The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine
Author(s): ,
Jay H. Hoofnagle
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States
Paul Brent Watkins
University of North Carolina, Chapel Hill, NC, United States
Naga Chalasani
Indiana University, Indianapolis, IN, United States
Huiman Barnhart
Duke University, Durham, NC, United States
Ryan Schutte
University of Florida College of Medicine, Gainesville, FL, United States
Elizabeth Phillips
Vanderbilt University School of Medicine, Nashville, TN, United States
David Ostrov
University of Florida College of Medicine, Gainesville, FL, United States
David Kleiner
National Cancer Institute, Bethesda, MD, United States
Jiezhun Gu
Duke University, Durham, NC, United States
Elizabeth Theresa Cirulli
Duke University, Durham, NC, United States
Robert John Fontana
University of Michigan, Ann Arbor, MI, United States
Corresponding author. Address: Michigan Medicine, 3912 Taubman Center, Ann Arbor, MI 48103, United States. Tel.: +1 734 936 4780; fax: +1 734 936 7392.
EASL LiverTree™. Fontana R. 12/01/18; 256741
Dr. Robert Fontana
Dr. Robert Fontana
Contributions Biography
Journal Abstract
Graphical abstract

Graphical abstract

Patients with terbinafine hepatotoxicity most often present with a mixed/cholestatic liver injury profile. Caucasian patients were more likely to be carriers of HLA-A*33:01, B*14:02, C*08:02 than controls (91% vs. 1.6%) A similar HLA haplotype of HLA-A*33:03 was also over-represented in Asian American terbinafine hepatotoxicity cases. Molecular docking studies suggest that terbinafine may interact with these HLA alleles.

Background & Aims

Terbinafine is an antifungal agent that has been associated with rare instances of hepatotoxicity. In this study we aimed to describe the presenting features and outcomes of patients with terbinafine hepatotoxicity and to investigate the role of human leukocyte antigen (HLA)-A*33:01.


Consecutive high causality cases of terbinafine hepatotoxicity enrolled into the Drug Induced Liver Injury Network were reviewed. DNA samples underwent high-resolution confirmatory HLA sequencing using the Ilumina MiSeq platform.


All 15 patients with terbinafine hepatotoxicity were more than 40 years old (median = 57 years), 53% were female and the median latency to onset was 38 days (range 24 to 114 days). At the onset of drug-induced liver injury, 80% were jaundiced, median serum alanine aminotransferase was 448 U/L and alkaline phosphatase was 333 U/L. One individual required liver transplantation for acute liver failure during follow-up, and 7 of the 13 (54%) remaining individuals had ongoing liver injury at 6 months, with 4 demonstrating persistently abnormal liver biochemistries at month 24. High-resolution HLA genotyping confirmed that 10 of the 11 (91%) European ancestry participants were carriers of the HLA-A*33:01, B*14:02, C*08:02 haplotype, which has a carrier frequency of 1.6% in European Ancestry population controls. One African American patient was also an HLA-A*33:01 carrier while 2 East Asian patients were carriers of a similar HLA type: A*33:03. Molecular docking studies indicated that terbinafine may interact with HLA-A*33:01 and A*33:03.


Patients with terbinafine hepatotoxicity most commonly present with a mixed or cholestatic liver injury profile and frequently have residual evidence of chronic cholestatic injury. A strong genetic association of HLA-A*33:01 with terbinafine drug-induced liver injury was confirmed amongst Caucasians.

Lay summary

A locus in the human leukocyte antigen gene (HLA-A*33:01, B*14:02, C*08:02) was significantly overrepresented in Caucasian and African American patients with liver injury attributed to the antifungal medication, terbinafine. These data along with the molecular docking studies demonstrate that this genetic polymorphism is a plausible risk factor for developing terbinafine hepatotoxicity and could be used in the future to help doctors make a diagnosis more rapidly and confidently.

Genetic polymorphisms, Drug-induced liver injury, Hepatotoxicity
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