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

Stefan Stender; Ruth Frikke-Schmidt; Børge G Nordestgaard; Anne Tybjærg-Hansen

doi:10.1001/jamainternmed.2013.6465

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

Stefan Stender, Ruth Frikke-Schmidt, Børge G Nordestgaard, Anne Tybjærg-Hansen

Department of Clinical Medicine

31 Citations (Scopus)

Abstract

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% (+0.09mg/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.

Original language	English
Journal	Annals of Internal Medicine
Volume	173
Issue number	13
Pages (from-to)	1222-1228
Number of pages	7
ISSN	0003-4819
DOIs	https://doi.org/10.1001/jamainternmed.2013.6465
Publication status	Published - 8 Jul 2013

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title = "Extreme Bilirubin Levels as a Causal Risk Factor for Symptomatic Gallstone Disease",

abstract = "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% (+0.09mg/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.",

author = "Stefan Stender and Ruth Frikke-Schmidt and Nordestgaard, {B{\o}rge G} and Anne Tybj{\ae}rg-Hansen",

year = "2013",

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doi = "10.1001/jamainternmed.2013.6465",

language = "English",

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T1 - Extreme Bilirubin Levels as a Causal Risk Factor for Symptomatic Gallstone Disease

AU - Stender, Stefan

AU - Frikke-Schmidt, Ruth

AU - Nordestgaard, Børge G

AU - Tybjærg-Hansen, Anne

PY - 2013/7/8

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N2 - 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% (+0.09mg/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.

AB - 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% (+0.09mg/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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DO - 10.1001/jamainternmed.2013.6465

M3 - Journal article

C2 - 23753274

SN - 0003-4819

VL - 173

SP - 1222

EP - 1228

JO - Annals of Internal Medicine

JF - Annals of Internal Medicine

IS - 13

ER -

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

Abstract

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