Bilirubin, a product of heme metabolism, is the most potent endogenous antioxidant which increases in many oxidative stress conditions such as stroke. It has been widely known to exert neuroprotective effect on stroke through mechanisms involved in development, therefore, it can influence the occurrence and prognosis of ischaemic stroke (IS). In this review, studies were identified by a comprehensive search of Pubmed, Embase, the Cochrane Library (Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Methodology Register) and Web of Science to examine the correlation between serum bilirubin levels and risks of developing IS as well as IS outcomes. Additional studies were identified by reviewing references and contacting authors.

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 (TBIL) level and the risk of ischemic stroke (IS). However, markedly elevated TBIL levels may exert neurotoxic effects. Based on this, we conducted a dose-response meta-analysis to quantify the relationship between blood TBIL and IS as well as between TBIL 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 TBIL 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 TBIL level was 0.978 (95% CI: 0.957–0.999). The summary OR of AS for every 1 µmol/L increment in TBIL level was 0.974 (95% CI: 0.956–0.992). Subgroup analysis based on gender showed a negative dose-response relationship between the circulating TBIL level and IS or AS in males, but not in females.Conclusions: The present study found a negative dose-response relationship between the circulating TBIL level and the risk of IS or AS within physiologic range of serum TBIL in males. Moderately elevated blood TBIL levels might be associated with a diminished prevalence of IS. Every 1 µmol/L increment in serum TBIL level was associated with a 2.2% decrease in the risk of IS and a 2.6% decrease in the risk of AS. However, due to the limitations in the number of included studies and their quality, large-scaled prospective cohort 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]).

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]).