Acute Hepatitis in a 19 Year Old Weightlifter on Dietary Supplements

Ann Sheehy Reed, M.D., M.S.

May 30, 2007

Case History

• 19 year old previously healthy male • 8 days of fatigue, malaise, painless jaundice • No travel history, high-risk sexual activity, tattoos, IVDU, transfusions, ill contacts, or family history of liver disease • • No acetaminophen or alcohol use

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use of nutritional supplements containing creatine and androstendione for two months prior to admission

Exam

• Vital signs normal • Alert and oriented in NAD • Scleral icterus, jaundice • Normal heart, lung, and abdominal exam • Subtle confusion (only apparent to family) • No asterixis

Admission Laboratory Tests

Total bilirubin Ammonia AST 40.8

162 1,129 ALT 1,512 Alkaline Phosphatase 225 INR 1.9

PTT 43.0

CBC and electrolytes normal

Acute Hepatitis

• Acetaminophen and ethanol negative • Hepatitis A, B and C negative • HIV, EBV, CMV negative • Ceruloplasmin 22 mg/dl (18-55) • Serum total copper 94 mcg/dl (70-140) • Kayser-Fleischer rings absent • Hepatic imaging: echogenic liver, normal blood flow, no masses

Further Studies

• Liver Biopsy: – Cirrhosis with areas of recent hepatocellular necrosis – Marked increase in copper staining – 199mcg/g dry hepatic weight (10-35) • 24 hour urine copper: – 408 mcg/L (2-30) fibrosis Apoptotic hepatocyte

Dietary Supplements

• Revealed copper concentrations of 0.42 and 0.70 mcg/g • Neither supplement listed copper as an ingredient

Diagnosis: Wilson’s Disease

(Hepatolenticular Degeneration)

• Discovered in 1912 by Kinnear Wilson • Prevalence of 30 cases per million • Autosomal recessive disease located on chromosome 13 involving P-Type ATPase (ATP7B), gene discovered 1993 • Disease causes impaired copper incorporation into ceruloplasmin and excretion into bile

Copper Metabolism

• RDA copper: 1.5 mg/day (average US consumption 0.96 mg/day) • Essential trace element • Catalytic activity of essential enzymes – Involved in collagen cross-linkage, myelin production, skin, hair, and eye pigmentation • Copper excretion – 40% not absorbed – 60% absorbed: bile, urine

Copper Homeostasis and the Effect of Wilson’s Disease

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Presentation

• Age: 5-45, almost all before age 30 – Case report of 3 year old and 62 year old • Liver 33%: – Acute hepatitis and/or fulminant hepatic failure – Chronic hepatitis/cirrhosis • Neurologic 33%: – Parkinsonism, tremor, dysarthria – May progress to total bedridden state • Psychiatric 33%: – Depression, personality changes, psychosis, decline in school/work performance

Diagnosis: A Challenge

• Serum copper: not helpful • Ceruloplasmin: acute phase reactant • Kayser-Fleischer rings: – 50% with hepatic presentation, 90% neuro • 24 hour urine copper – Virtually diagnostic if greater than 100 mcg/24 hours, must have copper free collection container • Liver biopsy: best test – Greater than 200-250 mcg/g dry hepatic weight – Variability if cirrhosis/fibrosis • Genetics: – >100 mutations, pts typically heterozygotes – Limited to siblings

Rx Dimercaprol (BAL) Penicillamine Triene (Trientine) Zinc

Treatment

Chelator Method Increase urinary excretion Chelator: reduce protein affinity for copper, copper binds penicillamine, excreted in urine Decreases intestinal copper absorption Comments •First Rx •Injections •Not used anymore •Pyridoxine deficiency •Rash, N/V, heme abnl, autoimmune disease •May initially worsen neuro disease, 10-50% •Decreases HDL •Few side effects •May be as effective, less well studied •Slow onset •Typically maintenance

Our Patient: 1Year Follow-up and Prognosis

• Asymptomatic, teaching martial arts • On penicillamine 250 mg QID, pyridoxine 25 mg qd • Bilirubin 2.1, AST/ALT 51/74 • Repeat liver biopsy: – Significant reduction in amount of stainable copper, mild to moderate nonspecific inflammation • May experience normal life expectancy and quality of life with early diagnosis and treatment with penicillamine

Summary

• Wilson disease is a rare and somewhat complicated diagnosis to make • Needs to be considered in young patients with acute or chronic hepatitis • 24 hour urine copper and liver biopsy – Serum tests not definitive • Early diagnosis can prevent neuro/psych complications and could permit normal life expectancy • Investigate supplement use

References

• www. fda. gov • Brewer GJ, et al. Wilson Disease. Medicine (Baltimore) 1992; 71 (3), 139-164.

• El-Youssef M. Wilson Disease. Mayo Clin Proc 2003; 78, 1126-1136.

• Roberts E and Schilsky M. A Practice Guideline on Wilson Disease. Gastroenterology 2003; 1475 1491.