosis: Apoptotic cell death with breach
   of "limiting plate", i.e. parenchyma-portal tract             Antibody:
   interface. Viral hepatitis is very random. Does not           HAV has long incubation period  get neutralizing Ab
   affect every lobule equally. Some are surrounded by               will prevent dz. Have preexposure Ig prophylaxis.
   fibrous septa and others not. Then can say that this              Standard practice for those in peace corp. Can also
   cirrhosis occurred from virus. Rule of                            give to household contacts of pts that have been
2) Spilling of chronic inflammatory cells** into                     infected.
   parenchyma. Mainly lymphocytes and macrophages                Take from pooled blood products. Levels used now are
3) Fibrosis - Continued tissue injury results in formation           much lower. May raise the levels.
   of fibrous septum, which, accompanied by                      Totally prevents infection in many. Are not protective in
   parenchymal regeneration, results in cirrhosis                    the long term after the Ig is metabolized.
Why biopsy (tissue pathology)?                                 Groups in whom vaccination recommended:
Viral hepatitis: serologic studies are sufficient to establish
                                                                   Travelers
   diagnosis. This is why biopsy is not needed for the
   diagnosis of acute viral hepatitis, unless other hepatic        Children and employees at daycare centers
   injuries need to be differentiated.                             Military
Chronic hepatitis: biopsies are useful in assessing the            Homosexual males
   severity and progression (i.e. extent of tissue injury          IV drug users
   and fibrosis), and in establishing diagnosis of cirrhosis.      Food Handlers
   It also helps to monitor the effectiveness of treatment.        Liver Transplant recipients
Duration of hepatitis can not be made by biopsy because            Lab Techs
   the rate of progression does not correlate with                 Healthcare workers
   histopathology. Therefore, duration of the dz must be           Native Americans
   dated clinically.                                               Sewage workers
                                                               Virus inactivated with formyl  killed vaccine that is
                HEPATITIS A                                          highly effective.
                                                               Within 5 to 18 days  There were cases in the vaccinated
Fecal oral in origin and transmission or ingestion of                group. Too late to have an effect. After 20 days was
     fecally contaminated water or food.                             effective.
PicoRNA virus: Only one human serotype with multiple
Replicates within hepatocyte cytoplasm.                                         HEPATITIS B
Clinical Presentation:                                         Mode of Replication: Reverse transcription in liver and
                                                                     other tissues.
Acute Self Limited Infection:
HAV progresses through normal life cycle and is usually
                                                               Puts out enormous amount of virus into blood.
     terminated by immune system.
                                                               Excess surface antigen (HbsAg)
Virus is shed in largest amounts and for the longest time
     in the stool. May also be shed in serum, urine, or        Transmission
     semen.                                                    Parenteral and mucous membrane exposure to infectious
IgG to capsid protein persists and protects host for life.         fluids (blood, serum, semen, and saliva.)
Time course: Infects  prolonged replication period  Only need to transmit a very low viral load to cause
     shed great amount in stool.                                   infection. Most of the transmission is covert. Can
                                                                   transmit very easily.
Symptoms:                                                      Hyperendemic in sub-Saharan Africa.
Nausea and vomiting                                            If infected as infant have 15% chance of getting
Jaundice                                                           hepatocellular carcinoma.
Dark urine                                                     Risk factors:
Light colored stool                                            Close personal or intimate contact with infected person
Abd pain                                                       IV drug abuse
Malaise/fatigue                                                Homosexual activity.
Fever/Chills                                                   Healthcare workers.
 appetite                                                     Tattooing and body piercing
Myalgias.                                                      Inapparent blood inoculations
                                                               Blood transfusions or exposure to blood products
Less frequently and less severely infected children than       Hemophilia
     adults.                                                   Hemodialysis.
In adults HAV manifests as clinical cases with                Serologic Markers of Infection:
     mortality. SGOT in the 1,000.
                                                               HBsAg: surface antigen of HBV virus
HAV does not cause chronic infection and long term
                                                               HBcAg: Ag from core of HBV. Never available in blood,
                                                                   but produced in hepatocytes that lyse. Important for
Transmission                                                       cell mediated immunity and antibody development.
Fecal-oral transmission.                                       Anti-HBs
Absence of Chronic carrier state                               Anti-HBc
Absence of transmission via blood: 10 day period before Anti-Hbe
     symptoms in which HAV is in blood. After that very DNA polymerase
     little in the blood.                                      Acute Hepatitis:
Diagnosis:                                                       90% of HBV infections with subsequent resolution of dz
Exposure History:                                                   in 3 to 6 months.
  Daycare based epidemics are relatively common                Will usually lead to recovery with persistent antibody vs.
  Homosexual men or alternative sexual practices                  HBsAb
  International Travel                                            HBcAg
                                                                    HBeAg.
Levels of antibody can fall below detectable levels, but            --Reported from pt to pt by a colonoscopy.
   are still present.                                               --Needle stick: HBV transmitted in 30% of
Production of HBV DNA parallels rise in HBsAg.                        exposures, HCV in 3%, and HIV in 0.3%.
HBsAg disappears  ―Window‖ HBcAg  Rise in Anti-               40% cannot tell.
   HBsAg. Look for HBcAg to indicate infection.
Non specific                                                 RNA virus. Natural targets are hepatocytes and possibly
Light colored stool                                               B lymphocytes.
Jaundice                                                     Robust viral replication: more than 10 TRILLION virion
Flu like disease                                                  particles are produced per day, even in chronic
GN                                                                infection
Rash                                                         RNA polymerase does not have proofreading function 
Arthritis                                                         rapid evolution.
Vasculitis                                                   Genotypes:
                                                             Six distinct, but related HCV genotypes. Genotype is
Chronic Hepatitis:                                                important because it has predictive value in response
5% of patients infected with HBV                                  to viral therapy.
Asymptomatic Carrier: 5%                                        US and Western Europe: 1a and 1b most common.
May be asymptomatic or may lead to damage, cirrhosis,             Followed by 2 and 3.
  and hepatocellular carcinoma.                                 Egypt: Type 4
Continued production of HBsAg and Anti-HBcAg Ab;                South Africa: Type 5
  possible Anti-HBeAg.                                          South East Asia: Type 6.
Usually no detectable Anti-HBsAg Ab.                         Type 2 and 3 have better response than Type 1.
Symptoms:                                                    Acute Infection
Progression to Cirrhosis  ~25% of chronic infection.        Infrequently diagnosed during this stage. Clinical
GN                                                                manifestations occur in 7 to 8 weeks w/mild
Rash                                                              symptoms or no symptoms.
Arthritis                                                     74% to 86% will have persistent viremia.
                                                             Chronic Infection:
Fulminant Hepatitis:                                         Will happen in most of infected pts. Spontaneous
1 to 2% of patients                                              clearance of viremia is rare.
                                                             Most chronic infections  hepatitis and some degree of
Immunization:                                                    fibrosis.
                                                             15 to 20% of pts  Severe complications and death occur
Exposure: Give high levels of Ig. From needle stick,             only in persons with cirrhosis.
   acute sexual contact, perinatal transmission.             Can proceed to cirrhosis and/or hepatocellular carcinoma.
Vaccine:                                                     Liver function tests cannot predict who gets cirrhosis or
Immunity is long lasting and most likely for life.               HCC.
Break the cycle:
1. Need to intervene in delivery room. Need to know if
   pregnant woman is carrier                                 Diagnostic Tests:
2. Give baby Hep B Ig                                        Serologic Assays:
3. Start 3 dose immunization process on first day of life.   Enzyme immunoassay: Core protein, and nonstructural
                                                                 proteins 3 and 4.
Vaccine: No Anti-HBcAg Only Anti-HBsAg antibody.             Can detect Ab w/in 4 to 10 weeks after infection.
                                                             False positives: Pts w/out risk factors, w/out signs or liver
                                                                 dz. Also pts with immune compromise, pt w/renal
               HEPATITIS C                                       failure, and pts w/HCV associated essential mixed
Infects 170 million persons worldwide. Highest number            cryoglobinemia.
    of infections in Egypt.                                  Recombinant Immunoblot: used to confirm (+) enzyme
In the US 1.8% of population is (+) for HCV antibodies           immunoassay.
    with 3 of 4 with active viremia  ~2.7 million in US
    with active HCV.                                         Molecular Tests:
 Shorter incubation period and less symptoms than HBV        Qualitative: PCR testing. Lower limit of detection is
    infection. More often asymptomatic.                           <100 copies of HCV RNA per ml.
Risk Factors:                                                Test of choice for:
Strongly associated with HCV: Injection drug use and            confirmation of viremia and assessment of treatment
   Blood transfusion before 1990                                  response.
Increased Risk of Infection: Poverty,  risk sexual             Pts w/(-) enzyme immunoassay, but in whom
   behavior, < 12 yrs of education, or being divorced or          infection is suspected
   separated                                                    pts w/hepatitis w/no identifiable cause.
                                                                Pts w/known reasons for false (-) results on Ab
Transmission:                                                     testing.
Lower concentration of HCV in blood than HBV. Chance
     of needle stick transmission is much lower.             Quantitative:
   IV needle                                               3 different tests to quantitate viral load. Results are
   Sexual contact: inefficient means of transmission.           reliable, but not easily comparable.
   Blood transfusion: Dramatically  since 1992 with      Advisable to use a single test system for each pt to
     screening for HCV antibodies. Window of 12 weeks             monitor viral load.
     before detectable antibodies. Risk is < than ` in
     103,000 transfused units. This risk is ½ that of        Genotyping: helps to predict outcome of therapy. Now
     getting HBV (1 in 63,000) and 5x> than HIV (1 in           only clinical relevant distinction is between genotype
     493,000). Now PCR screening   window to 3                1, and 2 and 3.
   Vertical transmission: infrequent. Often associated     Liver function Tests: Can use alanine aminotransferases
     with co-infection with HIV-1 in the mother.                 level to monitor HCV infection and efficacy of
   Nosocomial:                                                 treatment in the intervals between molecular testing.
                                                             1. Unlucky to get donation from IV user with both
                                                                viruses in it  acute hepatitis. More fulminant
Acute Infection: Not clear.                                     hepatitis.
                                                             2. Chronic infection with Hep B is super infected with
Chronic Infection:                                              Hep D. Severe aggravation of hepatitis. Will have
 liver enzymes, detectable HCV levels, liver biopsy            HbsAg and Anti-HBc protein. Then infected and will
     shows fibrosis or moderate necrosis and                    anti-HBd Ag.
     inflammation. Treatment.
 liver enzymes, but with minimal or mild necrotic           Prevention:
     changes on biopsy:                                      If HBV susceptible get vaccinated with HBV. Will
   may benefit from Tx, but are at  risk of progressive       prevent infection with HBV and HBD.
     liver dz                                                If chronic carrier: little to do. Avoid exposures. Limit
   Can follow up w/serial liver enzyme, & biopsy at 3 to       exchange of fluids.
     5 yrs.
 liver enzymes, but no histologic evidence of necrosis or
     inflammatory changes on biopsy  excellent                               Hepatitis E:
     prognosis w/out therapy.                                Epidemic traced to sewage contamination. Mean age 27.
                                                                Over all mortality is low like Hep A. Very high
Initial Therapy:                                                mortality in pregnant women.
Combination Therapy:
Interferon Alfa and Ribavirin.                               Hit and run. Waterborne epidemics  Water borne
Virologic response should be assessed at 24 weeks.              transmission
   (+) PCR assay for HCV RNA: No response to               40 day incubation.
     therapy. Treatment should be stopped  Controlled       Young adults mostly infected.
     clinical trials.                                        In pregnancy mortality 20% in third trimester.
   (-) PCR and Genotype 2 and 3. Can stop.
                                                             Endemic in Mexico. Not endemic in the US.
   (-) PCR and other genotypes  require 24 weeks
                                                             Immunity is life long. Distinct from Hep A and Hep B
     additional therapy.
                                                             Control: Do not drink sewage.
                                                             Our immune serum Ig is not protective. If use local
Contraindications to therapy:
                                                                 globulin  may be more effective.
Interferon Alfa:
   Absolute: Current psychosis or Hx of psychosis,
     severe depression, neutropenia or thrombocytopenia,         FULMINANT HEPATITS
     symptomatic heart dz, decompensated cirrhosis,          When hepatic functional insufficiency progresses from
     uncontrolled sz, and organ transplantation other than      onset of symptoms to hepaticencephalopathy within 2
     liver.                                                     to 3 weeks, it is termed fulminant hepatic failure. This
   Relative: Autoimmune disorders, and uncontrolled           is caused mainly
     DM.                                                     1) severe, rapidly progressive viral hepatitis: 50 - 65 % of
Ribavirin:                                                   2) drugs
   Absolute: Pregnancy, absence of reliable form of        3) chemicals
     contraception, ESRD, anemia, Hemoglobinopathies,        4) natural toxins: 20 - 30 %
     and severe heart disease.
   Relative: Uncontrolled HTN, and Old age.                Morphology of fulminant hepatitis appears identical
                                                                regardless of difference in causative agents. Therefore,
Side Effects of Combo therapy:                                  one cannot determine the etiology by morphologic
Very Common: >30%                                               examination only. The main feature is an extensive
Influenza like symptoms                                         parenchymal necrosis which usually involves the
HA                                                              entire liver (at times a part of it), causing a marked
Fatigue                                                         reduction in tissue volume.
Fever                                                        Liver weight may be reduced to as little as 500 - 700
Rigors                                                          grams. Parenchymal function really suffers.
Thrombocytopenia                                             Histologic:
Induction of autoantibodies.                                 1) parenchymal necrosis preferentially on the
                                                                downstream side of microcirculation, i.e. centro-
Pegylated Interferon: Extends half-life and duration of         lobular and mid-zonal parenchyma. Around central
    therapeutic activity. Only needs to be given once a         vein. Always with type of injury.
    week.                                                    2) Little inflammatory reaction except for some increase
Liver Transplantation                                           in lymphocytes and macrophages in portal tracts.
                                                             3) Severe functional failures:  synthetic capacity (ie
    Hepatitis D: Delta agent                                    longer PT. Has shorter half life of a few days.
                                                                Albumin has a longer half life).
Chronic active Hep B. Noticed that a pt would get a
  tremendous aggravation of dz and sometime survive.      Clinically, fulminant hepatitis manifests itself as acute
  Took convalescent serum to stain healthy liver. There      hepatic failure. The extent of tissue damage may be
  was antibody to some protein in nuclei. Called this the    best estimated by measuring synthetic products with
  Hep D antigen.                                             short half-life such as prothrombin.
Not independent virus. Satellite. Coat is Hep B surface
  antigen                                                     EtOH INDUCED LIVER DZ
Small circular ss RNA.
Can only replicate in cells that are actively replicating
                                                             Metabolism of Alcohol
  Hep B virus. Pt has superimposed Hep D on top of           The liver is the primary site of ethanol metabolism.
  Hep B infection. Also to provide the coat.                 ~ 80-90% of ethanol is oxidized by the liver, and the rest
                                                                is eliminated through the kidneys and lungs.
Two ways to get infected:
                                                             The first step in the hepatic oxidation of ethanol to acetate
                                                               may involve three enzymatic pathways.
1. Alcohol dehydrogenase (ADH) located in cytosol.            Isocaloric substitution of EtOH for carbos in an adequate
2. **Microsomal ethanol oxidizing system (MEOS).                 or high protein diet invariably  fatty liver
   Contains cytoplasmic P450. Inducible. If drink this          (accumulation of TG)
   in number.                                                 1. Upon cessation of EtOH intake  Readily reversible.
3. Catalase system: in peroxisome.                            2. With continued EtOH consumption  permanent
Under physiological conditions, however, ADH accounts              mitochondrial injury ( fatty acid oxidation and
  for most of ethanol oxidation in normal individuals,               membrane biogenesis)
  whereas the other 2 enzyme systems may catabolize a              proliferation of the SER with enhanced
  small fraction (10% or less) of ingested ethanol.                  biotransformation.
The acetaldehyde produced from ethanol is further             Clinical features.
  oxidated by aldehyde dehydrogenase (ALDH),                     hepatomegaly, often w/Abd pain and tenderness.
  primarily in the liver, into acetic acid which is carried      hepatic function tests are not remarkable except for
  by the blood stream to peripheral tissues where it is           mild  aminotransferases.
  eventually metabolized into carbon dioxide and water.       Diagnosis based on the association of biopsy with Hx of 
                                                                 EtOH intake. Fatty change resolves on cessation of
Ethanol oxidation  marked  in the NADH-NAD ratio               EtOH intake.
   and consequent  in reduction potential in the liver,
   primarily as NADH,  various metabolic alterations         Alcoholic hepatitis
   (fatty liver, acidosis, and  gluconeogenesis).         Does not occur in all. Tends to occur after binge
                                                               drinking. Chances of developing cirrhosis is high.
Pathogenesis of Alcoholic Liver Injury                     Pathologic features.
Although the pathogenesis of alcoholic liver injury is not May develop after a variable period of alcohol abuse,
   well established, the following factors are thought to      usually yrs.
   be involved:                                            Liver cell necrosis and inflammation associated w/fatty
Direct toxic effect: damage occurs downstream of               change  centrolobular fibrosis. Liver cells often
   circulation. Currently, direct toxic effects of EtOH        contain alcoholic hyaline (Mallory body aggregates
   thought to be the most likely mechanism of injury.          of cytoskeleton fibers) which is characteristic but not
   This concept is based on the following observations:        pathognomic of alcoholic injury. PMN are
   Good correlation between the amount of EtOH                 conspicuous in the inflammatory reaction.
   ingested & development of EtOH liver dz.                Determining injurious factors are not clearly understood.
Products of alcohol metabolism                                 Theory postulates that accumulation of PMN occur in
Acetaldehyde.                                                  response to elaboration of chemoattractants by
   Cell necrosis. Acetaldehyde  covalent binding to          hepatocytes as they metabolize ethanol. Liver cell
     proteins, and lipid peroxidation  injury to cell         injury may result from:
     organelles like mitochondria, microtubules, plasma        (1) action of neutrophil-derived free radicals &
     membrane  cell necrosis.                                 proteases, &/or
   Fibrogenesis. Acetaldehyde  direct stimulation of         (2) Ab directed vs. neoantigens created when
     fibrosis                                                  acetaldehyde forms covalent adducts with cell
Reactive free radicals Experimental studies suggest that       proteins.
     MEOS, like other cytochrome P-450 enzymes, can         Clinical features.
     generate reactive free radicals which are highly      Non specific symptoms: vague abdominal pain, nausea,
     cytotoxic.                                                vomiting, anorexia, weakness, weight loss, and fever.
Hypermetabolic state and hypoxia: EtOH can  metabolic         Few have jaundice, but may notice dark urine.
   oxygen consumption   vulnerability of liver cells     Physical Exam: Hepatomegaly, often with tenderness and
   near the central vein (where sinusoidal oxygen              fever. Signs of liver dysfunction (jaundice, spider
   concentration is )  hypoxic injury                        angiomata) and / or those of portal HTN (ascites,
Other Causes                                                   splenomegaly)
1. Difference among ethnic groups. Many Asians have        Lab studies: Not definitively diagnostic.
   an inactive form of acetaldehyde dehydrogenase              AST levels are usually < 300-500 U. Not like acute
   isoenzyme, ALDH2 Hence, they develop distressing              viral hepatitis.
   symptoms (e.g., flushing, nausea, etc.) after EtOH           AST/ALT ratio ( > 2)  alcoholic liver disease.
   ingestion due to accumulation of acetaldehyde in the    Diagnosis: Liver biopsy is essential because clinical
   serum. This propensity to adverse symptoms may              manifestations correlate poorly w/severity of tissue
   prevent them from excessive drinking and, in turn,          injury.
   account for the  incidence of alcoholism among         Clinical course: Morphological and functional changes
   them..                                                      mentioned above are usually reversible w/abstinence
2. Difference between sexes. Incidence of EtOH liver dz        from alcohol. However, alcohol hepatitis is a
   is  in  vs. . However,  develop EtOH hepatitis          potentially lethal condition, & in some pts may
   and cirrhosis with a shorter duration and lower intake      progress either to hepatic failure or to cirrhosis.
   of EtOH than do , ( are more vulnerable to the toxic Cirrhosis
   effects of EtOH than )                                 Progression to cirrhosis involves fibrogenesis, in addition
3. inadequate diets: Many alcoholics have poor diets.          to liver cell necrosis and regeneration. Following cell
   Hepatic injuries identical to those of EtOH liver dz        types are known to be involved:
   develop in non-alcoholics with nutritional imbalance    1. **Ito cells (or lipocytes) in the perisinusoidal space of
   (ileo-jejunal bypass, obesity) Imbalance in amino acid      Disse
   metab may be pathogenetic factor.                       2. **Hepatic macrophages (Kupffer cells)
  ALCOHOL-INDUCED LIVER DISEASE                              3. Hepatocytes
Injury to the human liver spans a spectrum that ranges       Principal effectors of fibrogenesis are Ito cells and their
   from EtOH fatty liver, EtOH hepatitis, &                     activated counterparts. Initial activation, possibly as a
   micronodular (EtOH) cirrhosis. Cirrhosis may                 result of liver cell injury, or release of mediators by
   develop w/out antecedent EtOH hepatitis.                     Kupffer cells,  onset of fibrogenesis  disruption of
                                                                pericellular matrix  stimulatory effects of its own.
Alcoholic fatty liver                                           Acetaldehyde and cytokines are thought to accelerate
Pathology and pathogenesis.                                     these processes.
Not specific histologic changes. Thought to be readily       Fibrogenesis begins within the perisinusoidal space in the
   reversible. Possible that the cell injury associated with    centrolobular region (near the central vein) 
   fatty liver may lead to more severe subsequent disease.      elsewhere  obliteration of central veins and the
  formation of fibrous septa which encircle nodules of        2. Acetyl cysteine (a GSH precursor, N-acetyl cysteine)
  parenchyma formed by regeneration from injury and              if given shortly after the acetaminophen ingestion.
  necrosis, i.e. cirrhosis.
                                                              Selective Hepatotoxins
What is the safe level of drinking? 8 gm /day or 8 beers or
  7 oz of 80 proof liquor. Cirrhosis develops in only 15      Antimetabolites which produce hepatic injury by:
  to 30% of heavy drinkers.                                    diversion or competitive inhibition of essential
                                                                metabolites or
                                                               other forms of interference with specific metabolic
           HEPATOTOXINS                                         processes.
The liver and kidney play key roles in the metabolism and
   elimination of drugs.                                      Cytotoxic type.
Liver: Removes water-insoluble drugs (bound principally       Antibiotics: tetracycline
   to albumin) from plasma and converts them into more        Antimetabolites: methotreaxate and other chemo agents.
   water-soluble forms which are excreted into bile and          Many of these agents produce fatty change by
   eliminated via the GI tract. The metabolic processes          interfering with synthesis of apoprotein or with
   involved in enhancing water solubility of drugs (or           assembly of lipoprotein complex required for the
   other substances) are referred to as biotransformation.       transport of lipid from the liver.
Kidney: Predominantly eliminates water-soluble drugs or       EtOH:
   their metabolites.
Hepatic Biotransformation                                     Cholestatic type. Selectively interfe with biliary
Phase I                                                         secretion. A number of C-17 alkylated anabolic
Oxidation: (1) Mixed-function oxidases  cytochrome-            steroids (e.g. methyl testosterone) fall into this
   P450  most lipid soluble drugs (2) Dehydrogenation          category. Hepatic dysfunction is produced in many
    alcohol dehydrogenase                                      individuals, but jaundice in only a few. It is presumed
Reduction  various reductases                                  that these steroids interfere with the transcanalicular
Hydrolysis  various esterases                                  transport of bile.

Phase II                                                           Host-dependent hepatotoxin
1. Glucuronidation                                            1. Their toxicity is not dose-dependent.
2. Sulfation                                                  2. They are recognized to depend on unique individual
3. Glutathione                                                   susceptibility rather than on the intrinsic toxicity of the
4. Others (e.g. acylation, hydration, methylation)               agents.
                                                              3. Reproduction of the hepatic damage in experimental
           Intrinsic hepatotoxin.                                animals is difficult.
Relatively few drugs in current use are hepatotoxins. This Metabolic idiosyncrasy.
   is not surprising considering that all new drugs are
   tested in animals and if found to be toxic are usually     Some drugs produce hepatic injury in small proportion of
   not released for clinical use, unless their hepatotoxicity    exposed individuals, under conditions that do not
   is only minimal or unless they possess unique and             conform to the criteria for hypersensitivity as the
   urgently needed therapeutic properties.                       mechanism. This form of hepatic injury is thought to
Injuries induced by these agents are characterized by the        result from metabolic abnormality that leads to
   following features:                                           accumulation of very high levels of the drug or its
1. Produce distinctive hepatic lesions in all individuals,       hepatotoxic metabolites.
   provided a large dose is administered.                     Isoniazid: Clinically, significant liver injury due to INH
2. The severity of lesions is dose-dependent.                    is uncommon (jaundice: 1 % of cases). Toxicity is age-
3. Identical lesions are readily reproducible in                 related: rare before age 20, but increases with age.
   experimental animals.                                         Transient liver dysfunction may occur, but this
                                                                 resolves despite the continuation of therapy, and is
Non-selective hepatotoxins.                                      unrelated to more severe form of injury, which
Food: Poison mushrooms.                                          resemble viral hepatitis histologically.
Carbon tetrachioride (CCl4): disrupts all elements of         Mechanism: production of metabolites that bind
   the hepatocyte including the endoplasmic reticulum,           covalently to macromolecules  necrosis. Clinical
   mitochondria, lysosomes and plasma membrane, and              course of this injury may be severe with mortality rate
   induces almost immediate breakdown of the cellular            as high as 10%.
   structure and function. The membrane injury appears        Hypersensitivity
   to result from peroxidative damage of the lipid
   components, caused mainly by a metabolite of CC14. a. Latent period of 1-4 weeks.
   The injury is initially recognized as centrolobular fatty b. If have continuous exposure  Prompt recurrence of
   change and subsequently as necrosis. Mushroom toxin           hepatic dysfunction.
   (phalloidin) also causes a similar severe cell injury.     c.  incidence of fever, rash and eosinophilia, and
Acetaminophen (Tylenol) in overdose:                             eosinophil-rich inflammatory infiltration, or
1. centrolobular distribution                                    granulomas in the liver.
2. severe hepatic injury and necrosis.
Major pathway: acetaminophen is conjugated and then           Allopurinol: < 0.1%
   excreted.                                                  Halothane: Uncommon < 0.01% incidence. It usually
Minor pathway: biotransformation (mixed function                 follows repeated anesthetics. A history of unexplained
   oxidase)  active (toxic) intermediate  detoxified           fevers five to seven days after a previous halothane
   by reacting with glutathione (GSH)  excreted. OD or          exposure is often obtained. A moderate to high fever
   enhancement of mixed function oxidase activity               develops, occasionally with a rash and arthralgia.
   toxic metabolite to the degree that exceeds that              Jaundice appears 3-4 days later.
   available tissue GSH for detoxification                    Cases example  pt had halothane anesthesia 3x.
Acetaminophen toxicity may be modulated by several               Although there was no fever after the first anesthetic, a
   factors. For example, induction of enzymes involved           fever developed 6 days after the second exposure, and
   in biotransformation (e.g. phenobarbital, chronic             1 day after the third. He then became jaundiced. He
   alcoholism) would enhance the toxicity, whereas               died 11 days after the third halothane exposure.
   starvation (which depletes GSH stores) makes the host         Autopsy revealed extensive necrosis in the
   vulnerable to the toxicity.                                   centrolobular zone (parenchyma around central
OD treatment:                                                    veins)..
1. Starvation
Chlorpromazine: Mainly cholestatic without                           Viruses: (B, C, not A) CMV, Yellow fever, etc.
   parenchymal injury with  Alk Phos and bile stasis on             Toxins Alcohol, Organics (CC14, halothane.), Drugs
   liver biopsy.                                                        (INH, aldomet, amiodarone)
Methyldopa: resembles viral hepatitis (high                          Metabolic (uncommon): Wilson's dz, Hemochromatosis,
   aminotransferase and focal liver cell necrosis).                     -antitrypsin deficiency, cystic Fibrosis, glycogen
Sulfonamide: mixed hepatocellular and cholestatic                       storage dz
   damage                                                            Autoimmune: autoimmune hepatitis, Primary biliary
                                                                        cirrhosis, Chronic biliary obstruction
Clinical manifestations
                                                                     Idiopathic: Steatohepatitis, indian childhood cirrhosis
Host-dependent drug injuries are seen much more
   commonly than those due to intrinsic toxicity.                    Pathogenesis:
   Nevertheless, the frequency of occurrence of the            Old simple viewpoint: necrotic cells become replaced by
   former is quite low and highly variable.                       fibrous tissue much as the process of scarring
Low               <1 % isoniazid                                  anywhere. This concept has a number of shortcomings.
Very low          < 0.1 % allopurinol, -methyldopa            1. Major acute hepatocellular necrosis does not produce
Rare              < 0.01% halothane                               cirrhosis.
                                                               2. There are well studied models in which progressive
When a drug injury is suspected, it is important to have an       fibrosis necrosis. occurs without hepatocellular
  accurate history regarding the temporal relationship         3. Compared to inflammatory states in other tissues,
  between the drug administration and the onset of                fibrosis in the liver is disproportionately great.
  clinical manifestations. Other plausible causes must be active fibrogenesis in response to a variety of stimuli.
  carefully ruled out (e.g. vital hepatitis).                     This is generally accepted; the major questions of
                                                                  interest now are what cell type produces the collagen,
               Hepatotoxin    Idiosyncrasy    Hypersensitivity    and what is the trigger for fibrosis?
Onset                      rapid variable (1wk-1 yr) variable
(often 1 6 wks)
Every individual Susceptible yes    no                    no         Liver cell types:
Dose-effect Relationship      pos   pos.?/neg             neg.       1/2 hepatocytes
Reproducible in animals       yes   no                    no
                                                                     1/3 nonparenchymal cells:
Reaction to Rechallenge       rapid delayed (1-2 weeks) rapid 1      sinusoidal endothelial cells
      few days
Hypersensitivity Features     neg.  neg.            pos./neg.        Kupifer cells
                                                                     Ito cells [fat storing cells, myofibroblasts]
As shown above, if a hepatic injury occurred within a
   very short span of time and severe, it is likely to be            The data: In the resting state, at least half of what little
   caused by an intrinsic hepatotoxin. If a liver disorder             collagen is produced is produced by the hepatocyte.
   developed upon repeated exposure to a given drug and                During inflammation, however, the Ito cell becomes
   after several weeks after the initial exposure, a                   activated and produces large amounts of collagen, and
   hypersensitivity injury is a possible cause. Association            are thought to contribute to most of the collagen
   of fever, skin rash, and eosinophilia adds support to               during the evolution of cirrhosis.
   such a possibility. The diagnosis may be further                  Mechanism:
   supported if the histopathologic changes revealed by
                                                                     Acetaldehyde (the first metabolite of ethanol) has been
   biopsy match what is expected. However, the
                                                                        shown to  collagen synthesis in cultured fibroblasts
   usefulness of histopathology is limited because
   morphologic changes are limited in their variety.                    and hepatocytes. It has been shown to transcription
Pathologic findings  Causative drugs                                   of procollagen mRNA.
Acute parenchymal necrosis                                           Protein adducts form with aldehydes. Aldehydes have
Zonal (centrolobular)  Acetaminophen, halothane                        been shown to be present in a variety of inflammatory
Diffuse (spotty) necrosis resembling viral hepatitis                   states (e.g., malondialdehyde, hydroxynonenal) and
                                                                        they all form adducts. It is thought that these
    Isoniazid, -methyldopa
                                                                        aldehydes may interact with cellular proteins which
Steatosis (microvesicular)  Tetracycline; vaiproic acid
                                                                        regulate transcription, although specific proteins have
                                                                        not been identified. Finally, certain aldehydes are
                                                                        known to be chemotactic for inflammatory cells which
Canalicular  C-17 alkyl-steroids; estrogens
                                                                        release the fibrogenic cytokine TGFB.
Cholangitis  Chlorpromazine; Sulindac
                                                                     This may be a final common pathway of inflammation
                                                                        and fibrosis in the liver. Cytokines released by
Mixed pattern
                                                                        inflammation are chemotactic and also stimulate
Atypical hepatitis  Sulfonamide
                                                                        granulocytes and mononuclear cells to produce free
Granulomatous hepatitis  Allopurinol; phenylbutazone,
                                                                        radicals and activated oxygen species. This gives rise
                                                                        to lipid peroxidation (with membrane damage) and
                                                                        production of aldehydes.
                   CIRRHOSIS                                         Adducts have been immunologically co-localized in liver
Definition:                                                             tissue with areas of active collagen formation during
Although the name cirrhosis was derived from the Greek                  experimental inflammatory states in animals and
   word "orange-yellow," it is a late stage of progressive              pathologic inflammatory states in man.
   liver disease defined by the following 3 characteristics:
1. Fibrosis, present in the form of fibrous septa encircling         Structure-Function Correlation.
   the parenchyma into nodules.                                      Two major abnormalities occur which produce disease.
2. Parenchymal nodules, formed by regeneration of                    1. Altered vascular architecture.
   hepatocytes.                                                      2. altered exchange barriers   hepatocellular function
3. Structural distortion of entire liver by the above two            3. hepatocellular mass   hepatocellular function
Parenchymal nodularity, which reflects the balance                   Altered vascular architecture.
   between regeneration and scarring, is requisite for the           1. Fibrotic obliteration of central veins.
   diagnosis of cirrhosis. The fibrosis, once developed, is          2. "Capillarization" of sinusoids
   usually irreversivle.                                              porosity of sinusoidal endothelium.
                                                                     Formation of basement membrane-like material
Etiology:                                                            Collagen deposition in perisinusoidal spce of Disse
Cirrhosis may be caused by chronic ongoing
   hepatocellular injury from one of a variety of causes..
Combination of the above decreases compliance and              If this structure is disturbed then called cirrhosis. Have
   increases resistance in sinusoidal bed, and results in          fine network of collagen. If do not destroy structure
   portal HTN.                                                     then liver will regenerate. As long as structure is
Deceased metabolic efficiency:                                     intact the liver will fill all of those spaces. Acute liver
1. Decreased Mass   metabolism.                                  failure  cells come back because reticular structure
2. The liver is an important clearance organ for                   was not disturbed. Called distortion in architecture.
   endogenous and exogenous substances (xenobiotics,           Portal circulation in cirrhosis: factors
   bilirubin, bile acids, lipoproteins, etc.). Clearance
   depends on the high permeability of sinusoids with          increasing resistance
   virtually no restriction barrier to passage from sinusoid   Fibrosis has several consequences.
   to space of Disse. Compliant sinusoidal walls promote       1. Sinusoidal walls become thickened and noncompliant.
   "cellular pumping" and circulation through the space        2. Sinusoidal diameter decreases.
   of Disse.                                                   3. Some sinusoids are even obliterated by the fibrotic
3. In cirrhosis,"capillarization" mentioned above reduces         process.
   sinusoidal permeability and interferes with uptake of       4. Resistance across the liver increases.
   metabolites. This creates functional "shunting" of
   blood around hepatocytes. In addition, a decrease in        Collateral circulation.
   surface to volume ratio of the parenchyma contributes       1.  resistance across the liver   portal pressure
   to the reduced metabolic exchange. This results from        2. This  flow through ordinarily insignificant vessels
   the formation of regenerative nodules, in which liver          which run between systemic and portal circulation
   cells form multicellular thick masses rather than single       ("portasystemic collateral vessels"). Subject to
   cell-thick plates.                                             constant increased pressure and flow, these vessels
Diminished hepatocellular mass.                                   become tortuous and large.
This is not so much related to cirrhosis itself as to the      3. Collateral sites include:
   causative injury. More often than not, this injury             a) Esophageal varices: Up the rt. coronary veins to the
   causes hepatocellular necrosis. Not only do we have                submucosal esophageal vein & thence to the
   uptake diminished but also we have reduced                         azygous vein
   biotransformation, synthetic function, and excretion.          b) Caput medusae: Along the recannulated umbilical
   Fortunately, the liver has great reserve capacity. We              vein from portal vein to periumbilical abdominal
   can probably lose about 2/3 of our hepatocellular mass             veins and thence to the intercostals (up) and
   and still get along so long as architecture is preserved.          femoral circulation (down)
                                                                  c) Duodenal varices: Superior mesenteric vein to
Physical findings.                                                    peripancreatic veins
A. Related to altered hemodynamics/vascular                       d) Rectal varicies: Inferior mesenteric vein to
   architecture.                                                      perirectal and hemorrhoidal veins
   1. Ascites.                                                    e) Any postoperative site involving organs receiving
   2. Abdominal wall collaterals.                                     portal circulation.
   3. Peripheral edema.                                           f) Other sites exist but they are rare.
B. Related to poor synthetic
   function/cytokines/biotransformation.                       Portal circulation in cirrhosis: increased flow
   1. Wasting.                                                 Circulation in cirrhosis is hyperdynamic w/AV shunts
   2. Bruising (coagulopathy).                                    through spider telangiectasia not just in skin but their
   3. Encephalopathy.                                             equivalent in lung and other organs as well. It is
   4. Signs of feminization (spider angiomata,                    possible there is a circulating vasodilator substance
      gynecomastia, female escutcheon).                           which is not inactivated by the liver, presumably
C. Related to poor uptake and/or excretory function.              because of portosystemic shunting. Candidates for this
   1. Encephalopathy                                              vasodilator substance are circulating bile acids,
   2. Jaundice.                                                   glucagon, and nitric oxide. There is some evidence
                                                                  that each may be important and there are probably
Laboratory abnormalities.
1) Leucopenia, anemia, thrombocytopenia.                       The portal system shares this hyperdynamic circulation.
2) Contributes to high bilirubin, serum bile acids, NH3.          Specifically, portal flow increases in experimental
3)  serum albumin.                                               models of portal hypertension and in experimental and
4) Prolonged prothrombin time (PT).                               clinical cirrhosis.
5) Abnormal tests of biotransformation (e.g., galactose
   tolerance test, aminopyrine clearance test, etc.).          Measurement of portal pressure
6) High serum NH3.                                         Direct methods.
7) High serum bilirubin, bile acids, NH3                   1. Splenic pulp pressure.
8) Prolonged retention of organic anionic test dyes, e.g., 2. Trans-hepatic catheterization of the portal vein.
   Bromosuslfophthalein, Indocyamne green).                3. Cannulation of recanalized umbilical vein.
                                                           These all allow direct and accurate measurement of portal
                                                              pressure. However they do not get inferior vena caval
               PORTAL HTN                                     (NC) pressure. Yet a very important measurement to
What is a "portal" circulation? Most of the blood             know is ti difference between the PV and NC pressure.
   comes from the portal circulation. There are many          It is this gradient which is responsible for formation of
   growth factors that come from that portal circulation.     varices and formation of varices gives rise to one of
   If stop the blood flow from that side will lead to some    the most life-threatening complications of cirrhosis.
   shrinking. Thrombus in hepatic vein  still have        Hepatic wedge (HW) and free hepatic vein (HV)
   circulation from hepatic artery.                           pressure.
Then to hepatic veins and will drain into inferior vena    HWP reflects sinusoidal pressure. This is equivalent to
   cava.                                                      portal vein pressure when the maj resistance site is
When normal liver cirrhosis  filter that is clogged. Will    post-sinusoidal. This is close to true in most forms of
   back up into all of these veins. See the gut getting       cirrhosis we common encounter (Laennec' s [or
   congested. Blood has to go somewhere. Will come out        alcoholic] cirrhosis, cirrhosis caused by chronic active
   in new veins.                                              hepatitis). Le true for biliary cirrhosis, not true for
Hepatic lobule central vein. Periphery is portal tract.      cirrhosis of Wilson's disease and schistosomiasis, for
   Now portal venues spill.                                   instance.
Bile comes in the opposite way.                            Consider extreme cases:
1) A patient with thrombosis of portal vein with severe          We know, for instance, that one of the earliest
   portal hypertension would manifest normal HWP but             abnormalities in progressive liver disease is abnormal
   nonetheless would eventually form esophageal                  retention by the kidney of salt and water. This occurs
   varices.                                                      before ascites formation, and if prevented (e.g., with
2) A patient with severe right sided congestive heart            the use of diuretics), ascites will not form. Plasma
   failure would have both a high HWP are high IVCP,             volume and ascites volume tend to parallel one
   but the PV-NC gradient would be normal. That                  another. The mechanical factors mentioned tend,
   patient would not for varices.                                however, to favor sequestration of fluid in the
                                                                 peritoneum. Nonetheless, except in the most advanced
                                                                 cirrhosis, patients with ascites also have peripheral
          HEPATIC FAILURE                                        edema--a manifestation of excess fluid and salt
           (Complications)                                       retention and expanded plasma volume. The causes of
                                                                 1* fluid retention in liver disease are not yet fully
Variceal hemorrhage.                                             sorted out.
1) Most commonly from esophageal or gastric cardia            1. Diuretics: dangers of electrolyte imbalance and
   varices. Uncommonly from other sites (rectum,                 prerenal azotemia.
   duodenum).                                                 2. Large-volume tap (paracentesis): same dangers as (1).
2) Portal pressures (portal vein pressure minus inferior      3.  sinusoidal pressure (side-to-side portasystemic shunt
   vena caval pressure) must exceed about l2mmHg for             or equivalent): danger of encephalopathy.
   varices for form and hemorrhage to occur.                  4. Peritoneo-venous shunt: danger of infection and
3) Although a result of architectural alteration, mortality      blockage.
   is directly related to severity of underlying              Complications of ascites.
   hepatocellular disease (as manifest by height of serum     1. Invalidism.
   bilirubin, depression of serum albumin, prolongation       2. Discomfort, hypoventilation.
   of prothrombin time, presence of muscle wasting,           3. Ruptured umbilical hernia.
   ascites and encephalopathy).                               4. Spontaneous bacterial peritonitis.
Therapies:                                                    5. Hydrothorax.
1. Transfuse, correct encephalopathy.                         Hepatorenal syndrome
2. Sclerose or band esophageal varices.
                                                              ―Functional‖ form of RF seen in advanced liver dz. No
3. Perform portacaval shunt (surgery or TIPS).
                                                                 histologic abnormality of the kidney.
4. Liver transplant.
Except for the latter therapy, long term survival not         Possible causes:  levels of bilirubin  activation of
   greatly influenced although bleeding is stopped. An           endothelin  afferent constriction  glomerular
   example of the importance of hepatocellular function          damage.
                                                              Liver transplantation restores renal function. Kidneys may
   as a determinant of survival.
Variceal hemorrhage, miscellaneous.                              be transplanted into someone w/intact liver and
1. When hepatocellular dz is severe, clotting factors,           function normally.
   especially vitamin K-dependent clotting factors, are       Clinical:
   not made (greatly prolonged PT) and a severe               very  uNa: Normal nNa is >80 and uK 40. This ratio
   coagulopathy is present.                                      flips w/hepatorenal. uNa can drop to <10 and  of uK
2. In portal HTN, the spleen becomes large and because           from 40.
   of congestion and stagnation of flow, blood element        progressive oliguria
   are sequestered and destroyed. Any one or all of the       azotemia.
   hematopoetic cell lines may be depressed (WBC,             Treatment: No specific therapy exists.
   RBC, platelets). If platelets are depressed below about    Infection
   50,000, that worsens coagulopathy. This is called        Defects in the immune system in cirrhosis (especially
                                                               alcoholic liver disease).
Ascites                                                     1.  clearance of substances from portal blood.
Peritoneal tumors, inflammation, ruptured organs,           2. Serum factors inhibit chemotaxis.
   infection can all cause ascites. Clinically by far the   3. Serum factors inhibit phagocytosis.
   commonest cause is liver disease.                        4.  cellular immune response.
Dynamics/mechanics of ascites formation.                    These defects are often potentiated by defects seen in
1. Comparison of liver sinusoid to classical "Starling         malnutrition and acute alcohol ingestion.
   capillary." In the sinusoid: there is no oncotic          rates of gram negative sepsis.
   gradient there is no interstitium there is probably a    In one study, cirrhosis admitted for 01 bleeding had 35%
   positive pumping through space of Disse.                    incidence of significant infection. Some advocate
2. The rate of sinusoidal fluid efflux is solely determined    antibiotic prophylaxis. Although incidence of infection
   by sinusoidal pressure.                                     is reduced (16%), mortality is unchanged This is
3. Hepatic lymphatics contain high protein. They drain         another example of the importance of hepatocellular
   down the porta hepatis and eventually into the thoracic     function as a determinant of prognosis.
   duct.                                                    Spontaneous bacterial peritonitis
4. When pressure in the sinusoidal bed , efflux rate      Clinically silent in 50%, high mortality (30-50%),
   When this exceeds the rate at which lymph can be            especially likely to occur in fluids with low protein
   removed, it leaks into the peritoneum.                      content The organisms entering the systemic
5. When the rate of leakage exceeds the maximal (fixed)        circulation colonize the ascites. Mortality, again, is
   rate of reabsorption, ascites occurs.                       ultimately related t severity of underlying
6. In portal HTN there is some contribution of exuded          hepatocellular disease.
   fluid from the splanchnic bed, but it is not great.      Encephalopathy
7. This accounts for the relatively high protein content of
   ascites in acute inflammatory states in the liver.       Porta-systemic encephalopathy.
8. Remember "capillarization" of sinusoids. As the          1) Caused by one or more "toxins" generated in the gut
                                                                 and absorbed via the portal vein. Because of porto-
   fibrotic process continues, the sinusoid becomes less
   permeable to large molecules (e.g., albumin) and              systemic shunting, these "toxins" escape usual
   ascitic fluid protein concentration falls.                    extraction and detoxification by the liver.
                                                            2) The shunts may be either spontaneous intrahepatic
"Cause" of ascites.
                                                                 (capillarized sinusoids) or extrahepatic (collateral
Although  sinusoidal pressure (simple mechanical
                                                                 pathways) shunts or they may be created shunts
   theory) does not completely explain ascites formation.
                                                                 (TIPS or portacaval shunts). At least one toxin in
     ammonia generated by deamination of amino acids                from heme containing enzymes (primarily from the
     and hydrolysis of urea by intestinal bacteria and by           liver; cytochrome P-450, catalase). Red blood cells are
     deamination of glutamine by intestinal mucosa (see             degraded mostly in the spleen.
     OP notes for metabolism of NH3).                            Heme: dissociated from its apoprotein (e.g. globin) 
3) Because there is not perfect correlation between stage           converted to biliverdin by heme oxygenase in RE cells
     of encephalopathy and arterial NH3 level, other                (hepatocytes, Kupifer cells and renal tubular cells).
     toxins have been postulated (GABAergic substances,          Biliverdin: green and water soluble pigment, is converted
     "endogenous" benzodiazepine-like compounds, short              to bilirubin by cytosolic NADPH dependent enzyme
     chain fatty acids, mercaptans, false                           biliverdin reductase in the RE cells.
     neurotransmitters). This is an area of active
                                                                 Sources of Bilirubin
4) Precipitating/potentiating factors:                           1) Bilirubin production is 250 - 350 mg daily in average
    High protein intake or GI bleeding                            adult.
    Constipation                                               2) Destruction of senescent RBC.
                                                                 3) Turnover of hemoproteins (e.g., cytochrome P-450
    Sepsis (catabolic state)
                                                                    and catalase).
    Sedatives/narcotics:  CNS threshold; 
                                                                 4)  rate of RBC breakdown from hemolysis and
        catabolism of drugs in liver dz
                                                                    resorbing hematomas may  unconjugated
    Hypokalemia, alkalosis:  deamination of
        glutamine by the kidney, shift in NH4-s-INH3
                                                                 5) Ineffective erythropoiesis: pernicious anemia,
                                                                    thalassemia, dyserthropoietic anemia, porphyria, lead
    Azotemia
                                                                    poisoning   heme release  unconjugated
Hepatic encephalopathy.
Occurs with extensive loss of hepatocellular function.
   Functional shunts need not be present. Arterial NH3           Transport and Conjugation of Bilirubin
   concentrations are less likely to be elevated. Although       Unconjugated bilirubin is primarily bound to albumin.
   it is likely that all of the aforementioned toxins are not    There is a small amount of unbound bilirubin in the
   detoxified, it is also possible that an as yet unidentified        plasma and is presumed to be the fraction available
   substance synthesized by the liver and necessary for               for the transit across the blood-brain barrier.
   normal CNS function is not being produced.                         Kernicterus (neonatal brain damage) may occur when
Most often seen in the acute syndrome of fulminant                    the unbound bilirubin level is increased by the
   hepatic failure (viral hepatitis, acute drug toxicity,             displacement of albumin-bound bilirubin by drugs
   acute Wilson's disease, etc.). Conventional therapies              (e.g., sulfonamides, anagelsics, diuretics), free fatty
   are less successful than in portasystemic                          acids or acidosis.
   encephalopathy. In fulminant hepatic failure, hepatic         Bilirubin uptake from the plasma occurs through
   encephalopathy may be accompanied by acute brain                   fenestrations in the hepatic sinusoids by a carrier-
   edema and intracranial pressure elevation. Mortality is            mediated mechanism. This permits the albumin-
   high.                                                              bound bilirubin direct access to the hepatocyte
Clinical findings:                                                    plasma membrane. The albumin to which the
1. Liver disease.                                                     bilirubin is bound does not accompany the pigment
    Stage 1: lethargy, mild confusion, disordered sleep             into the hepatocytes. Uptake is not rate-limiting.
        pattern.                                                 Intracellular transport occurs by the cytosolic carrier
    Stage 2: asterixis, somnolence, inappropriate                   proteins ligandin and fatty acid binding protein
        behavior, disorientation.                                     (glutathione-S-transferase B). These cytosolic
    Stage 3: stupor, speech incomprehensible                        macromolecules appear to limit the efflux of bilirubin
    Stage 4: coma.                                                  from the hepatocytes back to the plasma.
Therapy                                                          Bilirubin conjugation occurs in the hepatocytes'
1. Be sure hypoglycemia does not exist.                               endoplasmic reticulum (ER) by the enzyme system
2. Treat all reversible precipitating/potentiating factors            UDP-glucuronyltransferase. This makes the bilirubin
   present.                                                           soluble in water; bilirubin mono & diglucuronides
3. Purgation (enemas, cathartics), Abx, lactulose                     (conjugated bilirubin). Secretion of bilirubin
4. Liver transplant if fulminant hepatic failure and other            conjugates can then take place from the hepatocytes
   therapies not beneficial in reversing progressive stage            into the sinusoids.
   3-4 encephalopathy.                                           1) Bilirubin + UDP-glucoronic acid -* biilirubin
                                                                      monoglucoronide (BMG
                                                                 2) BMG + UDP-glucoronic acid -~ bilirubin
          BILIARY DISEASE                                             diglucoronide (BDG)
Bilirubin is a by-product of heme degradation. Initially it
   is water-insoluble and excreted in bile after its             Almost all bilirubin is excreted in bile in the conjugated
   conversion (via conjugation in the hepatocyte) to                 form.. Normal bile contains about 80% BDG and
   water-soluble glucoronides in the liver.                          20% BMG. Less then 1 % of the bilirubin excreted in
                                                                     the bile is unconjugated.
Hyperbilirubinemia: abnormal  in serum bilirubin 
   jaundice or icterus when the level > 2.5 - 3.0 mg/100         Conjugated bilirubin transport from the liver cell to the
                                                                     canalicular space involves a carrier-mediated process.
Cholestasis, or defective bile secretion, may be due to the          Membrane carriers appear to be involved (one of
   failure of the hepatocyte to secrete bile (intrahepatic           which is defective in Dubin-Johnson syndrome), the
   cholestasis) or due to disease processes that involve             Multi-Organic-Anion-Transplanter (aMOAT).
                                                                 Conjugated bilirubin is not reabsorbed by the gallbladder
   the intrahepatic or extrahepatic bile ducts.
                                                                     or intestine, and is secreted in bile and drained into
Bilirubin Formation                                                  the alimentary canal.
Heme + 02  Biliverdin, Fe, CO                                   Enterohepatic circulation results from the reduction of
Biliverdin   Bilirubin + 2H                                         bilirubin by intestinal bacteria mostly in the colon
                                                                     (some in the distal intestine). This results in the
Bilirubin: Orange-colored tetrapyrrole. Principal                    formation of urobilinogens. About 20% of
   degradation product of heme. The destruction of the               urobilinogen is reabsorbed via the portal circulation,
   heme moiety of hemoglobin in senescent RBC occurs                 and is promptly re-excreted by the liver into the bile
   in the reticulendothelial system (Bone marrow, spleen             (i.e., enterohepatic circulation) A small fraction of
   and liver) and accounts for 80% of the total bilirubin            the daily urobilinogen (-2%) is excreted in the urine.
   production. The remaining 20% of bilirubin comes
                                                             Relatively uncommon cause of liver dz but account for 5-
    Pathophysiology of Bilirubin                                10% of hospital cases of jaundice and hepatitis.
                                                             Fulminant hepatic failure: Acetaminophen toxicity is
           Metabolism                                           one of the leading causes of fulminant hepatic failure.
Normal serum values are:                                        If pt presents for medical care soon enough, specific
1. Total bilirubin <1.0 mg/l00 ml (<17 umol/L)                  therapy is available.
2. Direct reaction (conjugated fraction) is <0.3 mg/l00 ml Mild liver abnormalities: Majority of drug reactions are
   (<5)                                                         usually innocuous and associated with mild liver
Increased Production                                            chemistry abnormalities. Commonly used meds 
                                                                psychotropic drugs, NSAIDS, cardiac drugs, Abx, H2-
1. Hemolysis: Excessive destruction of circulating RBC.         receptor antagonists, troglitazone, nucleoside reverse
   May be intravascular (hemolytic anemias) or                  transcriptase inhibitors and chemotherapeutic agents.
   extravascular (hematomas-breakdown of extravasated Estrogens: can be associated with cholestasis  OCP,
   RBC‘s). Hemolysis is the most frequent mechanism             post-menopausal estrogen replacement therapy or even
   for bilirubin overproduction. It is uncommon for the         pregnancy.
   bilirubin to > 4 mg/dl w/hemolysis if hepatic clearance
   is Nl.                                                    Viral Hepatitis
2. Ineffective Erythropoiesis: RBC are not produced          Acute inflammation of the liver from any of the hepatitis
   normally as in pernicious anemia, thalassemia and            viruses can be associated with jaundice. May be more
   sideroblastic anemia  excess heme production.               common with acute Hep A.
Impaired Hepatic Uptake                                      Chronic Hep B and Hep C are more often asymptomatic.
                                                             Delta hepatitis, EBV, HSVand CMV all can cause an
Drugs may compete with bilirubin for sinusoidal                 acute icteric hepatitis.
   membrane transport or with binding to the cytosolic
   binding proteins. Examples include rifampin,              Primary Biliary Cirrhosis (PBC)
   probenicid, rifamycin, and some radioplaque dyes.         Chronic progressive often fatal dz. Destruction of
   These defects are rare and ill-defined.                      intrahepatic bile ducts, portal inflammation 
Impaired Bilirubin Conjugation                                  cirrhosis and liver failure.
                                                             Peak incidence between 40 and 50.
(Bilirubin UDP-glucoronosyl transferase activity)            Autoimmune dz. Systemic polyclonal hypergamma-
1) Crigler-Najjar disease, Type I: severe unconjugated          globulinemia.
     hyperbilirubinemia due to lack of hepatic bilirubin-    Clinical:
     UDP-glucuronyltransferase activity. This is fatal in    Asymptomatic ♀ (~90%) perhaps c/o pruritis. Not EtOH
     early youth. Liver transplant. Unconjugated bilirubin      abuser. No evidence of viral hepatitis.
     > 20                                                    Hepatomegaly
2) Crigler-Najjar disease, Type II:  activity of            Xanthomas
     hepatic bilirubin- UDP glucuronyltransferase            Fatigue
     activity; responsive to enzyme induction with           Extrahepatic autoimmune: Sjogren syndrome,
     phenobarbital; rare and less severe.                       Scleroderma, Hashimoto's thyroiditis, RA, Raynaud‘s,
3) Gilbert's syndrome:  activity. Benign condition,            GN, & celiac dz.
     occurs in about 8% of the normal adult population;      Associated manifestations: metabolic bone dz,
     mild unconjugated hyperbilirubinemia (T bili of 2.5        hyperlipidemia & fat-soluble vitamin deficiencies.
     with direct fraction of 0.1 mg/dl). Mild jaundice may
     occurs with stresses such as dehydration or infection. Lab:
     Later in life and asymptomatically.                      Alk Phos: usually > 300. Combination of  of
4) Physiologic jaundice of infancy (Neonatal                    Cholestatic picture and with development of
     Jaundice):  level of bilirubin-UDP                        osteomalacia   bone turnover.
     glucuronyltransferase activity at birth which soon       cholesterol:
     corrects itself. Thought to be due to the immaturity of Antimitochondrial Ab (AMA) in 95 %.
     the conjugating and possibly the hepatic transport      Treatment:
     steps (e.g. ligandin). When associated with hemolysis Ursodiol  clinical and lab improvement. Improvement
     (e.g. erythroblastosis fetalis),  in serum                in mortality & survival free of transplantation.
     unconjugated bilirubin  kernicterus (a syndrome of Liver Transplantation.
     brain damage). Tx includes phototherapy and
     exchange transfusion.                                   Primary Sclerosing Cholangitis
Impaired Canalicular Biliary Secretion of                    Progressive fibrosing inflammation of bile ducts 
                                                                cirrhosis and portal HTN.
Conjugated Bilirubin                                         Associated w/UC in ~ 75 % of pts, however < 5 % of pts
1) Dubin-Johnson syndrome: Inherited, autosomal                 w/UC will develop PSC. Less commonly associated
     recessive and benign defect in the transport of            with Crohn's disease.
     conjugated bilirubin across the canalicular             Pts are young, usually <50 yo.  /  ratio is 3:1.
     membrane. This is an uncommon condition and is           risk of progressing to cholangiocarcinoma
     associated with a benign brown pigmentation in the
     hepatocyte. A mutated MOAT, an isoform of the           Clinical:
     resistance protein Mrp2, is a possible candidate for    Progressive fatigue
     this defect                                             Pruritis
2) Rotor syndrome: resembles D-J but without                 Jaundice
     pigmentation. Presumably a separate but similar
     defect in bilirubin uptake and storage of bilirubin.    Lab:
                                                              Alk Phos: persistent elevation.
             CHOLESTASIS                                     AMA: Present in < 10%.
Intrahepatic bile ducts: Cholangioles (ducts of Herring),
   intralobular & septal ducts, & right & left main hepatic
                                                            Cholangiography: ―beading‖ of intrahepatic ducts &
                                                               occasional strictures of extrahepatic ducts.
Extrahepatic bile ducts: common hepatic duct and CBD.
Other: gallbladder, cystic duct, ampulla of Vater &
   sphincter of Oddi.                                       Medical management:
                                                            No real good medical Tx. Tx aimed at complications of
Drug Induced Cholestasis                                       cholangitis w/palliative endoscopic stricture dilation.
Ursodiol: improved biochemical tests. Does not change       Charcot's triad: Fever, Abd pain, and jaundice. Present in
   PSC's natural history.                                      70% of pts w/cholangitis
Transplantation: Pts w/intractable symptoms or ESLD         Lab:  Bilirubin, alkaline phosphatase and transaminases
Gallstones                                                  Imaging:
                                                            1) US: dilated intra and extrahepatic ducts, possible
Occur in at least 10 % of the adult population. Majority of      gallstones
   gallstones remain silent throughout life.                2) Endoscopic US: endoluminal imaging of the bile duct
Most commonly cholesterol. Occasionally pigmented.               adjacent to the duodenum
Incidence:  in , in association w/multiple pregnancies, 3) Cholangiography: uses a contrast agent in the bile
   obesity, and rapid weight loss. Also in older pts and in      duct to highlight filling defects that may be stones,
   certain ethnic groups. Only 1-4% per year of                  done by endoscopy (ERCP) or percutaneously.
   asymptomatic pts will develop symptoms or a              Bacterial cholangitis may result from any condition which
   complication of gallstone dz.                               produces bile duct obstruction most commonly is
Almost all pts will develop symptoms for a period of time      associated with benign conditions such as stones or
   before they develop complications.                          structures. This can be a medical emergency.
Stones:                                                     Tx consists of stabilization with IVF and Abx followed by
1. Cholesterol: 80 %. Occur w/supersaturation of               drainage of the obstructed biliary tree by ERCP
   cholesterol in bile. Most common in , obesity,
   pregnancy, ileal dz, TPN pts, PBC, Native American       Benign Biliary Strictures
   Indians & w/exogenous estrogens.                         Associated w/prior surgical manipulation of the biliary
2. Brown pigment: form de novo in                              tree in 95% of cases (usually CBD exploration,
   postcholecystectomized pts bile ducts especially            laparoscopic cholecystectomy and liver transplants).
   w/obstruction and subsequent infection. However, they Other causes: CBD stones, chronic pancreatitis or Abd
   are common in Asians with gallbladders.                     trauma.
3. Black pigmented: pt w/cirrhosis, alcoholic liver dz, & Presentation: cholangitis or benign cholestasis. Can lead
   hemolysis.                                                  to so called "secondary biliary cirrhosis."
                                                            Repair is usually surgical and difficult.
Biliary Colic
Gallstone in the gallbladder  transiently obstructs the     Cholangiocarcinoma
   cystic duct  elevation of pressure in gallbladder       Tumor is located anywhere along the extrahepatic ducts.
   pain (colic)                                                 Adenocarcinoma arising from biliary epithelium.
Clinical feature:                                            Klatskin' s tumor: tumor situated at bifurcation of the
1) severe, episodic, epigastric or right upper quadrant in      CHD (confluence of the right and left hepatic ducts).
    location                                                 Presentation: jaundice, pruritus, weight loss, and pain.
2) lasting 1 to 5 hours                                      Associated conditions include liver fluke infestation in 3rd
3) often waking the patient at night.                           world, congenital biliary cysts & primary sclerosing
4) Occasionally nausea and vomiting develop.                    cholangitis.
Pts w/symptoms 2* to gallstones are more likely (25% in      Lab: Alk Phos is more sensitive than the bilirubin but
   10-20 years) than asymptomatic patients to develop           both are usually abnormal. A bilirubin >12 mg/dl in
   complications. For these reasons, Tx is indicated for        the setting of obstruction implies malignancy.
   pts w/ symptomatic cholelithiasis.                        Diagnosis: direct cholangiography.
Treatment: Laparoscopic cholecystectomy.                     Treatment: surgical resection for attempted cure or with
                                                                placement of a stent for palliation (these can be placed
Acute Cholecystitis                                             endoscopically or percutaneously).
Acute inflammation of the gallbladder wall, usually          Prognosis is poor w/5-10% 5 yr survival & 20 mo median
   accompanied with transient obstruction of the cystic         survival.
   duct by gallstones.
Clinical symptoms:                                           Pancreatic Carcinoma
1) pain localized to the RUQ.  on deep inspiration.         Distal CBD runs through pancreatic head. Pancreatic Ca
     Murphy sign.                                               most often occurs in this area making this tumor the
2) Anorexia                                                     most commonly associated with malignant biliary
3) Fevers to 102°                                               obstruction.
4) Nausea and vomiting.                                      Courvoisier' s law: Obstructing malignancies of the distal
Biochemical abnormalities                                       CBD produce a palpable non-tender gallbladder.
1) Mild  WBC and liver chemistries.                         Vast majority of patients present w/unresectable disease
2) Bilirubin may be as high as 4 mg/dl                          & 5 yr survival is approximately 5%. Pancreatic
3) Rarely elevation in Alk Phos                                 cancer is 4th leading cause of cancer deaths in  and .
May be confused with CBD stones and cholangitis,             Treatment: "Whipple procedure" extensive resection of
   however cholecystitis does not cause biliary                 the pancreas, part of the stomach and duodenum.
   obstruction.                                                 Represents only real chance for cure.
Diagnosis:                                                   Most pts can only be treated palliatively and this may
transabdominal US  gallbladder wall thickening,                include placement of stents as for
   pericholecystic fluid, distention                            cholangiocarcinomas.
(+) sonographic Murphy's sign  pain over gallbladder
   w/transducer pressure
Biliary scintigraphy can detect cystic duct obstruction in
                                                                   PANCREATIC TESTS
   cholecystitis.                                            Radiographic Tests of Pancreatic Structure
Therapy: Definitive therapy  early laparoscopic             1. Abdominal radiograph:. In acute pancreatitis may
   cholecystectomy. However, asymptomatic gallstones            see focal ileus. In chronic pancreatitis characteristic
   should not lead to cholecystectomy.                          finding is calcifications.
                                                             2. Ultrasound: Allows visualization of bile ducts. Can
        Extrahepatic Cholestasis                                detect bile duct dilation which may be caused by
Choledocholithiasis (Bile Duct Stones)                          common bile duct stone or pancreatic head tumor
                                                                compressing bile duct. May show pancreatic swelling,
10% of pts undergoing cholecystectomy have CBD                  calcification, dilated pancreatic duct, masses. Gastric
   stones. 5% of pts after cholecystectomy demonstrate          air may prevent adequate ultrasound imaging of
   retained or recurrent stones                                 pancreas.
Presentation: chronic or transient abdominal pain,           3. Endoscopic ultrasound (EUS). Involves use of
   jaundice, pancreatitis or cholangitis.                       endoscope with ultrasound transducer on tip which is
   placed through patient's mouth and into stomach and          Limitations: Amylase not  in all cases of
   duodenum. Provides excellent imaging of pancreas,            pancreatitis.
   and can detect small masses and changes suggestive of Lack of specificity: Acute pancreatitis, pancreatic
   subtle chronic pancreatitis.                                 carcinoma, acute cholecystitis, common bile duct
4. CT: Excellent imaging of pancreas and surrounding            obstruction, perforation of viscous, intestinal
   structures. Able to show pancreatic edema and                ischemia, intestinal obstruction ,acute appendicitis,
   necrosis. Detects pseudocysts and masses.                    renal insufficiency, and many more.
5. Endoscopic Retrograde Cholangiopancreatogram             Lipase:  in pancreatitis to 3x normal. Normal is 20-250.
   (ERCP). Involves placing endoscope through patient's         More specific. Almost all lipase originates from the
   mouth and into duodenum. Cannula is then placed              pancreas.
   through the ampulla of vater and into the pancreatic or Limitations:
   bile duct. Contrast injected into ducts, and image of       Renal insufficiency: Lipase  only when creatinine
   pancreatic or bile duct viewed radiographically. ERCP        clearance is < 20 ml/min. Lipase level is usually 2x
   also allows therapeutic interventions such as bile duct      normal.
   stone removal or placement of a stent across a              Acute intra-abdominal conditions: Usually less than
   malignant stricture to relieve jaundice.                     3x normal.
Tests of Exocrine Pancreatic Function                       Standard blood tests:
1. Direct stimulation of pancreas: Intravenous infusion         WBC, serum glucose, AST, ALT, Alk phos, and
   of secretin and/or cholecystokinin (CCK) followed by         serum bilirubin.
   nasoduodenal tube aspiration of duodenal fluids.            Biliary vs. alcoholic pancreatitis: ALT > 150 96%
   Secretin stimulation measures pancreatic juice flow          specific for gallstone pancreatitis. However,
   and bicarbonate concentration. Combined secretin-            sensitivity was only 48%. Therefore a level of < 150
   CCK measures pancreatic enzymes (i.e. amylase or             does not exclude gallstone pancreatitis
   lipase). Abnormal tests suggest chronic pancreatitis.    Radiologic features:
   Infrequently performed test because technically          Survey film: Anterior displacement of the stomach. Ileus
   difficult.                                                   of one or more loops of jejunum (called the sentinel
2. Indirect stimulation of pancreas: Bentiromide test.          loop), or any of the small intestine. Colon cutoff
   Synthetic peptide (Bz-Ty-PABA) given orally, which           sign: Inflammation from head of pancreas that
   is cleaved in duodenum by chymotrypsin into Bz-Ty            spreads to the proximal transverse colon that leads to
   and PABA. PABA is absorbed and excreted in urine.            spasm of this area and dilatation of the ascending
3. Stool examination for fat: Fat in stool                      colon. Possible calcified gallstones.
   ("steathorrhea") suggests lack of digestion by lipase,   Chest radiography: limited diaphragmatic excursion,
   implying pancreatic insufficiency. Need >90%                 pulmonary infiltrates, or pleural effusion.
   reduction of pancreatic enzymes before exhibit           Barium Studies: Replaced by CT
   exocrine insufficiency. Steatborrhea usually associated Ultrasound: Presence of gallstone. Dilated CBD.
   with chronic pancreatitis. Visible oil droplets in stool     Enlargement of pancreas
   suggests steatorrhea due to pancreatic insufficiency.    CT: Most common technique for evaluation of acute
      Sudan stain: Qualitative test detects increased          pancreatitis. The indications are:
       neutral fats and/or fatty acids in stool.
                                                               If mesenteric infarction or perforated ulcer cannot be
      Quantitative Fecal Fat. Stool collected for 24-72        excluded.
       hours while patient ingests lOOg fat per day.           Staging pancreatitis
       Normal <7 gm fat per day in stool.
                                                               Defining the complications.
                                                            MRI: Same information as CT. Not currently used.
   ACUTE PANCREATITIS:                                      Differential Diagnosis:
Symptoms:                                                   Biliary Colic
Abdominal pain: Diffuse throughout the entire upper         Perforated hollow viscus
   abdomen. May be localized in the midepigastrum           Mesenteric ischemia
   and LUQ or RUQ. Radiation to the back. Pain              Closed loop intestinal obstruction
   reaches maximum intensity within 10-20 min and           Inferior wall MI
   may appear like a perforated ulcer. Pain is moderate     Dissecting aneurysm
   to severe. Can be unbearable and refractory to PO        Ectopic pregnancy
   narcotics. Steady and boring. Little fluctuation in      Predisposing conditions:
   pain. No relief by change of position of bed.
                                                           Gallstones: Responsible for 30 to 75% of all cases of
Nausea and vomiting: Frequent. May be severe and last
                                                               acute pancreatitis. Caused by lodging of gallstone in
   several hours. May turn into dry heaves. Vomiting
                                                               the ampulla of vater. Pathogenesis remains
   does not relieve the intensity of the pain. Even with
                                                               undetermined. Thought to be obstruction of
   gallstone pancreatitis, there is no temporal
                                                               pancreatic outflow rather than regurgitation of bile
   relationship between eating and the onset of pain.          into the pancreas. Others cases are caused by stones
Physical Exam:                                                 too small to image.
Vitals: HR may be  to 100 to 150. BP may start high and   Alcohol: 30% of cases. Mechanism is unclear.
    then go lower as there is third spacing. Temp: may     Hyperlipidemia: 4% of cases. Most occur in pts with
    be normal and then rise to 101 to 103.                     uncontrolled DM and a Hx of hypertriglyceridemia.
Respiration: May be shallow if there inflammatory              Typically pts will need levels greater than 1000.
    exudate on the diaphragm. Limited diaphragmatic            Levels between 500 and 1000 may occasionally
    excursion if abd causes splinting of the abdomen.          cause pancreatitis.
    Dullness to percussion due to pleural effusion.        Hereditary pancreatitis: Autosomal dominant with
Abdomen: Tenderness in upper abdomen. Guarding,                variable penetrance. Need identification of at least
    percussion tenderness. Distention of abdomen.              two family members. Episodes begin in childhood.
    Rarely rigid. Grey Turner sign: ecchymoses in one      Hyperparathyroidism and Hypercalcemia: 0.5% of
    or both flanks. Cullen sign: ecchymoses of the             cases. Mechanism unclear.
    periumbilical region due to pancreatic exudate         Structural abnormalities:
Lab diagnosis:                                                Immunosuppressive agents
Amylase: Reflects leakage of pancreatic isoamylase into       Sulfonamides
    the systemic circulation.  75% of acute pancreatitis.    Abx: Metronidazole, tetracycline, and nitrofurantoin
    Remains  for 5 to 10 days. Usually 3x Nl.                Valproic acid
   Corticosteroids                                              lessened, organ dysfunction improved, and pt is
   Furosemide                                                   hungry. Start with small feedings.
   Estrogens                                               Local Complications
   Aldomet                                                 1. Pancreatic inflammatory mass (phlegmon).
   Pentamidine                                             2. Pancreatic infection of necrotic tissue
   Octreotide                                              3. Pancreatic abscess (bacterial infection)
   Didanosine                                              4. Pancreatic pseudocyst (collection of fluid and debris
Infectious agents:                                             which, in contrast to true cysts, do not have epithelial
   Viral: Coxsackie B, EBV, CMV, varicella, and Hep           lining)
    A, Hep B, Hep C.                                        5. Pancreatic ascites (leak of pancreatic duct)
   Bacterial: Tb, leptospirosis, brucellosis.              6. Involvement of adjacent organs by necrotizing
   Candida albicans                                           pancreatitis
   Parasitic: C. Sinensis and ascaris.
                                                            Systemic Complications
Other: Vascular dz, ERCP, post-operative, pancreatic
    trauma, cystic fibrosis, pregnancy, and                 1) Pulmonary: Hypoxia and ARDS can occur due to 
    miscellaneous.                                               surfactant due to circulating phospholipases, alveolar
                                                                 capillary leak.
Classification by Ranson criteria:                          2) Cardiovascular:  intravascular vol or shock may
These are signs that have prognostic significance. The           occur due to "third spacing" of fluid into edematous
    criteria on admission are measures of the intensity of       retroperitoneal space. Kallikrein activation and
    local inflammation. The other 6 reflect the                  bradykinin production can cause  capillary
    development of systemic complications and the                permeability, vasodilation, and hypotension.
    harmful effects of third spacing fluid. The higher the 3) Hematologic: Circulating trypsin activates thrombin
    number of Ranson criteria a pt has the more severe           and plasmin with resulting DIC.  Hct may occur due
    the pancreatitis. A large study showed that a ranson         to retroperitoneal bleeding.
    score of 1.6 correlated with mild pancreatitis, 2.4     4) Gastrointestinal: GI bleeding may occur due to
    with severe pancreatitis, and 5.6 with lethal                pancreatic inflammation affected the stomach,
    pancreatitis.                                                duodenum, or peri-pancreatic blood vessels, or due to
On admission:                                                    gastric varices resultant from splenic vein
Age > 55                                                         thrombosis. Nausea and vomiting may occur due to
WBC > 16,000                                                     ileus of small bowel adjacent to pancreatic
Glucose > 200                                                    inflammation.
AST >250                                                    5) Renal: Impaired kidney function due to
LDH > 350                                                        hypoperfusion of the kidneys from  intravascular
During first 48 hrs                                         6) Metabolic: Hypocalcemia may occur due to
1) Hct  of > 10: a measure of hemoconcentration                 precipitation of Ca in fatty soaps in the
2) BUN  of >5: reflects renal failure                           retroperitoneum (saponification of Ca by fatty acids
3) Ca <8: loss of nonionized calcium associated w/loss           in areas of fat necrosis),  serum albumin, and/or 
    of serum albumin, fat saponification, and complex            PTH secretion.
    cascade  calciuria.                                    7) CNS (psychosis)
4) Pa O2 < 60: respiratory failure                          8) Fat necrosis. Occurs in pancreas and in other sites,
5) Base deficit > 4: metabolic acidosis and shock                such as subcutaneous tissue. Related to release of
6) Fluid sequestration > 6 L: difference between amount          lipase and phospholipase.
    of fluids administered IV vs. losses from urine and     9) Endocrine. Hyperglycemia may occur if insulin
    NGT.                                                         production is impaired. Need to have 90% destroyed
                                                                 before get problem.
These criteria are good only for the first 48 hrs. These    10) Fevers. Related to pancreatic inflammation and
    criteria are most useful to exclude severe disease.          cytokine release.
    The overall sensitivity for the criteria is 57 to 85%,  11) Ascites: fluid leaking from pancreas.  amylase and
    specificity is 68 to 85%, the positive predictive value      lipase.
    is 50% and negative predictive value of 90%.            12) Pseudocyts: Not true cysts. Still dealing with
Medical Management:                                              residual and fluid collection. About 6 weeks. Some
                                                                 will resolve on their own. Some need more active
Fluid Resuscitation: Large amounts of fluid are lost
    secondary to exudation of blood and plasma protein           treatment.
    into the retro peritoneal space. There is also  the
    formation and release of kinin peptides                 CHRONIC PANCREATITIS
    vasodilatation and  vascular permeability. Fluid       Chronic inflammatory process of the pancreas which
    resuscitation prevents hypotension and renal               generally manifests as pain and/or malabsorption. It
    insufficiency. Requirements may be in excess of 6 L        can cause exocrine and endocrine insufficiency,
    per day and can exceed 10L to maintain adequate vol.       especially when >90% of pancreatic function
    Swan-Ganz may be helpful in determining adequacy           impaired.
    of fluid resuscitation. Colloid should be used if       Etiology
    albumin is < 2 g/l. If Hct  to 25 then PRBC should *****Alcohol >80%****
    be used to maintain Hct at 30.                          Idiopathic
Respiratory care: Major problems are atelectasis,           Cystic Fibrosis: cause of occult pancreatitis.
    pneumonia, pleural effusions, CHF and fatigue.          Hereditary
    ARDS may also develop. O2 should be measured            Protein malnutrition
    constantly and given if needed. ARDS occurs on 2nd Pathophysiology
    to 7th day of illness.                                  Uncertain. Associated with  precipitation of protein
Cardiovascular care:  in cardiac index and  in               (inspissated enzymes) w/in ducts  duct obstruction,
    peripheral vascular resistance. IV use of dopamine         dilation, fibrosis, and calcification. Induced stone
    can help maintain systemic blood pressure.                 formation w/in ducts in pancreas.
Relief of pain: PCA MSO4 is preferred over Meperidine. Recurrent pancreatitis  Chronic pancreatic changes.
Nutritional support: TPN for 3 to 6 weeks. Switch to        Alcohol toxic to pancreas. Disrupts normal defenses
    oral feedings if abdominal pain and tenderness have        against autodigestion.
                                                            Abnormal trypsin resistance to trypsin degradation.
                                                              hereditary pancreatitis, activated trypsin will not be
Clinical Features
                                                              inactivated, and therefore will lead to generalized
1) Epigastric pain: constant or intermittent. Etiology of     digestive enzyme activation leading to pancreatitis.
   pain unclear, but may be related to pancreatic
   duct/tissue HTN (actual stretching) or to peri-
   pancreatic nerve damage.
2) Steatorrhea occurs when >90% of gland ceases to
   function. If from pancreatic. Do they see oil drops in
   stool. Has to be pancreatic insufficiency.
3) DM:
4) Protein maldigestion is less common than fat
5) Malabsorption of fat soluble vitamins (ADEK) and
   vitamin B12 may occur. Vitamin B12 deficiency
   occurs because B12 binds to non-intrinsic factor
   proteins which must be cleaved by pancreatic
   enzymes to allow binding to intrinsic factor for
Diagnostic Evaluation
Unfortunately no clinical "gold standard" exists.
   Pancreatic biopsy is generally not performed for fear
   of inducing acute pancreatitis. Severe cases are easy to
   diagnose with pancreatic calcifications on xray,
   steatorrhea, and diabetes mellitus.
Anatomic Imaging Studies
   Abd radiograph  calcification in severe cases.
   Ultrasound (trans-abdominal or endoscopic) - shows
    calcification, thickening pancreatic duct wall, dilated
    and irregular pancreatic duct, and lobular appearance
   CT scan - shows calcifications and a dilated
    pancreatic duct
   ERCP - shows dilated and irregular pancreatic duct
    with strictures, possible stones, and dilated side
Functional Studies
1. Qualitative and quantitative fecal fat: > 7 gm in 24 hrs
   will confim diagnosis.
2. Secretin stimulation test.: release of pancreatic
   enzymes and release of bicarb.
3. Bentiromide test.
1. *****Avoid alcohol *****
2. Long-term narcotic pain medication is often required.
3. Tricyclic antidepressants can help raise sensory pain
4. Surgical or endoscopic treatment may help if there is a
   focal pancreatic duct stricture.
5. Oral ingestion of pancreatic enzymes results in
   negative feedback to the pancreas, decreases enzyme
   secretion, improves steatorrhea, and may improve pain
   in mild-moderate severity cases.
6 Octreotide may have a role in selected cases.

Autosomal dominant disease with 80% penetrance.
Symptoms: begin before age 20. Epigastric pain and 
  pancreatic enzymes. Symptoms may be mild, or may
  appear as acute or chronic pancreatitis.
Abd radiographs  calcification in approximately 50% of
There is  risk of pancreatic cancer  ~ 40% risk by age
Mutation in the cationic trypsinogen gene on Ch 7 
    abnormality in the trypsinogen molecule which
    inhibits degradation by trypsin in a feed-back ioop.
    Under normal circumstances, there is a low level of
    trypsinogen autoactivation in the pancreas. Any
    activated trypsin within the pancreas is inhibited by
    trypsin inhibitor. However if there is excessive
    trypsin activation which exceeds the amount of
    trypsin inhibitor, then trypsin can feedback on itself
    and hydrolyze trypsin to prevent activating the
    cascade of pancreatic enzymes. In patients with

                                                             1st generation:
     DIABETES MELLITUS                                       2nd generation: glimepiride, Glipizide, and Glyburide
           TYPE 2                                            Mechanism: Activate sulfonylurea receptors on
                                                                  pancreatic beta cells   K influx, depolarization of
Clinical Presentation:                                            beta cell membrane, and  Ca influx  secretion of
Incidental finding on screening UA or blood sugar                 insulin   hepatic glucose output   peripheral
    measurement.                                                  glucose disposal.
                                                             Adverse Effects.
With more significant hyperglycemia:                         Hypoglycemia: ~ 4% with the use of glyburide and 2% to
Polyuria                                                          4% with glipizide. Risk is greatest with potent, long-
Polydipsia                                                        acting sulfonylureas
Polyphagia with weight loss                                  Weight gain: enhanced insulin secretion stimulated by
                                                                  oral agent therapy  5 to 10 lbs.
Diagnosis:                                                   Mild GI upset
Impaired Glucose Tolerance.                                  Lipids: Triglycerides decrease modestly. Overall effects
Fasting glucose between 110 mg/dL and 125.                        on lipids are minimal.
Diagnostic Criteria.                                         Skin reactions: Rashes, purpura, and pruritis.
Presence of any 1 of 3 Glu abnormalities found on 2          Efficacy.
    separate days:                                           25%: treatment goals are achieved w/sulfonylurea therapy
1. Fasting plasma glucose >126 mg/dL                              alone.
2. Random plasma glucose >200 mg/dL in a person              50% to 60%: initial response is good, but an additional
    w/diabetic symptoms, or                                       agent is required over time to achieve treatment
3. Two-hour-postprandial plasma glucose level >200                goals.
    mg/dL after administration of the equivalent of a 75-    15%: fail to exhibit 1* response probably have more
    g glucose load                                                advanced dz

Pathogenesis Type 2 disease is characterized by defects      Thiazolidinediones:
    in both the production and peripheral action of          Preparations: Rosiglitazone
    insulin: impaired insulin secretion and decreased        Mechanism of Action: Reduce insulin resistance in
    muscle glucose uptake                                        skeletal muscle, fat tissue, and liver.
                                                             Adverse Effects:
Gestational Diabetes                                         ALT elevation: Test liver enzymes at baseline, every
In pregnancy, even minor degrees of glucose intolerance          other month for 1st year, and periodically after that.
     can be important. Screening is done.                    Weight gain
Low risk: < 25 yo, w/out DM in 1st degree relative,          Anemia
     normal prepregnancy weight, and no prior Hx of poor
     Ob outcome.                                             Repaglinide
High risk: marked obesity, DM in 1st degree relative,        Closes ATP K channel in pancreatic beta-cells  release
     previous Hx of glucose intolerance, or macrosomia in        of insulin in glucose dependent manner. Rapid rise
     prior pregnancy.                                            and fall of insulin secretion when ingested 30 min
Risks of gestational diabetes:  frequency of                    prior to a meal.
     preeclampsia in the mother, and increased frequency     Adverse Effects: Small weight gain. Small incidence of
     of macrosomia, and postpartum hypoglycemia in the           hypoglycemia.
     fetus.                                                  Cleared by liver, so can be used in pts w/renal
Diet and Exercise
Most pts with DM are obese. Initial weight loss of 10-20     Insulin Therapy:
   lbs can help with fasting glu/                            Subcutaneous        Onset             Peak        Duration
                                                             Regular             30 min – 1 hr     2-4 hrs     4-6 hr
Acarbose                                                     Lispro Insulin      15 min – 30 min   1-2 hrs     3-5 hrs
                                                             NPH 1-4 hr          8-10 hrs          12-20 hrs
Alpha glucosidase inhibitors  slow breakdown of             Ultralente          3-5 hrs           10-16 hrs   18-24 hrs
    complex carbos to glucose  delayed absorption of        Glargin insulin     2-4 hrs           None        ~24 hrs
    glucose   of post-prandial glu levels.                 IV insulin bolus    Immediate         20-30 min   2-3 hrs
Adverse effects: Flatulence. Dose related and transient.
                                                             Insulin Sliding Scale:
Metformin                                                    Blood Glucose Regular Insulin SQ
Metformin should not be Rx for pts with serum Creatinine     0-70             D50 ½ Amp IV, or OJ Call HO
    > 1.5 in ♂, or > 1.4 in ♀.                               71-150           No insulin
Preparations: Glucophage                                     151-200          2 Units
Mechanism: Suppresses excessive hepatic glucose              201-250          4 Units
    production and  glucose uptake in peripheral tissues.   251-300          6 Units
Adverse Effects:                                             301-350          8 Units
GI: mild diarrhea, anorexia, and Abd discomfort. Can        351-400          10 Units
    by slow dose titration,  dosage, and taking             >400             12 Units, Call HO
    metformin with meals.
Lactic acidosis: Rare complication, but high mortality       Basic Mixed/Split Insulin Regimen:
    rate.                                                    Total insulin in 24 hrs = Weight in kg x 0.5
Contraindications: Cr > 1.4-1.5, significant hepatic dz,     Divide by 3: 2/3 in AM, 1/3 in PM
    cardiac insufficiency, EtOH abuse, hypoxic               Divide by 3: 2/3 NPH, 1/3 Regular
    condition, or Hx of lactic acidosis.                         (for 60 kg pt  30 U total  AM NPH 14 U, Reg 6
Stop Metformin 48 hrs prior to any contrast study.                       U, PM NPH 7U , and Reg 3 U
    Restarting Metformin should only be done after           Complications:
    testing of Cr.
                                                             Macrovascular Disease:
Sulfonylureas                                                Diabetic Nephropathy:
Microangiopathic changes                                            with larger doses being used for those persons with
Peripheral neuropathy:                                              severer disease and larger goiters.
Autonomic neuropathy:
Diabetic mononeuropathy:
                                                                Duration of inhibition 12 hours. Effect lost after 24 hrs.
                                                                    15 to 20 times as potent as PTU.
       HYPERTHYROIDISM                                          Dosing: Start at 30 to 60 mg per day divided into BID.
Clinical Presentation:                                          PTU
Warm, moist skin.                                               Duration of inhibition is slightly shorter. Blocks
Oligomenorrhea                                                      extrathyroidal conversion of T4 to T3 (Methimazole
Nervousness                                                         does not) so that large doses of PTU cause a rapid fall
Brisk reflexes                                                      in serum T3 levels.
Tachycardia                                                     Dosing: Start at 300 to 600mg per day divided q8*.
Increased appetite
Weakness                                                        F/u initially at mo intervals until controlled. At or before
Retraction of upper lid                                              each visit —> serum free T4 , free or total T3 , and
Proptosis                                                            TSH levels.
                                                                Control based on clinical assessment and normalization of
                                                                     serum free T4 and T3 levels. Normalized —> Dose
Grave‘s dz:                                                          by 1/3 to 1/2. Then f/u q 2-3 mo. Maintain therapy
Subactue thyroiditis                                                 drug for 18 mo before stopping.
Toxic multinodular goiter
Single follicular adenoma                                       Side Effects:
Toxic thyroid carcinoma                                         1) Skin rash
Pituitary tumors secreting TSH                                  2) Hepatic reactions
Struma ovarii                                                   3) Arthralgia
Hydatidiform moles producing beta-HCG                           4) serum sickness
Thyrotoxicosis factitia: too much exogenous hormone.            5) Vasculitis
Diagnosis                                                       6) Agranulocytosis: incidence of is about 0.4%; it
                                                                    usually appears within the first few months of
 levels of thyroid hormones are the hallmark of the
                                                                    therapy and is reversible. Get CBC if infection such
                                                                    as pharyngitis, develops. Need baseline CBC and
   T4 , T3 , free T4 , and free T3 levels are  [T4] and       LFT for comparison.
     [T3] saturate the binding proteins so that the free T4
     and T3 tend to be proportionally higher than the total
     hormone levels in relation to the normal ranges.
                                                                30 to 70% —> long-term remission defined here as
   TSH .                                                         remission persisting for 2 years after cessation of
   5% of hyperthyroid pts: free T4 is normal and only             therapy. Most recurrences show up within 1 year
     serum T3 and free T3 levels are   to T3 -                    after the drugs are stopped.
     thyrotoxicosis.                                            Long-term remission rates of more than 50%.
   In some older pts w/poor nutrition, free T4 is  while     1) No absolutely reliable indicators of long-term
     total and free T3 are normal.                                  remission.
High degree of correlation between the severity of the          2) Low dose (50 mg PTU or 5 mg methimazole) = Good
     disorder based on clinical features and the thyroid            response
     hormone concentrations. This correlation does not          3) Large dose = active disorder.
     hold for older patients who tend to have a paucity of       size of goiter suggests remission but is seldom
     typical clinical features.                                     apparent.
Serum TSH level:                                                5) Measurements of TSI have an 80% predictive value;
< 0.1 in nearly all hyperthyroid patients.                          Not used because of the expense, the uncertainty of
Nl or  TSH level in a clearly hyperthyroid pt  rare               the prediction, and the fact that cure of the disease is
     forms of TSH-induced hyperthyroidism.                          indicated by normal thyroid hormone measurements
Thyroid Radioiodine Uptake: Helpful if a solitary                   while the patient is on a low dose of drug.
     hyperfunctioning thyroid adenoma is being
     considered as the cause in a pt w/palpable nodule.         Beta-Adrenergic Blocking Drugs
 TRU: Most forms of hyperthyroidism. Graves' dz               Acute management. Inhibits catecholamines  rapid
     diffuse uptake.                                                symptomatic relief and improve anxiety,
 TRU : lymphocytic thyroiditis, subacute thyroiditis, or           nervousness, tachycardia, sweating, tremor, and
     ingestion of thyroid hormone. A large iodine load,             muscle weakness.
     such as contrast material for angiography,  thyroid       Helpful for symptomatic pts until T4 and T3 levels
     uptake by  the pool of iodide.                                normalize
Thyroid-stimulating IgG: Useful in diff of Graves'              Atenolol or Propranolol or Metoprolol
disease vs. lymphocytic thyroiditis.                            Discontinue gradually over 1 to 2 weeks when the
   TSI: stimulation of cAMP generation in cultured                hyperthyroidism is controlled biochemically, usually
     thyroid cells (TSI)                                            after 6 to 12 weeks of the antithyroid drug.
   TSH-R antibody: displacement of labeled TSH from           Radio-iodine 131 I
     the TSH receptor.  TSH-R ab indicates Graves' dz          Most common therapy for Graves' hyperthyroidism.
     and makes the radioiodine uptake test unnecessary.         Main complication —> Hypothyroidism:
                                                                    Occurs in the majority of patients, often years later,
                 TREATMENT                                            despite the attempt to tailor the dose to avoid
Antithyroid Drugs                                                     hypothyroidism.
Inhibit thyroid peroxidase —> synthesis of thyroid                Hypothyroidism w/in 1st 6 months after 131 I may be
    hormone.                                                          temporary.
Concentrated in thyroid —> longer T1/2 than plasma T            If first dose of 131 I does not work w/in 6-12 mo another
    1/2 of 1 hour for PTU and 3 to 6 hours for                        dose is given.
The initial dose should be based on assessment of the           Effect of Antithyroid drugs on Radioiodine therapy:
    severity of the condition and the size of the goiter,
Very ill pts  preferable to control first w/antithyroid       Other: infection, CVA, PE, labor, DKA, stress, severe
    drugs 1st.     I therapy may  discharge of hormone                 trauma.
    from the gland  in both T3 and T4 levels by as          Treatment:
    much as 2x 10 days after 131 I given.                      1) PTU or methimazole
Antithyroid drug must be stopped 2 to 3 days before            2) Beta blocker: Propranolol or Esmolol drip
    giving the therapeutic dose. A 25 to 50% more than         3) Iodine
    the usual dose of 131 I is given.                          4) Hydrocortisone: taper as pt improves
Antithyroid drugs therapeutic effect of I. doses are
                                                               5) Tylenol
    necessary to cure pts who have taken antithyroid
    drugs up to a few days before the I dose.
Radioprotective effect may last 1 week after stopping
    antithyroid drug. PTU more potent than methimazole.        CLINICAL MANIFESTATIONS
                                                               Fatigue and lethargy
After administration of the 131 I, patients may begin taking   Dry skin
     the antithyroid drug again 2 to 3 days later. Some of     Slight weight gain
     the manifestations of hyperthyroidism may be              Cold intolerance
     controlled w/ beta-adrenergic blockers.                   Heavy menstrual periods
Radioiodine therapy and Graves Eye dz:
                                                                mental acuity
Because 131 I therapy may worsen pre-existing Graves' eye      Hair loss
     disease, patients with active Graves' eye disease
     should not be given 131 I until the eye disease           Physical Exam:
     stabilizes.                                               +/- goiter
If I is given to a patient with active Graves' eye             Bradycardia
     disease, a course of prednisone in a dose of 1mg per      Diastolic HTN
     kg tapered over 2 to 3 months prevents the                Cold skin
     deleterious effect of 131 I on the eye condition.         Nonpitting edema (myxedema)
Surgical Thyroidectomy                                         Hair loss
Dramatically effective for the eradication of                  Delay in DTR relaxation phase.
   hyperthyroidism. 1% are now treated by surgery.             Lab Evaluation
   Reserved for special situations:                            TSH and thyroxine, T4 concentration have an inverse
1) Obstructing goiters
                                                                   logarithmic relationship. A 50%  in free T4 causes a
2) Allergy to antithyroid drugs
3) noncompliance with medical therapy                              90-fold  in TSH.
4) refusal to take I.                                             Normal TSH: no additional studies.
Common practice  restoration of the euthyroid state               TSH: free T4 concentration or index is performed.
   with antithyroid drugs followed by stable iodine for        Measurement of T-3 concentration is rarely necessary.
   10 days before surgery.                                     Causes:
                                                               Hashimoto’s Thyroiditis:
Complications:                                                 Chronic Thyroiditis:
1) Permanent hypoparathyroidism: 1% of pts                     Subacute Thyroiditis:
2) 30% become permanently hypothyroid                          Iodine deficiency: Not a problem in the United States but
3) recurrent laryngeal nerve palsy: 1% of patients.                is the most common worldwide cause of goitrous
4) Trauma                                                          hypothyroidism.
Expense of surgery                                             Drugs:
About 10% of patients develop a recurrence
                                                                  Inhibit thyroid hormone biosynthesis: PTU or
 Pregnancy and Hyperthyroidism                                    Thyroid hormone release: lithium
Hyperthyroidism occurs in about 1 per 1000 pregnant               Both: iodides, and Amiodarone.
    women.                                                     Atrophic Hypothyroidism: Hypothyroidism w/out goiter
Can be treated effectively with antithyroid drugs, but,             iatrogenic due to radioiodine therapy of Graves'
    because these drugs cross the placenta, lowest                 hyperthyroidism, surgery, or neck external radiation
    possible doses should be used                                  for malignancy.
Pregnancy ameliorates autoimmune disease                      Autoimmune thyroid atrophy: profound
    antithyroid drug can often be discontinued in the 3rd          hypothyroidism, in some cases due to TSH receptor-
    trimester.                                                     inhibiting Ab.
Surgical thyroidectomy can be performed safely during
    the 2nd trimester after control of the hyperthyroidism     Levothyroxine Therapy
    with antithyroid drugs but is a less desirable             Goal  symptomatic improvement and TSH
    alternative.                                                    normalization.
Radioiodine should not be given because it crosses the         [TSH] slightly  or  normal range (0.5 to 5 muU per
    placenta and could cause permanent hypothyroidism               mL) may be followed in asymptomatic patients.
    in the fetus, which has a functional thyroid by the        [TSH] <0.1 or <0.01 muU per mL) may  thinning
    10th week of gestation                                          bones or A fib and is best avoided for most
                                                                    hypothyroid patients.
                Thyroid Storm                                  Levothyroxine: (Levothroid, Levoxyl, Synthroid)
1) Tachycardia and Arrhythmia                                  QD dosing. 7-day half-life.
2) Fever: T > 106                                              ~ 70% of an oral dose is absorbed. The full replacement
3) Agitation                                                        dose of is 1.6 mug per kg per day. Meaningful TSH
4) Psychosis                                                        is measured after 6 or more weeks at a given dosage.
5) N/V/D                                                       Initial therapy:
6) Sweating                                                       younger pts: near full replacement
Pecipitating factors:                                             older patients or those with or at  risk for heart dz: 
Thyroid surgery                                                     doses (e.g., 12.5 to 25 mug per day).
Withdrawal of anti-thyroid medication                          Altered Thyroid Hormone Requirements
Radioiodine therapy                                            When compliance is variable, serum TSH may remain
Vigorous thyroid palpation                                          elevated despite escalating levothyroxine dosages.
                                                               Increased requirements occur with
1.   levothyroxine metabolism: rifampin, phenytoin,               excessive fluid administration, sedating drugs, or
    carbamazepine, and phenobarbital. Requirements                 unrecognized sepsis.
    may  2x.                                                  Treatment:
2. Interfere with absorption: iron (including                  Levothyroxine IV until able to take PO meds
    multivitamins containing iron), Maalox, sucralfate,        Liothyronine IV: Severely ill patients are unable to
    and cholestyramine.                                            convert T4 to T3
3. Pregnancy: may  levothyroxine requirement by 40%           Stress doses of steroids: steroid deficiency may
    or more beginning in the 1st trimester, independent of         accompany profound hypothyroidism.
    Fe administration.
4. Misc Drugs: Zoloft, estrogens, calcium, and                         Central Hypothyroidism
    lovastatin, whose effects on levothyroxine                 Although hypothyroidism secondary to pituitary or
    requirements are uncertain.                                    hypothalamic disease is uncommon, it deserves
Increased requirements occur in ♀ taking androgens (e.g.,          special consideration. Adrenocorticotropic hormone
    danazole [Danocrine]).                                         (ACTH) and other pituitary hormone deficiencies
Levothyroxine should be taken on an empty stomach                  may accompany TSH deficiency.
    w/out any food or other medications.                       Disparity between a very low free T4 with minimal TSH
Although different brands are thought to be identical,             elevation must alert the clinician to the dangers of
    brand interchange is often associated with significant         central hypothyroidism.
    TSH alterations. When a new brand is selected,             Treatment: cortisol should be administered with
    thyroid function must be rechecked.                            levothyroxine. Unfortunately, no early warning
Other Preparations:                                                system exists to detect mild central hypothyroidism.
                                                               With known pituitary or hypothalamic disease, a low
Liothyronine: rapid onset, high peak, and low trough               normal free T4 suggests hypothyroidism.
    concentrations, as well as the difficulty in thyroid       TSH is not useful to monitor therapy of central
    function test interpretation associated with its use, is       hypothyroidism; clinical features and serum free T4
    usually not recommended for chronic therapy.                   must be followed.
Rapid onset of action may be advantageous in
    hypothyroid emergencies.
Desiccated thyroid: 1 grain of USP Thyroid contains ~                 Euthyroid Sick Syndrome
    40 mug of levothyroxine and 10 mug of T3 . Doses            T3
    prescribed range from one-half to three grains.             T4: falls last
                                                                rT3
Subclinical Hypothyroidism                                     TSH: Nl to 
 TSH and a normal free T4 SCH affects 10 to 20% of            Pts are not producing enough T3. This is due to excess
    those older than 65 years of age.                               rT3. This is produces a feedback mechanism to 
Other causes of  TSH                                               production of all other thyroid hormones.
   mouse antibodies                                           Found mainly in pts w/poor liver function. The liver
   untreated adrenal insufficiency                                 metabolizes rT3. Liver failure   metabolism of
   recovery from severe illness.                                   rT3   rT3   inhibition of production of thyroid
Progression to Hypothyroid: Young pts w/SCH are at 
    risk  hypothyroid over time. Some pts
    spontaneously return to Nl                                                THYROIDITIS
High prevalence of antithyroid Ab  HT.                     Hashimoto's Thyroiditis
 TSH and (+) Ab become frankly hypothyroid at the rate Most common form of autoimmune thyroiditis. Usually
    of 4.3%/yr.
                                                                 occurs in middle aged adult women. The condition
Either  TSH or antithyroid Ab alone  hypothyroid               can last for years.
    incidence of 2%/yr.                                     Autoimmune do w/lymphocytic infiltration of thyroid
 CV Risk: TSH > 10 LDL elevation. Treatment will          Antibodies vs. specific thyroid cell antigens
     LDL by an average of 14, corresponding to a 28%           Thyroid peroxidase (TPO) a biosynthetic enzyme.
     in CV risk.                                                Anti-TPO Ab (antimicrosomal Ab): present in > 98%
Therapy is recommended for SCH:                                  of pts w/hypothyroidism, but relationship is
   TSH > 10,                                                    uncertain; cell-mediated immunity is a more likely
   symptoms suggestive of hypothyroidism                        culprit.
   strongly positive thyroid antibodies                        Thyroglobulin: thyroid hormone precursor
   absence of cardiac disease                                  TSH receptor or iodide symporter (iodine transport
   younger age.                                                 protein).
Follow pts w/TSH 5 and 10 who are asymptomatic, older,
    antibody negative, and with concomitant heart           Clinical:
    disease.                                                Hypothyroidism
                                                            Thyroid gland enlargement  firm, irregular, non-tender
               Myxedema Crisis                                   goiter
Occurs when a profoundly hypothyroid patient becomes        Antimicrosomal Ab: Over 95% (+)
    severely ill.                                           Other Ab may be present. Some of the Ab are the same as
Clinical Presentation:                                           those in Grave's disease but in general, Ab in
Symptoms of hypothyroidism                                       Hashimoto's  thyroid growth, while Ab in Graves
Altered mental status: lethargy, psychosis, confusion,            thyroid function.
    coma                                                    Diagnosis:
Thermoregulatory deficiency                                 Presence of a diffuse goiter and  TSH.
Precipitating event: UTI, PNA, flu, cold exposure,          If diffuse goiter is present w/Nl serum TSH  test
    narcotics, sedatives, hospitalization, surgery, trauma,      antithyroid Ab
    CVA, hypoglycemia, CO2 narcosis, drug overdose,         Pathology: normal sized or moderately, asymmetrically
    diuretics                                                    enlarged. Cut section shows a grey-white surface.
                                                            Histology: Plasma cells.
Approximately half of these patients become comatose        Treatment: Usually asymptomatic and do not require
    after hospital admission, possibly because of                treatment.
                                                            If hypothyroid then treat with T-4
Annual assessment of thyroid function.                       Mass effect:
High Antimicrosomal levels > 1:1,600 place pt at high        HA (pull on diaphragm of sella)
     risk of becoming hypothyroid in the future.             Nausea and vomiting
Patients are at risk for B cell lymphomas.                   Visual field defects: Bitemporal hemianopsia. Nerve
                                                                 fibers run in the middle of the optic chiasm.
Subacute Lymphocytic Thyroiditis
                                                             Suppression of normal pituitary function.
Variant of HT.                                               Hormone secretion: acromegaly, gigantism, galactorhea.
In US develops in 5 to 9% of all ♀ after parturition
     (postpartum thyroiditis). Occurs in 35% of pts w/HT     Radiographic findings:
     and 25% of those w/DM type 1. Recurrent episodes        1. erosion of bones around sella turcica
     are common and need not be related to pregnancy.        2. enlargment of sella turcicia
Initial phase: 1 to 3 mo. Transient hyperthyroidism with     3. expansion up through the diaphragma sella.
     zero radioiodine uptake because of leakage of thyroid
     hormone.                                                Lab Findings:
Hypothyroidism follows but may occur w/out prior             1.  in baseline GH
     hyperthyroidism                                         2. Stimulatory test
Most pts recover, but persistent hypothyroidism or goiter    3. Suppression test: drink glucose  Glu should have
     is found in 25 to 50% of patients after 2 years.           dropped to below 2. If it did not then there is excess
Chronic/Silent Thyroiditis:                                     GH.
Occurs in young women.
Clinical Manifestations: Painless thyroiditis with           Diagnosis: MRI
    thyrotoxicosis.                                          1.  in baseline GH
Hyperthyroidism results from release of thyroid hormone      2. Stimulatory test
    rather than increased synthesis of hormone and thus      3. Suppression test: drink glucose  Glu should have
    the hyperthyroid state usually resolves in 4-8 weeks.        dropped to below 2. If it did not then there is excess
Pathology: Gland is normal sized to minimally enlarged.          GH.
    Cut surface can look normal to focally pale.             Specific Types of Pituitary Adenomas
Histology: lymphocytic infiltration and destruction of       Somatotroph adenomas (Growth hormone producing).
    follicles but no plasma cells (as in Hashimoto's) and    1) Usually discovered when large.
    no granulomas.                                           2) Produce gigantism in those whose epiphiseal plates
Treatment:                                                       have not yet fused.
Beta blockers for acute symptoms of hyperthyroidism.         3) Produce acromegaly in adults. Mostly monoclonal.
Antithyroid drugs not indicated                                  Have defect in Gs protein. Are not shut off. Are
Thyroid replacement in the hypothyroid phase is indicated        continuously on. Have continuous production of
    if the patient's symptoms are severe or of long              cAMP  continuous production of GH.
    duration. If the hypothyroid phase lasts longer than     4) Frequently accompanied by diabetes, osteoporosis or
    six months, permanent hypothyroidism is likely.              HTN.
Subacute Thyroiditis                                         5) 30% of these tumors produce a 2nd hormone, usually
Also known as granulomatous or DeQuervain's                      prolactin.
    Thyroiditis.                                             6) Occur in lateral anterior areas of pituitary.
Usually occurs in middle aged ♀. Associated w/prior viral 7) bone and cartilage growth over bony joint leading to
    infection                                                    severe joint pain,  in gluconeogenesis.
Clinical Manifestations:                                     8) Need to distinguish between mass effect and direct
   Acute or subactue presentation                               effect of GH (closing of the growth plates.). Also
   Thyroid pain swelling or tenderness in one or both           will have organomegaly. Indirect  glucose
    lobes. Often radiation of pain to ear.                       intolerance.
    ESR                                                    9) Galactorhrea. Also  risk of adeno Ca of GI.
                                                             10) Giganitism: if over production occurs before the
   Fever
                                                                 growth plate is closed  continue to grow.
                                                             11) Acromegaly diagnosis: IGF-1 above normal.
Usually 4 phases over 4-6 months.
                                                                 Glucose tolerance test: GH < 2. TRH stimulation
   Acute phase: Thyroid pain and Thyrotoxicosis. 3-6
    weeks.                                                       test: > 750%  than baseline. MRI. Most have a
   Transient asymptomatic euthyroidism
                                                             Therapy: 1 is surgical. No medical therapy to suppress
   Hypothyroidism: Lasts weeks to months. May be
                                                                 GH. Dopa-agonists are somewhat efficient in
                                                                 suppressing these levels  lead to hypotension and
   Recovery: Thyroid tests begin to normalize.                  can get in trouble. Can use octreotide. (somatostatin
Pathology: gland is enlarged 2-3 times normal. Cut               analog).
    surface shows patchy areas of fibrosis.
Histology: there is rupture of the follicles with subsequent Prolactinoma (Prolactin producing).
    formation of granulomas with giant cells. The
                                                             1. Most common type of functioning pituitary tumor.
    condition resolves by fibrosis
                                                             2. May be small or large.
Treatment:                                                   3. Produce amenorrhea and galactorrhea.
Antithyroid drugs not indicated                              4. Occur in lateral posterior areas of pituitary.
Beta blockers for thyrotoxicosis.
NSAIDS to  thyroid pain.                                    Corticotroph ademonas (ACTH producing).
Steroid taper for more severe pain.                          1. 1 corticotrophic adenomas: usually small. Produce
                                                                  Cushing's disease. Some produce precursor hormone
    ANTERIOR PITUITARY                                            rather than the functional hormone and are thus
                                                                  clinically silent.
                                                             2.   2 corticotroph adenomas: usually large. Results from
        HYPERPITUITARISM                                          adrenalectomy. Produce Nelson's Syndrome.
Almost always, adenoma  hyperfunction of pituitary.
   Pituitary hyperplasia or carcinoma is rare.
                                                             Gonadotroph adenomas (LH or FSH producing).
   Hypothalamic disease is rare. Secondary
                                                                Usually large and Produce hormones which have
   hyperpituitarism is rare.
                                                                little clinical effect.
General Features of Adenomas.                                Thyrotropic adenomas (TSH producing).Very Rare.
                                                           Volume expansion without edema
Pituitary Carcinoma.
1.   Very Rare.                                            Hypouricemia
2.   Usually non functional.                               Normal or reduced serum creatinine
3.   As with other endocrine neoplasms, many are           Normal thyroid and adrenal function.
     cytologically bland and are only defined as malignant
     by their metastatic behavior.
                                                                    ADRENAL CORTEX
          HYPOPITUITARISM                                           HYPERFUNCTION
Almost always, hypofunction of the pituitary results from
    destruction of the gland. Congenital defects are        Cushing's Syndrome  Excess cortisol.
    uncommon. Hypothalamic diseases are rare.              Prolonged exposure to  circulating levels of
Most of the gland must be destroyed before symptoms are         glucocorticosteroids
    produced.                                              Clinical syndrome:
Panhypopituitarianism: tumor  GH, prolactin, FSH.         1) Truncal obesity
                                                           2) Increased fat pad at back of neck
Destruction of the gland by mass effect of a non secreting 3) Polyuria and polydipsia
    adenoma (25-30 % of adenomas are nonsecreting).        4) Hirsutism
    Most common cause of hypopituitarism.                  5) Thin skin with stria
Destruction of the gland by necrosis.                      6) Menstrual dysfunction
Sheehan’s Syndrome: Post partum pituitary necrosis. 2nd 7) Proximal muscle weakness
    most common cause of hypopituitarism. Results from 8) Osteoporosis
    rapid loss of the blood supply to an enlarged,         9) Mental changes (depression)
    susceptible pituitary gland.
Pituitary necrosis: Other causes  DIC, Sickle Cell        Lab Values:
    Anemia, cavernous sinus thrombosis, arteritis,          Na and  K: Due to hyper aldo.
    trauma.                                                Other: Glycosuria, neutrophilia, lymphopenia,
Pituitary apoplexy. Bleeding into sella tursica.                hyperglycemia, and hyperlipidemia
Empty Sella Syndrome: Absence of the pituitary.            Plasma cortisol: If Cushing‘s will lose diurnal variation in
    Possibly secondary to pressure atrophy or                   cortisol
    unrecognized infarction followed by fibrosis.          24 hr urinary cortisol: (+) if > 20-181
    Diaphragm does not cover pituitary completely.         Plasma ACTH: baseline
    Pushes it. Most do not have panhypopituitarianism.        > 15 pg per mL suggests Cushing‘s dz.
                                                              >200 pg per mL  ectopic ACTH production
      POSTERIOR PITUITARY                                     < 5 pg per mL  primary adrenal tumor
                                                           Overnight Dexamethasone suppression test: 1 mg given at
Posterior pituitary makes two hormones, antidiuretic
    hormone and oxytocin. Most lesions are secondary            11 pm. Cortisol measured in AM. If < 2 mug/ml 
    to mass effect from a suprasellar tumor or a                Cushing‘s is excluded.
                                                           Low Dose Dexamethasone Suppression Test: Give Dex
    metastatic tumor.
                                                                0.5 mg Q 6 hrs for 8 doses and measure 24 hr urinary
ADH deficiency                                                  excretion of 17-hydroxysteroids during the final 24
Diabetes insipidus: Inadequate secretion of vasopressin         hrs of Dex doses. (+) if excrete more than 4 mg/day.
    may be due to loss of or malfunction of the                 95% sensitive and ~100% specific. False (+) if taking
    neurosecretory neurons that make up the                     phenytoin.
    neurohypophysis (posterior pituitary)  polydipsia                                   Low Dose        High Dose
                                                                        Serum ACTH         Dex              Dex
    and polyuria
                                                           Adrenal tumors    Low      No suppression   No suppression
Onset of polyuria is often relatively abrupt and occurs    Cushing‘s Dz      High     No suppression   No suppression
    over a few days.                                       Ectopic ACTH      High     No suppression   No suppression.

Clinical Manifestations:                                    Causes of Cushing's Syndrome.
Thirst/Polydipsia                                           1) Adrenal tumors: Adenoma and Carcinomas.
Polyuria                                                    2) Cushing‘s Dz: Bilateral adrenal hyperplasia due to
Nocturia                                                       pituitary adenoma secreting ACTH.
Dehydration                                                 3) Ectopic ACTH non-endocrine neoplasm: Will get
Headache                                                       bronzing of the skin
Visual Disturbances                                               Lung cancer: esp. oat cell carcinoma.
                                                                  Thymic tumors
Lab Values:
                                                                  Pancreatic islet cell tumors
Inability to concentrate urine  Osmolality:                      Renal cell Ca.
                                                            4) Chronic steroid therapy:
   Urine osmolality = 2(u[Na + K]) + uGlucose/18 +
    UUN/2.8                                                 5) Psuedo Cushing‘s:  EtOH ingestion, endogenous
   Urine osmolality < 200                                     depression, and eating disorders   ACTH
Specific Gravity < 1.005                                       production  adrenal hyperplasia. Plays a role in
Urinary glucose                                                HTN in alcoholics. Will have elevated free urinary
Plasma vasopressin after osmotic stimulus.                     cortisol.

Treatment: DDAVP                                            Pathology:
                                                            Adrenal gland changes depend on the cause of the
ADH excess (SIADH).                                             syndrome.
1. Water resorption                                         1) Diffuse hyperplasia can be 2/2 any  in ACTH.
2. Usually SIADH is 2/2 other tumors producing ADH.         2) Nodular hyperplasia is usually seen as part of a
Have  GFR, tubular sodium wasting, and  net tubular           familial syndrome.
   absorption of creatinine and uric acid, but no edema     3) True tumor masses can be benign or malignant.
   formation.                                               4) Adrenal gland atrophy is due to exogenous
                                                                administration of ACTH.
Clinical Characteristics:                                   Treatment: Surgical resection.
Excess aldosterone (mineralocorticoid)
Clinical Syndrome:
                                                                       Addison's Syndrome
Symptoms: HA, muscle weakness, and cardiac                  Results when > 90 % of the adrenal is destroyed.
    conduction problems due to hypokalemia.                 Causes:
metabolic:                                                  Steroid Therapy: Suppression of hypothalamic-pituitary-
   loss of potassium  hypokalemia                              adrenal axis  adrenal atrophy leaving adrenal gland
   Sodium retention  hypernatremia                             unable to produce and release hormone when
   HTN                                                          confronted w/stress.
Lab Values:                                                 Hemorrhage: 2 leading cause. Sepsis, trauma,
Plasma renin activity: Low                                       anticoagulant therapy
Aldosterone: > 20.                                          Autoimmune:
PRA/Aldosterone ratio: > 30 for ―certain‖ diagnosis. >      Infection: usually Tb
    20 for ―probable‖ diagnosis.                            Infiltrative dz: Leukemia, amyloidosis, and metastatic
                                                                 tumor  lung, breast and melanoma
Diagnosis:                                                  Idiopathic:
CT: Preferred over MRI. CT gets better images of small      Hypopituitarism:
    tumor.                                                  Hypothalamic dz:
Causes:                                                     AIDS: CMV destruction
1. 1* hyperaldosteronism: adenoma or hyperplasia.
    plasma renin level is low                               Clinical presentation
2. Secondary:  plasma levels of renin  pregnancy,         Weakness, fatigue, and lethargy
    RAS, CHF, hypoalbuminenic states.                       Hyperpigmentation
                                                            Orthostatic hypotension
Pathology.                                                  Dehydration
1. Most hyperaldosteonism is due to adrenal adenoma         Anorexia and Weight loss
    (Conn's Syndrome).                                      Nausea and diarrhea
2. Some is due to bilateral hyperplasia.                    Lab Values:
                                                             Na,  Glu,  K,  Ca
Unilateral dz: Surgery                                       Eosinophil:
Bilateral: Medical management                               Plasma ACTH: 1* failure   ACTH levels
    dose HCTZ w/ dose spironolactone. May add on          24-hr urinary free cortisol and 17-
    Ca Channel Blocker.                                         hydroxycorticosteroids.
   Eplereone: New mineralocorticoid receptor                cortisol response to ACTH stimulation.
    antagonist in development.                              Treatment:
Adrenogenital Syndromes                                     Empiric Tx should be started immediately in all severely
Rare, autosomal recessive disorders of metabolism.             ill patients with shock refractory to volume expansion
Results from a block in the production of cortisol             or pressors  Glucocorticoids
    secondary to enzyme deficiencies (21-hydroxylase,       Maintenance Tx: Daily hydrocortisone or prednisone.
    11-beta hydroxylase, 3 beta hydroxysteroid
The most common deficiency, 21-hydroxylase results in a
                                                            Chromafin cell cancer  secrete epinephrine but may
    variety of clinical manifestations depending on which   also make norepinephrine, ACTH, calcitonin and other
    adrenal cell types are enzyme deficient.                hormones
   Salt losing AG  no enzyme in zona glomerulosa or
    fasciculate                                             Clinical features.
   Virulizing AG  no enzyme in zona fasciculate           Accounts for 0.1% of cases of HTN. Occurs in 30-50
   Late onset AG  partially deficient function of the         year olds with incidence Male=female.
    enzyme                                                  10 % are malignant. 10% extra-adrenal. 10% malignant.
Clinical manifestations range from virulization of female       10% familial. 10% pediatric. 10% without blood
    fetuses to precocious puberty to hirsutism in women         pressure .
    or oligospermia in men. if a lack of aldosterone        Classic presentation:
    production accompanies the enzyme block, electolyte     Paroxysmal symptoms. Begin abruptly, may last for
    problems result.                                            minutes to hours, and subside gradually.
Pathology is always adrenal hyperplasia                     Frequency varying from many times daily to one or more
                                                                per week (most commonly) or even every few
        ADRENAL CORTEX                                         episodic headache
         HYPOFUNCTION                                          heart palpitations
Hypofunction can be primary due to loss of function of         anxiety
   the adrenal cortex or secondary due to a pituitary          HTN: refractory to HTN medications.
                                                            Diagnosis: Test for catecholamines, metanephrines, and
     Acute Primary Hypofunction                             Urinary Catacholamines: Should be collected in container
1.   Iatrogenic due to sudden withdrawal of exogenous
     steroids.                                              Urinary metabolites of Catacholamines: Vanillylmandelic
2.   Stress in a patient with chronic hypofunction.             acid (VMA) or metanephrines. Total metanephrine
3.   Massive hemorrhage into the gland.
                                                                excretion is  in 85-100% of pts. VMA  in 71-97%
      Birth trauma.                                            of pts. Need to use a brown bottle or there will
      in anticoagulated patients.                              breakdown of the metabolites.
      Septicemia (Waterhouse Friedrichsen Syndrome)        Plasma Catacholamines: Should be reserved for
        due to meningococcemia, pneumococcus, Staph or          diagnostic dilemmas.
        H. flu.
                                                            Pathologic Features
1) Usually single, discretely encapsulated tumors.             cAMP content of parathyroid cells may  PTH
2) Cut surface is grey-pink but turns brown if it is           secretion.
   exposed to dichromate ( a distinct feature).            Aluminum accumulation in the parathyroid glands  
3) Cytologically pleomorphic polygonal cells with              secretion of PTH and suppression of bone turnover.
   bizarre nuclei. The only criteria for malignancy is         In addition, Al inhibits renal and intestinal C1-alpha-
   marked local invasion and the presence of metastasis        hydroxylase activity   levels of calcitriol.
                                                           Sources of Al:  concentrations in the water used for
            RENAL                                              dialysis, use of Al-containing phosphate binders, and
                                                               Al in drinking water, infant formula, and other
       OSTEODYSTROPHY                                          liquids or solid food.
Metabolic bone dz that develops 2/2 chronic failure of the Bone is an important buffer for excess acid production in
    kidneys' excretory and endocrine functions.                patients with ESRD. Metabolic acidosis has been
Earliest histologic abnormalities of bone are seen after a     shown to stimulate bone resorption and suppress
    relatively mild  in the GFR  CrCl 40-70                  bone formation, thereby resulting in negative bone
Factors involved in development of 2*                       Clinical Manifestations
     Hyperparathyroidism.                                 Pts w/mild to mod renal insufficiency are rarely
In advanced RF direct stimulators of PTH secretion            symptomatic.
      Hypocalcemia                                       Clinical manifestations are preceded by Abnl labs and
       levels of circulating calcitriol                     should prompt steps to prevent more severe
      hyperphosphatemia.                                     complications.
However, most pt w/mild CRF exhibit  serum PTH           Symptoms appear in pts w/advanced RF and are usually
     levels w/out alterations in serum levels of calcium,     insidious, subtle, non-specific, and slowly
     phosphorus, & calcitriol.                                progressive.
Early Renal Failure (RF).                                 Bone pain and Fractures usually vague, ill defined, and
                                                              deep seated. May be diffuse or localized in the lower
End-organ resistance to Vit D, mild  in intestinal Ca        part of the back, hips, knees, or legs.
     absorption and an altered calciuric response to oral Skeletal deformities
     supplementation of calcitriol.                       Children: growth retardation, and bone deformities may
Calcitriol binds w/ Vit D receptors  forms complex.          develop from vitamin D deficiency (rickets) or
     Complex interacts w/Vit D response elements             secondary hyperparathyroidism
     control genomic synthesis of many proteins,          Adults: skeletal deformities can be observed in cases of
     including PTH.                                           severe osteomalacia or osteoporosis  lumbar
In early RF binding of the complex to the response            scoliosis, thoracic kyphosis, and recurrent rib
     elements    suppressive effects of physiologic        fractures.
     blood levels of calcitriol on PTH synthesis  PTH    Myopathy  Proximal Muscle Weakness: Gradual
     overproduction.                                          onset. Mainly lower extremities. Difficulty rising out
Advanced RF.                                                  of a chair or climbing stairs
more advanced nephron loss.  production of PTH and 
                                                          Soft Tissue Calcifications
     parathyroid gland mass.
                                                             Eyes: band keratopathy in the sclerae. Red eye
                                                              syndrome in the conjunctiva.
Role of Phos:
GFR < 25% ability to increase Phos excretion is              Lungs: restrictive lung disease.
     exhausted                                               Cardiac: arrhythmias, annular calcifications, or
 Phos  intrarenal inhibition of C1--hydroxylase (ie,       myocardial dysfunction.
     inhibition of enzyme responsible for conversion of   Tumoral calcinosis Soft tissue calcifications that usually
     25-hydroxy-Vit D  1,25-dihydroxy-Vit D (ie active       involve the periarticular tissues. Ca deposits may
                                                              grow to enormous size and interfere with function of
     metabolite--calcitriol))   calcitrol.
                                                              adjacent joints and organs.
                                                          Calciphylaxis Vascular calcification  painful
Results of Calcitriol deficiency
                                                              violaceous skin lesions  ischemic necrosis.
 intestinal Ca absorption   blood [ionized Ca] 
                                                          Dialysis Dementia dysarthria, dysphagia, amnesia,
     rapid PTH secretion.
                                                              apraxia, mutism, myoclonic jerks, facial grimacing,
 # of Vit D receptors, esp receptors in parathyroid          seizures, and ultimately, severe dementia and death.
     glands.                                                  This condition is usually associated with severe
 suppression of PTH mRNA   synthesis & secretion           aluminum accumulation.
     of PTH
Prolonged hypocalcemia:                                     Bone biopsy:
Intracellular PTH degradation with reutilization of         Hypercalcemia.
     degraded hormone and mobilization of secondary         Hyperphosphatemia.
     storage pool.                                          High serum levels of alkaline phosphatase.
Within days or weeks of the onset of hypocalcemia,         Aluminum accumulation
     calcitrol   expression of (-) Ca response element
       pre-pro-PTH mRNA expression                                Prevention and Therapy
Parathyroid hyperplasia:                                    Phosphorus
 in size is mainly due to diffuse cellular hyperplasia.    Dialysis removes ~ 3 g of Phos/week, so not effective in
Parathyroid gland resistance to calcitriol and Ca:               Phos.
     Monoclonal cell growth may also develop               Dietary Phos restriction. Phos is present in most protein-
     formation of tumor-like nodules that have less or no       containing food products, Phos restriction is limited
     Vit D and Ca-sensing receptors.                            by the need for appropriate dietary protein intake.
                                                            Protein intake of dialyzed patients should be at least 1
Factors Affecting PTH Production and Its                        g/kg/day  ~ min. of 1 g of Phos QD. Need Phos
Effects on Bone.                                                binders in most pts.
alpha-adrenergic agonists, dopamine, prostaglandin E,       Phosphate binders:
    secretin, and phosphodiesterase inhibitors alter the    Ca carbonate and Ca acetate: Most effective when given
                                                                w/meals & in proportion to size of meal.
Ca citrate: avoided because it promotes intestinal Al         Unequivocal documentation of Al overload required
    absorption.                                                  before long-term therapy started.
Aluminum-containing Phos binders: Used in severe cases
    of hyperphos. More potent than Ca salts, but  risk
    of Al-related bone dz. With severe hyperphos add 
    doses of Al-containing Phos binders to Ca salts for a
    limited period.
Hypocalcemia in CRF may be corrected by control of
   serum phosphorus and also by administration of
   calcium salts between meals.
Vit D and Metabolites
Calcitriol therapy:
Effective in  2* hyperparathyroidism. usually  [sPTH],
     bone turnover, and  mineralization.
Rocaltrol 0.25 - 2.0 mug PO QD. Start w/ dose.
    Evaluate after 2 weeks  if sCa levels do not  at
    least 0.5 mg/dL then  QD dose in steps of 0.25 mug.
Need to  PO Ca salts and/or by  the dialysate Ca
    content to avoid episodes of hypercalcemia. Despite
    these measures hypercalcemia may persist.
Alternative approaches:
pulse oral (Rocaltrol) or intravenous (Calcijex) calcitriol
    administration two or three times per week at doses
    as high as 3 mug. Both measures are effective even
    though the positive response is clearly  if deposits
    of stainable Al present in bone or when the
    parathyroid glands undergo monoclonal growth
    transformation and become refractory to the action of
To prevent severe osteomalacia, deficiency in the parent
    vitamin D, 25(OH)-vitamin D should be ruled out
    and corrected if found abnormally low.
(1) persistent hypercalcemia despite no Vit-D treatment
     and modulation of the dialysate [Ca]
(2) persistent hyperphosphatemia and  Ca Phos
     production despite aggressive dietary counseling &
     compliance w/meds.
(3) progressive and symptomatic soft tissue calcification
     with  bone turnover (including calciphylaxis)
(4) severe progressive and symptomatic
     hyperparathyroidism when rapid  PTH is required
     and Vit-D pulse therapy has failed
(5) refractory pruritus.

Subtotal parathyroidectomy: possibility of inadequate
    reduction in parathyroid gland mass or recurrence of
    hyperparathyroidism in the remaining tissue.
Total parathyroidectomy with parathyroid
    autotransplantation in the forearm allows easy access
    to the residual parathyroid tissue if necessary.
    However, migration of the transplanted cells into the
    venous circulation and the muscles of the forearm has
    been reported.
Postoperative hypocalcemia should be anticipated and
    treated with Ca PO and IV. Use of Calcitriol may 
    need for  doses of Ca salts; however, it may
    interfere with successful uptake of the transplanted
    gland. Give calcitriol IV at the end of each dialysis
    Tx for 2 to 3 Tx before parathyroidectomy, then
    followed by the lowest dose of PO calcitriol needed.
Removal of Aluminum
Al 80% protein bound; therefore, only 20% of total
    aluminum is ultrafilterable. Elimination of Al from
    bone through Nl turnover and by completely
    withdrawing Al intake is very slow and may take
Deferoxamine Therapy:
 complex bound fraction of Al and facilitates its removal
    through dialysis.
Dose range 5 to 15 mg/kg 1-3x/week infused slowly over
                                                                            RHEUMATOLOGY --107

                                                               X-rays are confirmatory and not useful for following pts
         OSTEOARTHRITIS                                            because there is a poor relationship between X-ray
Acquired, noninflammatory, MS disorder that results                findings and symptoms.
    from slow progressive loss of articular cartilage
    without adequate regeneration.                             Management:
Prevalence: 90% of the U.S. population > 65 yo has             Prevention: ID and modification of risk factors for
    radiographic evidence of dz.                                    occupational and athletic joint injury, such as
                                                                    repetitive, unsupported motion, poor conditioning,
Etiology and pathophysiology                                        and poor technique.
Risk factors                                                   Cognitive and Behavioral Control of Arthritis Pain:
1) Age: predominant risk factor for all sites of OA            Highly motivated pts and those w/favorable rational
2) Obesity: for weight-bearing joints, such as the knee             thinking indices have significantly  levels of pain
    and hip. Added mechanical stress on the joints.                 and psychological distress, and better overall health.
3) Previous joint damage from trauma/infection: esp. at        Psycho-educational interventions are effective in  pain,
    the DIP and PIP joints of the hand and, to a lesser             disability, and medication and health resource
    extent, at the knee. Causes stiffness of the                    utilization.
    subchondral bone  excessive wear of overlying             Biomechanical Factors
    cartilage. Also involving the articular surface, or s/p
                                                                joint loading on weight-bearing joints: weight loss or
    knee meniscectomy.                                              the use of aids, such as a cane in the contralateral
4) Congenital defective joints: mechanical incongruity              hand, crutches, or appliances such as heel or insole
    of joints.                                                      wedges, as indicated.
5) Family History: Particularly in PIP‘s/DIP‘s and hip.
                                                               Weight loss: modest loss can dramatically  joint-loading
Normal: Cartilage remodeling  equilibrium between
    cartilage matrix degradation & chondrocyte-mediated
    synthesis of type II collagen and
                                                               Exercise regimens in patients with OA have discernible
Cartilage degradation exceeds its regeneration 
    progressive erosion and fissuring of cartilaginous         Fitness walking  pain and disability over the short term
    joint surfaces.                                            Continued exercise in people with mild to moderate OA
                                                                   does not damage cartilage and may in fact slow the
Insult  release of enzymes from chondrocytes 
    degrade collagen and proteoglycans  repartive                 progression of disease.
    process w/ bone formation.                                Acute MS pain  cold applied to the joint may 
Clinical Features:                                             Subacute pain  heat applied superficially or deeply, is
AM stiffness generally short in duration < 30 min.                 preferable to  pain threshold  muscle relaxation.
Pain: Progressive. ―Deep ache.‖ Made worse by
    movement, especially movement and weight bearing.                    Medical Management:
    Made better with rest. Prolonged AM stiffness.
No systemic symptoms                                           Analgesics
Crepitus                                                       Acetaminophen: First-line therapy. Up to 4 gm/day for
Deformity: Joint enlargement. Also varus or valgus                 OA of the hip and knee. Same efficacy as NSAIDs
    bowing of knee.                                                w/ SE. Acts centrally   pain threshold. It has no
Limited ROM                                                        anti-inflammatory properties at therapeutic doses.
Joint contraction                                              Opioids: can be added to analgesic regimens in OA for
Common Joints/Spine:                                               short periods.
Need to distinguish between OA (involving facet joints)
                                                               NSAIDS, Including Cox-2 Inhibitors
    and degenerative disk disease with disk space
    narrowing and osteophytes on vertebrae.                    Exert their anti-inflammatory and SE through
Hips: Earliest abnormality  restricted ROM, w/limited             cyclooxygenase (COX) inhibition.
    internal rotation (<35*) and abduction (<45*) Pain.        Similar efficacy among the different agents in this class.
    Symptoms are aggravated by excessive weight
    bearing and prolonged immobility.                          Toxicity
Knees: Pain on weight bearing, descending stairs more so       Gastropathy: most common complication. Dyspepsia,
    than by climbing stairs, rising from a sitting position.        ulceration, or perforation of GI tract. Elderly are
Spine: Lower C and L spine. Pain is often poorly                    more prone to NSAID-induced GI ulceration, and
    localized. Muscle spasm and stiffness often                     endoscopic evidence of this complication is seen in
    accompany it, and restricted ROM develops with                  up to 20% of users.
    progression of dz. .                                       Aspirin: more ulcerogenic than other NSAIDs.
Neck: Limited extension and lateral bending and rotation       Platelet dysfunction: All NSAIDs inhibit platelet adhesion
    are the first motions.                                           potentiate GI bleeding and perforation.
Hand: Small joints. Pain  aching and stiffness of                  Misoprostol w/NSAIDs may  GI bleeding, but may
    fingers, worsened by repetitive finger use                      not reduce other GI symptoms.
   Heberden Nodes: DIP                                        Acute renal insufficiency: more commonly seen in the
   Bouchard‘s Nodes: PIP                                           elderly
Wrist, elbow, shoulder and ankle are usually spared.           CNS: Indomethacin  mental confusion, HA.
                                                               Hepatotoxicity: diclofenac.
Diagnosis                                                      Aseptic meningitis: Very rare toxicity of all NSAID‘s.
Clinical findings confirmed by x-ray changes w/typical         Others: Skin reactions, CNS disturbances, and
    features of localized narrowing of the joint space.             interference with diuretics and antihypertensive..
X-ray features that must all be present for diagnosis:
Early unequal joint space narrowing (<4 mm in the hip)         COX-2:  GI ulceration vs. conventional NSAID.
                                                               Chondroprotective Agents
Juxta-articular sclerosis ("eburnation")
Subchondral bone cysts.
Documented symptomatic benefit for knees. Benefit to               joint capsule, tendons, and ligaments and the clinical
     other joints unknown.                                         indicators of an inflammatory process are much more
Glucosamine: may provide pain relief, reduce tenderness,           evident compared to osteoarthritis.
     and improve mobilityimprovement is generally              Compared to OA, Amyloidosis is not frequent and when
     delayed compared vs. conventional OA meds.                    it occurs is mostly due to fibrosis and not bony
Chondroitin sulfate:OTC med. Preparations have
                                                               Clinical Presentation:
     variable amounts of Chondroitin. May slow or
     prevent tissue damage in the joint in addition to         History: Ask min of AM stiffness and relationship to
     alleviating symptoms.                                         activity and stress.
                                                                  RA  pain and stiffness improved with mild activity
Intra-articular Therapy                                            but stressing joints remains painful.
Intra-articular steroid injection:                                OA  pain and stiffness worse with activity.
Short term relief of symptoms.
   Synovitis                                                  Articular Manifestations:
   inflamed Heberden's nodes.                                 Generalized stiffness esp after inactivity.
   large, painful, inflammatory effusions of                  Symmetric arthritis: characteristic involvement of PIP and
     osteoarthritic knees  arthrocentesis  steroid               MCP. DIP are rarely involved.
     injection and topical anesthetic agents effective in  Synovitis of wrist: Carpal tunnel syndrome
     symptoms                                                  Grip strength and ROM:  by pain or tightness of joint
Pt should minimize joint loading for some period after             capsule because of inflammation, joint deformities,
     injection  longer period of improvement                      subluxation, fibrosis, and contractures.
Should not be repeated > 3 to 4 x/yr in any given joint        Joint effusions
     because of the possibility of steroids potentiating       Baker‘s cyst: hypertrophy of gastroc bursa.
     rapidly progressive joint failure.
Hyaluronic acid: prototype glycosaminoglycan that is           Extra-articular Manifestations:
normally produced by chondrocytes and synoviocytes.            Constitutional symptoms: weakness, easy fatigability,
Sustained pain relief, comparable w/naproxen, w/ SE               anorexia, and weight loss.
     but  cost                                               Rheumatoid nodules: Extensor surfaces and over pressure
Onset of pain relief less rapid than intra-articular steroid       points. # of nodules does not correlate w/severity of
     injection                                                     dz.
Duration of pain relief may be much longer.                    Rheumatoid vasculitis: Can affect any organ. Occurs in
Used in pts who fail non-drug management and NSAIDS                pts w/severe dz and  circulating RF. In the skin
                                                                   can get palpable purpura, & vasculitic ulcers
Surgery:                                                       Eyes: Scleritis (deeper layers and more serious) and
Arthroscopy: Surgical removal of loose bodies and                  episcleritis (mild and transient). Usually in pts
     fragments                                                     w/long standing dz and nodules.
Osteotomy: Tibial osteotomy  symptomatic relief in pts
     w/varus angulation < 10* and good ligamentous             Labs:
     support.                                                  Rheumatoid Factor: Should be ordered if physical
Joint replacement:                                                 findings document synovitis compatible with RA.
   Considered with severe pain and end-stage structural          IgM antibody to the Fc portion of IgG. (+) is not
     dz.                                                           necessary for diagnosis, but RF is found in ~ 75%
   Better results if profound muscle weakness has not            titers correlate w/systemic dz and more severe dz
     set in so that postop rehab is possible.                  Need to relate results to pretest probability of RA. Should
   Pain relief is achieved in > 90% who undergo total             not be used as screening test in pts with inflammatory
     joint replacement of the knee or hip.                         arthritis.
                                                               Conditions that  Rheumatoid Factor:
                                                               Rheumatic dz: RA, SLE, and Sjogren's syndrome
 RHEUMATOID ARTHRITIS                                          Chronic bacterial infections: SBE, Leprosy, Tb, and
Chronic inflammatory disease with symptomatic large                Syphilis
     and small joint distribution.                             Viral dz: Rubella, CMV, EBV, influenza, HBV and HCV
Pathophysiology                                                Parasitic dz
                                                               Chronic inflammatory dz: Sarcoidosis, periodontal dz,
Main events contributing to the pathogenesis of                    pulmonary interstitial dz and liver dz
     rheumatoid arthritis:                                     Mixed cryoglobulinemia
   Influx of inflammatory cells including neutrophils,        Hypergammaglobulinemic purpura
     lymphocytes, plasma cells, and macrophages into
     synovium                                                  Other Labs:
   Activation and hyperplasia, respectively. Of the           ESR:  in nearly all pts with active dz.
     resident inflammatory cells and synoviocytes              Anemia: Normochromic, normocytic. Decreased
   Destruction of cartilage and bone by the synovial              production.
Cytokines are involved in one way or another in all three Diagnosis:
     events. These include but are not limited to, Il 2, 6, 8, Presence of 4 or more of these criteria must be present for
     TNF, Vascular Endothelial Growth Factor and many              >6 weeks are required for a ―definite‖ diagnosis of
     others. In another group of chronic inflammatory              RA.
     joint diseases collectively called                        1) Morning stiffness
     spondyloarthropathies (including psoriatic arthritis,     2) Arthritis of three or more joint areas
     ankylosing spondylitis and Reiter‘s syndrome), the        3) Arthritis of hand joints: PIP, MCP or wrist.
     inflammation is usually centered at the sites of          4) Symmetrical soft tissue swelling.
     insertions of ligaments onto bones (entheses). In         5) Rheumatoid nodules
     inflammatory arthritis, the synovium is the primary       6) Serum rheumatoid factor
     site of involvement; the articular cartilage and bone     7) Radiographic changes: erosions and/or periarticular
     are secondarily involved.                                     osteopenia in hand or wrist joints
Compared to OA, RA is considerably more destructive to
     the joints with much less repair. Thus, ankylosis is
     frequent while osteophytes are rare. Also, the            Course is variable and individual.
     inflammation involves periarticular soft tissues, i.e.,
                                                                          RHEUMATOLOGY --109
Rate of progression toward joint destruction and disability Hydroxychloroquine: Used in mild RA with no poor
    is proportional to:                                         prognostic factors. Response to therapy is delayed for
  intensity of inflammatory and proliferative reactions        3 to 6 mo w/plateau at ~ 9 mo.
    w/in the joints                                         Gold Compounds: Efficacy questionable. Short-term
  persistence of dz over time.                                 efficacy comparable to MTX, but long-term gold
Most important prognostic factors for destructive               loses its effectiveness over time. Subset of patients
    rheumatoid dz:                                              (young women with early dz) experience significant
  Strongly (+) RF                                              dz control and/or remission with gold therapy.
  Presence of rheumatoid nodules
  Extra-articular manifestations of rheumatoid dz such                             GOUT
    as pericarditis, pleuritis, scleritis, and vasculitis.
                                                            Precipitation of  amounts of monosodium urate (MSU)
                                                                in body fluids and tissues.
Current treatment strategies are to be very aggressive very
                                                            50 yo ♂ most common. Premenopausal ♀ rarely
    early in the dz. Bony erosions and joint space
                                                                experience gout  estrogen promotes renal excretion
    narrowing occurs and progresses most rapidly during
                                                                of urate.
    the first 2 years of the dz.
                                                            Major manifestations:
                                                            1. recurrent attacks of inflammatory arthritis  single
  ADJUNCTIVE TREATMENT                                          joint, esp. 1st toe MTP joint. Can manifest for 1st time
These drugs help to relieve the pain caused by                  in multiple joints.
   inflammation in the joints, but do not change the        2. tophaceous deposits
   natural course of RA. Are useful in the short term,      3. kidney stones
   but the goal is to control the dz and not make these     4. urate nephropathy.
   adjuncts needed.
NSAIDS                                                       Primary Hyperuricemia: Rare  Overproduction due to
Used for pain control as an initial therapeutic goal.            genetic defects in key metabolism enzymes.
    Without such control patients may become                     Common  Under secretion by kidney
    discouraged and noncompliant.
NSAIDS may be supplemented with acetaminophen for            Secondary Hyperuricemia:
    additional analgesia.                                    EtOH:
When NSAID medications are used continuously, the            Myeloproliferative dz:
    addition of misoprostol or other GI agents is              Myeloid dysplasia and polycythemia
    indicated for most.                                        Hemoglobinopathies: Sickle cell dz
Corticosteroids                                              Drugs:
Used in low dose oral form for bridging control while           Diuretics: Initial transient urcosuria then tubular
    waiting for DMARD‘s to take effect.                          reabsorption of filtered urate. This may not occur
                                                                 w/sufficient hydration.
                                                                Anti-Tb: Ethambutol and Pyrazinamide. Uric acid
     DISEASE MODIFYING Tx                                        had been used to follow compliance with anti-Tb
Definition: Tx that changes the natural course of RA.            meds. Response is seen in 1 to 90 days. See level of
    These drugs do not exert anti-inflammatory effects,          > 7. Mechanism not known.
    so NSAIDS must be continued while being used.               Low Dose ASA: < 1.2 gm/day.
    Benefits are delayed for weeks to months.                Cancer: Most often w/disseminated undifferentiated
Methotrexate:                                                    cancers.
Gold standard for efficacy and documented reduction in       Renal:  in GFR   in filtered uric acid. Hyperuricemia
    joint damage.                                                does not develop until  by > 50%. Uremia and
Effects w/in 4 weeks and plateau at ~ 6 mo. ~ 80% will           periodic hemodialysis.
    experience moderate to excellent symptomatic             Chronic lead poisoning:
    benefit from Tx, but remission is rare.                  Sarcoid:
Persistent activity supplemented with Anti-TNF drugs         Other: Starvation, exercise, psoriasis, obesity, DM,
    (Etanercept [Embrel], Infliximab [Remicaide]) or             hyperlipidemia.
    Leflunominde.                                            Asymptomatic Hyperuricemia:
Methotrexate add-ons/alternatives:                           Pts frequently have  urate concentration, but no
Soluble TNF-alpha Receptor-Fc Fusion Protein:                     symptoms. Prevalence of hyperuricemia is 5 to 8%
Etanercept (Embrel): Inhibits binding of TNF- to its             in adult American ♂.
   receptor. Also used in pts w/poor response to MTX.        Symptomatic manifestations appear usually only after 20-
   Possible future role in early RA.                              30 yrs of sustained hyperuricemia.
                                                             Hyperuricemia has no clinical importance in determining
Infliximab (Remicaide): Chimeric mouse/human anti-                course of renal function.
    TNF monoclonal antibody. Lead to  in pain,              Diagnosis
    swelling, and tenderness of joints. Approved for pts     Analysis of synovial fluid under the polarizing
    that have inadequate response to MTX alone.
Leflunomide: Indication in pts with poor response to        Joint Aspiration:
     MTX or instead of MTX when MTX poorly                   MSU crystals:
     tolerated. Inhibits pyrimidine synthesis pathway that
                                                                needle-shaped
     is in low numbers in activated T and B cells 
     inhibition of T and B cells.                               bright under polarized light (strongly birefringent).
Cyclosporine: Second line drug after MTX found                  "Negative birefringence": axis of the MSU crystal
     unacceptable. Inhibits activation of CD4 T-cells.           appears yellow when it is parallel to the axis of the
     Some improvement w/in 3 to 6 weeks after initiation.        microscope's first-order red compensator ("yellow-
                                                                 parallel gout").
Other drugs:
Minocycline: Used in mild RA. Tetracycline Abx           Aspiration of tophi: easy to do  thick, white "milk of
    demonstrated to superior to placebo. Efficacy may be     urate," which can be examined w/polarizing
    less than that of HDC and/or oral gold.                  microscope.
Sulfasalazine: Used for milder dz. Within 4 to 12 weeks,
    most pts experience some improvement.
Xray of affected joints: tophaceous erosion into                Hypersensitivity reactions: skin rash, fever, malaise
    subchondral bone  punched-out lesion                       Acute gouty attack during initial treatment may
    w/overhanging osteophyte.                                    require prophylactic colchicine
Lab values: Serum uric acid should be elevated, by may          Target organ damage: WBC, liver, kidney
    be in normal range.
                                                             Clinical use
             DRUG THERAPY                                    1) Primary hyperuricemia
Gout is treated in two phases—                               2) Secondary hyperuricemia: myeloproliferative. Need
1 to control the acute attack                                    to use w/ fluid intake
2nd to prevent recurrence: this takes the form of finding    3) Chronic gout; esp. with tophi, renal stones,
     and treating a secondary cause, lower uric acid (          nephropathy
     production w/Allopurinol, or  excretion
     w/Probenecid).                                          Goal is to reduce uric acid to <6 mg/dl
Need to continue anti-inflammatory Tx through induction      Do not use during acute gouty attack.
     phase of uric acid lowering Tx.                         Use  doses to avoid precipitating acute attack  use
                                                                 w/colchicine & adequate fluids
Useful to treat acute inflammation/pain                      Probenecid
1. Do not use ASA   doses   uric acid.                   Uricosuric Drug:
2. Not useful to alter uric acid levels.                      renal excretion of penicillin
Pts not good candidates for NSAID: therapeutic                excretion of uric acid  blockade of reabsorption
    anticoagulation, no PO, volume depletion, CHF, or
    renal insufficiency. COX-2 inhibitors do not inhibit     Usually well tolerated except for GI irritation,
    plt function. May prove useful in pts in whom                 hypersensitivity reactions
    anticoagulation contraindicates use of the traditional   For hyperuricemia use w/ fluid intake to prevent uric
    NSAIDs . ??safety in pts with renal insufficiency is          acid stones from forming.
    unclear.                                                 May precipitate acute gouty attack: use with colchicine or
Response to maximal doses of NSAIDs is usually                    NSAID
    excellent in pt who can take these medications.          Salicylate blunts probenecid action
    Indomethacin may be considered the drug of choice        Salicylate blocks sulfinpyrazone-induced urcosuria
    but may not be well tolerated by elderly patients.
After several days of high-dose NSAID therapy, the
    patient can gradually  dose over a period of a week.               SYSTEMIC LUPUS
Colchicine                                                              ERYTHEMATOUS
Tx of acute attacks and for prophylaxis of acute attacks     ANA Ab                  99%   Anorexia, nausea, vomiting   53%
                                                             Non-erosive arthritis   92%   Myalgia                      48%
Mechanism of action:                                         Fever                   84%   Renal Dz                     46%
   Inhibition of microtubular (MT) polymerization          Photosensitivity        72%   Pericarditis or pleuritis    45%
    disappearance of MT from PMNs  inhibition of            Adenopathy              59%   Leukopenia                   43%
                                                             Anemia                  56%   Psychosis or seizures        26%
    PMN migration and phagocytosis of urate crystals,
    and release of lactic acid, proinflammatory enzymes,     Malar or discoid rash. Oral or nasopharyngeal ulcers
    and glycoprotein
   Block cell division
                                                             Clinical Manifestations
   Inhibits release of histamine from mast cells          Kidney Glomerulonephritis:
Pharmacokinetics: Well absorbed PO. Metabolized by         Mesangial: Mildest. Pts with minimal clinical
    liver; primarily GI Liver excretion contributes to       manifestations (mild hematuria or transient proteinuria.)
    toxicity. Long T ½ in PMN.                               Slight  in mesangial matrix and  in # of mesangial
Toxicity:                                                    cells.
GI: Substantial  Nausea, vomiting, diarrhea, pain limits  Focal Proliferative: 20% of initial biopsy specimens.
    oral use.                                                Affects < 50% of glomeruli and only portions of each.
Hemorrhagic gastroenteritis: occasionally                    1 or 2 areas show swelling and proliferation of
Other toxicities: Leukopenia, leukocytosis, myopathy;        endothelial and Mesangial cells Hematuria, and
    neuropathy; azospermia                                   proteinuria. Many progress to diffuse proliferative.
                                                           Diffuse Proliferative: Most serious. Found in 40 to 50%
Clinical use                                                 of pts who undergo biopsy. Overtly symptomatic.
Acute attack: With nl renal function PO dosing 0.5 mg or     Gross hematuria and proteinuria. HTN and mild to
    0.6 mg hourly until relief or toxicity (diarrhea), but   severe renal insufficiency are also common.
    max dose is 5-6 mg per day (10-12 tablets). Then         Proliferation of endothelial, mesangial, and sometimes
    change to bid dosing. IV not preferred because of        epithelial cells. Most or all glomeruli are involved in
    loss of early signs of toxicity  GI SE (diarrhea).      both kidneys.
Prophylactic use: PO BID dosing (<2 mg/day). Esp.          Membranous: Almost always have severe proteinuria.
    useful in peri-operative period                          15% of pts. Widespread thickening of capillary walls.
                                                             Similar to idiopathic membranous Glomerulonephritis.
Inhibits xanthine oxidase  enzyme that forms uric acid Skin: Facial butterfly rash. Similar rash found on the
    from oxidation of hypoxanthine, xanthine. Also its 1*   extremities and trunk. Uticaria, bullae, and
    metabolite  alloxanthine                               maculopapular lesions also occur. Exposure to sunlight
1) Allopurinol: Competitive and noncompetitive              incites or accentuates the erythema.
2) Alloxanthine: Noncompetitive inhibition                Joints: Frequent involvement. Non-erosive synovitis
3) Change urinary purines from solely uric acid to also     w/little deformity. Acute phase  exudation of
    hypoxanthine, xanthine: can get xanthine-stones         neutrophils into synovium.
Drug interactions
1) Allopurinol   probenecid half-life                   CNS: Non-inflammatory occlusion of small vessels by
2)  metab of mercaptopurine & azathioprine  must         intimal proliferation  damage to endothelium by anti-
    dosage                                                  phospholipid antibodies. Also some antibodies vs.
3)  metab of warfarin                                      synaptic membrane protein.
                                                          CV involvement:
                                                                             RHEUMATOLOGY --111
1) Pericarditis: Symptomatic or asymptomatic present in     2) Dosage: Prednisone 1-2 mg/kg PO QD divided until
   pts.                                                      stable. Then tapered. Reduce only 10% every 7-10
2) Myocarditis: Non-specific mononuclear cell infiltration.      days.
3) Valvular abnormalities: Mainly mitral & aortic.          Steroid Tx not sufficient alone for most forms of GN.
   Diffuse valve thickening.                                     Diffuse proliferative and Membranoproliferative GN
4) Coronary artery disease                                       requires cyclophosphamide + steroids to preserve
                                                                 renal function.
Spleen: Moderately enlarged w/capsular thickening.
   Plasma cells are numerous in pulp and can be shown to Immunosuppressive therapy: Indications: same as
   have IgG and IgM. Central arteries  thickening.           steroids. Use is individualized. Cyclophosphamide.
   ―Onion-skin‖ lesions.                                      Azathioprine.

Lungs: Pleuritis and pleural effusions affect 50% of pts.       Transplantation: Effective. Clinical and serological
                                                                  manifestations disappear. Recurrence of nephritis in
Diagnosis                                                         graft rarely occurs.
American College of Rheumatology criteria for diagnosis
   of SLE                                                       Clinical Course
if any 4 or more of the 11 criteria are present, serially or    Highly variable
   simultaneously, during any interval of observation.          1) Typically young  pt, w/butterfly rash over face,
1. Malar rash: Fixed erythema, flat or raised, over the             fever, pain but no deformity in one or more
   malar eminences, tending to spare the nasolabial folds           peripheral joints, pleuritic chest pain, and
2. Discoid rash: Erythematous raised patches w/adherent             photosensitivity.
   keratotic scaling & follicular plugging; atrophic scarring   2) Antibodies vs. DS DNA is diagnostic of SLE.
   may occur in older lesions                                   3) Anemia or thrombocytopenia can be presenting
3. Photosensitivity: Skin rash as a result of unusual               symptom and main problem.
   reaction to sunlight, by pt Hx or MD observation             4) Most often seen as chronic w/flare-ups and
4. Oral ulcers: Oral or nasopharyngeal ulceration, usually          remissions.
   painless, observed by physician                              5) Exacerbations  treated w/corticosteroids.
5. Arthritis: Non-erosive arthritis involving  2 peripheral    6) 80% 10 yr survival.
   joints, characterized by tenderness, swelling, or effusion   Cause of death  renal failure, recurrent infections, then
6. Serositis:                                                     CNS.
a) Pleuritis: convincing Hx of pleuritic pain or rubbing        Etiology and Pathogenesis
   heard by a MD or evidence of pleural effusion OR
b) Pericarditis: documented by ECG or rub or evidence of        Cause remains unknown. Defect in regulatory
   pericardial effusion                                           mechanisms that sustain self-tolerance. Antibodies vs.
7. Renal disorder:                                                nuclear and Cytoplasmic components of the cell. Also
a) Persistent proteinuria > 0.5 gm/day or > 3+ on urine dip       antibodies directed against cell surface antigens of
   OR                                                             blood components.
b) Cellular casts: may be RBC, Hgb, granular, tubular, or
   mixed                                                        Genetic Predisposition:
8. Neurologic disorder                                          1) Family members have  risk of developing SLE.
a) Seizures--in the absence of offending drugs or known         2) Up to 20% of clinically unaffected 1 relatives reveal
   metabolic derangements; e.g., uremia, ketoacidosis, or          auto-Ab and other immunoregulatory abnormalities.
   electrolyte imbalance OR                                     3)  rate of concordance in monozygote twins.
b) Psychosis--in the absence of offending drugs or known        4) HLA associations support MHC genes regulate
   metabolic derangements, e.g., uremia, ketoacidosis, or          production of specific autoantibodies rather than
   electrolyte imbalance                                           conferring a generalized predisposition to SLE.
9. Hematologic disorder:                                           Specific polymorphisms of HLA-DQ locus linked to
a) Hemolytic anemia: with reticulocytosis OR                       production of anti-DS DNA, anti-Sm, and
b) Leukopenia: < 4,000 on  2 occasions OR                         antiphospholipid antibodies.
c) Lymphopenia: < 1,500 on  2 occasions OR                     5) Some SLE pts have deficiencies of early complement
d) Thrombocytopenia: < 100,000 in absence of offending             components such as C2 or C4.
10. Immunologic disorder:                                       Non Genetic Factors:
a) (+) LE cell preparation OR                                   Hydralazine, procainamide, and D-penicillamine induce
b) Anti-DNA Ab to native DNA in abnormal titer OR                 SLE-like in human.
c) (+) Anti-Sm Ag OR                                            Frequency during reproductive years is 10X  women
d) False (+) serologic test for syphilis known to be (+) for      than men.
   at least 6 mo. Confirmed by MHA-TP or FTA-ABS
11. Antinuclear antibody: An abnormal titer of                  Immunologic Factors:
   antinuclear Ab by immunofluorescence or an equivalent        Oligoclonal B-cell response  antibodies driven by self-
   assay at any point in time and in the absence of drugs         antigens. Most visceral lesions are mediated by
   known to be associated with "drug-induced lupus"               immune complexes.
   syndrome                                                     Inflammatory myositis on an autoimmune basis may
                                                                  affect the skin. Although histologically similar to SLE
Treatment                                                         and 1* occurring in sun-exposed areas, has a distinct
General supportive therapy:                                       distribution.
1) Adequate sleep & avoidance of fatigue. Avoid sun
   exposure. Sunscreen is not sufficient.
2) NSAID for arthritis, arthralgias, and fever. Avoid in               DERMATOMYOSITIS
   pts w/active nephritis.                                      Clinical Presentation:
3) Hydroxychloroquine: to control rash, arthritis, and
   mild to moderate systematic symptoms.                         Onset of symmetrical weakness
                                                                 Neck flexors, shoulder girdle, and pelvic girdle muscles
Glucocorticoid therapy:                                            earliest and most severely affected muscle groups.
1) Indications: GN, CNS, thrombocytopenia, hemolytic             Subacute presentation over weeks or several months.
   anemia, debilitating manifestations                          Bimodal peak incidence:

                                                                Skin Manifestations:
 Heliotrope rash: faint, lilac-colored rash on the upper   HA
  eyelids                                                   Paresthesias
 Gottron's sign: raised, red or violaceous, sometimes      Psychological abnormality
  scaly lesions over the knuckles. May also be found over   Subjective swelling
  the elbows or knees.                                      Functional disability
 V sign: macular, erythematous, sun-sensitive rash on      Diagnosis:
  the face, neck, and anterior chest
                                                            Based on a characteristic history
 Shawl sign: macular, erythematous, sun-sensitive rash     1) Exclusion of systemic dz that may cause MS pain:
  on the shoulders and upper back.
                                                                RA, SLE, inflammatory muscle disease, polymyalgia
 Periungual erythema due to dilated capillary loops with       rheumatica, and hypothyroidism.
  thrombi or hemorrhage.                                    2) Nonarticular tender points w/ normal joint exam
                                                            3) Normal labs: CBC, acute phase response, and thyroid
Lab Values:                                                     functions.
 CK: Can also be used to follow response to therapy.
Sed Rate: Normal                                            Pathophysiology:
ANA: Can be positive.                                       Not well understood
Anti-Jo: ~ 10% of adult pts. More specific. Association     May occur following MVA or other trauma.
    w/interstitial lung dz.                                 Association w/psychological abnormalities has been
Muscle biopsy  perifascicular atrophy.                        suggested.
Specific Therapies                                          Depression:  incidence of depression in 1* relatives of
                                                               fibromyalgia pts. Most pts w/fibromyalgia are not
General Treatment Approaches                                   depressed.
Complete work up for malignancy not cost effective.         sleep abnormality: loss of "slow wave" deep sleep with a
  Should do age appropriate cancer screening.                  relative loss of the restorative phase of sleep. Sleep
Patients with amyopathic dermatomyositis may develop           apnea may be seen disproportionately in ♂ pts
  an inflammatory muscle disorder, and muscle enzymes          w/fibromyalgia, and polysomnography is a reasonable
  should be obtained every few months.                         consideration for selected pts
                                                            Natural history:
Specific Therapies
                                                            Although symptoms may be chronic, perhaps lasting 10 to
Hydroxychloroquine: intervention of choice for the rash       15 years or longer, a majority of pts show symptomatic
 of dermatomyositis. Is not effective if an underlying        improvement when fully informed and optimally
 malignancy is present. Its application may not be            managed.
 necessary if inflammatory myositis necessitates
 corticosteroid therapy because that therapy also           Treatment
 eliminates the rash.                                       Sleep abnormality:
Corticosteroids: Mainstay of Tx. Need to measure            1) Tricyclic: amitriptyline
 response to therapy w/functional improvement the most      2) SSRI:
 important. May take 1-3 mo for improvement. Taper          3) Muscle Relaxants: Help w/pain symptoms
 steroids after improvement.                                4) NSAIDs should be minimally utilized.
Methotrexate: Pts with rashes refractory to antimalarials
 and steroids frequently respond. Doses of 10 to 25 mg      Steroids: For selected pts, tender point injections
 per week.                                                    w/corticosteroids or lidocaine may be useful.
                                                            Nonpharmacologic modalities:
                                                            Meditation, relaxation techniques, and biofeedback, may
           FIBROMYALGIA                                       be useful in lessening tension.
                                                            Physical fitness training resulting in cardiovascular
Common pain amplification syndrome characterized by           conditioning is beneficial. Aerobic activity three to five
  generalized chronic pain (longer than 3 months in           times per week.
  duration), stiffness, gelling, and fatigue.
Typically, patients are ♀ of middle age with predictable
  tender points on PE and a disturbed sleep pattern such                  ANKYLOSING
  that they awaken nonrefreshed from sleep (a
  nonrestorative sleep pattern).                                          SPONDYLITIS
                                                            Chronic inflammatory disease of the axial skeleton
Affected sites include bilaterally:                           (sacroiliac joints and spine), although peripheral joints
1) Occiput                                                    may be involved.
2) Low cervical region                                      Tendency toward bony ankylosis, especially in the
3) Midpoint of the trapezius                                  vertebrae,
4) Supraspinatus at the medial border of the scapula        Enthesitis: inflammation at sites of bony insertions for
5) 2nd ribs at costochondral junctions                        tendons and ligaments.
6) 2 cm distal to the lateral epicondyles of the elbow      Epidemiology and Genetics
7) Gluteal area in the upper-outer quadrants of the
    buttocks                                                Prevalence: caucasian 0.1 to 0.2%.  in Asians and Af-
8) 2 cm posterior to the greater trochanter                   Am. 1st degree relatives of pts/w AS  risk of
9) Medial fat pads of the knees proximal to the joint         spondylitis of 5 to 10%, if HLA-B27 (+) risk is
    line.                                                     doubled. (-) HLA-B27 virtually excludes the
                                                              development of familial AS.
Predictable features: 100% incidence                        Genetic factors:
Generalized pain for at least 3 months                      HLA-B27: Found in 5 to 15% of most white populations.
Widespread local tenderness at 11 or more of the              90% of pts with AS have HLA-B27.
  aforementioned 18 anatomic sites                          HLA-B60
Characteristic features: > 75% incidence                    Types:
Fatigue                                                     Primary
Sleep disturbance                                           Secondary: associated w/another dz (Reiter's syndrome,
AM stiffness                                                  IBD, and psoriasis (especially psoriatic arthritis).) AS is
                                                              not 2/2 IBD but associated with it.
Common features: > 25% incidence                            Clinical Features
                                                                             RHEUMATOLOGY --113
Onset: 20‘s to 30‘s first clinical manifestations. Onset
  after 40 is rare                                              Heart:
Juvenile onset: hip and knee involvement, which may             1) Aortic ring dilatation & regurgitation: < 5%.
  precede sacroiliac and spinal involvement by many yrs         2) Conduction disturbances: < 5%: AV blocks, bundle
Adult onset: buttock pain that often radiates  lower              branch block, fascicular block, & WPW. May be
  limbs as far as the knee in association w/nocturnal pain         intermittent. Independent of aortic ring involvement.
  & AM stiffness, which usually lasts for at least 1 hr.           Prevalence  w/duration, presence of peripheral
Abrupt onset: ~ 10% abrupt onset. may more closely                 arthritis, and uveitis.
  mimic sciatica; if the onset is associated with trauma,
  the diagnosis can easily be missed.                           Lungs:
                                                                1) Apical pulmonary fibrosis. Very rare.
Symptoms:                                                       2) Severe kyphosis or kyphoscoliosis can  progressive
Stiffness and pain: Typically after resting. Worse when            pulmonary dysfunction.
  getting out of bed. Stiffness lasts 1-2 hrs and is relieved
  by exercise and NSAIDS.                                       Osteoporosis and Spinal Fractures.
Bilateral Hip involvement: ~25%. Associated w/poor              Vertebral osteoporosis  fractures of the spine occur
  prognosis.                                                        with relatively minor trauma.
Shoulder: less common                                           Fractures in the cervical spine are the most common,
Peripheral arthritis: Characteristic distribution of large          usually at the C5-6 or C6-7 level.
  joint dz Less common. Associated with dz with IBD
  and psoriasis.                                                Secondary Renal Amyloidosis and Cauda Equina
Plantar Fasciitis:                                                  Syndrome: very rare complications.
Uveitis: Unilateral anterior. Severe pain, photophobia, &       Proteinuria in pt w/AS think renal amyloidosis.
  blurred vision
Other Late manifestations: AV conduction abnormalities,
  apical lung fibrosis, amyloidosis, and cauda equina           Non-Pharm:
  syndrome                                                      Exercise: Swimming is the ideal exercise. Goal is to
                                                                  achieve and retain spinal mobility.
Physical examination:                                           Patient education: essential for long-term cooperation
Stiff back: Even in the early stages.                             through exercise.
Limited Lumbar Flexion: Schober test  measure a 10-            Medical Management:
  cm segment up from the L5-S1 junction that should             NSAIDs: Effective except Salicylates. Indomethacin
  expand at least 4 cm on full forward flexion. Used to           most effective. Should be used at max recommended
  follow progression of dz.                                       dose as long as dz active. Cox-2 may be effective.
 lateral flexion, extension, and rotation of the back.         Sulfasalazine: useful w/pts w/active peripheral synovitis
Diminished chest expansion: Nl > 5 cm from full                      and may be esp. useful in enteropathic AS.
  inspiration to end expiration. Often .                       Intra-articular Steroid Injection: Can be done CT guided.
Pain with palpation of inflamed Enthesitis: Pain over             Sacroiliac joint. Lasts for months. Long term PO
  spinous processes, ischial tuberosities, greater                steroids not useful. Can use short course (3 days) for
  trochanters, iliac crest, costovertebral and                    very active dz.
  costochondral junctions, Achilles tendons, and plantar        Surgical Management: Hip replacement for end stage
  fascia.                                                       refractory dz.
Loss of the lumbar lordosis:
Stoop: progressive dorsal kyphosis. Assess by distance
  from occiput to wall: pt stands erect with heels and
  buttocks against the wall and attempts to have the
  occiput also in contact with the wall, as it should be,
  when looking straight ahead.
AP of Pelvis: symmetric sacroiliitis  sclerosis, erosions,
  and, later, fusion.
Spine X-ray: bony erosions, osteitis, ossification, or
  syndesmophytes (ossification of the outer layers of the
  annulus fibrosis of the disk  bamboo appearance)
CT scan more sensitive.
Requires relevant symptoms:
   back pain with morning stiffness
   associated sacroiliitis.

Lab tests:
1) Sed rate: normal.
2) HLA-B27: (+) 90% No value in making the
Uveitis: Acute unilateral anterior uveitis. 25 to 40% of
    pts. Both eyes may be involved but usually at
    different times. Pts should be warned of the
    possibility of this complication at the outset and to
    seek immediate medical advice on developing a
    painful red eye.
  ocular pain
  redness
  photophobia
  blurred vision.
Management: pupillary dilators and steroids
                                                                               NEPHROLOGY --115

                                                                               Angiotensin II
     RENAL REGULATORS                                      Mechanism:
                         ADH                               Constricts afferent arterioles and  GFR
                                                           Activates Aldosterone (Main effect)
Made in hypothalamus and lung tissue. Is stored in
    pituitary. Degraded in liver.                                       Secretion                Secretion
CD: insertion of aquaporin II   reabsorption                        PGE and PGI                   ANP
CD:  permeability to water                                       sympathetic activity           NSAIDS
CD:  permeability to Urea   secretion.                                  BP                 Alpha-2 agonists
                                                                     renal pressures             plasma Ca
            Secretion                 Secretion                     blood volume
                                                                      NaCl delivery
          in Plasma Vol                in ANP
                                                                       Plasma Ca
                                   Diabetes Insipidus
                                                            Na-H antiport H+ secretion
Actions:                                                    HCO3 reabsorption  Alkalosis
Retention of Water                                          K secretion   plasma K
 in PVR and BP                                            Na Reabsorption   plasma Na
 in UureaV                                                 water reabsorption   ECW
 in BUN ( secretion   BUN)                              reabsorption of uric acid   plasma Uric acid.
 Urine Osm
Concentrated Urine (Negative Free water clearance)           ACUTE RENAL FAILURE
                     Aldosterone                        DEFINITIONS
 Mechanism:                                             Oliguria- < than 400 ml urine/day. This definition is
 # of NaCl Channels in DT                                   based on urinary concentrating ability and solute
 # of Open Na Channels
                                                        For example, if Max urinary concentrating ability is ~
 K permeability of apical membrane
                                                             1200 mOsm/L, solute load is ~ 500 mOsm/day, then
 H-ATPase action   H secretion                            that solute load would require 416 ml of urine to be
 synthesis of Na-K ATPase                                   excreted. Any lower volume of urine would result in
 Na reabsorption  increased PD difference   K            retention of nitrogenous waste. (The corollary of this
excreted                                                     is that for individuals with lower maximum urinary
                                                             concentrating abilities, oliguria should be defined as
             Secretion                      Secretion      a larger number.)
      Increased Ang II levels                           ―Pt is oliguric" = 24 hr urine vol < ~ 400 ml.
        Increased Plasma K                              Azotemia:  in serum nitrogenous wastes, w/out
       Decreased Plasma Na                                   specifying cause.
          Trauma, Stress                                Acute renal failure (ARF): an abrupt  in renal function
          Decreased ANP                                        in serum BUN and creatinine
                                                        Acute tubular necrosis (ATN)- most common cause of
Actions: Main regulator of K balance. Acts only on DT        "intrinsic" ARF. Pathologically, not always
and CD                                                       characterized by overt necrosis.
H+ secretion             Alkalosis
Na reabsorption           Plasma Na
                                                        Prerenal azotemia
 K Secretion             plasma K                     RBF. GFR is highly dependent on RBF. Therefore  in
Water Reabsorption   TcWater (neg free water)              RBF   in GFR, and  in the BUN and serum
                                                             creatinine. Functional renal failure, since if the RBF
                         PTH                                 is returned to normal, the  in GFR will be readily
 Actions:                                                    reversible. Nothing wrong with kidney just low
PT:  PO4 reabsorption                                       blood flow. Is reversible with  blood flow.
 Calcium reabsorption
                    K Regulators                        The fall in RBF can occur because of:
                                                        1. true intravascular volume depletion  hemorrhage,
             Secretion                Secretion            diarrhea, overdiuresis.
               Diet                       Diet          2. redistribution of intravascular volume/low effective
            Metolozone                 Amiloride             arterial volume  ascites, edema, CHF, end stage
              HCTZ                    Triamterene            liver dz.
               Lasix                Spironolactone      Also compromised blood flow to other organs as well.
           Bumetamide                Trimethoprim       Compensation  vasoactive substances (angiotensin II
          Acetazolamide             ACE inhibitor            and sympathomimetic amines) )are released locally
            Aldosterone                 Insulin              and systemically  arteriolar constriction.
             Atrial Naturetic Peptide
                                                           In the kidney, the vasoconstricting effects of angiotensin
            Secretion                        Secretion        II are somewhat counterbalanced by the production
     Increased blood volume                                     of vasodilatory compounds, such as prostaglandin
                                                                E2. PGE2 helps to maintain GFR in settings of
Actions: stored in myocytes of atria and released with         hypoperfusion, systemic vasoconstriction, and high
    blood volume or high filling pressures.                     angiotensin II levels.
CD:  Na reabsorption                                      Clinical correlate: in the setting of hypoperfusion, the use
 ANP   Ang II                                                of drugs which inhibit prostaglandin production
 ANP   Aldo                                                  (ASA, NSAIDS) can lead to "unopposed"
    vasoconstriction and significant decrements in RBF    Female reproductive system: pregnancy (functional effect
    and GFR.                                                  of fetus pushing on ureter) , tumors (cervical,
Common causes of prerenal azotemia:                       Gastrointestinal tract: diverticular disease , malignancy,
1) Hypotension                                                abscesses
2) Renal sodium loss: Diuretics, osmotic diuresis, salt   Retroperitoneal processes: fibrosis, tumors
   wasting                                                Lower tract obstruction bladder: blood clots, stones,
3) Extrarenal sodium loss: GI-vomiting, diarrhea,             tumors, Neurogenic, BPH.
   nasogastric suction, intestinal fistula, bleeding      Approach to oliguria or rise in sBUN &
4) Skin- sweating, burns
5) "Third-spacing" (low effective arterial volume):       creatinine
   CHF, nephrotic syndrome, cirrhosis, peritonitis,       Urine Volume
   pancreatitis.                                          Prerenal  typically oliguric. ATN can be oliguric or
6) Drug effects: NSAIDs, ACE inhibitors, cyclosporine.        nonoliguric
   All alter balance between vasodilation and             Anuria-suggests obstruction or vascular catastrophe.
   vasoconstriction. Generate more Angiotensin II.
   PGE-2 unbalanced. Only have problems if volume         FeNa: 100 x (UNa x SCr)/(SNa x UCr)
   depleted or have pathological process. ACEI may        FeUrea:
   lead to loss of compensatory mechanism.
7) Hepatorenal syndrome: Severe cirrhosis. Imbalance.                    Prerenal Azotemia          ATN
   Filtration ceases.                                     Urine Na               <20             >40
                                                          Ucr/Pcr                >40             <20
Uremic syndrome: Does not mean certain value of BUN. Uosm                        >500            <350
    Nausea, vomiting, pneumonitis, mental status          FeNa                   <1              >1
    changes. Clinical finding. Pts with ARF may have      FeUrea                 <30
    uremic syndrome at much lower BUN than CRF.
                                                          Medical Record Review:
Intrarenal disease                                        1) Prior documentation
Even if the insult is associated with tubular necrosis,   2) Infection
    typically only a portion of the nephron is damaged.   3) Taking nephotoxic drugs
    However, since the portions of the nephron function 4) Radiocontrast agents: contrast used?
    in series, damage to a portion can lead to excretory  5) Blood transfusion
    failure.                                              6) Anesthesia and intraoperative history.
                                                          7) volume depletion: weight loss, vomiting, diarrhea, GI
Why does tubular damage result in a decline in                bleeding, diuretics
    glomerular GFR (i.e. excretory failure)? There are    8) cardiac failure: weight gain, edema, dyspnea,
    three proposed contributors:                              orthopnea radiocontrast exposure
1. intratubular obstruction (by damaged and sloughed      9) pigment injury: excessive exercise, immobility, loss
    cells) Block excretion of urine.                          of consciousness, skeletal muscle trauma, seizures,
2. backleak of filtrate across the tubular epithelium.        ethanol
3. primary reductions in filtration                       10) vasculitis/proliferative GN: recent strep infection,
                                                              fevers, skin rash, arthralgias, IVDA
Common causes of intrarenal acute renal failure:          11) hypotension, shock
1. Ischemia: Prolonged prerenal azotemia, Hypotension, 12) new medications
    Major surgery associated with decr. RBF (AAA,
    open heart surgery . Cross clamping or aorta).        Physical Examination:
    Prologned azotemia can become permanent. When         1) Weight loss.
    pt has pre-renal azotemia need to correct.            2) Orthostatic hypotension,  skin turgor, dry mouth,
2. Nephrotoxins:                                              cool extremities  pre-renal azotemia
     Antibiotics (aminoglycosides)                       3) JVD, rales, 3rd heart sound, edema, H-J reflux,
     Radiocontrast agents                                    hepatomegaly, jaundice, spiders, ascites,
     Endogenous toxins (myoglobin, hemoglobin,               gynecomastia
       myeloma light chains, uric acid)                   4) Distended bladder  obstruction, or enlarged
3. Vascular events: Atheroembolic disease, Renal artery       prostate
    stenosis/thrombosis, Vasculitis                       5) Fever and rash: interstitial nephritis
4. Acute glomerulonephritis                               6) Livido reticularis:  limbs &  truck of pt
5. Acute interstitial nephritis                               w/atheroembolism. Also have distal emboli and
Post-renal disease                                            fever
                                                          7) Muscle tenderness  rhabdomyolysis
Urinary tract obstruction  renal failure can occur       8) Rash, palpable purpura, arthritis  vasculitis.
    anywhere along the urinary tract from the urethral    9) splinter hemorrhage, new murmur, impetigo, fever 
    meatus to the renal pelves.                               GN infection:
   Upper tract obstruction: lesions proximal to the
    bladder                                               Diagnostic Tests:
   lower tract obstruction: at the bladder or below.     1) Bladder ultrasound or catheterization
Obstruction can be acute or chronic, complete or          2) Fluid diuretic challenge
    incomplete, intermittent or sustained, unilateral or  3) Renal scan
    bilateral. In order for renal failure to occur, the   4) Renal biopsy
    obstruction must involve both kidneys, or a solitary
    kidney, or one kidney in the presence of pre-existing Management of ARF
    intrinsic renal disease.                              Distinguish between acute and chronic renal failure.
                                                          1) Hospitalized pts w/previously Nl lab values  easy
Common causes:                                                distinction.
Upper tract obstruction                                   2) Outpt who presents for the 1st time with an 
   intratubular: urate, myeloma light chains, acyclovir,     creatinine  more difficult. Useful features
    methotrexate (Can crystallize and cause obstruction.)     suggesting ARF include previously known Nl renal
   intrapelvic: stones, clots, tumors                        function, normal kidney size, no evidence of renal
   intraureter: stones (unilateral usually)                  osteodystrophy, and absence of anemia.
                                                                                 NEPHROLOGY --117
Restore normal volume status                                 3) If patients recover from episode of ARF, typically the
Maintain fluid and electrolyte balance                          residual findings are modest reduction in GFR and
Provide adequate nutrition                                      inability to maximally concentrate and acidify the
Treat infections.                                               urine
Attempt to  UOP in oliguric intrarenal ARF by a trial of    4) infection important cause of death
    loop diuretics. If successful in  UOP, fluid and        5) mortality rates still significant (50%)
    electrolyte abnormalities are easier to manage. if
    unsuccessful, do not continue the drugs.                 Given such outcomes, it is important to realize that the
Adjust doses of drugs metabolized/excreted by the kidney         physician can take certain steps to anticipate and
    to avoid further toxicities.                                 prevent the development of ARF:
Avoid unnecessary catheters, as infection is the most        1. Recognize settings and patients at risk:-the most
    common cause of mortality in patients with ARF.              significant risk factor for ARF is pre-existing renal
Watchful waiting for recovery                                    disease Kidney is much more sensitive to toxins.
Experimental modalities being tested: Insulin growth like    2. Avoid volume depletion
    factor, ANP, NO synthase inhibitors.                     3. Limit exposure to radiocontrast agents in patients at
                                                                 risk, and use pre-exposure volume expansion
Acute                           Chronic                      4. Be attentive to the use of nephrotoxic drugs (esp
Previous lab tests              Previous lab tests               NSAIDS and Aminoglycosides) and carefully
Normal or large kidneys         Kidney size can be small         monitor drug doses and therapeutic levels.
No renal osteodystrophy         Renal osteodystrophy
+/- anemia
Poor tolerance of symptom
                                                             CHRONIC RENAL FAILURE
                                                             CRF: slowly progressive & typically irreversible  in
Consequences of Acute Renal Failure                          Chronic renal insufficiency:  GFR that has not reached
Excretory loss:                                                  the point at which uremic symptoms appear. Lab
1.  BUN/creatinine. Rate of rise dependent on residual          values show a  of GFR below 20-25 ml/min.
   renal function                                            Uremia: widespread organ dysfunction since the loss of
2. Metabolic acidosis due to inability to excrete an acid        kidney function has multiple systemic effects.
   load  hyperkalemia, hypocalcemia,                        ESRD: End stage renal dz.
   hyperphosphatemia, and uremic toxins (responsible
   for many of the symptoms of renal failure)                Progressive Loss of Nephron Function:
3. fluid overload                                            Although most forms of chronic renal insufficiency lead
Endocrine loss:                                                  to progressive deterioration of renal function, the rate
1) Kidney makes epo. With ARF will have anemia &                 of loss of function is variable between patients, and
   new epo production stops and persistent anemia.               depends on the kind of kidney disease, the presence
2) 1,25 OH-vitamin D deficiency: functionally hypo               and control of hypertension, and complicating
   Vit-D.                                                        illnesses and drug therapy.
Complications of ARF:                                        For a given pt, the rate of decline in GFR tends to be
                                                                 constant and predictable in the absence of
1) Infectious: Reason why pts die from ARF. 35% of               superimposed insults.
   pts die from ARF due to infections. Prolongs stay in      Use the reciprocal of the serum creatinine concentration
   ICU. Get sepsis.  risk for infection, PNA, UTI,              plotted against time and observe a linear plot over
   wound infection, sepsis, abnormal cell-mediated               months or years. Can predict time when dialysis will
   immunity.                                                     be needed.
2) Metabolic: acidosis, electrolyte disturbances
3) GI: nausea, vomiting. Early sign of ARF.                Factors that lead to progressive nature of CRF include:
4) CV: pericarditis, arrhythmias. Particularly             1) Persistent activity of the initiating insult: Pt with
   ventricular. Uremic toxins and electrolyte                  uncontrolled HTN with scaring. DM with persistent
   imbalances.                                                 HTN. Persistent.
5) Neurologic: asterixis (flap if doing stop sign),        2) Renal parenchymal calcification secondary to high
   neuromuscular irritability, somnolence, seizures,           calcium phosphate product:
   coma.                                                   3) Intraglomerular hypertension, hyperfiltration leading
6) Hematologic: anemia, coagulopathies, hemorrhagic            to sclerosis and loss of residual nephron: This
   diathesis (abnormal platelet function. Lack of vWF.         hyperfiltration is associated with stretch and then
Indications for dialysis are:                                  activation of extracellular scaring and fibrosis. Loss
                                                               of residual nephrons.
1. Uncontrollable electrolyte abnormalities: hyperkalemia,
     metabolic acidosis.                                      Therapeutic interventions that lower intraglom
2. Fluid overload: if pt is unable to excrete fluid due to     filtration
     need for large volumes of infused fluid for drugs and    ACEI: Control of BP slows progression. an accepted
     nutrition. May have pts that do not have oliguria.        piece of the pharmacologic armamentarium for the
     However they do not excrete nitrogenous wastes.           treatment of chronic renal insufficiency.
3. Uremic symptoms                                            MDRD: modification of diet. yielded striking results
4. Arbitrary lab values: creatinine >10 mg/dl, BUN >100        in clinical trials
     mg/dl                                                 Pathophysiology of the uremic state
                                                             Urea itself is not a uremic toxin. BUN used as a surrogate
Most pts w/prerenal azotemia or urinary tract obstruction
                                                                 marker for whatever true toxins do accumulate in RF.
   do not progress to this point, because they are treated       When BUN is consistently > 100 mg/dl, uremic
   with either volume expansion (e.g. prerenal
                                                                 symptoms occur. However, malnourished pts who
   azotemia) or relief of the obstruction.
                                                                 may have  synthesis of urea may manifest uremic
Typical outcome of pts with intrarenal ARF:                      symptoms at  BUN values.
1) oliguric phase and/or progressive azotemia typically      Other uremic toxins: include guanidines, polyamines,
   last 1-2 weeks. This will prolong their stay in the           phenols, methylamines, and "middle molecules."
   hospital.                                                     Middle molecules are peptides and other nitrogen
2) diuretic phase, which precedes fall in serum                  containing compounds with molecular weights
   creatinine. Heralds an improvement in nitrogenous             between 500-3,000 daltons. Protein is the principal
   excretion.                                                    source of such molecules, and therefore, the
    concentration of middle molecules can be reduced by      Some pts will develop DM II.
     dietary protein or through dialysis.                   Lipid metabolism: Atherosclerosis is markedly  CRF.
-2 Microglobulin: Dialysis pts cannot excrete -2 part          Usually the levels of VLDL and LDL are  in uremic
    of MHC I  destructive spondyloarthropathy 2/2               patients.
    amyloid deposits.                                        Thyroid metabolism: Free thyroxin levels are typically
"Trade-off' hypothesis: mechanisms in pts w/RF permit            normal in CRF while serum triiodothyronine levels
    a balance between the intake and excretion of various        are . Typically only pts w/ TSH levels are treated
    substances, but at the price of producing symptoms           for hypothyroidism.
    that contribute to the uremic syndrome.                  Sexual dysfunction:
1) secondary hyperparathyroidism which develops to              Men: Testosterone levels are low and/or depression.
    maintain phosphate and calcium balance.                     Most women w/CRF of reproductive age are infertile,
2) Impaired renal clearance of phosphates leads to               however, occasionally a viable pregnancy occurs in a
    lowering of ionized Ca concentration, resulting in           pt on dialysis.
    stimulation of PTH release. Hten serves to increase      Hematologic Suppressed erythropoiesis due to
    renal phosphate excretion. Leads to Higher levels of         erythropoietin deficiency: anemia, normochromic,
    parathyroid hormones increase renal phosphate                normocytic. Patients with CRF are treated with epo.
    excretion, however, this high level of PTH promotes      bleeding diathesis: abnormal platelet function and an
    bone damage and renal osteodystrophy. The low                abnormal platelet vessel wall interaction. Can correct
    level of 1 ,25-D3 contributes to bone disease.               with ddAVP and with estrogens. These are . Do
3) Kidney damage reduces 1-hydroxylation of 25-                  not treat with chronically. If have invasive procedure
    dihydroxy-cholecalciferol. Reduced production of             can do both of these things.
    1,25-vitamin D3 limits intestinal calcium absorption.
    Contributes to osteomalacia.
                                                                            Clinical features
Alterations in fluids and electrolytes in CRF                Asymptomatic until GFR  below 20 ml/min
Sodium: Na balance is typically maintained until renal       1) GI: anorexia, nausea & vomiting. Meat & protein do
     function falls below 10% of normal. This can occur         not taste good.
     because there is increased function of individual       2) CV: accelerated atherosclerosis
     surviving nephrons, and therefore increased Na          3) NM: drowsiness, decreased attentiveness,  cognitive
     excretion per surviving nephron.                           function and peripheral neuropathy. Do not good
Pt‘s with CRF cannot adjust rapidly to changes in dietary       info from pt.
     Na:                                                     4) Pruritus. Related to secondary hyperparathyroidism.
   sudden increases in dietary salt —> HTN & vol
     overload                                                History: Evidence of CRF can be obtained by BP, the
   sudden restriction in dietary sodium —> uNa losses           presence of protein or blood in the urine. Life
     in excess of intake —> volume depletion.                    insurance, military service exams are frequently
Water Balance: uOsm tends to become relatively fixed             helpful in this regard. Patients with CRF are
     (300) at sOsm. The kidney can no longer concentrate         frequently tired and have little energy.
     or dilute the urine. This leads to nocturia and a       Physical exam:
     limited capacity to excrete free water. This can lead   Appearance of chronic illness with weight loss and
     to hyponatremia in the setting of excess oral or IV         muscle wasting,
     water ingestion.                                        Skin: typically pale, or in Caucasian people may have a
                                                                 yellow/brown discoloration due to the accumulation
Potassium: K secretion per nephron increases in chronic          of non creatinine chromogens.
    renal insufficiency, does as GI loss of K'. Most         CV:  BP (vol responsive), cardiomegaly, edema, and
    patients do not become hyperkalemic until renal              very late in RF  pericardial friction rub (indication
    failure is advanced, less than 20 ml/mm and urine            that pt should start dialysis).
    volume below 500 ml/day. Now 50% loss of GI of           Breath: fish-like or urea-like odor. Presence of urea in all
    K.                                                           parts of body.
Some pt with prominent interstitial disease do develop       NM: myoclonic twitches, asterixis, and mental status
    hyperkalemia with better preserved GFR because of            changes. DTR may be diminished.
   Hypoaldosteronism
   tubular resistance to the action of aldosterone.         Diagnosis:  BUN and serum creatinine. Other laboratory
Acid Base Balance in CRF : Metabolic acidosis                    abnormalities include anemia, metabolic acidosis,
    develops in uremic patients because of their inability       hyperphosphatemia, hypocalcemia, hyperuricemia,
    to excrete acid generated each day on a normal diet          and hyperkalemia.
    (approximately 1 mEq H ion generated per kg of
    body weight each day). In RF, this is partly due to             Approach to pt with CRF
    inadequate production of ammonia. Cannot excrete         Determine whether this is chronic or acute.: Serial
    NH4+.                                                        measurements may be required to make this
   GFR=30-60 ml/min: hyperchloremic metabolic                   determination.
    acidosis develop.                                        Previous records that may show Evidence for chronicity
   GFR <20 ml/min: acidosis is replaced by a high           Kidney size: if small is chronic
    anion gap acidosis which is attributable to the          Evidence of renal osteodystrophy by radiograph: takes
    accumulation of non-volatile acids. These acids are          years to develop.
    no longer filtered by kidney.                            FH of hereditary renal dz.
Unexcreted acid is buffered by bone —> bone
    demineralization.                                      reversible factors contributing to or aggravating renal
Metabolic & endocrine manifestations of                        failure.
                                                           Perhaps there may be an acute component to the RF.
uremia                                                     1) Hypovolemia
Glucose and insulin: Insulin is partly degraded in the     2) HTN: can lead to scaring.
    kidney. When GFR , T ½ of insulin . However,         3) CHF: reduction in blood flow
    this is off-set by the development of insulin          4) Nephrotoxic drugs
    resistance in progressive RF.                          5) Hypercalcemia: Directly suppresses ?? Remove and
In patients who received administered insulin, T ½ will be     can lead to improvement of GFR.
     in progressive renal insufficiency, which if unnoted 6) Underlying infections
     hypoglycemia.
                                                                                 NEPHROLOGY --119
7) Atheroembolic disease: Accelerated atherosclerotic        Dose adjustment of chronically administered medications,
     dz. May have emboli and then inflammatory response          taking into account their handling by the kidney.
     and scaring.                                                Drugs to avoid at all costs that are particularly
                                                                 dangerous in renal insufficiency.
Is clinical presentation consistent w/dz that may be         1) Mg containing compounds
     remediable?                                             2) NSAID: Alter renal blood flow and K secretion.
1) Malignant hypertension leading to renal failure           3) K sparing diuretics: lead to hyperkalemia
2) Renal artery stenosis                                     4) Radiographic contrast materials
3) Wegener' s granulomatosis
4) SLE                                                       Protein intake:
5) Multiple myeloma: deposition of light chains and          Reduction of dietary protein to improve uremic
     electrolyte abnormalities.                                  symptoms: particularly GI symptoms. However, the
6) Urinary tract obstruction                                     reduction must be balanced against the possibility of
7) Hypercalcemic nephropathy                                     this leading to inadequate caloric intake and
8) Interstitial nephritis                                        inadequate essential AA intake.
9) Cholesterol embolization                                  Use mixed protein diet w/0.6 g/kg body weight.
10) Lead nephropathy
11) Analgesic nephropathy.                                   low protein diets to try to retard the progression of renal
                                                                 disease: Modification of Diet in Renal Disease Study
What are the common causes of CRF in outpatients?                long-term adherence to a low-protein diet could be
1) Glomerulopathy: 30% of patients with CRF. DM                  well tolerated and may slow the progression of renal
     most common.                                                failure. However, the effect is quite small and
2) Interstitial renal dz: 15 - 20% of pts with ESRD.             requires several years of follow-up to be apparent.
3) Polycystic renal dz: 10% of pts with ESRD.                BP control with ACE inhibitors and glu levels are more
4) HTN: contribution varies with race and is more                effective.
     common in African Americans than in Caucasians.         Anemia:Epo has eliminated need for blood transfusions.
5) Idiopathic: In many patients, the exact cause of CRF
     is never established because the patient presents at a                 Treatment of CRF
     time when the disease is irreversible and the cause
     cannot be determined.                                   Hemodialysis:
Management of patients with CRF:                             An extracorporeal therapy in which blood is removed
                                                                 from the body, has its chemical composition
1) Rule out treatable causes.                                    modified by diffusion across a semi-permeable
2) BP control: can stop progression of scaring.                  membrane, with an external device referred to as an
3) Diabetes control: Can slow progression.                       artificial kidney, and then is returned to the patient
4) Phosphate intake restricted and if on phosphate               continuously over a 2-4 hour period. Requires a shunt
     restriction the serum phosphate continues to be             or fistula.
     elevated,                                               Typically performed 3 times a week and requires trained
5) Phosphate binding agents with meals (typically                personnel in attendance during the treatment. It can
     calcium carbonate).                                         be conducted by the patient with a helper in the home
6) Calcitriol supplementation in conjunction with the Ca         setting, although the majority of patients are dialyzed
     supplements.                                                in centers.
7) Mg containing antacids are avoided 2/2 risk of            Net removal of fluid and of electrolytes.
     hypermagnesemia.                                        Complications:
8) Danger of Al in Phos binding agents. Al can be            1) vascular access problems: may have to insert temp.
     absorbed from the GI tract and after long-term              catheter. Predisposes to infection.
     therapy can accumulate in the bone, brain, and other 2) Metabolic complications in terms of patient
     tissues. Al toxicity  osteomalacia, which is               responses to the synthetic membrane dialyzers:
     resistant to treatment with 1,25-dihydroxy vitamin          allergic reaction. Rare.
     D3. Also can get dialysis dementia, characterized by 3) hypotension during the procedure and myocardial
     seizures, aphasia and paralysis.                            ischemia and dysrhythmia associated with electrolyte
Sodium and water intake:                                     Although dialysis maintains their electrolyte and body
In general patients are instructed to follow a diet              fluid composition in an acceptable state, the
     containing 4-6 grams of Na, which can be reduced            rehabilitation of patients on hemodialysis is relatively
     further if there is edema or significant hypertension.      poor, with the majority of patients not able to return
     However, it should be liberalized if hypotension or         to full-time employment.
     salt wasting occurs.
Patients are typically instructed to monitor their body      Peritoneal dialysis
     weight daily and adjust their salt intake to maintain a This involves the placement of an aqueous solution of
     constant weight.                                            dialysate into the peritoneal cavity where it bathes
Potassium intake is usually not problematic as stated            peritoneal capillaries. These capillary walls act as a
     earlier until the development of ESRD. However,             semi-permeable membrane across which solutes and
     superimposed factors such as the use of salt                water move by diffusion. After the fluid has remained
     substitutes, or increased K intake                          in the peritoneal cavity for a variable period of time,
Drug therapy that alters K homeostasis, may lead to              removal of the fluid effects the removal of toxins,
     premature hyperkalemia. In such cases, K restriction        electrolytes and excess volume from the patient. This
     of the diet is helpful, as is the occasional use of ion     form of dialysis, which the patient can perform by
     exchange resins. SE: abdominal cramping and                 themselves at home, requires a sterile access to the
     diarrhea. Not well tolerated by pts on a chronic basis.     peritoneal cavity, typically a Silastic catheter which
Treatment of acid-base balance:                                  remains in place.
Maintain a sHCO3 level at 18 or above.                       Complications:
Treatment is with NaCHO3, or Na citrate (metabolized to 1) Peritonitis:
     HCO3).                                                  2) New onset diabetes: Large glucose load. related to
Chronic metabolic acidosis with a serum pH < 7.3 —>              the glucose contained in the dialysate to affect water
     diminished bone density, impairs CV catecholamine           removal
     responsiveness and aggravates muscle catabolism.        3) Lose proteins. results in loss of at least 10 g/day of
                                                                 protein which must be compensated for through
Adjustment of drug dosages:                                      increased dietary intake.
Renal Transplantation
Currently, 1 yr renal allograft survival rates are ~ 84%
     and 96% for recipients of 1st cadaveric renal
     transplant or a 2 haplotype identical transplant from a
     sibling. The corresponding 1-yr pt survival rates are
     95% and 98%. Pt undergoing renal transplantation
     must be carefully evaluated prior to the
     transplantation for their appropriateness for
     transplantation. Some pts have other underlying dzs
     which carry with them an excessive risk of morbidity
     or mortality from the transplant surgery or the
     immunosuppressive drugs required to maintain the
     allograft. 75% of transplant recipients in this country
     obtain their allografts from cadavenc donors.
     However, living related and living unrelated
     donations are increasing.
Complications once the allograft has been successfully
1) Infections: related to the immunosuppressive therapy
2) Malignancies; Related to immunosuppressive therapy
3) CV disease: some of the immunosuppressive drugs
     may exacerbate through increasing hyperlipidemia.
In addition, the allograft may be slowly lost through a
     process poorly understood referred to as chronic
     rejection. However, most people who have a
     successful allograft are loathe to return to chronic
     dialysis as a form of ESRD therapy, since the
     independence provided by a functioning allograft
     returns them to a lifestyle which closely
     approximates their pre-morbid state.
                                                                                 NEPHROLOGY --121

     POLYCYSTIC KIDNEY                                             Infantile Polycystic Kidney
        DISORDERS                                                            Disease
                                                             Inheritance: autosomal recessive. Death usually in
                                                               perinatal period 2/2 pulmonary failure due to
 Adult Polycystic Kidney Disease                               compression by subdiaphragmatic renal masses. Rarely
                                                               survive perinatal period; die in early childhood from
           (APCKD)                                             CHF 2/2 HTN. Rarely survivors may live to
Most common hereditary dz in US  500,000 affected             adolescence and develop partial HTN with bleeding
    pts. Accounts for 10% of all renal failure.
                                                               varices and die
Bilateral expanding cysts.
   kidneys large w/less of normal shape with multiple
    cysts; cluster of grapes distributed throughout cortex        Acquired Polycystic Kidney
    and medulla                                                            Disease
   cysts vary in size from a few mm to several cm in       seen in patients who are on hemodialysis
    diam. Present in all parts of nephron in both cortex    underlying etiology of ESRD not a factor
    and medulla.                                            kidneys may be small, normal or large in size
Inheritance                                                 cysts may vary from few subcapsular to several
                                                            microscopic exam shows cysts arise from tubules lined
Autosomal dominant, males = females affecting 1 in 1000
                                                                with cuboidal epithelium
ADPKD1: Short arm of Ch 16. Gene responsible for ~
                                                            high percentage of cysts have tumors arising from them--
     85% of cases in the white population of European
                                                                adeno Ca or renal cell adenomas
     ancestry. Lack gene for polycystin which is involved
                                                            can present as intrarenal hemorrhage
     in cell-cell/matrix interactions that plays a role in
                                                            may require nephrectomy, particularly if malignant
     forming developed kidney. Here abnormal
                                                            These disorders involve the distal tubules and collecting
     development of extracellular matrix by tubules leads
                                                                ducts and have varying degrees of interstitial fibrosis
     to cysts.
                                                                and inflammation.
ADPKD2: chromosome 4. Same spectrum of organ
     involvement, but with milder clinical phenotype
At least one more gene for ADPKD is also known to                     URINARY STONES
     exist.                                                 Hx and PEx
Clinical                                                    1) Renal colic: pain begins suddenly and  over 15-
1) + Family history                                             30 min. into steady, unbearable pain  nausea and
2) Onset: do not usually develop renal cysts or                 vomiting. Unilateral intermittent flank pain that can
     symptoms of kidney dz until after 20-25 years of age       radiate to ipsilateral groin/testes
     usually 30‘s or 40‘s.                                  2) Hematuria
3) fullness in flanks and episodic abdominal pain: due to 3) Low grade fever
     renal cyst infection, hemorrhage into renal or hepatic 4) Infections, IBD, gout, renal dz, FH of stones.
     cysts, nephrolithiasis, or presumably due to           5) Guarding with nausea & vomiting
   mechanical factors 2/ to cyst size.
4) hypertension                                              WORK-UP
5) ureteral colic (blood clots from ruptured cysts),         CBC:  WBC if infected
   polycythemia, uremia                                      Chem 7, serum Ca, phos, Uric acid
                                                             UA: hematuria; pyuria, stone analysis, 24hr urine Cx.
Assoc. abnormalities:                                        KUB: 90% of stones detected. Will not pick up
     polycystic liver                                           radiolucent uric acid stones.
                                                             IVP: Useful if anatomical defect suspected.
     berry aneruysm. Can rupture.
                                                             CT scan: test of choice.
     pancreas cysts
                                                             US: can detect stones >4 mm.
     Miral Valve Prolapse: 25% of pts.
                                                             Calcium stones                                 (75-85%)
                                                             Diamond shaped.
Many diagnosed through screening (renal US) because of       Ca-oxalate  major comp of most urinary stones
    + FH. ~ 15% of individuals harboring the defective
                                                             1* Hyperparathyroidism:  PTH &  serum Ca.  
    gene will still have a Nl renal US at the age of 30.
                                                                  supersaturation of calcium. Ca level > 10.
Diagnosis  GN ultrasonic evidence of multiple cysts
                                                                surgery if 1 hyperPTH
    throughout the renal parenchyma, associated with
                                                             Idiopathic hypercalciuria: Normal Ca levels. Pts absorb
    renal enlargement.
                                                                  and excrete in their urine a  fraction of dietary Ca.
Complications                                                Treatment:
Therapy for all pts is supportive  control of HTN and        Thiazides:  urinary Ca excretion by  Ca reabsorption
    Tx of UTI                                                  in distal nephron and  reabsorption in intestine. Can 
1) hematuria and intrarenal hemorrhage                         likelihood of stone formation. Benefits not seen until
2) renal infection: Abx w/good cyst penetration                after 2 yrs of Tx.
    (trimethoprim-sulfa, ciprofloxacin, or                    Low Ca diet:
    chloramphenicol).                                         Low protein diet:
3) nephrolithiasis                                           Low urine citrate:  intestinal absorption. Tx: Potassium
4) HTN                                                            citrate.
5) ruptured cerebral aneurysm                                Hyperoxaluria:
                                                             1) Genetic: rare congenital, no drugs effective.
Causes of death (Ave age: 50-60), uremia (50%),              2) Malabsorption syndromes: IBD, Small-bowel bypass
    cerebral hemorrhage (10-15%), MI (10%), CHF                   surgery for morbid obesity, chronic pancreatitis. Will
    (10%), & other (15-20%)                                       have  fecal fat  chelation of calcium not leaving
Progression: Progresses to ESRD in ~ 50% of pts by age            enough to bind oxalate. Have Hyperoxaluria in range
    70.                                                           of 100-300.
External influences that influence dz progression           3)  oxalate intake: Spinach.
    ADPKD1 gene, , black race, HTN, UTI's (in ), and
    episodic hematuria.
4)  intake of oxalate precursors: Vit C, Ethylene glycol Uncontrolled pain needing parenteral analgesics
    (will have gap met acidosis), and anesthetic          severe nausea w/dehydration  IV Fluids
    methoxyflurane.                                       1 functional kidney at risk of ARF
5) Pyridoxine deficiency:
Treatment:  oxalate intake (spinach, cocoa, peppers,     ESWL: shock waves - poor response w/cystine stones)
    pecans, peanuts, chocolate), Ca supplements (will     Stone extraction: basket-like wire instrument
    help to precipitate oxalate in intestine),                w/fragmentation
    Cholestyramine, citrate supplements.                  Lithotripsy: electrohydraulic, ultrasonic, laser

Hyperuricosuria: Diagnosis made w/urine uric acid >750                      Prophylaxis  nd
   mg/24 hr.                                           In 10 yrs, 50% of pts develop 2 stone.
  low protein diet.                                   Follow up labs: @ 6 weeks after stone has passed and pt
  allopurinol: will  uric acid excretion.                 back on regular diet  24 hr urine collection  vol,
                                                            creatinine, pH, calcium, phosphorous, sodium, uric
Ca-phos: 2nd most common stones Tx w/potassium              acid, oxalate, citrate, and cystine.
   citrate.                                            All stones:  fluid intake >2 L urine output/d, and 
Uric acid                                     (5-8%)        proteins or phosphate excess
Purine metabolism. 50% pts have Hx of gout
Low urine vol, low pH,                                                  DISORDERS of Na
Hyperuricosuria. in urine, appears red-orange
Radiolucent urinary calculi therefore not seen on KUB                      EXCRETION
                                                              Determination of total body sodium (TBNa)
Normal urine: Uric acid excretion 600 to 800 mg/day.
 pH: caused by chronic diarrhea, acidifying meds,            Principle:
    excessive water loss from GI, uricosuric drugs            Na is the principal extracellular fluid (ECF) cation.
    (salicylates, thiazides)                                  Na determines ECF volume. More Na more ECF fluid
                                                                  vol. Determine from physical exam.
 protein diet
                                                              Na excluded from intracellular space.
                                                              ECF volume of total body Na (TBNa).
 urinary vol: > 2L/day                                       40% total body weight = Intracellular.
 purine diet:  red meats. Can add allopurinol 300-600
    mq qid if unresponsive to diet                           Hypervolemia
Alkalinize urine: pH 6.5 to 7. KCitrate 15-20 mEq PO         1) TBNa excess
    tid/qid                                                  2) Interstitial fluid (ECF): edema. Edema suggests an
                                                                 increase in interstitial fluid volume by at least 2.5 to 3
Hyperuricemia: Uric acid excretion > 1200 mg/day.                L. Pitting edema typically. Diagnostic. Symmetric
myeloproliferative dx, neoplasm, Lesch-nyhan                     and generalized.
Treatment: allopurinol + above measures                      3) Intravascular fluid (ECF): jugular venous distention.
Styruvite stones                                  (10-15%)       JVP normal 1-8 cm H20.
Urea splitting organisms: Proteus, pseudomonas,              4) Edema where gravity dependent.
     Klebsiella and Enterococci   urinary pH                  Standing: pedal (lower extremities). Over dorsum
     solubility of stones.                                          of foot.
E. Coli never causes.                                             Recumbent: sacral, pulmonary, peri-orbital.
Predisposing factors: Neurogenic bladder, catheters,
     ♀>♂; men ♂ predisposed if have Foleys.                  Hypovolemia
Treatment:                                                   1) TBNa deficit = ECF fluid volume depletion.
Surgical removal. Can use lithotripsy to  damage caused 2) Intravascular compartment most reliable.
     by growth and spread of these stones.                   3) Orthostatic tachycardia  orthostatic hypotension 
Abx: not effective until stones are first removed. . Then        hypotension with tachycardia.
     can get Abx Tx directed at specific organism.           4) Lab: Kidney holding on to Na like crazy. Filtered Cr
 urine vol,  urinary phos levels  phos-bindinq                cannot be held.
     alumOH gels                                                   uNa <10-15
                                                                   uOsm >450
Cystine stones                                          (1%)       plasma BUN/creatinine > 20:1
Refer to urology                                                   hematocrit
Inherited autosomal recessive defect in RTA Cystine                plasma albumin
     excretion: normal < 100
   Homozygous: >600mg/d                                     Serum Sodium:
   Heterozygous: >300 mg/d                                  NO!!!!. sNa only reflects relative water balance (with
FH of stone dx                                                   respect to Na) and not TBNa. When TBNa is , sNa
Hexagonal crystals                                               can be ,  or normal.
Alkalinize urine: target of pH >7.5 use Kcitrate             Local edema with no  TBNa
 fluid intake: > 4 L/day                                    Causes: Inflammation, venous outflow obstruction,
D-penicillamine to complex Cystine.                              lymphatic outflow obstruction
                                                             Findings: Local inflammation, asymmetry or very
                    Management                                   localized, not pitting, not gravity dependent, surface
OutPt management If stones < 5 mm  drink plenty of              venous dz, surface lymphatic dz, LN enlargement,
     fluids, strain urine to catch stones for analysis, oral     absence of signs of systemic dz.
     analgesics, and KUB                                     Normal Physiology of renal Na Excretion
Indications for Hospitalization:                              Ingest 150 mEq per day. So must excrete 150 mEq/day.
Immediate care if >10mm stone (obstructed)  Need             GFR (Normal is 120 ml/min. Low is below 30
    ureteral stents or percutaneous nephrostomy.                  ml/min)  Na filtration   Na excretion.
>101 fever  start IV Abx (Amp & Gent)
                                                                                   NEPHROLOGY --123
 Aldosterone  distal Na reabsorption   Na                 Glucocorticoid deficiency: Addison's disease. Become
    excretion.                                                    hypotensive. Requires glucocorticoid to correct
Other ("third") factors.                                          hypotension.
1) ANF: Homeostatic role: Negative feedback role. 
    blood volume   atrial distension  ANF release                               EDEMA
      kidney Na excretion   blood volume.
2) Angiotensin II (local effect in proximal tubule)          Pathophysiology:
    renal Na reabsorption.                                     Two factors are crucial in  ECF fluid movement from
3) Norepinephrine   renal Na reabsorption.                      intravascular to extravascular (interstitial).
4) Peritubular capillary oncotic pressure (PTC ):            1) Hormonal and renal
    Efferent arteriolar constriction   filtration fraction   2) Starling forces
    (GFR/RPF)   PTC    renal Na + H20