Prolonged Intrahepatic Cholestasis After Acute Hepatitis E Infection: A Case Series and Genetic Analysis

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide. Whereas HEV infection is typically self‐limiting, rare cases of prolonged cholestasis have been reported. The underlying mechanisms remain unclear, though host genetic variation may contribute. This study aimed to investigate the role of genetic predisposition in HEV‐induced prolonged cholestasis by analysing variants in genes associated with hepatocanalicular transport. We performed a retrospective review of medical records from three university centres in Switzerland and Germany and identified five immunocompetent patients with prolonged cholestasis following acute HEV infections. Genetic analysis using next‐generation sequencing included a panel of five genes involved in cholestatic liver diseases ( ATP8B1, ABCB11 , ABCB4, ABCC2 and MYO5B ). Variant frequencies were evaluated using population reference databases and compared with a genetically characterised cohort of asymptomatic HEV‐infected blood donors. All five patients were male, with a median age of 59 years. The median duration of cholestasis exceeded 77 days. Two patients exhibited potentially pathogenic heterozygous variants: ATP8B1 p.N45T in one patient and MYO5B p.K429R in another. Additionally, common ABCB11 variants were detected in all patients, which might have contributed to cholestatic clinical presentation. In the asymptomatic HEV‐infected controls, the MYO5B p.K429R variant was absent, whereas the ATP8B1 p.N45T variant was detected in only one individual in a heterozygous state. These case series illustrate that host genetics might influence the severity of HEV infection, particularly prolonged cholestatic jaundice. Further research is needed to explore the interaction between viral infections and host genetics in liver disorders.