ArticleBMC gastroenterology2026
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.
Article in BMC gastroenterology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundUnexplained 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.
methodsSeventeen 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.
resultsPatients 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.
conclusionsThe 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.
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