Extreme Bilirubin Levels as a Causal Risk Factor for Symptomatic Gallstone Disease

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In individuals without blockage of their bile ducts, levels of plasma bilirubin likely reflect levels of biliary bilirubin; higher biliary bilirubin levels may increase the risk of gallstone disease.


To test the hypothesis that a lifelong increase in plasma bilirubin levels is a causal risk factor for symptomatic gallstone disease in the general population.

Design, Setting, and Participants

In a prospective study of the Danish general population (N = 61 212), we first tested whether elevated levels of plasma bilirubin predicted greater risk of symptomatic gallstone disease. Second, taking advantage of mendelian randomization, we tested whether a genetic variant in the bilirubin glucoronidating enzyme UGT1A1 (rs6742078) was associated with increased plasma bilirubin levels and, in turn, with an increased risk of symptomatic gallstone disease.

Main Outcomes and Measures

Plasma bilirubin level and symptomatic gallstone disease.


During 34 years of follow-up, 3374 individuals developed symptomatic gallstone disease. In adjusted analyses, persons with plasma bilirubin levels in the 10th decile had a greater risk of symptomatic gallstone disease compared with those with plasma bilirubin levels in deciles 1 through 9; the hazard ratios (HRs) (95% CIs) were 1.57 (1.26-1.96) overall, 1.36 (1.02-1.82) in women, and 2.00 (1.41-2.83) in men. UGT1A1 genotype explained 20% of the total variation in plasma bilirubin levels and was associated with increases in the mean plasma bilirubin level overall of +16% (+0.09 mg/dL) in GT heterozygotes and +90% (+0.50 mg/dL) in TT homozygotes compared with GG homozygotes, with similar effects in women and men (P for trend <.001 for all). The corresponding HRs (95% CIs) for symptomatic gallstone disease were 1.09 (1.02-1.17) for GT heterozygotes and 1.22 (1.09-1.36) for TT homozygotes vs GG homozygotes and similar in women and men (P for trend = .04-<.001).

Conclusions and Relevance

These results are compatible with a causal association between extreme levels of plasma bilirubin and increased risk of symptomatic gallstone disease.

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