Clinical and histologic features of azithromycin-induced liver injury

Abstract

Background & aims: Rare cases of azithromycin-induced hepatotoxicity have been reported, with variable clinical and histologic features. We characterized clinical features and outcomes of azithromycin-induced liver injury.

Methods: We identified patients with azithromycin-induced liver injury from the Drug-Induced Liver Injury Network Prospective Study who had causality scores of definite, highly likely, or probable. Demographic, clinical, and laboratory data and 6-month outcomes were examined.

Results: Eighteen patients (72% female; mean age, 37 y) had causality scores of definite (n = 1), highly likely (n = 9), or probable (n = 8). Common presenting symptoms were jaundice, abdominal pain, nausea, and/or pruritus. For 16 patients, abnormal results from liver tests were first detected 14 days after azithromycin cessation (range, 9-20 d). The median duration of azithromycin treatment was 4 days (range, 2-7 d). The pattern of injury was hepatocellular in 10 patients, cholestatic in 6 patients, and mixed in 2 patients. The mean peak level of alanine aminotransferase was 2127 IU/L, of alkaline phosphatase was 481 IU/L, and of total bilirubin was 9.2 mg/dL. Liver histology showed ductopenia and veno-occlusive changes in a few patients. Two individuals had severe hypersensitivity cutaneous reactions. After 6 months, 8 patients had recovered, 4 patients had chronic injury, 1 patient died, and 1 patient underwent liver transplantation (outcomes were unavailable for 4 patients). Two of the patients who died or underwent liver transplantation had underlying chronic liver disease.

Conclusions: Azithromycin-induced liver injury occurs within 1 to 3 weeks after azithromycin initiation and predominantly is hepatocellular in nature. Although most patients recover fully, severe cutaneous reactions, chronic injury, and serious complications leading to death or liver transplantation can occur (ClinicalTrials.gov identifier, NCT00345930).

Keywords: Antibiotic; DILI; Liver Toxicity; Macrolide.

Conflict of interest statement

Disclosures

Dr. Martinez: No potential conflicts to declare

Dr. Vuppalanchi: Received compensation for consulting related to drug hepatotoxicity from BMS and served on the Speaker’s Bureau for Gilead. Received grant support from Intercept and Lumena Pharmaceuticals.

Dr. Fontana: Received grant support from Gilead and Vertex and served as a paid consultant to Tibotec, Merck and GSK.

Dr. Stolz: No potential conflicts to declare

Dr. Kleiner: No potential conflicts to declare

Dr. Hayashi: No potential conflicts to declare

Dr. Gu: No potential conflicts to declare

Dr. Hoofnagle: No potential conflicts to declare

Dr. Chalasani: Served as a paid consultant to Abbvie, Salix, BMS, Aegerion, Lilly, Nimbus and Merck in the past 12 months. Received grant support from Intercept, Cumberland, Gilead, Takeda and Enterome.

Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1

Study flow describing number of azithromycin cases and their salient characteristics among all cases enrolled into the DILIN Prospective Study

Figure 2

Liver histology in patients with azithromycin hepatotoxicity. A. (Patient 3) An 11 year old Caucasian female with azithromycin hepatotoxicity underwent a liver biopsy at 20 days after DILI onset. Ductopenic portal area with mild inflammation. B. Zone 3 cholestasis with both hepatocellular and canalicular (arrows) bile accumulation. (A and B taken from the same case, both H&E, 600×). C. (Patient 11) A 45 year old Caucasian male with azithromycin hepatotoxicity underwent a liver biopsy at day 139 after DILI onset. Chronic hepatitis with perivenular inflammation and hemorrhage. (P – Portal area; V – Vein; H&E 200×). D. (Patient 10) Mild veno-occlusive changes. There is a layer of fibroinflammatory tissue inside the vein (arrowheads). (Masson trichrome, 600×).