Association of circulating total bilirubin level with ischemic stroke: a systemic review and meta-analysis of observational evidence

Abstract

Background: Circulating total bilirubin is a biomarker of ischemic stroke and may serve as a potential prognostic factor. It is imperative to systemically evaluate the correlation between circulating total bilirubin and risk for stroke. This systematic review and meta-analysis investigated the relationship between total serum bilirubin and risk for stroke. Methods: Studies published before 30 June 2017 were searched in four databases (PubMed, EMBASE, Web of Science and Cochrane Central). Additional studies were searched by reviewing references and contacting authors. Cohort, cross-sectional and case-control studies in adults that examined the association between serum total bilirubin and stroke were included irrespective of language and date of publication. The primary outcome of this study was ischemic stroke, and the secondary outcome was stroke. Abstract and full-text were reviewed by two independent reviewers, and disagreement was resolved by consulting a third reviewer. Data were extracted by two independent reviewers using a pre-designed data collection form. Results: Eleven observational studies (5 prospective and 6 cross-sectional studies) involving 131,450 subjects were included for analysis. In four studies with 83,380 subjects, the relationship between circulating total bilirubin and ischemic stroke was investigated, ischemic stroke was found in 2,496 patients, and the total odds ratio (OR) of the highest bilirubin and the lowest bilirubin for the occurrence of ischemic stroke was 0.66 (95% CI: 0.58-0.74). Eleven studies with 131,450 subjects explored the correlation between bilirubin and stroke, stroke was reported in 5,060 patients, and the total OR of the highest bilirubin and the lowest bilirubin for the occurrence of stroke was 0.73 (95% CI: 0.68-0.79). A stratified analysis based on the gender showed that the total bilirubin level in males correlated with ischemic stroke or stroke, which was not noted in females. Conclusions: The available studies support an inverse association between circulating total bilirubin and risk for ischemic stroke and stroke in males. Prospective studies with large sample size are needed to establish the role of circulating bilirubin in the prevention of stroke.

Serum bilirubin and ischaemic stroke: a review of literature

“…Kimm et al found that every 1 µmol/L increment in bilirubin concentration was associated with 2% reduction in the HR in a multivariate-adjusted model for IS in men and 1% reduction in the HR for all types of stroke in a prospective cohort study in which 1964 out of 78 724 developed stroke 42. A meta-analysis of 11 population-based observational studies involving 5060 stroke cases among 131 450 subjects showed an inverse relationship between the level of TBIL and the risk of IS in males, but not in females 12. The difference in the level of serum bilirubin between males and females might be attributed to differences in the level of serum oestrogen, iron storage, heme oxygenase and lifestyle (drinking, smoking, diet and antioxidant supplements (such as vitamin C)) 43–45…”

“…Bilirubin, a compound used to diagnose conditions such as hepatobiliary disorders,7 haemolytic anaemia8 and dyserythropoiesis,9 also known as a potential toxic factor causing severe brain damage in newborns,10 is not only the end product of the heme catabolic pathway but also the most potent endogenous antioxidant 11. It has been shown to protect from diverse diseases associated with increased oxidative stress, such as IS 12. In addition, accumulating evidence has shown that bilirubin harbours anti-inflammatory,11 neuroprotective13 and platelet activation inhibiting14 effects.…”

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

“…AS in males through meta-analysis which included 11 observational studies involving 5,060 stroke cases among 131450 subjects, but it is not a dose-response analysis [21].…”

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

“…Subsequently, a meta-analysis of 12 population-based prospective studies involving 9378 incidental cardiovascular disease (CVD) cases showed that every 1-SD increase in the TBIL level was associated with a 7% reduction in the relative risk of CVD, but stroke was not the end point [11]. Zhong et al reported an inverse relationship between the level of circulating TBIL and the risk of IS or AS in males through meta-analysis which included 11 observational studies involving 5,060 stroke cases among 131,450 subjects, but it is not a dose-response analysis [21].…”