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A Year Old Woman With Jaundice and Fever

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					A 28-Year-Old Woman With Jaundice and
Fever – Chapter 22

                 Eugene G. Martin, Ph.D.
                 Associate Professor of Pathology & Laboratory Medicine

       Based upon: LABORATORY MEDICINE CASEBOOK.
       An introduction to clinical reasoning

       Jana Raskova, MD
         Professor of Pathology & Laboratory Medicine
       Stephen Shea, MD
         Professor of Pathology & Laboratory Medicine
       Frederick Skvara, MD
         Associate Professor of Pathology & Laboratory Medicine
       Nagy Mikhail, MD
         Assistant Professor of Pathology & Laboratory Medicine
       UMDNJ-Robert Wood Johnson Medical School
       Piscataway, NJ
History and Presentation
   28 y.o ♀ known to be HIV + for 6 years
   Admitted to hospital because of jaundice and a fever of 102o F
   Contracted HIV from an old boyfriend who subsequently died. Husband refused to be tested
   Previously treated with anti-retroviral drugs – poorly tolerated
   Developed Progressive Wasting Syndrome and anemia. Previous fever treated with antibiotics.
   Current problems: Progressive Liver Failure with ↑ liver enzymes and jaundice occuring during
    the past five days accompanied by fever.
   Physical Exam
        Cachectic ♀, oriented
        Temp. 101.8 oF
        BP: 100/40
        HR: 88 bpm and regular
        Skin and sclerae were icteric. No lymphadenopathy. Chest clear.
        Ascites. Liver and spleen markedly enlarged. Lower extremities were
         edematous
What is Progressive Wasting Syndrome? Is
HIV-related anemia related to CD4 or viral
load?
Progressive Wasting Syndrome                                                   HIV Anemia
   Clinical syndrome in which an                                   Anemia is associated with HIV
    individual has lost more than 10%                                disease progression, independent
    of his or her body weight in the                                 of CD4 count and viral load. Most
    absence of active infections or any                              common in patients with
    other identifiable cause of weight                               CD4<200.
    loss.                                                           Common causes of HIV-related
   One of the most common                                           anemia:
    symptoms of HIV infection                                           Infections e.g. B19 parovirus
   Associated with malnutrition,                                       cancers of the bone marrow
    which may contribute to increased                                   drugs which suppress the bone
    immune suppression                                                   marrow as a side-effect of therapy
   http://www.aidsmap.com/treatments/ixdata/english/CEFC89BA-
    7146-4966-8F39-701651DD559D.htm
                                                                             AZT, foscarnet, ganciclovir, co-
                                                                              trimoxazole (at the high doses
                                                                              used to treat PCP – anaemia is
                                                                              rare at the doses used for PCP
                                                                              prophylaxis) and dapsone
                                                                        Bleeding most common reason in
                                                                         HIV-negative m
Is HIV anemia related to CD4
count?
   Anemia is associated with HIV disease progression,
    independent of CD4 count and viral load. Most
    common in patients with CD4<200.
   Common causes of HIV-related anemia:
       Infections e.g. B19 parovirus
       cancers of the bone marrow
       drugs which suppress the bone marrow as a side-effect of
        therapy
           AZT, foscarnet, ganciclovir, co-trimoxazole (at the high
            doses used to treat PCP – anaemia is rare at the doses used
            for PCP prophylaxis) and dapsone
       Bleeding most common reason in HIV-negative patients
 HEMATOLOGY
         Patient           Normal
WBC      3.09 X 103/uL     (3.3-11.0)
 Neut    56 %              (44-88)
 Band    37 %              (0-10)
 Lymph   3%                (12-43)
 Mono    2%                (2-11)
 Eos     1%                (0-5)

 Baso    1%                (0-2)
RBC      3.04 X 106/uL     (3.9-5.0)
Hgb      8 g/dL            (11.6-15.6)
HCT      26.4 %            (37.0-47.0)
MCV      86.7 fL           (79-99.0)
MCH      26.4 pg           (26.0-32.6)
MCHC     30.4 g/dL         (31.0-36.0)
Plts     55 thousands/uL   (130-400)
CHEMISTRY
Test                    Patient                  Normal
Glucose                 100 mg/dL                (65-110)
Creatinine              .7 mg/dL                 (0.7-1.4)
BUN                     12 mg/dL                 (7-24)
Uric Acid               3.5 mg/dL                (3.0-8.5)
Cholesterol             145 mg/dL                (150-240)
Calcium                 7.6 mg/dL                (8.5-10.5)
Protein                 4 g/dL                   (6-8)
Albumin                 2 g/dL                   (3.7-5.0)
LDH                     223 U/L                  (100-225)
Alk. Phos.              1620 U/L                 (30-120)
AST                     75 U/L                   (0-55)
GGTP                    862 U/L                  (0-50)
Bilirubin/Bil. Direct   8.8 mg/dL/(5.67 mg/dL)   (0.0-1.5)/(.02-18)
Amylase                 12 U/L                   (23-85
Why was Alk. Phosphatase Increased?

   Alk. Phosphatase                         Hepatic ALP Elevation
       Sources:                                 Extrahepatic bil. Tract
           Liver – hepatocytes and               obstruct.
            biliary tract mucosal cells          Intrahepatic bil. Tract
           Bone                                  obstruct.
           Intest. Mucosa                           Liver cell acute injury
           Placenta                                 Liver passive congestion
       Normal adolesc. 3-5x                         Drug-induced liver cell
        adult values (bone                            dysfunction
        growth)                                  Space occupying lesions
       Greater sensitive to biliary             Primary biliary cirrhosis
        tract obstruction whether                Sepsis
        intra or extrahepatic. Does
        increase with liver cell             Don’t forget bone or
        acute injury                          placental origin
Why do you think AST is increased so modestly
(1.3 x Upper Range Normal (URN) << ALP (13x
URN)?

   AST                                          In extrahepatic obstruction there
         Sources:                                usually is no elevation unless
              Liver                              secondary parenchymal acute
              Heart
              Sk. Musc.                          injury occurs
              RBCs                              AST/ALT ratio is elevated (>1) in
   Diseases with mild – moderate                 active alcoholic cirrhosis, liver
    abnormality (<10xURN)                         congestion and metastatic tumor
         Acute hepatitis – resolving phase       to the liver
         Chronic hepatitis
         Active cirrhosis                       Etiologies for AST Elevation)
         Liver passive congestion                   Heart – MI, Pericarditis
         Drug induced liver dysfunction             Sk. Mus. – Inflammation, MD,
         Metastic liver tumor                        recent surgery, DTs
         Bile duct obstruction                      Kidney – Acute injury or damage,
         CMV, inf. Mono                              Renal infarct
                                                     Other – Intest. Infarct.,
                                                      Cholecystitis, shock, acute
                                                      panreatitis, hypoparathyroidism
GGTP
   GGTP has equal to or greater sensitivity than ALP
    in obstructive liver disease and greater sensitivity in
    hepatocellular injury (16x URN)
   Etiologies for GGT Elevation
       Liver, space-occupying lesion (M-H)
       Alcoholic active liver disease M)
       Common bile duct obstruction (M)
       Intrahepatic cholestatis (M-H)
       CMV infection, Mono infection (S/M)
       Tylenol overdose (S/M)
       Severe liver congestion (S)
       Reye’s syndrome (S)
       S= small, M=medium, H=high
Questions
   Discuss the status of the patient’s liver
        Hyperbilirubinemia – Impaired hepatic excretion of conjugated bilirubin. This is not of hemolytic
         origin  unconjugated bilirubin
        Hypoalbuminemia and ↓ protein – impaired hepatic synthesis and malnutrition
              ↓ Calcium as a consequence of ↓ albumin
                    ~ 50% of total Ca is ionized, the remainder protein bound.
                    A ↓ in serum albumin will  ↓ total serum Ca
        Only hepatitis marker – HBsAb. Consistent with:
              Immunization
              Long ago exposure and recovery with loss of HBcAb
              No active infection (No HBeAg). No Carrier state: (No HBsAg + HBcAb)
              Transaminases (AST, ALT) are only modestly elevated
        Ascites and splenomegaly – common in patients with portal hypertension
   What is the significance of the depressed amylase level?
        Amylase is typically elevated in pancreatitis, in biliary tract disease (cholecystitis, tumor, spasm of
         sphincter of Oddi). In this instance it is low
        Pancreatitis can occur in association with HIV therapy (DDI) or more commonly in alcoholic
         patients
        Because in requires good renal function to clear, serum amylase is sometimes elevated in renal
         failure.
        Pancreatic enzymes are important in the digestion of carbohydrates. In a patient losing weight it
         may be helpful to rule/out a digestive disorder
What are the 3 stages of HIV
infection?
   Acute –
       3-6 weeks after initial infection
       Non-specific symptoms – resolves spontaenously
           Fever
           Rash
           Myalgia
   Middle –
       Clinical latency – patient asymptomatic, mild constitutional
        symptoms, lymphadenopathy
   Crisis –
       Immune system breakdown
       Fever
       Loss of Weight
       Diarrhea
       Opportunistic infections and secondary neoplasms
       Urinalysis
Test           Patient   Normal      Test           Patient   Normal
pH             6         (5.0-7.5)   Sp. Grav.      1.004     (1.010-1.055)
Protein        Neg       (Neg)       WBC            1/HPF     (0-5)
Glucose        Neg       (Neg)       RBC            0/HPF     (0-2)
Ketone         Neg       (Neg)       Epith. cell    0/HPF     (0)
Bile           Neg       (Neg)       Bacteria       0         (0)
Occult blood   1+        (Neg)       Urobilinogen   Neg       (Neg)
Color          Yellow    (Yellow)    Bilirubin      2+        (Neg)
Clarity        Clear     (Clear)
Miscellaneous Tests
Test        Patient             Normal
Na          134 mEq/L           (134-143)
K           3.5 mEq/L           (3.5-4.9)
Cl          95 mEq/L            (95-108)
CO2         24 mEq/L            (21-32)

Test           Patient   Test      Patient   Normal
HBcAb IgM      Neg       PT        15        (11-14)
HBsAg          Neg       aPTT      34        (19-28)
HBsAb          Pos
                         Test                  Normal
HC Ab          Neg
HA Ab          Neg       Blood Culture         Pending
                         Urine Culture         Pending
T Lymphocyte Subsets
Percent T Lymphocytes       Patient       Normal
 CD3 +                      63%           (68 + 7%)
 CD3+/CD4+                  1%            (45 + 7%)
 CD3+/CD8+                  59%           (27 + 6%)


T Lymphocytes Absolute Ct   Patient       Normal
 CD3 +                      58 cells/µL   (1554 + 355)
 CD3+/CD4+                  1 cells/µL    (1026 + 233)
 CD3+/CD8+                  55 cells/µL   (621 + 192)
CHEMISTRY
Test               Normal       Day 2       Day 4       Day 5
Glucose            (56-110)     93 mg/dL    89          86
Creatinine         (0.7-1.4)    .6 mg/dL    .8          .9
BUN                (7-24)       13 mg/dL    15          14
Uric Acid          (3.0-8.5)    3 mg/dL     3           2.7
Cholesterol        (150-240)    117mg/dL    151         130
Calcium            (8.5-10.5)   7.3 mg/dL   5.8         5.8
Protein            (6-8)        3.5 g/dL    3.5         3.2
Albumin            (3.7-5.0)    1.8 g/dL    1.9         1.7
LDH                (100-225)    222 U/L     370         319
Alk. Phos.         (30-120)     1255 U/L    1740        1154
AST                (0-55)       63 U/L      65          41
GGTP               (0-50)       797 U/L     1023        807
T.Bil./Bil. Dir.   (0.0-1.5)    12.6/9.57   15.6/11.2   15.8/11.6
                   (.02-18)
 HEMATOLOGY
         Patient            Normal
WBC      2.59 X 103/uL      (4.5-11.0)
 Neut    75 %               (44-88)
 Band    15 %               (0-10)
 Lymph   1.2%               (12-43)
 Mono    7.8%               (2-11)
 Eos     1%                 (0-5)

 Baso    1%                 (0-2)
RBC      2.76 X 106/uL      (3.9-5.0)
Hgb      7.2 g/dL           (11.6-15.6)

HCT      24.4 %             (37.0-47.0)
Plts     105 thousands/uL   (130-400)
Clinical Course
   Treatment:
       Treated empirically for CMV and mycobacterium
        intracellulaire
       Diuretics and salt-poor albumin for ascites
       Liver function continued to deteriorate
       Patient developed electrolyte imbalance that req’d.
        correction
       Cytopenia worsened req’d transfusion of several units of
        packed red blood cells
       Blood and urine culture – negative
       One week later – oral and esophageal lesions
       Grim prognosis discussed. Patient died at home 2 days
        later.
       Antemortem stool culture positive for acid fast organisms
Autopsy results
Liver Biopsy – H&E x120




                     Poorly defined granuloma
                     composed of epitheliod
                     cells
Liver Biopsy – Acid Fast x120



                       Numerous filamentous
                       acid-fast organisms
                       consistent with
                        Mycobacterium
                       avium intracellulare.
Impact of HIV on acquisition,
activation and outcome of TB?
   Acquisition: 113 x higher risk of being infected
    than a person with no risk factors
   Mechanism: HIV infects helper-T-cells leading to a
    decrease in cell-mediated immunity. Absence of
    immunity development or activation of the
    disease
   37% of HIV-infected individuals develop TB within 5
    months of exposure as compared to 5% of patients
    with normal immune system
   Assessment: PPD in HIV – ONLY 30-50% of TB
    infected HIV patients will respond with an induration
    > 10mm. THUS: induration > 5mm is considered +
HIV Positive Patient.
What do you do?
   Ordinarily: INH daily for 12 months
   Some recommend INH for life since eventual
    failure of the immune system will allow infection to
    progress to active disease
   If drug-resistant strain start on two drug
    regimen – INH and EMB or INH and cipro for
    preventive therapy
   If an HIV-infected patient develops drug-resistant
    TB the chances of dying from the disease are
    between 72-89%, even with aggressive therapy!!
   AIDS patients progress to MDR-TB immediately
    after infection and die within 4-19 weeks
Esophagus
               H&E x 31
                  Esophagus covered by
                   adherent grey-white
                   membrane
                  Note: numerous fungal
                   organisms as bluish wavy
                   band across bottom of iimage
                  Inflammatory cells, necrotic
                   debris and collections of
                   bacteria near lumen at top
               Gomori silver stain x100
                   Fungi, numerous yeast and
                    pseudohyphal forms are
                    present consistent with
                    Candida species
Lymph node – H&E x12
                 Atrophic lymph
                  node
                 Marked depletion
                  of lymphocytes in
                  both mantal and
                  germinal centers
                 Germinal centers
                  are small and show
                  signs of
                  hyalinization
Organization of spleen

                   Marginal zone -
                    assortment of
                    mononuclear cells
                   Principal function of
                    the marginal zone
                    is antigen trapping.
                   SECONDARY LYMPHOID ORGANS,
                    Art Anderson's Immunology Lecture

                    Notes
Spleen
            Patient
                Lymphoid depletion of
                 the spleen – severe
                White pullp is nearly
                 devoid of lymphocytes



            Normal
                White pulp containing
                 numerous lymphocytes
                Clearly delineated from
                 the surrounding red
                 pulp
Case Summary

   Final Diagnosis:
       AIDS
       Liver Failure
       Mycobacterium Avium intracellulare
        infection
       Esophageal Candidiasis
References
   Prog. Wasting Syndrome -
    http://www.aidsmap.com/treatments/ixdata/english/CEFC89B
    A-7146-4966-8F39-701651DD559D.htm
                                                                  Websites
   HIV anemia -
                                                                   containing
    http://www.aidsmap.com/treatments/ixdata/en
    glish/4B95EF8B-A38A-4FFB-BD5B-
                                                                   information on HIV
    4D87339162B4.htm

   Splleen –
   SECONDARY LYMPHOID ORGANS, Art Anderson's
    Immunology Lecture Notes

				
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