PMID- 30138689 OWN - NLM STAT- MEDLINE DCOM- 20191230 LR - 20200820 IS - 1600-0641 (Electronic) IS - 0168-8278 (Print) IS - 0168-8278 (Linking) VI - 69 IP - 6 DP - 2018 Dec TI - The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine. PG - 1317-1325 LID - S0168-8278(18)32283-9 [pii] LID - 10.1016/j.jhep.2018.08.004 [doi] AB - 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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. CI - Copyright (c) 2018 European Association for the Study of the Liver. All rights reserved. FAU - Fontana, Robert John AU - Fontana RJ AD - University of Michigan, Ann Arbor, MI, United States. Electronic address: rfontana@med.umich.edu. FAU - Cirulli, Elizabeth Theresa AU - Cirulli ET AD - Duke University, Durham, NC, United States. FAU - Gu, Jiezhun AU - Gu J AD - Duke University, Durham, NC, United States. FAU - Kleiner, David AU - Kleiner D AD - National Cancer Institute, Bethesda, MD, United States. FAU - Ostrov, David AU - Ostrov D AD - University of Florida College of Medicine, Gainesville, FL, United States. FAU - Phillips, Elizabeth AU - Phillips E AD - Vanderbilt University School of Medicine, Nashville, TN, United States. FAU - Schutte, Ryan AU - Schutte R AD - University of Florida College of Medicine, Gainesville, FL, United States. FAU - Barnhart, Huiman AU - Barnhart H AD - Duke University, Durham, NC, United States. FAU - Chalasani, Naga AU - Chalasani N AD - Indiana University, Indianapolis, IN, United States. FAU - Watkins, Paul Brent AU - Watkins PB AD - University of North Carolina, Chapel Hill, NC, United States. FAU - Hoofnagle, Jay H AU - Hoofnagle JH AD - National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States. LA - eng GR - U01 DK065211/DK/NIDDK NIH HHS/United States GR - UL1 RR025761/RR/NCRR NIH HHS/United States GR - UL1 TR001105/TR/NCATS NIH HHS/United States GR - U01 DK083020/DK/NIDDK NIH HHS/United States GR - U01 DK065201/DK/NIDDK NIH HHS/United States GR - U01 DK065238/DK/NIDDK NIH HHS/United States GR - U01 DK065193/DK/NIDDK NIH HHS/United States GR - U01 DK065176/DK/NIDDK NIH HHS/United States GR - U01 DK083023/DK/NIDDK NIH HHS/United States GR - UL1 RR024982/RR/NCRR NIH HHS/United States GR - P50 GM115305/GM/NIGMS NIH HHS/United States GR - UL1 RR024150/RR/NCRR NIH HHS/United States GR - U24 DK065176/DK/NIDDK NIH HHS/United States GR - R13 AR071267/AR/NIAMS NIH HHS/United States GR - R01 AI103348/AI/NIAID NIH HHS/United States GR - U01 DK083027/DK/NIDDK NIH HHS/United States GR - P30 AI110527/AI/NIAID NIH HHS/United States GR - U01 DK058369/DK/NIDDK NIH HHS/United States GR - UL1 TR002240/TR/NCATS NIH HHS/United States GR - UL1 TR000083/TR/NCATS NIH HHS/United States GR - UL1 RR024986/RR/NCRR NIH HHS/United States GR - U01 DK065184/DK/NIDDK NIH HHS/United States GR - UL1 RR024134/RR/NCRR NIH HHS/United States GR - U01 DK082992/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20180821 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Antifungal Agents) RN - 0 (Biomarkers) RN - 0 (HLA-A Antigens) RN - 0 (HLA-A*33 antigen) RN - 0 (HLA-B*14:02 antigen) RN - 0 (HLA-B14 Antigen) RN - EC 2.6.1.2 (Alanine Transaminase) RN - EC 3.1.3.1 (Alkaline Phosphatase) RN - G7RIW8S0XP (Terbinafine) SB - IM MH - Adult MH - Aged MH - Alanine Transaminase/blood MH - Alkaline Phosphatase/blood MH - Antifungal Agents/administration & dosage/*adverse effects/chemistry MH - Biomarkers/chemistry MH - Chemical and Drug Induced Liver Injury/diagnosis/*etiology/*genetics MH - Cholestasis/*chemically induced MH - Female MH - Follow-Up Studies MH - HLA-A Antigens/chemistry/*genetics MH - HLA-B14 Antigen/chemistry/genetics MH - Haplotypes MH - Humans MH - Liver/pathology MH - Male MH - Middle Aged MH - Molecular Docking Simulation MH - Polymorphism, Genetic MH - Prospective Studies MH - Protein Binding MH - Terbinafine/administration & dosage/*adverse effects/chemistry PMC - PMC6472700 MID - NIHMS1019582 OTO - NOTNLM OT - Drug-induced liver injury OT - Genetic polymorphisms OT - Hepatotoxicity COIS- Potential conflicts of interest Dr. Fontana has received research support from BMS and Gilead and has consulted for Alnylam Dr. Phillips has consulted for Biocryst Pharmaceuticals Inc. and Xcovery Pharmaceuticals Drs Hoofnagle, Kleiner, Barnhart, Ostrov, Schutte and Gu have no potential conflicts Dr. Cirulli is currently an employee of Human Longevity but was at Duke University when studies were completed. Dr. Watkins consults for Novartis which is a producer of terbinafine, but has not consulted with the company regarding any issues related to terbinafine. Dr. Chalasani consults for several pharmaceutical companies but has no reported conflicts for this manuscript. EDAT- 2018/08/24 06:00 MHDA- 2019/12/31 06:00 PMCR- 2019/04/18 CRDT- 2018/08/24 06:00 PHST- 2018/04/27 00:00 [received] PHST- 2018/07/27 00:00 [revised] PHST- 2018/08/02 00:00 [accepted] PHST- 2018/08/24 06:00 [pubmed] PHST- 2019/12/31 06:00 [medline] PHST- 2018/08/24 06:00 [entrez] PHST- 2019/04/18 00:00 [pmc-release] AID - S0168-8278(18)32283-9 [pii] AID - 10.1016/j.jhep.2018.08.004 [doi] PST - ppublish SO - J Hepatol. 2018 Dec;69(6):1317-1325. doi: 10.1016/j.jhep.2018.08.004. Epub 2018 Aug 21.