Beyond Gilbert syndrome: exploring the heterozygous UGT1A1 c.41_40dup variant as a potential modifier of bile composition associated with a cholangiopathic phenotype in adults with unexplained chronic cholestasis.

BACKGROUND: Unexplained chronic cholestasis (UCC) in adults is traditionally interpreted as a hepatocellular or canalicular disorder; however, a subset of patients may instead exhibit a cholangiopathy-driven phenotype. Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) plays a key role in bilirubin conjugation and bile composition. The heterozygous UGT1A1 c.41_40dup variant, classically associated with Gilbert Syndrome (GS), is frequently observed in individuals without overt GS. In this setting, reduced UGT1A1 activity has been associated with the production of a bile characterized by an increased proportion of bilirubin monoglucuronide (BMG) and a reduced proportion of bilirubin diglucuronide (BDG). The present study investigates whether this variant contributes to a bile composition-driven cholangiopathic phenotype characterized by chronic biliary epithelial injury.

METHODS: Seventeen UDCA-naïve, GS-free adults with UCC were enrolled and stratified according to genetic profile: Group A (UGT1A1 c.41_40dup), Group B (UGT1A1 c.41_40dup plus additional variants), and Group C (non-carriers). Biochemical, histological, and clinical features were assessed. UGT1A1 activity and bilirubin conjugate composition (BMG/BDG ratio) were evaluated using high-performance liquid chromatography. At 6 months, biochemical evolution was assessed using ALP levels (> 1.9 × ULN) as a pragmatic benchmark.

RESULTS: Patients carrying the UGT1A1 c.41_40dup variant (Group A and B) exhibited significantly reduced enzymatic activity and an increased intrahepatic BMG/BDG ratio compared with non-carriers (both p < 0.0001), along with a higher prevalence of gallstone-related manifestations. Despite normal serum bilirubin, they showed a biochemical profile characterized by persistent ALP and GGT elevation, along with a descriptive pattern of more frequent advanced fibrosis among variant carriers. The overall clinical and biochemical pattern was consistent with a cholangiopathy-associated, ascending cholestasis phenotype. At 6 months, ALP levels > 1.9 × ULN were observed in 70% of variant carriers and 28% of non-carriers; however, this difference did not reach statistical significance after re-analysis using Fisher's exact test and should be interpreted as exploratory.

CONCLUSIONS: The heterozygous UGT1A1 c.41_40dup variant may contribute to a bile composition-driven cholangiopathic phenotype, promoting secondary biliary injury, consistent with a hypothesis-generating model. These findings support its role as a non-canonical modifier of cholestatic disease and underscore the importance of bile composition in shaping disease expression.