Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B*35:02 as a risk factor

Thomas Jacob Urban, Paola Nicoletti, Naga Chalasani, José Serrano, Andrew Stolz, Ann K. Daly, Guruprasad P. Aithal, John Dillon, Victor Navarro, Joseph Odin, Huiman Barnhart, David Ostrov, Nanye Long, Elizabeth Trilby Cirulli, Paul Brent Watkins, Robert John Fontana

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Background & Aims: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients. Methods: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. Results: Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B*35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p =2.5×10-8). Verification of HLA-B*35:02 imputation was confirmed by sequence-based HLA typing. HLA-B*35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI. Conclusion: HLA-B*35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI. Lay summary: Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B*35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.

Original languageEnglish (US)
JournalJournal of Hepatology
DOIs
StateAccepted/In press - Jan 19 2017

Fingerprint

Minocycline
HLA Antigens
Chemical and Drug Induced Liver Injury
Population Control
Liver
Alleles
Wounds and Injuries
Acne Vulgaris
Bilirubin
Computer Simulation
Adrenal Cortex Hormones
Odds Ratio

Keywords

  • Autoimmunity
  • Drug-induced liver injury
  • Genetic association
  • Human leukocyte antigen
  • Single nucleotide polymorphism

ASJC Scopus subject areas

  • Hepatology

Cite this

Minocycline hepatotoxicity : Clinical characterization and identification of HLA-B*35:02 as a risk factor. / Urban, Thomas Jacob; Nicoletti, Paola; Chalasani, Naga; Serrano, José; Stolz, Andrew; Daly, Ann K.; Aithal, Guruprasad P.; Dillon, John; Navarro, Victor; Odin, Joseph; Barnhart, Huiman; Ostrov, David; Long, Nanye; Cirulli, Elizabeth Trilby; Watkins, Paul Brent; Fontana, Robert John.

In: Journal of Hepatology, 19.01.2017.

Research output: Contribution to journalArticle

Urban, TJ, Nicoletti, P, Chalasani, N, Serrano, J, Stolz, A, Daly, AK, Aithal, GP, Dillon, J, Navarro, V, Odin, J, Barnhart, H, Ostrov, D, Long, N, Cirulli, ET, Watkins, PB & Fontana, RJ 2017, 'Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B*35:02 as a risk factor', Journal of Hepatology. https://doi.org/10.1016/j.jhep.2017.03.010
Urban, Thomas Jacob ; Nicoletti, Paola ; Chalasani, Naga ; Serrano, José ; Stolz, Andrew ; Daly, Ann K. ; Aithal, Guruprasad P. ; Dillon, John ; Navarro, Victor ; Odin, Joseph ; Barnhart, Huiman ; Ostrov, David ; Long, Nanye ; Cirulli, Elizabeth Trilby ; Watkins, Paul Brent ; Fontana, Robert John. / Minocycline hepatotoxicity : Clinical characterization and identification of HLA-B*35:02 as a risk factor. In: Journal of Hepatology. 2017.
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T2 - Clinical characterization and identification of HLA-B*35:02 as a risk factor

AU - Urban, Thomas Jacob

AU - Nicoletti, Paola

AU - Chalasani, Naga

AU - Serrano, José

AU - Stolz, Andrew

AU - Daly, Ann K.

AU - Aithal, Guruprasad P.

AU - Dillon, John

AU - Navarro, Victor

AU - Odin, Joseph

AU - Barnhart, Huiman

AU - Ostrov, David

AU - Long, Nanye

AU - Cirulli, Elizabeth Trilby

AU - Watkins, Paul Brent

AU - Fontana, Robert John

PY - 2017/1/19

Y1 - 2017/1/19

N2 - Background & Aims: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients. Methods: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. Results: Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B*35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p =2.5×10-8). Verification of HLA-B*35:02 imputation was confirmed by sequence-based HLA typing. HLA-B*35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI. Conclusion: HLA-B*35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI. Lay summary: Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B*35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.

AB - Background & Aims: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients. Methods: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina. Results: Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B*35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p =2.5×10-8). Verification of HLA-B*35:02 imputation was confirmed by sequence-based HLA typing. HLA-B*35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI. Conclusion: HLA-B*35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI. Lay summary: Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B*35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.

KW - Autoimmunity

KW - Drug-induced liver injury

KW - Genetic association

KW - Human leukocyte antigen

KW - Single nucleotide polymorphism

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