david e. kleiner, m.d., ph.d
DESCRIPTION
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. - PowerPoint PPT PresentationTRANSCRIPT
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