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									Introduction to Disease
Spring 2009

                              Tuesday March 10, 2009 - Mid-Term Review

Mid-Term Review Handout
The handout is designed to organize, synthesize, and logically apply basic science knowledge to cases. The
purpose is to integrate material between the basic sciences and clinical disorders. Questions after each
case are written to illustrate basic concepts in pathology and pathophysiology. Each question is
accompanied by an answer and paragraph explanation.

An effective way to study is to read the clinical scenario and answer each question in the set. After you
finish going through the questions in the set, spend as much time as you need verifying your answers and
carefully read the explanations provided. If you feel you need additional information about the material,
consult and review your notes and textbook. This method of review is a not only beneficial for the
midterm examination, but also to prepare students for system courses and clinical experiences.

Objectives
This is a mid-term review of concepts presented from Robbins Basic Pathology Chapters 1-7. On
completion of this review, students should be able to apply basic concepts in pathology to common
clinical disorders.




                                               Page 1 of 16
Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009

CASE 1- ABDOMINAL PAIN
S: A 72 y/o Hispanic male comes to clinic because of worsening epigastric pain. He has had this pain on
    and off for 3 months but in the last week it has become constant even awakening him from sleep. At
    the beginning he was getting relief with OTC Pepcid but now that doesn’t seem to help at all. He
    describes the pain as a dull burning that neither gets better or worse with meals. He denies diarrhea,
    constipation, melena and hematochezia.
O: Hemoccult positive stool in rectal vault has a melanous appearance
Diagnosis after Complete Work-Up: Peptic Ulcer Disease (PUD)

Inflammation and Repair Review- Robbins Chapters 2 and 3
1. What are the important underlying factors in any disease/disorder?
             a. Etiology: inflammation due to acid injury. Infection due to H. pylori (bacteria)
             b. Pathogenesis: inflammation due to loss of balance between acid exposure and mucosal
                  protective factors. H. pylori initiates mucosal inflammation.
             c. Lesions: chronic ulcer – with acute inflammation and chronic inflammation with fibrous
                  tissue repair.
             d. Clinical presentation - most common are pain and bleeding
             e. Course and prognosis – resolution with treatment. Complications due to ongoing
                  inflammation (more bleeding, repair with scar may obstruct the outlet of stomach,
                  inflammation continues to extend through the full thickness of the stomach, perforate)
             f. Therapy: anti acid therapy, either medical or surgical
2. What is the underlying pathophysiology as it relates to the histology of the stomach, gastric
     metaplasia in the esophagus, and duodenum and the physiology of acid production?
             a. Acid production is the function of acid secreting mucosa in the stomach.
             b. Persistent injury due to impaired/insufficient protection against the acid.
             c. The type of epithelium is important if other protective features are insufficient. Mucus
                  producing glands is optimal; has protective mechanisms against acid injury (surface
                  glands in stomach and duodenum produce mucus and other agents to counteract the
                  acid).
             d. Mucosal cells are stem cells (labile tissue) capable of driving continuously to regenerate
                  the epithelium unless the ulcer is deep and there are not residual cells to regenerate
                  then scar forms.
3. What are the complications of this disorder as it relates to healing and repair?
             a. Based on morphology: chronic deep ulcers are present, histology is characteristic: as the
                  inflammation produces progressive zones of acute and chronic changes in the tissue.
                         i. Because the surface is most vulnerable to ongoing acid, a thin layer of
                            liquefactive necrosis due to neutrophils with necrotic mucosal cells covers the
                            ulcer; followed by a deeper…
                        ii. Zone of inflammation –neutrophils, macrophages, lymphocytes, and plasma
                            cells overlie…
                       iii. Granulation tissue that covers a deeper layers of repair…
                       iv. Scar the most remote area of inflammation and repair; healing by connective
                            tissue replacement (Chronic ulcer scar)
             b. Complications
                         i. Pain
                        ii. Anemia: chronic low grade bleeding from small sites
                       iii. Upper GI Bleeding: inflammation and necrosis erodes into a blood vessel
                       iv. Obstruction: fibrous tissue replacement because injury is too deep into the wall
                            to regenerate the labile/stem surface cells; outlet from stomach and
                            duodenum distorted and obstruction by fibrous tissue repair.
                        v. Perforation: progression of the injury rather than complete resolution


                                               Page 2 of 16
Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009

REVIEW CASES #2 AND #3 TOGETHER

CASE 2- EPIGASTRIC/RIGHT UPPER QUADRANT PAIN
S: A 20 y/o Native American who is pregnant reports to the Emergency Room with constant, severe
    epigastric pain for the last 8 hours. She has never experienced pain like this and worries she is in
    labor. She has had worsening nausea and vomiting in the last 4 hours. She has not had a bowel
    movement in the last 24 hours and last ate mutton stew about 10 hours ago. She has received no
    prenatal care and had planned to deliver at home with a mid-wife. She denies vaginal DC or bleeding.
O: She is tender to palpation in the RUQ and has a positive Murphy’s sign.
Diagnosis after Complete Work-Up: Acute Cholecystitis

CASE 3-ABDOMINAL PAIN
S: An 86 y/o male visited the Emergency Room last night for vague abdominal pain. He was evaluated
    and released and told to follow-up with his primary care physician today. He is in the clinic still
    complaining of abdominal pain that is periumbilical, constant and dull. He also complains of anorexia,
    followed by nausea and vomiting.
O: Abd: hypoactive BS Ø bruits or visible peristalsis; Diffuse abdominal pain with guarding more
    pronounced in RLQ; Ø masses; Positive obturator sign on the right; Rectal: localized rectal tenderness
    and Ø masses. LABS: Hemoccult negative; CBC: high white blood cell count with increased
    neutrophils (Neutrophilic leukocytosis)
Diagnosis after Complete Work-Up: Acute Appendicitis

Acute Inflammation and Pattern of Necrosis- Robbins Chapters
1. Describe how the morphology of the organ contributes to mechanism of injury.
2. What factors other than inflammation lead to the tissue necrosis?
3. What is the expected type of necrosis?
4. On the lab reports, what are the expected white blood cell findings? In gallbladder disease what are
    the possibilities for biliary tact and/or liver injury?

CASE 4- ABDOMINAL PAIN
S: A 44 y/o male presents to the Emergency Room with abrupt, severe epigastric pain radiating to the
    back and accompanied by severe N/V. He denies having had any previous history of epigastric pain.
    He did attend a large wedding last night. SH: Tobacco: 25 pack years; Alcohol and Illicit Drugs: he
    denies use of these substances
O: Gen: sitting on gurney leaning forward with an emesis basin in his hands. He is covered in
    perspiration and appears ill; Skin: Ø jaundice; Eyes: mildly icteric sclera; Abd: Visibly distended, bowel
    sounds are sporadic, Ø bruits; There is mild-moderate diffuse epigastric and RUQ and LUQ pain.
    There is Ø rebound or guarding and no there is Ø HSM
Diagnosis after Complete Work-Up: Pancreatitis

Cell Injury, Mechanism of Injury, and Type of Necrosis Review- Robbins Chapter 1
1. Explain how histology and physiology underlie the response to injury in the pancreas.
2. How does the cell damage contribute to the laboratory evaluation of pancreatic injury?

CASE 5-CHEST PAIN
S: A 42-y/o male presents to the Emergency Room by ambulance with sub-sternal chest pressure and
    epigastric pain of 30 minutes duration that began after a large meal. He also reports mild dyspnea as
    well. The symptoms appeared while lying down and he has never experienced any sensations of this
    nature before. He also reports mild nausea but no vomiting. He confides to you that he is afraid that
    something terrible is happening to him. PMH: DM type 1 and HTN; SH: Pt lives alone. He sacks and
    carries out groceries for a living; Tobacco: 20 pack yr history; ETOH: never; Illicit drugs: marijuana, 20
    yrs ago
A: EKG: diffuse S-T segment changes
                                                 Page 3 of 16
Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009

Diagnosis after Complete Work-Up: Acute Myocardium Infarction (MI)

Cell Injury, Mechanism of Injury, and Type of Necrosis Review-Robbins Chapter 1
1. Explain the mechanism of the necrosis.
          a. Left ventricular hypertrophy *adaptation* reversible. This occurs due to increased HTN, once
              HTN decreases this will go away.
          b. Hypoxia – not enough oxygen to the tissue
          c. Ischemia – not enough blood flow to the tissue (more likely of an MI or arrhythmia) Loss of
              cardiac muscle results in collection of fibrosis tissue – these do not conduct  arrhythmia.
2. How does the cell damage contribute to the laboratory evaluation of myocardium injury?
3. How does the myocardium repair?
4. Why is hypertension important in the pathophysiology of his disease?
5. Explain the expected findings in the coronary arteries.
Fatty change and hydrotic changes. Alcohol and fatty changes with pregnancy are reversible. Liver disease
is most important and most commonly seen.



CASE 6-CHEST PAIN
S: A 32-y/o female comes to clinic today with increasing episodes of chest pain over the last 3-4 mos.
    This gripping pain is most notable after meals, with activity and at bedtime. The pain can last for
    hours and she often wakes in the AM with a dry bothersome cough. She believes she is having heart
    attacks as her mother died from one at age 74. Each time she gets the chest pain she takes 2-3
    aspirin as she heard this can “cure” heart attacks. Current Meds: just the ASA as described above; SH:
    Tobacco: ½ pack per day x 14 yrs; ETOH: 1-2 wine coolers per weekend.        Drugs: none; Caffeine: 4-5
    beverages per day
Diagnoses: Gastroesophageal Reflux (GERD) with possible Esophagitis

Cell Injury and Adaptation Review -Robbins Chapter 1
1. Define adaptation.
2. How do the anatomy, histology, and physiology contribute to the adaptive response?
3. What are the complications of this disorder as it relates to healing and repair?
4. Explains the complication of the adaptive process due to persistent injury rather than healing and
     repair.

CASE 7- ACUTE BACTERIAL INFLAMMATION
S: A first-grade teacher comes to clinic with complaints of a “horrible” sore throat for 5 days and fever
    she says of 102.2°. She denies cough and runny nose. She has tried Sudafed, Tylenol and other cold
    and flu preparations with no relief.
O: Gen: 24 y/o female in no apparent distress; VS: BP 110/68 P 106 R 18 unlabored T 102.1°; Ears:
    TMs pearly bilaterally; Eyes: Conjunctiva clear; Nose: Mucus membranes are dry and only slightly
    erythematous; Oropharynx: Tonsils and posterior pharynx are exudative; Lymph: Tender, enlarged
    cervical lymphadenopathy bilaterally; Lungs: CTA bilaterally; Labs: Rapid Streptococcus antigen assay
    is negative
Diagnosis after Complete Work-Up: Streptococcal Pharyngitis
What cells do you see in case 7 – gram positive cocci. Bacterial in origin. Her CBC will have leukocytosis
with neutrophils.

Inflammatory Response to Bacteria Robbins Chapter
Describe the expected inflammatory response.

CASE 8-ACUTE VIRAL INFLAMMATION


                                               Page 4 of 16
Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009

S:  A 28 y/o male bank teller comes to clinic with complaints of malaise, mild dry cough, congestion,
    PND, sore throat and a runny nose that “just won’t quit”. These symptoms have been present for 2
    days. He feels miserable.
O: en: 28 y/o B/M in NAD; VS:         BP 126/78 P 80 R 18 T 97.6°; HEENT:        Ø discrete facial
    tenderness. TMs c mild injection, conjunctiva injected bilaterally, nares red transudate, oropharynx
    erythematous, mild tonsillar edema; Neck: supple Ø nodes;
Diagnosis after Complete Work-Up: Viral URI
URI – if this pt is sick enough to have leukocytosis, this will be lymphocytes.

Inflammatory Response to Viruses- Robbins Chapter
Describe the expected inflammatory response.
REVIEW CASES #9 AND #10 TOGETHER

CASE 9-IMMUNE RESPONSE
S: A 14 y/o is brought to clinic for 7-10 d of sore throat and malaise. He also has experienced anorexia
    and gagging when trying to swallow. He is not improving and can’t remember having any ill contacts.
    He has NKDA.
O: Gen: 14 y/o male who appears fatigued; VS: BP 120/70; P 72; Respiratory 14; Temp 98.8°; Head:
    NC/AT ø tenderness at either frontal or maxillary sinuses; Ears: TMs pearly and canals free of
                                                                               +
    cerumen; Eyes: conjunctiva clear; Nares: pink and moist; Mouth: tonsils 3 with exudates, uvula is
    midline and there are a number of petechiae on the soft palate; Neck: several, large, tender, mobile
    posterior cervical nodes are present; Chest: LCTA bilateral; HRRR without murmur; Abd: BSx4, tip of
    spleen palpable 1cm below left costal margin O/W no tenderness, masses or hepatomegaly
Diagnosis after Complete Work-Up: Infectious Mononucleosis with Splenomegaly

CASE 10- IMMUNE RESPONSE
A 65 year old female has a 3-cm, solitary, left upper lobe mass discovered by chest x-rays. The mass is
removed at thoracotomy by wedge resection. The lung has extensive caseous necrosis and cavitation. The
microscopic appearance of the necrosis shows granulomas with central caseating necrosis, Langhans giant
cells, and numerous mononuclear cells. Malignant infiltrates are not identified. Acid fast stain
demonstrates bacilli.
Diagnosis after Complete Work-Up: Mycobacterium Tuberculosis

Chronic Inflammation and Cellular Response Review-Robbins Chapter
1. What is the expected cellular response to a viral infection, to a fugal infection, to a mycobacterial
infection?
2. Define granuloma and granulomatous reaction.
3. Why do granulomas develop?
4. Why is an acid fast stain done in this case?
5. What is the expected immune response to an Epstein Barr virus (EBV) infection, and why?
6. What is the expected immune response to the Mycobacterium tuberculosis, and why?
Type 4 reactions – has two types of reactions. How do granulomas develop – macrophages engulf, can’t
eliminate so they build up granulomas.

CASE 11-ACUTE INFLAMMATORY RESPONSE
S: A 19 y/o female comes to the clinic for a very tender right knee. Prior to her knee hurting she states
    that all of her joints were hurting – but now she says it is mostly the right knee.
PHM: G2 P1 T1 P0 A1 L1; Allergies: NKDA; FH: Ø family members with arthritis; SH: lives with her husband
    and one child and she sells clothing at a retail outlet
O: Gen:19 y/o F sitting on exam table with right knee held in slight flexion; VS: BP 122/78 P 88 R 20 T
    100.1°; Skin: several pustular lesions are scattered over the right lower extremity; M/S: the right knee
    is erythematous, swollen and warm to touch compared to the left. She resists full flexion of her right
    knee 2° to pain. Her right wrist is also mildly swollen and she says movement seems to produce pain.
                                                 Page 5 of 16
Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009

    The remainder of her exam is normal. No facial rash, joint pain is limited to one knee; Labs: HCG =
    negative
Diagnosis after Complete Work-Up: Septic arthritis 2° to disseminated gonococcal infection

Acute Inflammation and Clinical Response-Robbins Chapter 2
1. What are the classic clinical signs of inflammation, especially acute?
2. Review the case and identify all the signs and symptoms of acute inflammation.

REVIEW CASES #12-14 TOGETHER ANSWER THESE QUESTIONS
1. Compare and contrast hemostasis and thrombosis.
2. Which of the three Virchow’s risk factors predispose to the thrombosis in this case?
3. How do you classify this thrombus and/or embolus?
4. What is the expected fate of each thromboembolus?

CASE #12-THROMBOSIS AND EMBOLISM
A 64 -year -old white female complains of sudden onset of severe pain in her left leg with associated
weakness of the left foot. The pain intensifies when she moves her leg. She cannot move her toes at all.
She is a smoker and has limited exercise due to pain in her lower extremities (intermittent claudication)
Her vital signs are stable; LE: Popliteal, dorsalis pedis, and posterior tibial pulses lost on the left side;
femoral pulses easily palpable; left leg cold and mottled; anesthesia over lower left leg; Lab work-up
shows only leukocytosis. Imaging studies with Ultrasound-Doppler: obstruction of left femoral artery at
origin and Angiography confirm the obstruction.
Diagnosis after Complete Work-Up: Peripheral Artery Embolism
Treatment:        Thrombolysis; consider embolectomy
Additional Review Questions-Robbins Chapter 4
1. Compare and contrast hemostasis and thrombosis.
2. What is a hypercoagulable state?

CASE #13-THROMBOSIS AND EMBOLISM
60 –year- old female who had undergone right total hip replacement presents on the sixth postoperative
day with central chest pain and acute onset dyspnea. She has been immobile since the surgery.
O: Low grade fever; tachycardia; tachypnea; hypotension. Central cyanosis (face, lips, nose); elevated
    jugular venous pressure; right ventricular gallop rhythm with widely split S2. Arterial Blood Gases:
    hypoxia and hypercapnia: Imaging studies with Ultrasound-Doppler demonstrate clot in the right
    femoral vein. CXR show right lower lobe atelectasis. Ventilation/Perfusion scan: three areas with
    ventilation-perfusion mismatch in right lung. Angio-Pulmonary: confirm large occlusive thrombus in
    pulmonary artery
Diagnosis after Complete Work-Up: Pulmonary Vein Embolism
Treatment: Supportive; thrombolytic therapy; consider embolectomy; prophylaxis with heparin, then
Coumadin

Additional Review Questions-Robbins Chapter 4
1. Describe the pathway of the embolus from the site of formation to the final obstruction.

CASE #14- THROMBOSES AND EMBOLISM
S: 35-year-old woman awakens in the morning to find the right side of her body paralyzed. She also
   complains of palpitations. She has no history of fever, neck stiffness, vomiting, headache, or transient
   ischemic attacks (TIAs)
PMH: Known to have rheumatic mitral valve stenosis
O: VS stable; no fever; irregularly irregular pulses; right sided hemiplegia; brisk reflexes on the right side;
   right sided Babinski present; loud S1; apical mid-diastolic murmur and opening snap. EKG: presence
   of atrial fibrillation; routine culture sterile; clotting studies, bleeding time, and complete blood cell

                                                 Page 6 of 16
Linda F. Cunningham, MD
March 9, 2009
    Introduction to Disease
    Spring 2009

        counts are within reference ranges. Imaging Studies-Echocardiogram: a left atrial thrombus; CT scan
        after 24 hours: a left cerebral infarct.
    Diagnosis after Complete Work-Up: Cerebrovascular Accident (Stroke) due to Thromboembolism
    Treatment: Heparin and Digoxin; valve replacement after appropriate medical treatment.
    Additional Review Questions-Robbins Chapter 4
    1. Describe the pathway of the embolus from the site of formation to the final obstruction.
    2. What anatomy is needed to understand paradoxical embolus?

    Use this work table to make the diagnosis for each case below (Cases 15-17)

                                                                      Case #15     Case #16        Case #17
Is the bleeding problem acquired or inherited? What information
supports your decision?
If it is inherited, what is the pattern of inheritance?
Is the onset secondary to a drug or another illness?
Is there a history of spontaneous bleeding or bleeding after
minor trauma or minor surgical procedures?

Describe the bleeding-
Is it mucosal with petechiae, ecchymoses, hematuria (bladder
mucosa), epistasis (nose mucosa), increased menstrual bleeding
(endometrium), and bleeding gums?
Secondary defect with clotting factors (Factors 7, 8, 9): Are there
hematomas and/or bleeding into large cavities?

Do the lab tests suggest a primary hemostatic defect?
Are there adequate platelets and/or platelet function?
Do the lab tests suggest a secondary hemostatic defect?
Are there adequate clotting factors (review the PT and PTT)?
Is the patient plasma missing a factor that is replaced when
mixed with normal patient plasma?

Diagnosis
What is the defect? Is it primary, secondary, or both?
What is the most likely diagnosis?




    Hemostasis and Bleeding Disorders- Primary and Secondary Defects

    Case 15
    What is the defect? Is it primary, secondary, or both? What is the diagnosis?
    A 36-year-old man has had a history of bleeding all of his life. He has other relatives who have similar
    problems. His bleeding time for platelet function is prolonged, but the platelet count is normal, partial
    thromboplastin time (PTT) for intrinsic clotting factors is prolonged, and prothrombin time (PT) for
    extrinsic clotting factors is normal. A 1:1 dilution of the patient’s plasma with normal pooled plasma
    replaces the missing clotting factor(s) and corrects the prolonged PTT.

    Case 16
    A 42- year- old female presents with several month history of nosebleeds, mucosal gingival bleeding, easy
    bruising and increased bleeding with menstrual periods (menorrhagia). There are no other symptoms and
                                                  Page 7 of 16
    Linda F. Cunningham, MD
    March 9, 2009
Introduction to Disease
Spring 2009

signs. She described a rash on her legs but the physical examination reveals scattered petechiae over the
distal extremities. The peripheral blood smear shows a decreased in platelets. Examination of the bone
marrow biopsy shows a marked increase in megakaryocytes producing and releasing platelets. Her PT and
PTT for clotting factors are within reference range.
What is the defect? Is it primary, secondary, or both? What is the diagnosis?

Case 17
A 60-year-old male has a lifelong history of prolonged and spontaneous bleeding, including hemarthroses,
intramuscular hematoma, and subcutaneous ecchymoses. Other family members have a similar problem.
Although he has three sisters, they do not have a bleeding problem. Two of his three brothers developed
AIDS due to transfused blood components. His sons and daughters are not affected, but one of his four
grandsons has bleeding problems. During a laboratory work-up prior to a cancer screening colonoscopy,
he has a prolonged PTT for intrinsic clotting factors, normal PT for extrinsic clotting factors, normal
bleeding time for platelet function, and normal platelet count. 2 weeks ago, he was forced by the
admitting doctor to stop taking large doses of aspirin daily, as his self-medication against “strokes” to
prevent platelet aggregation. A 1:1 dilution of the patient’s plasma with normal pooled plasma replaces
the missing clotting factor(s) and corrects the prolonged PTT.
What is the defect? Is it primary, secondary, or both? What is the diagnosis?

                                                     Discussion


                                       Acute Inflammation and Necrosis
                                    Abdominal Pain Cases 2 and 3 Answers
Question #1 Pathophysiology of Anatomy
The gallbladder and the vermiform appendix are pouch like structures that that a single inflow and outlet.
Mechanical blockage leads to buildup of intraluminal pressure, ischemic injury, and bacterial invasion. The
end result is ischemia and acute infection.
The gallbladder obstruction is due to gallstones, more likely a small to moderate size rather than large
stones. Obstruction of the vermiform appendix is most likely due to a fecalith.

Question #2 Mechanism of Tissue Necrosis
Mechanical blockage leads to buildup of intraluminal pressure compressing vessels and causing ischemia.
Impaired outflow from the organ increases the necrosis and inflammation. Suppurative inflammation,
abscess formation, and necrosis due to secondary bacterial invasion follow. The bacteria are the normal
flora of the gastrointestinal tract.

Question #3 Pattern of Necrosis
Initially the necrosis is purely due to ischemia, so it is coagulative necrosis. AS the coagulative necrosis
progresses, inflammation is the predominant finding with neutrophils, fibrinopurulent inflammation,
abscesses, and suppurative necrosis masking the ischemic necrosis. As the inflammation with necrosis
extends through the wall, the complication is perforation. Perforated appendix is due to the severity of
the necrosis and inflammation.

Question #4 Laboratory Manifestations
The complete blood cell count (CBC) will show a leukocytosis, due to increased neutrophils. Neutrophils
are the first to respond to bacterial inflammation and necrosis; but neutrophils have a short half life and
are not long lived in the inflammatory process.

Serum enzyme elevations appear in the lab work up because irreversible cell injury impairs membrane
integrity and the cells release their cell content. If the gallstones lead to acute obstruction of the biliary
tract (common bile duct flow of bile) transient elevations of certain enzymes occur. The injury damages
the membrane permeability of the bile duct canaliculi between the hepatocytes. The enzymes alkaline
                                                  Page 8 of 16
Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009

phosphatase (AP) and gamma glutamyl transpeptidase (GGT) are released into circulation. Additionally,
transient hepatocyte necrosis occurs. Irreversibly injured hepatocytes release alanine transaminase (ALT)
and aspartate transaminase (AST) into circulation. Bilirubin is also released from injured cells.

                          Cell Injury, Mechanism of Injury and Type of Necrosis
                                      Abdominal Pain Case 4 Answers

Question #1 Pathophysiology
The pancreas secretes 22 enzymes. Most are secreted as proenzymes and require activation. Amylases
and lipases are secreted in an active form. Pancreatic ducts and acini are injured when obstructed by
gallstones, damages by viruses (mumps), alcohol, and trauma. Acute pancreatitis varies from interstitial
edema and inflammation to necrosis, and hemorrhage. These are the result of the destructive effects of
the pancreatic enzymes released from the injured acinar cells. Necrosis of regional fat by lipases occurs
(fat necrosis).

Question #2 Cell Damage and Laboratory Evaluation
         The exocrine pancreas and salivary glands produce amylase. The pancreatic amylase (p-amylase)
provides a useful test of pancreatic tissue damage than the total amylase. Serum lipases are elevated in
pancreatic damage.

                          Cell Injury, Mechanism of Injury, and Type of Necrosis
                                        Chest Pain Case 5 Answers

Question #1 -Pathophysiology of the Injury and Necrosis
The major underlying factor is an imbalance between the supply and demand of the heart for oxygenated
blood. Reduced coronary blood flow and/or increased myocardial demand cause ischemia of the
myocardium. Reduced blood flow is the most common and is due to atherosclerosis and/or thrombosis.
Increased myocardial demand is due to myocardial hypertrophy (adaptation) secondary to hypertension.
During ischemia, there is progressive compromise of the cells’ metabolic and structural integrity, up to a
certain point the damage is repairable and reversible. With further progression of the ischemia, the cells
pass a “point of no return” after which the damage is irreversible and leads to coagulative necrosis.

Question # 2 -Cell Damage and Laboratory Evaluation
Troponin is a myocardial protein present in the cytoplasm. It is released from the damaged cells early
after myocardial injury, becomes elevated 4-8 hours after the onset of myocardial necrosis and remains
elevated for 14 days. Creatine phosphokinase is a mitochondrial enzyme. The subunit MB (CK-MB) is
called heart specific. When there is myocardial injury, the total CK and CK-MB are increased.

Question #3- Myocardial Repair
With chronic myocardial ischemia, the cardiac fibers show atrophy, interstitial fibrosis, and confluent
fibrosis. Myocardial fibers are permanent cells and do not divide. Permanent cells cannot regenerate and
a scar forms. The patient is at risk for sudden cardiac death due to arrhythmia triggered by scarring of the
conduction fibers.

Question #4- Hypertension
The striated muscle cells in the heart are capable of tremendous hypertrophy, perhaps because they
cannot adequately adapt to increased metabolic demands by mitotic division and production of more cells
to share the work. The most common stimulus for hypertrophy of muscle is increased workload. In the
heart, the stimulus for hypertrophy is usually chronic hemodynamic overload, resulting from either
hypertension or faulty valves. Synthesis of more proteins and filaments occurs, achieving a balance
between the demand and the cell's functional capacity. The greater number of myofilaments per cell
permits an increased workload with a level of metabolic activity per unit volume of cell not different from
that borne by the normal cell.
                                              Page 9 of 16
Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009


Question #3- Hemodynamic Disorders and Thrombosis
The limiting factors for continued myocardial hypertrophy and the causes of the cardiac dysfunction
include limitation of the vascular supply to the enlarged fibers, leading to ischemia and necrosis. The
dominant influence in the causation of the myocardial ischemia and/or necrosis is diminished coronary
perfusion relative to myocardial demand, owing largely to a complex and dynamic interaction among
fixed atherosclerotic narrowing of the epicardial coronary arteries, intraluminal thrombosis overlying a
disrupted atherosclerotic plaque, platelet aggregation, and vasospasm.


                                         Cell Injury and Adaptation
                                         Chest Pain Case 6 Answers

Question #1 Define adaptation
Adaptation is the morphologic and physiologic changes in a cell to adjust (adapt) to excessive stress. This
is a reversible change.

Question #2: Explain the pathophysiology of the adaptive process.
Long-standing gastroesophageal reflux of acid on the esophagus leads to inflammation and ulceration of
the squamous mucosa. Resolution of the acute inflammation leads to healing by regenerating the
epithelium (labile/stem cells), which in the setting of low pH differentiate into more resistant gastric-type
or intestinal type epithelium. Metaplasia is a reversible adaptive change in which one cell type is replaced
by another epithelial cell type. In this case, the change is from squamous to glands. Although the
metaplastic epithelium is benign, the stress that influences the metaplasia, if persistent, may induce
atypical changes (dysplasia) in the metaplastic cells, which may progress to cancer. Metaplasia can
progress to dysplasia; dysplasia can progress to carcinoma.
Thus in the esophagus which is originally lined by squamous cells, the patient with GERD can develop an
adenocarcinoma from the dysplastic epithelium.

Question #3 Complications due to normal healing and repair
The gastroesophageal reflux of acid on the esophagus leads to acute inflammation with neutrophils,
edema, and congestion, then ulceration of the squamous mucosa. The outcomes for any acute
inflammatory process are complete resolution, healing by fibrosis, and progression to chronic
inflammation. Long-standing gastroesophageal reflux of acid can progress to chronic inflammation
(mononuclear cells, plasma cells, lymphocytes, macrophages) and fibrosis. Chronic inflammation has more
mononuclear cells and fibrosis. Excessive formation of granulation and fibrous tissue may block the
outflow tract of the esophagus, producing a stricture.

Question #4 Complications due to chronic injury
Although the metaplastic epithelium is benign, the stress that influences the metaplasia, if persistent, may
induce atypical changes in the metaplastic cells, which may progress to cancer. Adenocarcinoma of the
esophagus arises from dysplastic changes in the metaplastic glands.

                             Inflammatory Response to Bacteria and Viruses
                                        Cases 7 and 8 Answers


Inflammatory Response to Bacteria
Question #1: Describe the expected inflammatory response.
Polymorphonuclear leukocytes (neutrophilic leukocytosis, neutrophilia) accompany acute inflammation
associated with bacterial infections. This is seen in the tissue and in the peripheral blood.

Eosinophils increase in allergic reactions and helminth infections.
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Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009



Inflammatory Response to Viruses
Question #1: Describe the expected inflammatory response.
Lymphocytosis is seen in viral disorders, such as viral hepatitis and infectious mononucleosis. Tissue and
peripheral blood lymphocytosis accompanies monocytosis in many disorders associated with chronic
immunologic stimulation such as tuberculosis.



                           Chronic Inflammation and Cellular Response Review
                                        Case 9 and Case 10 Answers

Question #1: What is the expected cellular response to a viral infection?
Compared to bacteria, viruses cause a less intense inflammatory response characterized by lymphocytes
and monocytes. Patients may present with a leukocytosis due to a lymphocytosis. In most instances the
lymphocytes are atypical with reactive features. The lymphocytes and macrophages (blood monocytes)
have a reciprocal relationship in chronic inflammation. Activated lymphocytes and macrophages influence
each other, and both cell types release inflammatory mediators that affect other cells.
         In infectious mononucleosis, the total white cell count increases to as high as 18,000/mm3
(Reference Range: 5,000 – 10,000/mm3) with as many as 95% lymphocytes (Reference Range: 16 – 46%).
Many of these are T lymphocytes. T cell areas of the lymph nodes and spleen are enlarged.

Question #2: What is the expected cellular response to a fugal infection, to a mycobacterial infection?
Inert foreign bodies, fungi, and mycobacterium can incite a granulomatous reaction. The reaction is a
distinctive- chronic inflammatory reaction in which the predominant cell is an activated macrophage
surrounded by other mononuclear cells such as lymphocytes and plasma cells. The macrophages may
coalesce to form multinucleated giant cell. The macrophages undergo characteristic changes in structure,
developing a large amount of cytoplasm. These activated macrophages are called epithelioid cells.
Nodular aggregates of the epithelioid cells and lymphocytes are granulomas. Granuloma form with
Mycobacterium tuberculosis, fungi, and inorganic materials (crystals, suture, silica).

Define granuloma and granulomatous reaction:

Question #3: Why do granulomas develop?
Granulomas protect the body from substances that cannot be digested.

Question #4: Why is an acid fast stain done in this case?
Granuloma form with Mycobacterium tuberculosis, fungi, and inorganic materials (crystals, suture, and
silica), so a stain is done to confirm the etiology. Cultures are also done.

Question #5: What is the expected immune response to an Epstein Barr virus (EBV) infection, and why?
In T-cell-mediated hypersensitivity, sensitized CD8+ T cells kill antigen-bearing target cells. Such effector
cells are called cytotoxic T lymphocytes (CTLs). Tissue destruction by CTLs may be an important
component of many viral diseases. CTLs directed against cell surface histocompatibility antigens play an
important role in resistance to virus infections. In a virus-infected cell, viral peptides associate with the
class I molecules within the cell, and the two are transported to the cell surface in the form of a complex
that is recognized by cytotoxic CD8+ T lymphocytes. The lysis of infected cells leads, in due course, to the
elimination of the infection.
The symptoms of infectious mononucleosis appear upon initiation of the host immune response. Cellular
immunity mediated by cytotoxic CD8+ T cells and natural killer cells is the most important component of
this response. The atypical lymphocytes seen in the blood, so characteristic of this disease, are mainly

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Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009

CD8+ cytotoxic T cells, but also include CD16+ NK cells. The reactive proliferation of T cells is largely
centered in lymphoid tissues, which accounts for the lymphadenopathy and splenomegaly.

Question #6: What is the expected immune response to the Mycobacterium tuberculosis, and why?
With certain persistent or nondegradable antigens, such as tubercle bacilli colonizing the lungs or other
tissues, the accumulated macrophages often undergo a morphologic transformation into epithelium-like
cells and are then referred to as epithelioid cells. A microscopic aggregation of epithelioid cells, usually
surrounded by a collar of lymphocytes, is referred to as a granuloma. This pattern of granulomatous
inflammation is type IV hypersensitivity.

                             Acute Inflammation and Clinical Response Review
                                            Case 11 Answers

Question #1: What are the classic clinical signs of inflammation, especially acute?
   Heat (Calor)
   Redness (Rubor)
   Edema (Tumor)
   Pain (Dolor) and
   Loss of function (Functio laesa)

Question #2: Review the case and identify all the signs and symptoms of acute inflammation.
   See bold text.

                             Hemostasis, Thrombosis, and Embolism Answers
                                              Cases 12-14

Question #1: Compare and contrast hemostasis and thrombosis.
   Hemostasis and thrombosis are both dependent on the vascular endothelium (stage #1), platelets
   (Stage #2 primary hemostasis), and clotting factors (stage #3, secondary hemostasis). Hemostasis is a
   normal physiologic process to keep blood in a flowing clot free state and to induce rapid and localized
   hemostatic plug at sites of vascular injury. Thrombosis is a pathologic state. It is due to inappropriate
   activation of hemostasis in uninjured vessels or thrombotic occlusion after minor injury.

Question #2: Which of the three Virchow’s risk factors predispose to the thrombosis?
   Case #1: Endothelial injury due to atherosclerotic plaque
   Case #2: Immobilization leading to vascular stasis
   Case #3: Thrombus forms in the left atrium due to atrial fibrillation

Question #3: How do you classify each thrombus and each embolus?
   Case #1: Arterial Thrombosis. Abdominal aorta and femoral artery atherosclerosis; leads to insidious
   narrowing of the vascular lumen; ischemia of the legs causes the claudication; ulceration of the aortic
   atherosclerotic plaque predispose to thrombosis and provides embolic debris to the femoral artery
   leading to thromboemboli to left femoral artery.

    Case #2: Venous thrombosis leading to Pulmonary Artery Embolism. Describe the pathway of the
    embolus from the site of formation to the final obstruction. Deep venous thrombosis in large leg
    veins travel to the pulmonary circulation to become a pulmonary thromboembolus.

Case #3: Cardiac Mural Thrombosis leading to intra-cerebral artery embolism. Describe the pathway of
the embolus from the site of formation to the final obstruction. Atrial fibrillation leads to cardiac mural
thrombosis, fragment break off, travel, and obstruct the cerebral arteries. What anatomy is needed to
understand paradoxical embolus? Right to left shunts permit emboli from venous circulation to pass into
the systemic circulation. Emboli pass through atrial and ventricular septal defects.
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Linda F. Cunningham, MD
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Introduction to Disease
Spring 2009


Question #4: What is the expected fate of each thromboembolus?
        a. Propagation, causing progressive occlusion
        b. Embolization
        c. Dissolution by Thrombolysis
        d. Organization and Recanalization

Question #5: Define Hypercoagulable state:

                                      Primary and Secondary Hemostasis
Is the bleeding problem acquired or inherited? What information supports your decision?
Congenital: Most likely if there a family history of bleeding.
Congenital: Most likely if the first episode occurred as a baby.
Acquired: If he has a late onset of bleeding.

If it is inherited, what is the pattern of inheritance? What sexes are affected- females, males, or both?
Sex Linked: Males and female carriers

Is the onset secondary to a drug or another illness?
Aspirin impairs platelet function, the platelet count is normal.

Is there a history of spontaneous bleeding or bleeding after minor trauma or minor surgical
procedures? Suggests a bleeding disorder

Describe each stage of hemostasis. What is the clotting cascade?

How can you use the clinical manifestations to determine the type of defect and limit your differential
diagnoses? Describe the bleeding-
 Primary Defect with platelets: Is it mucosal with petechiae, ecchymoses, hematuria (bladder
    mucosa), epistasis (nose mucosa), increased menstrual bleeding (endometrium), and bleeding
    gums?
 Secondary defect with clotting factors (Factors 7, 8, 9): Are there hematomas and/or bleeding into
    large cavities?

Do the lab tests suggest a primary hemostatic defect? Are there adequate platelets and/or platelet
function?
Decreased platelet count is thrombocytopenia and if the count is low enough, the patient has mucosal
bleeding. If the count is normal and patient has mucosal bleeding may have a problem with platelet
function. Aspirin impairs platelet function.

Do the lab tests suggest a secondary hemostatic defect- Prothrombin Time (PT) or Partial
Thromboplastin Time (PTT)? Are there adequate clotting factors? Consider factor VII (and extrinsic
factors) if the PT is abnormal and consider factors VIII or IX (and other intrinsic factors) if the PTT is
abnormal.

Is the patient plasma missing a factor that is replaced when mixed with normal patient plasma?
A mixing study is used to investigate the cause of a prolonged PT, PTT result. By repeating the test, using
patient plasma that has been mixed with an equal volume of normal pooled plasma, the cause of the
initial prolong result may be determined to be a deficiency of one or more factors. Correction of the
prolonged test result generally indicates a factor deficiency.



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Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009


Primary and Secondary Hemostasis Case Answers- Case #15:
Is the bleeding problem acquired or inherited? What information supports your decision?
Inherited; family history; manifest in grandsons and brothers.

At what age did the first episode occur?
Not given (probably developed hematomas when starting walking or had excessive bleeding during
circumcision)

Is there a history of spontaneous bleeding or bleeding after minor trauma or minor surgical
procedures?
He has a history of prolonged and spontaneous bleeding, including hemarthroses, intramuscular
hematoma, and subcutaneous ecchymoses.

If it is inherited, what is the pattern of inheritance? What sexes are affected- females, males, or both?
Manifest in males, only so, that suggests the gene is located on X chromosome. Affected males transmit
to daughters, not to their sons; daughters who are carriers transmit to their sons. Hemophilia A is a sex-
linked recessive disease.

Is the onset secondary to a drug or another illness? What effects does aspirin have on platelet function?
No other illnesses indicated. Aspirin affects platelet function, not clotting factors. The aspirin inhibits
platelet aggregation. This patient has no mucosal bleeding so a platelet defect is not considered.

How can you use the clinical manifestations to determine the type of defect and limit your differential
diagnoses?
Bleeding from large vessels is usually due to defects in the clotting cascade- Hemarthroses, intramuscular
hematoma, and subcutaneous ecchymoses are manifestations.

Do the lab tests suggest a secondary hemostatic defect?
The labs show a defect in the coagulation cascade (secondary defect) with a prolongation of a test that
evaluates Factors 8, 9, 11, and 12.

Is the patient plasma missing a factor that is replaced when mixed with normal patient plasma?
The abnormality is due to a deficiency of a factor, which is replaced when mixed with normal pooled
patient plasma. This is not due to impaired function of the factors.

Diagnosis: Hemophilia (Factor VIII) deficiency

Primary and Secondary Hemostasis Case Answers - Case #16:
Is the bleeding problem acquired or inherited? What information supports your decision?
Acquired, older patient with new onset bleeding problems; no known family history

At what age did the first episode occur? Adult

Is there a history of spontaneous bleeding or bleeding after minor trauma or minor surgical
procedures?
Patient has a history of easy bruising.

Is the onset secondary to a drug or another illness? What effects does aspirin have on platelet function?
The bleeding disorder appears acquired with no known associated diseases/disorders. Aspirin is an
inhibitor of cyclooxygenase and can suppress the synthesis of thromboxane A2, which is needed for
platelet aggregation. The anti-platelet effect of aspirin forms the basis of its use in the prevention of
strokes and myocardial infarctions.
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Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009


How can you use the clinical manifestations to determine the type of defect and limit your differential
diagnoses?
Vascular or platelet bleeding is usually from small vessels and manifest as skin or mucosal petechiae. This
patient has nosebleeds, mucosal gingival bleeding, easy bruising and increased bleeding with menstrual
periods (menorrhagia).

Do the lab tests suggest a primary hemostatic defect? Are there adequate platelets and/or platelet
function?
The platelet count is low, without adequate platelets the bleeding time is prolonged due to the lack of a
primary hemostatic plug.
Megakaryocytes are making platelets, so the platelets are either destroyed in the circulation or
consumed.
In idiopathic thrombocytopenia purpura (ITP) decreased platelet survival results from antibody mediated
destruction of platelets.

Diagnosis: Thrombocytopenia due to immune destruction of the platelets (immune Mediated
Thrombocytopenia, ITP)

Primary and Secondary Hemostasis Case Answers - Case #17:

Is the bleeding problem acquired or inherited? What information supports your decision?
Inherited, because lifelong history and has a family history.

At what age did the first episode occur? Is there a history of spontaneous bleeding or bleeding after
minor trauma or minor surgical procedures?
Not given.

If it is inherited, what is the pattern of inheritance? Not given.

Describe each stage of hemostasis.
Stage#1:         Vascular factors stop bleeding by vasoconstriction and maintaining an intact
                 endothelium
Stage #2:         Primary hemostasis; platelet adhesion to damaged endothelium, platelet activation and
                 release of secretory products to recruit more platelets, platelet aggregation to form a
                 temporary hemostatic plug; occurs within minutes
Stage #3:        Secondary hemostasis; clotting factors; activates the coagulation cascade resulting in
                 the thrombin generation from Prothrombin and fibrin from fibrinogen.
Stage #4:        Thrombolysis (Fibrinolysis0 occurs as a counter-regulatory mechanism to control and
                 localize the hemostatic plug.

How can you use the clinical manifestations to determine the type of defect and limit your differential
diagnoses? Describe the bleeding-is it mucosal with petechiae, ecchymoses,
GI/bladder/endometrial/nasal bleeding? Are there hematomas and/or bleeding into large cavities?
Clinical manifestations are not given. The lab findings can be used to predict the type of bleeding.

Do the lab tests suggest a primary hemostatic defect? Yes
The platelet count is within reference range, but the bleeding time is prolonged due to the lack of a
primary hemostatic plug. The platelets are present, but their function is impaired. Bleeding due to
defective platelet function is characterized by prolonged bleeding time in association with normal platelet
count.

Do the lab tests suggest a secondary hemostatic defect? Yes
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Linda F. Cunningham, MD
March 9, 2009
Introduction to Disease
Spring 2009

The labs show a defect in the coagulation cascade (secondary defect) with a prolongation of a test that
evaluates Factors 8, 9, 11, and 12.

Is the patient plasma missing a factor that is replaced when mixed with normal patient plasma?
The abnormality is due to a deficiency of a factor, which is replaced when mixed with normal pooled
patient plasma. This is not due to impaired function of the factors.

Diagnosis: This patient has a compound defect involving platelet function and the coagulation pathway.
The disorder, von Willebrand disease, is due to reduced quantity or defective von Willebrand factor. VWF
stabilizes factor 8 so without it there is less factor 8 (looks like a coagulation cascade defect). VWF is
needed for platelet adhesions during primary hemostasis. So platelet function is impaired.




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Linda F. Cunningham, MD
March 9, 2009

								
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