2. Acute Hepatitis in a 19 Year Old Weightlifter on Dietary Supplements Ann Sheehy Reed, M.D., M.S. May 30, 2007

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

4. 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

5. Admission Laboratory Tests Total bilirubin 40.8 Ammonia 162 AST 1,129 ALT 1,512 Alkaline Phosphatase 225 INR 1.9 PTT 43.0 CBC and electrolytes normal

6. 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

7. 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

8. Dietary Supplements Revealed copper concentrations of 0.42 and 0.70 mcg/g Neither supplement listed copper as an ingredient

9. 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

10. 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

11. Copper Homeostasis and the Effect of Wilson’s Disease X

12. 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

13. 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

14. Treatment Rx Dimercaprol (BAL) Penicillamine Triene (Trientine) Zinc Method Increase urinary excretion Chelator: reduce protein affinity for copper, copper binds penicillamine, excreted in urine Chelator 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

15. 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

16. 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

17. 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.