Original article—liver, pancreas, and biliary tract
Clinical and Histopathologic Features of Fluoroquinolone-Induced Liver Injury

https://doi.org/10.1016/j.cgh.2011.02.019Get rights and content

Background & Aims

Fluoroquinolone-induced liver injury is rare; no prospective studies of well-characterized case series have been published. We studied patients with fluoroquinolone-induced hepatotoxicity from the Drug-Induced Liver Injury Network (DILIN) to characterize injury patterns, outcomes, and associated features.

Methods

We identified subjects with fluoroquinolone hepatotoxicity enrolled in the DILIN from September 2004 to January 2010. Demographic, clinical, and laboratory data were analyzed by descriptive statistical methods.

Results

Of the 679 registrants in the DILIN prospective study, 12 had fluoroquinolone hepatotoxicity (6 ciprofloxacin, 4 moxifloxacin, 1 levofloxacin, and 1 gatifloxacin). Seven were women; median age was 57 years (range, 23–80 years), and median time from fluoroquinolone start to symptoms was only 4 days (range, 1–39 days). Nine patients developed symptoms on medication; 3 did so 2, 8, and 32 days after stopping the medication. Cases were equally distributed among hepatocellular injury (predominantly increased levels of alanine aminotransferase), cholestatic injury (predominantly increased levels of alkaline phosphatase), and both. Seven patients had immunoallergic features. Patients with mixed hepatocellular and cholestatic injury had mild disease without jaundice; all recovered. In contrast, 2 of 4 patients with hepatocellular injury and jaundice died, 1 of acute liver failure. One patient with cholestatic injury developed vanishing bile duct syndrome and required liver transplantation; another had a persistently increased serum level of alkaline phosphatase.

Conclusions

Fluoroquinolone liver injury is rapid in onset and often has immunoallergic features, indicating a hypersensitivity reaction. The pattern of injury can be hepatocellular, cholestatic, or mixed; mixed cases are the least severe. Acute and chronic liver failure can occur.

Section snippets

Overall Design

The study design of the DILIN prospective study has been described previously.9, 37 Briefly, patients aged 2 or older were enrolled on the basis of clinical suspicion of liver injury caused by a medication or herbal product within 6 months of clinical onset. Inclusion criteria included aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels >5 times the upper limit of normal (or pretreatment baseline if abnormal) on 2 consecutive occasions, or alkaline phosphatase (AP) levels

Subjects

Among 679 cases enrolled in the DILIN database that had undergone causality assessment by February 2010, fluoroquinolones were listed as a potential cause in 30. In 15 cases, fluoroquinolone was the only implicated drug, of which 3 were considered definite, 4 highly likely, 3 probable, and 5 possible or unlikely. Only the 10 single-drug cases that were considered definite, highly likely, or probable were included in this study. Among the other 15 cases in which fluoroquinolones were one of

Discussion

Hepatotoxicity from fluoroquinolones has been described in multiple case reports and summarized in several reviews. However, there are no well-characterized and prospectively followed groups of cases published on hepatic injury from this important class of antibiotics. The 12 cases presented here confirm that hepatic injury from fluoroquinolones has a “class effect,” and the clinical presentation and phenotype of injury are similar with the different agents. The predominant feature of the

Acknowledgments

A full list of DILIN investigators, co-investigators, and staff is shown in Appendix 1 of the supplementary materials. The authors thank our referring providers and patients for participation in this study. We also thank Jay H. Hoofnagle and Robert J. Fontana for their advice and help in preparing this article.

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    Conflicts of interest The authors disclose no conflicts.

    Funding The DILIN Network is structured as a U01 cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grants: 2U01-DK065176-06 (Duke), 2U01-DK065201-06 (UNC), 2U01-DK065184-06 (Michigan), 2U01-DK065211-06 (Indiana), 5U01DK065193-04 (UConn), 5U01-DK065238-08 (UCSF/CPMC), 1U01-DK083023-01 (UTSW), 1U01-DK083027-01 (TJH/UPenn), 1U01-DK082992-01 (Mayo), 1U01-DK083020-01 (USC). Additional funding is provided by CTSA grants: UL1 RR025761 (Indiana), UL1 RR025747 (UNC), UL1 RR024134 (UPenn), UL1 RR024986 (Michigan), UL1 RR024982 (UTSW), UL1 RR024150 (Mayo) and in part by the Intramural Research Program of the NIH, National Cancer Institute.

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