The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine

Robert John Fontana, Elizabeth Theresa Cirulli, Jiezhun Gu, David Kleiner, David Ostrov, Elizabeth Phillips, Ryan Schutte, Huiman Barnhart, Naga Chalasani, Paul Brent Watkins, Jay H. Hoofnagle

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
JournalJournal of Hepatology
DOIs
StateAccepted/In press - Jan 1 2018

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terbinafine
HLA Antigens
Hepatitis
Chemical and Drug Induced Liver Injury
Liver
Wounds and Injuries
African Americans
Population Control

Keywords

  • Drug-induced liver injury
  • Genetic polymorphisms
  • Hepatotoxicity

ASJC Scopus subject areas

  • Hepatology

Cite this

Fontana, R. J., Cirulli, E. T., Gu, J., Kleiner, D., Ostrov, D., Phillips, E., ... Hoofnagle, J. H. (Accepted/In press). The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2018.08.004

The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine. / Fontana, Robert John; Cirulli, Elizabeth Theresa; Gu, Jiezhun; Kleiner, David; Ostrov, David; Phillips, Elizabeth; Schutte, Ryan; Barnhart, Huiman; Chalasani, Naga; Watkins, Paul Brent; Hoofnagle, Jay H.

In: Journal of Hepatology, 01.01.2018.

Research output: Contribution to journalArticle

Fontana, RJ, Cirulli, ET, Gu, J, Kleiner, D, Ostrov, D, Phillips, E, Schutte, R, Barnhart, H, Chalasani, N, Watkins, PB & Hoofnagle, JH 2018, 'The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine', Journal of Hepatology. https://doi.org/10.1016/j.jhep.2018.08.004
Fontana, Robert John ; Cirulli, Elizabeth Theresa ; Gu, Jiezhun ; Kleiner, David ; Ostrov, David ; Phillips, Elizabeth ; Schutte, Ryan ; Barnhart, Huiman ; Chalasani, Naga ; Watkins, Paul Brent ; Hoofnagle, Jay H. / The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine. In: Journal of Hepatology. 2018.
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abstract = "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.",
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T1 - The role of HLA-A*33:01 in patients with cholestatic hepatitis attributed to terbinafine

AU - Fontana, Robert John

AU - Cirulli, Elizabeth Theresa

AU - Gu, Jiezhun

AU - Kleiner, David

AU - Ostrov, David

AU - Phillips, Elizabeth

AU - Schutte, Ryan

AU - Barnhart, Huiman

AU - Chalasani, Naga

AU - Watkins, Paul Brent

AU - Hoofnagle, Jay H.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

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.

KW - Drug-induced liver injury

KW - Genetic polymorphisms

KW - Hepatotoxicity

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