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Peer-reviewedCC BYActa pharmaceutica Sinica. B

Antihypertensive drug-induced liver injury is rare, but strongly associated with HLA-B∗35:01.

  • Lily Dara1
  • Paola Nicoletti2
  • Chaudry Nasir Majeed3
  • Andrew Dellinger4
  • David E Kleiner5
  • Mahmoud G Mohamed1
  • Tatyana Kushner6
  • Raj Vuppalanchi7
  • Elizabeth J Phillips8
  • David A Ostrov9
  • Mohammed Umair Masood2
  • Huiman Barnhart10
2 more authors
  • Jiezhun Gu10
  • Herbert L Bonkovsky3
10 affiliations
  1. 1Division of Gastrointestinal and Liver Diseases, Research Center for Liver Diseases, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA.
  2. 2Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  3. 3Section on Gastroenterology and Hepatology, Department of Medicine, Wake Forest University School of Medicine and Advocate Health Wake Forest Baptist, Winston-Salem, NC 27101, USA.
  4. 4Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC 27710, USA.
  5. 5Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
  6. 6Department of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY 10065, USA.
  7. 7Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine and Indiana University Health, Indianapolis, IN 46202, USA.
  8. 8Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  9. 9Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610, USA.
  10. 10Duke Clinical Research Institute, Durham, NC 27710, USA.
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Abstract

Anti-hypertensive (anti-HTN) drugs are widely prescribed, but the features of associated drug-induced liver injury (DILI) are poorly defined. A total of 2207 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2003 to 2024 were adjudicated as definite, highly likely, or probable DILI. Of these, 44 cases were attributed to anti-HTN drugs. These were compared with non-anti-HTN DILI cases and population controls. Human Leukocyte Antigen (HLA) sequencing was performed, and allele frequencies were analyzed using Fisher's Exact Test. Among the 44 anti-HTN DILI cases, 14 were caused by ACE inhibitors/ARBs, 13 by methyldopa, 11 by hydralazine, and 3 each by beta-blockers and calcium-channel blockers. Methyldopa DILI presented with hepatocellular injury in young women (prescribed mainly for pregnancy-related HTN). Non-methyldopa cases were 60% hepatocellular, 28% cholestatic, and 9% mixed. Severe outcomes included two liver transplants and two deaths (lisinopril and hydralazine). HLA-B∗35:01 was markedly enriched (50% vs. 13% in controls; OR 6.0; P = 1 × 10⁻⁸) and was linked to shorter latency (50 vs. 109 days; P = 0.02) but not severity. HLA-B∗35:01 was overrepresented across all drug classes, including 66% of methyldopa cases, 27% of hydralazine cases, and 42% of ACE/ARB cases. DILI from anti-HTN medications is very rare but strongly associated with HLA-B∗35:01, especially for methyldopa. Carriers display a shorter latency, potentially indicating an accelerated adaptive immune response, that warrants further exploration.

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Cite

BibTeXRIS
BibTeX
@article{dara2026antihypertensive,
  title = {{Antihypertensive drug-induced liver injury is rare, but strongly associated with HLA-B∗35:01.}},
  author = {Lily Dara and Paola Nicoletti and Chaudry Nasir Majeed and Andrew Dellinger and David E Kleiner and Mahmoud G Mohamed and Tatyana Kushner and Raj Vuppalanchi and Elizabeth J Phillips and David A Ostrov and Mohammed Umair Masood and Huiman Barnhart and Jiezhun Gu and Herbert L Bonkovsky},
  journal = {Acta pharmaceutica Sinica. B},
  year = {2026},
  month = jun,
  doi = {10.1016/j.apsb.2026.06.003},
  url = {https://europepmc.org/article/MED/42948728},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Antihypertensive drug-induced liver injury is rare, but strongly associated with HLA-B∗35:01.
AU  - Lily Dara
AU  - Paola Nicoletti
AU  - Chaudry Nasir Majeed
AU  - Andrew Dellinger
AU  - David E Kleiner
AU  - Mahmoud G Mohamed
AU  - Tatyana Kushner
AU  - Raj Vuppalanchi
AU  - Elizabeth J Phillips
AU  - David A Ostrov
AU  - Mohammed Umair Masood
AU  - Huiman Barnhart
AU  - Jiezhun Gu
AU  - Herbert L Bonkovsky
PY  - 2026
DA  - 2026/06/10
JO  - Acta pharmaceutica Sinica. B
DO  - 10.1016/j.apsb.2026.06.003
UR  - https://europepmc.org/article/MED/42948728
AB  - Anti-hypertensive (anti-HTN) drugs are widely prescribed, but the features of associated drug-induced liver injury (DILI) are poorly defined. A total of 2207 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2003 to 2024 were adjudicated as definite, highly likely, or probable DILI. Of these, 44 cases were attributed to anti-HTN drugs. These were compared with non-anti-HTN DILI cases and population controls. Human Leukocyte Antigen (HLA) sequencing was performed, and allele frequencies were analyzed using Fisher's Exact Test. Among the 44 anti-HTN DILI cases, 14 were caused by ACE inhibitors/ARBs, 13 by methyldopa, 11 by hydralazine, and 3 each by beta-blockers and calcium-channel blockers. Methyldopa DILI presented with hepatocellular injury in young women (prescribed mainly for pregnancy-related HTN). Non-methyldopa cases were 60% hepatocellular, 28% cholestatic, and 9% mixed. Severe outcomes included two liver transplants and two deaths (lisinopril and hydralazine). HLA-B∗35:01 was markedly enriched (50% vs. 13% in controls; OR 6.0; P = 1 × 10⁻⁸) and was linked to shorter latency (50 vs. 109 days; P = 0.02) but not severity. HLA-B∗35:01 was overrepresented across all drug classes, including 66% of methyldopa cases, 27% of hydralazine cases, and 42% of ACE/ARB cases. DILI from anti-HTN medications is very rare but strongly associated with HLA-B∗35:01, especially for methyldopa. Carriers display a shorter latency, potentially indicating an accelerated adaptive immune response, that warrants further exploration.
SN  - 2211-3835
SN  - 2211-3843
ER  -