Risk of Ischemic Stroke and Decreased Serum Bilirubin Levels

Targher, Giovanni

doi:10.1161/atvbaha.114.303279

Cited by 15 publications

(11 citation statements)

References 28 publications

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“…Thus, increasing blood TB level has a number of health benefits. Previous studies showed that a mild-tomoderate increase in the bilirubin level might be a promising strategy for preventing cardiovascular events [39][40][41]. The result of the present study coincided with previous reports that bilirubin might be an independent predictor of stroke incidence [19,20].…”

Section: Discussionsupporting

confidence: 91%

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

Wang

Zhou

et al. 2019

Preprint

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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]).

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Section: Discussionsupporting

confidence: 91%

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

Wang

Zhou

et al. 2019

Preprint

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“…Kurzepa et al indicated that the serum bilirubin level is a poor prognostic factor for ischemic stroke [41]. Previous studies also showed that a mild-to-moderate increase in the bilirubin level might be a promising strategy for preventing cardiovascular events [42][43][44]. The result of the present study coincided with previous reports that bilirubin might be an independent predictor of stroke incidence [19,20].…”

Section: Dose-response Analysissupporting

confidence: 89%

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

Wang

Zhou

et al. 2020

Preprint

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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]).

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“…Lifestyle interventions (such as smoking cessation, weight loss, and physical activity) and pharmacological agents (HO‐1 inducers such as statins, aspirin, resveratrol, and niacin and drugs that inhibit hepatic uptake) may cause safe elevations in circulating levels of bilirubin, but there is limited evidence on their potential effects on blood pressure. These pharmacological agents cause mild‐to‐moderate elevations in circulating levels of bilirubin and have been proposed as future tools for CVD prevention and treatment . It has been suggested that the HO‐1 pathway may represent a novel therapeutic target for the prevention of CVD .…”

Section: Discussionmentioning

confidence: 99%

“…These pharmacological agents cause mild-to-moderate elevations in circulating levels of bilirubin and have been proposed as future tools for CVD prevention and treatment. 62 It has been suggested that the HO-1 pathway may represent a novel therapeutic target for the prevention of CVD. 39 The measurement of circulating total bilirubin involves a routinely available blood test, which is simple, cheap, and well standardized; therefore, it would be of immense clinical benefit if bilirubin is demonstrated to have a role in preventing hypertension as well as CVD.…”

Section: Implications Of Findingsmentioning

confidence: 99%

Circulating Total Bilirubin and Future Risk of Hypertension in the General Population: The Prevention of Renal and Vascular End‐Stage Disease (PREVEND) Prospective Study and a Mendelian Randomization Approach

Kunutsor

Kieneker

Burgess

et al. 2017

JAHA

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BackgroundCirculating total bilirubin is known to be inversely and independently associated with future risk of cardiovascular disease. However, the relationship of circulating total bilirubin with incident hypertension is uncertain. We aimed to assess the association of total bilirubin with future hypertension risk and supplemented this with a Mendelian randomization approach to investigate any causal relevance to the association.Methods and ResultsPlasma total bilirubin levels were measured at baseline in the PREVEND (Prevention of Renal and Vascular End‐Stage Disease) prospective study of 3989 men and women without hypertension. Hazard ratios (95% confidence intervals) of total bilirubin with incident hypertension were assessed. New‐onset hypertension was recorded in 1206 participants during a median follow‐up of 10.7 years. Baseline total bilirubin was approximately log‐linearly associated with hypertension risk. Age‐ and sex‐adjusted hazard ratio for hypertension per 1‐SD increase in loge total bilirubin was 0.86 (0.81–0.92; P<0.001), which was attenuated to 0.94 (0.88–0.99; P=0.040) after further adjustment for established risk factors and other potential confounders. The association was marginally significant on further adjustment for high‐sensitivity C‐reactive protein (0.94; 0.88–1.00; P=0.067). A genetic variant at the UGT1A1*28 locus consistently shown to be strongly associated with circulating bilirubin levels—rs6742078—was not significantly associated with blood pressure or hypertension (P>0.05 for all), arguing against a strong causal association of circulating bilirubin with blood pressure.ConclusionsThe weak and inverse association of circulating total bilirubin with future hypertension risk may be driven by biases such as unmeasured confounding and/or reverse causation. Further evaluation is warranted.

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Risk of Ischemic Stroke and Decreased Serum Bilirubin Levels

Cited by 15 publications

References 28 publications

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

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

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

Circulating Total Bilirubin and Future Risk of Hypertension in the General Population: The Prevention of Renal and Vascular End‐Stage Disease (PREVEND) Prospective Study and a Mendelian Randomization Approach

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