1. David E. Kleiner, M.D., Ph.D Staff Surgical Pathologist, Laboratory of Pathology, NCI (1992-Present) Hepatic Pathologist –Collaborations with Dr. Jay Hoofnagle and others since 1990 Section Chief, Post-mortem Section (1996- Present)

2. Patient 502/1069 Biopsy #1 99-4879 3/2/1999

3. Transaminase (ALT) Changes at the Time of First Biopsy Rx Bx

10. Histologic Diagnoses Biopsy 99-4879 Zone 3, centrilobular necrosis with mixed infiltrate of eosinophils, plasma cells, lymphocytes and macrophages Moderate interface hepatitis No significant periportal or sinusoidal fibrosis No cholestasis

11. Etiologic Differential Diagnosis of Zone 3 Necrosis Hypoxic/Ischemic insults Veno-occlusive disease Drug/Toxic injury The mixed infiltrate with prominence of eosinophils and plasma cells is strongly suggestive of a hypersensitivity reaction.

12. Patient 502/1069 Biopsy #2 99-28804 12/27/1999

13. Laboratory Results Preceding Second Liver Biopsy Results from 11/12/1999 –ALT 1331 U/L (NR < 49 U/L) –T. Bili 25 umol/L (NR 2-20 umol/L) –IgG 18.1 g/L (NR 5.0-12.0 g/L) –ASMA (+) at 1:1000 –ANA, AMA (-) –Viral serologies for HAV, HBV, HCV (-)

19. Histologic Diagnosis Biopsy 99-28804 Chronic hepatitis –Infiltrate suggestive of autoimmune etiology –Marked inflammatory activity –Bridging fibrosis Fibrosis pattern consistent with scarring matching injury pattern following hepatitis episode in February/March

20. Patient 2004/002 Biopsy # 02-598 1/23/2002

21. ALT and T. Bili Changes at the Time of Biopsy Rx Bx and Cholecystectomy

30. Histologic Diagnoses Combined cholestatic and hepatocellular injury, mild Sinusoidal and periportal fibrosis (history of diabetes mellitus)

31. Etiologic Differential Diagnosis of Combined Cholestasis & Hepatitis Sepsis Acute large duct obstruction, early Drug/Toxic injury

32. Practical Evaluation of Drug Toxicity Irey’s Methodology Temporal eligibility Exclusion of other drugs, toxins, diseases Known potential for injury Precedent for injury pattern De-challenge/Re-challenge Toxicologic analysis

33. Categorization of Drug Toxicity (after Irey) Causitive - confirmed by toxicologic analysis Probable - good circumstantial evidence without other conflicting evidence Possible - consistent with drug toxicity, but other factors cannot be ruled out Coincidental - association without supporting data Negative - the drug is ruled out as cause

34. Categorization of Biopsies Reviewed Patient 502/1069 –99-4879 Probable drug toxicity –99-28804 Possible persistent drug toxicity, cannot rule out an independent AIH Patient 2004/002 –02-598 Possible drug toxicity, cannot rule out coincidental early acute large duct obstruction