Temporal Evolution of Amoxicillin-Clavulanate Induced Liver Injury
H Mani, R Saxena, JH Hoofnagle, DE Kleiner. NCI, NIH, Bethesda; Indiana University, Indianapolis; NIDDK, NIH, Bethesda; For the Drug Induced Liver Injury Network (DILIN)
Background: Although the widely used combination of amoxicillin-clavulanate is a well known cause of idiosyncratic hepatotoxicity, the temporal course of its associated liver disease is not adequately documented.
Design: Cases of amoxicillin-clavulanate-induced liver injury with liver biopsies available for review were identified in the data set of DILIN, a prospective study and database on drug-induced liver disease. Liver biopsies were independently reviewed in a blinded manner and injury patterns classified as one of 4 patterns: acute hepatitis, acute cholestasis, chronic cholestasis, or mixed hepatocellular-cholestatic. R ratio (ALT to alkaline phosphatase) was used to classify biochemical profiles, using standard criteria. Pathology injury patterns were compared to temporal biochemical profiles, based on the date the implicated drug was begun.
Results: Among 122 DILIN cases with available causality review and biopsies, 9 were attributed to amoxicillin-clavulanate, making it the second most common drug associated with DILI. Patients were 42-87 (mean 61) years old; 7 were males. Patients presented with cholestatic (2 cases), mixed (5 cases) or hepatocellular (2 cases) biochemical profiles, 10 to 36 (mean 25) days after starting therapy. 7 cases were considered definite DILI, 1 very likely and 1 probable DILI; 1 biopsy was inadequate. Of the 8 cases with biopsies, 6 had similar temporal biochemical profiles, with R rising to a mixed or hepatocellular profile before declining to the cholestatic range. In these patients, the 2 earliest biopsies showed acute cholestasis with little inflammation, and the 4 biopsies at later time points showed mixed hepatocellular-cholestatic pattern, irrespective of R at biopsy. One patient biopsied during a sharp rise in R value showed acute hepatitis without cholestasis and the last with a persistent cholestatic biochemical profile showed chronic cholestasis with bile duct paucity.
Conclusions: Amoxicillin-clavulanate-induced liver injury progresses temporally from a hepatocellular or mixed to a cholestatic biochemical profile in most cases. Biopsy reveals acute cholestasis in the early phase progressing later to a mixed hepatocellular-cholestatic injury pattern. Pathologic patterns in the two variant cases corresponded with their biochemical profiles. These findings suggest that, in amoxicillin-clavulanate induced liver injury, biopsy pathology reflects temporal biochemical injury profiles as a whole.
Category: Liver & Pancreas
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 160, Tuesday Morning