title: Association of circulating total bilirubin with the metabolic syndrome and type 2 diabetes: A systematic review and meta-analysis of observational evidence.
abstract: OBJECTIVE
  Emerging evidence suggests that bilirubin levels might be associated with the metabolic syndrome (MetS) and type 2 diabetes (T2D), although the nature of the association remains unclear.
  
  
  METHODS
  This systematic review and meta-analysis investigated the relationship between total plasma bilirubin and the risk of MetS and T2D.
  
  
  METHODS
  Relevant studies were identified using five databases (Embase, Medline [Ovid], Web of Science, PubMed, Cochrane Central and Google Scholar), with the last search done on 21 October 2015. Study references were checked and authors contacted to identify additional studies.
  
  
  METHODS
  Randomized controlled trials, and cohort, case-control and cross-sectional studies of adults examining the association between blood bilirubin levels and MetS and T2D were included, irrespective of language and date of publication. Abstract and full-text selection was done by two independent reviewers, with a third reviewer available in case of disagreement.
  
  
  METHODS
  Data were extracted by two independent reviewers using a predesigned data collection form.
  
  
  METHODS
  MetS and T2D.
  
  
  METHODS
  Summary estimates were obtained by random-effects meta-analysis.
  
  
  RESULTS
  Of the 2313 searched references, 16 observational studies (11 cross-sectional, two prospective, one that was both cross-sectional and prospective, two retrospective and one national survey) met our inclusion criteria. Overall, data were available for 175,911 non-overlapping participants, including 7414 MetS cases and 9406 T2D cases. In the meta-analysis of seven cross-sectional studies, the pooled odds ratio (95% confidence interval) for MetS in a comparison of extreme tertiles of serum bilirubin levels was 0.70 (95% CI: 0.62, 0.78), whereas no significant association was found for the pooled estimated relative risk between two prospective studies (0.57, 95% CI: 0.11, 2.94). The corresponding estimate was 0.77 (95% CI: 0.67, 0.87) for T2D from four cross-sectional studies.
  
  
  CONCLUSIONS
  The available evidence, mainly from cross-sectional studies, supports an inverse association of bilirubin levels with adverse metabolic outcomes. Large-scale prospective studies are now needed to establish whether bilirubin levels may be useful in the prevention of MetS and T2D.
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Nano
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Muka
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Cepeda
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Voortman
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Dhana
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Brahimaj
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Dehghan
authors.affiliation: Department of Epidemiology, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands. Electronic address: o.franco@erasmusmc.nl.
authors.forename: O H
authors.initials: OH
authors.lastname: Franco
mesh_terms: D000328:Adult; D001663:Bilirubin / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000453:epidemiology*; D005260:Female; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood* / Q000453:epidemiology*; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D055815:Young Adult
chemical_list: D001663:Bilirubin
keywords: Bilirubin; Meta-analysis; Metabolic syndrome; Systematic review; Type 2 diabetes