Dose-Response Association Between Bilirubin and Cardiovascular Disease: A Systematic Review and Meta-analysis

Lei Zuo, Jun Huang, Hongyue Zhang, Bing Huang, Xiaoyi Wu, Li Chen, Sujian Xia, Xiaomei Dong, Guang Hao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


The association between bilirubin (BIL) and cardiovascular disease (CVD) remains controversial. We performed a meta-analysis of prospective studies to evaluate this association in the general population. We searched PubMed, EMBASE, Web of Science, Cochrane, and Scopus databases through to September 2021. The Newcastle-Ottawa Quality Assessment Scale was used to assess study quality. The pooled effect estimate was calculated by the fixed-effect model or random-effect model. We included 12 prospective studies (368 567 participants). The pooled risk ratio of CVD for the lowest vs highest groups of BIL levels was .75 (95% CI: .58-.97) with high heterogeneity (I2 = 87.5%, P < .001). Similar associations were observed for coronary heart disease and stroke. We further performed a "dose-response" meta-analysis, and a significant U-shaped relationship between circulating (most values were serum bilirubin, but a few were plasma bilirubin) BIL and CVD (P < .01) was observed. The lowest risk of CVD events was observed in participants with a BIL of 17-20 µmol/L in serum and/or plasma. In conclusion, there was a U-shaped dose-response relationship between BIL and CVD, especially for men. Further studies are needed to confirm our findings and identify the mechanisms involved as well as any prognostic or therapeutic potential.

Original languageEnglish (US)
Pages (from-to)33197211059693
StateE-pub ahead of print - Jan 11 2022


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