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Original Investigation |

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

Stefan Stender, MD1; Ruth Frikke-Schmidt, MD, DMSc1,2; Børge G. Nordestgaard, MD, DMSc2,3,4; Anne Tybjærg-Hansen, MD, DMSc1,2,4
[+] Author Affiliations
1Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
2The Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
3Department of Clinical Biochemistry, Herlev Hospital,Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
4The Copenhagen City Heart Study, Bispebjerg Hospital,Copenhagen University Hospitals and Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
JAMA Intern Med. 2013;173(13):1222-1228. doi:10.1001/jamainternmed.2013.6465.
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Importance  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.

Objective  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.

Results  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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Figures

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Figure 1.
The Mendelian Randomization Design

A, Comparison of the randomized trial and mendelian randomization study designs. B, The mendelian randomization design underpinning the present study. If factors 1 through 3 are all documented firmly, the interpretation would be that the data are compatible with a causal relationship between elevated bilirubin level and increased risk of symptomatic gallstone disease (factor 4). Upward arrow indicates increased; downward arrow, decreased. Adapted from Nordestgaard and Tybjærg-Hansen.14

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Figure 2.
Cumulative Incidence of Symptomatic Gallstone

Cumulative incidence of symptomatic gallstone disease as a function of age in individuals in the general population (available for analysis) with plasma bilirubin levels in the 10th decile (blue line) vs deciles 1 through 9 (gray line). To convert bilirubin to micromoles per liter, multiply by 17.1.

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Figure 3.
Prospective Risk of Symptomatic Gallstone Disease as a Function of Baseline Plasma Bilirubin Level

Prospective risk of symptomatic gallstone disease as a function of baseline plasma bilirubin level (10th decile vs deciles 1-9) in the general population in both sexes combined and in women and men separately. Hazard ratios (HRs) (95% CIs) were multifactorially adjusted for age, sex, body mass index, physical activity, hormone therapy, and alcohol consumption. To convert bilirubin to micromoles per liter, multiply by 17.1.

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Figure 4.
Plasma Bilirubin Levels, Theoretically Predicted Risks, and Observed Risks

Plasma bilirubin levels, theoretically predicted risks, and observed risks of symptomatic gallstone disease as a function of the UGT1A1 rs6742078 genotype in the general population in both sexes combined and in women and men separately. Hazard ratios (HRs) (95% CIs) were multifactorially adjusted for age, sex, body mass index, physical activity, hormone therapy, and alcohol consumption. P values are for tests for trend of HRs. To convert bilirubin to micromoles per liter, multiply by 17.1.

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