The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine
Author(s): ,
Jay H. Hoofnagle
Affiliations:
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States
,
Paul Brent Watkins
Affiliations:
University of North Carolina, Chapel Hill, NC, United States
,
Naga Chalasani
Affiliations:
Indiana University, Indianapolis, IN, United States
,
Huiman Barnhart
Affiliations:
Duke University, Durham, NC, United States
,
Ryan Schutte
Affiliations:
University of Florida College of Medicine, Gainesville, FL, United States
,
Elizabeth Phillips
Affiliations:
Vanderbilt University School of Medicine, Nashville, TN, United States
,
David Ostrov
Affiliations:
University of Florida College of Medicine, Gainesville, FL, United States
,
David Kleiner
Affiliations:
National Cancer Institute, Bethesda, MD, United States
,
Jiezhun Gu
Affiliations:
Duke University, Durham, NC, United States
,
Elizabeth Theresa Cirulli
Affiliations:
Duke University, Durham, NC, United States
Robert John Fontana
Affiliations:
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. Dec 1, 2018; 256772
Dr. Robert Fontana
Dr. Robert Fontana

Access to this content is an EASL members and LiverTree™ Privileged Users benefit.

Journal Abstract
References
Discussion Forum (0)
Rate & Comment (0)
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.

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.

Keyword(s)
Genetic polymorphisms, Drug-induced liver injury, Hepatotoxicity
[1]. N.F. Fernandes - Terbinafine hepatotoxicity: case report and review of the literature
[2]. S.L. Iverson - Identification of a reactive metabolite of terbinafine: insights into terbinafine-induced hepatotoxicity
[3]. F.A. Anania - Terbinafine hepatotoxicity resulting in chronic biliary ductopenia and portal fibrosis
[4]. Z. Perveze - Terbinafine-induced hepatic failure requiring liver transplantation
[5]. R.J. Fontana - Drug-Induced Liver Injury Network (DILIN) prospective study: rationale, design and conduct
[6]. M.I. Lucena - Susceptibility to amoxicillin-clavulanate-induced liver injury is influenced by multiple HLA Class I and II alleles
[7]. P. Nicoletti - Association of liver injury from specific drugs, or groups of drugs, with polymorphisms in HLA and other genes in a genome-wide association study
[8]. N. Chalasani - Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study
[9]. R.J. Fontana - Idiosyncratic drug-induced liver injury is associated with substantial morbidity and mortality within 6 months from onset
[10]. D.E. Kleiner - Hepatic histological findings in suspected drug-induced liver injury: systematic evaluation and clinical associations
[11]. A.L. Price - Principal components analysis corrects for stratification in genome-wide association studies
[12]. F.F. Gonzalez-Galarza - Allele frequency net 2015 update: new features for HLA epitopes, KIR and disease and HLA adverse drug reaction associations
[13]. L. Gragert - Six-locus high resolution HLA haplotype frequencies derived from mixed-resolution DNA typing for the entire US donor registry
[14]. A.H. Schmidt - Estimation of high-resolution HLA-A, -B, -C, -DRB1 allele and haplotype frequencies based on 8862 German stem cell donors and implications for strategic donor registry planning
[15]. J. Pingel - High-resolution HLA haplotype frequencies of stem cell donors in Germany with foreign parentage: how can they be used to improve unrelated donor searches?
[16]. F. Williams - High resolution HLA-DRB1 identification of a Caucasian population
[17]. S. Manor - High-resolution HLA A∼B∼DRB1 haplotype frequencies from the Ezer Mizion Bone Marrow Donor Registry in Israel
[18]. L. Bordolo - Protein structure homology modeling using SWISS-MODEL workspace
[19]. S. Zhang - Structural basis of cross-allele presentation by HLA-A*0301 and HLA-A*1101 revealed by two HIV-derived peptide complexes
[20]. P. Kumar - Structural basis for T cell alloreactivity among three HLA-B14 and HLA-B27 antigens
[21]. P. Emsley - Features and development of Coot
[22]. G.M. Morris - AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility
[23]. D. Weininger - SMILES, a chemical language and information system. 1. Introduction to methodology and encoding rules
[24]. Y.S. de Boer - Genome wide association study identifies variants associated with autoimmune hepatitis type 1
[25]. E. Raschi - Assessing liver injury associated with antimycotics: concise literature review and clues from data mining of the FAERS database
[26]. N. Adriaenssens - Outpatient systemic antimycotic and antifungal use in Europe: new outcome measure provides new insight
[27]. W.Y. Kao - Risk of oral antifungal agent-induced liver injury in Taiwanese
[28]. B. Elewski - Safety and tolerability of oral antifungal agents in the treatment of fungal nail disease: a proven reality
[29]. L.A. Garcia Rodriguez - A cohort study on the risk of acute liver injury among users of ketoconazole and other antifungal drugs
[30]. R.J. Fontana - Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug induced liver injury
[31]. J. Yang - Systematic review of severe acute liver injury caused by terbinafine
[32]. A. Mallat - Terbinafine-induced prolonged cholestasis with reduction of interlobular bile ducts
[33]. Y.S. DeBoer - Features of autoimmune hepatitis in patients with Drug-induced liver injury
[34]. US Census 2010; .
[35]. D.A. Ostrov - Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire
Code of conduct/disclaimer available in General Terms & Conditions
Anonymous User Privacy Preferences

Strictly Necessary Cookies (Always Active)

MULTILEARNING platforms and tools hereinafter referred as “MLG SOFTWARE” are provided to you as pure educational platforms/services requiring cookies to operate. In the case of the MLG SOFTWARE, cookies are essential for the Platform to function properly for the provision of education. If these cookies are disabled, a large subset of the functionality provided by the Platform will either be unavailable or cease to work as expected. The MLG SOFTWARE do not capture non-essential activities such as menu items and listings you click on or pages viewed.


Performance Cookies

Performance cookies are used to analyse how visitors use a website in order to provide a better user experience.



Google Analytics is used for user behavior tracking/reporting. Google Analytics works in parallel and independently from MLG’s features. Google Analytics relies on cookies and these cookies can be used by Google to track users across different platforms/services.


Save Settings