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

Based upon: LABORATORY MEDICINE CASEBOOK.

An introduction to clinical reasoning

Jana Raskova, MD Professor of Pathology & Laboratory MedicineStephen Shea, MD Professor of Pathology & Laboratory MedicineFrederick Skvara, MD Associate Professor of Pathology & Laboratory MedicineNagy Mikhail, MD Assistant Professor of Pathology & Laboratory Medicine

UMDNJ-Robert Wood Johnson Medical SchoolPiscataway, NJ

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

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?

Clinical syndrome in which an individual has lost more than 10% of his or her body weight in the absence of active infections or any other identifiable cause of weight loss.

One of the most common symptoms of HIV infection

Associated with malnutrition, which may contribute to increased immune suppression

http://www.aidsmap.com/treatments/ixdata/english/CEFC89BA-7146-4966-8F39-701651DD559D.htm

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 m

Progressive Wasting Syndrome HIV Anemia

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 Sources:

Liver – hepatocytes and biliary tract mucosal cells

Bone Intest. Mucosa Placenta

Normal adolesc. 3-5x adult values (bone growth)

Greater sensitive to biliary tract obstruction whether intra or extrahepatic. Does increase with liver cell acute injury

Hepatic ALP Elevation Extrahepatic bil. Tract

obstruct. Intrahepatic bil. Tract

obstruct. Liver cell acute injury Liver passive congestion Drug-induced liver cell

dysfunction Space occupying lesions Primary biliary cirrhosis Sepsis

Don’t forget bone or placental origin

Why do you think AST is increased so modestly (1.3 x Upper Range Normal (URN) << ALP (13x URN)?

AST Sources:

Liver Heart Sk. Musc. RBCs

Diseases with mild – moderate abnormality (<10xURN) Acute hepatitis – resolving phase Chronic hepatitis Active cirrhosis Liver passive congestion Drug induced liver dysfunction Metastic liver tumor Bile duct obstruction CMV, inf. Mono

In extrahepatic obstruction there usually is no elevation unless secondary parenchymal acute injury occurs

AST/ALT ratio is elevated (>1) in active alcoholic cirrhosis, liver congestion and metastatic tumor to the liver

Etiologies for AST Elevation) Heart – MI, Pericarditis Sk. Mus. – Inflammation, MD,

recent surgery, DTs Kidney – Acute injury or damage,

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

HBcAb IgM Neg

HBsAg Neg

HBsAb Pos

HC Ab Neg

HA Ab Neg

Test Patient Normal

PT 15 (11-14)

aPTT 34 (19-28)

Test Normal

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) (.02-18)

12.6/9.57 15.6/11.2 15.8/11.6

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 epitheliodcells

Liver Biopsy – Acid Fast x120

Numerous filamentousacid-fast organismsconsistent with Mycobacteriumavium 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/CEFC89BA-7146-4966-8F39-701651DD559D.htm

HIV anemia - http://www.aidsmap.com/treatments/ixdata/english/4B95EF8B-A38A-4FFB-BD5B-4D87339162B4.htm

Splleen – SECONDARY LYMPHOID ORGANS, Art Anderson's I

mmunology Lecture Notes

Websites containing information on HIV