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 #199-48793/2/1999

Transaminase (ALT) Changesat the Time of First Biopsy

0

5

10

15

20

25

30

35

0 10 20 30 40 50 60 70 80 90 100

Days after first dose

x U

LN

Rx Bx

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

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.

Patient 502/1069

Biopsy #299-28804

12/27/1999

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 (-)

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

Patient 2004/002

Biopsy # 02-5981/23/2002

ALT and T. Bili Changes at the Time of Biopsy

0

2

4

6

8

10

0 10 20 30 40 50 60 70

Days from first dose

x U

LN ALT

T. Bili

RxBx and Cholecystectomy

Histologic Diagnoses

• Combined cholestatic and hepatocellular injury, mild

• Sinusoidal and periportal fibrosis (history of diabetes mellitus)

Etiologic Differential Diagnosis of Combined Cholestasis & Hepatitis

• Sepsis• Acute large duct obstruction, early• Drug/Toxic injury

Practical Evaluation of Drug Toxicity

Irey’s MethodologyTemporal eligibility

Exclusion of other drugs, toxins, diseasesKnown potential for injuryPrecedent for injury patternDe-challenge/Re-challenge

Toxicologic analysis

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

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