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

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.