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David E. Kleiner, M.D., Ph.D

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

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David E. Kleiner, M.D., Ph.D

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  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) Changesat the Time of First Biopsy Rx Bx

  4. Histologic DiagnosesBiopsy 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

  5. 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.

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

  7. 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 (-)

  8. Histologic DiagnosisBiopsy 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

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

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

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

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

  13. 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

  14. 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

  15. 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

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