The level of Bilirubin and the risk of ischemic stroke: a systematic review and dose-response meta-analysis of real-world studies

Background: Bilirubin, a marker of hepatic and hematological diseases in clinical practice, is not only a waste end-product but also an antioxidant that may protect against diseases associated with oxidative stress. Numerous epidemiological studies have shown an inverse relationship between the serum total bilirubin (TB) level and the risk of ischemic stroke (IS). However, markedly elevated TB levels may exert neurotoxic effects. Based on this, we conducted a dose-response meta-analysis to quantify the relationship between blood TB and IS as well as between TB and all types of stroke (AS) in the physiological range of bilirubin.Methods: PubMed, Embase, Web of Science, and Cochrane Central databases were searched up to March 2019. Additional studies were identified by reviewing references and contacting authors. Categorical and dose-response meta-analyses were performed to quantify the relationship between TB and IS. The primary outcome was ischemic stroke, and the secondary outcome was all types of stroke.Results: Nine observational studies (seven publications) involving 110,032 participants and 3710 stroke cases were included for analysis. The average OR of IS for every 1 µmol/L increment in TB level was 0.978 (95%CI: 0.957–0.999). The summary OR of AS for every 1 µmol/L increment in TB level was 0.974 (95%CI: 0.956–0.992). Subgroup analysis based on gender showed a negative dose-response relationship between the circulating TB level and IS or AS in males, but not in females.Conclusions: The present study indicates a negative dose-response relationship between the circulating TB level and the risk of IS or AS within physiologic range of serum TB in males. Moderately elevated blood TB levels were associated with a diminished prevalence of IS. Every 1 µmol/L increment in serum TB level was associated with a 2.2% decrease in the risk of IS and a 2.6% decrease in the risk of AS. Large-scaled prospective studies are needed to confirm the conclusion of the current analysis.Trial registration: This study was registered at PROSPERO(https://www.crd. york.ac.uk/PROSPERO/[CRD42017075988]).