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      Is serum total bilirubin a predictor of prognosis in arteriosclerotic cardiovascular disease? A meta-analysis

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          Abstract

          The protective role of serum total bilirubin, a widely recognized antioxidant, has been approved by numerous updating studies. However, regarding the effect of high serum total bilirubin level (STBL) in arteriosclerotic cardiovascular disease (ASCVD) are conflicting in different sources of data. We, therefore, performed this meta-analysis to evaluate the influence of STBL on risk of ASCVD.

          Four databases were used to identify the literature with a date of search of January, 2019. Finally, a total of 20 studies had been adopted. ASCVD was defined as acute coronary syndrome, stable angina, coronary revascularization, atherosclerotic stroke or transient ischemic attack, and peripheral arterial disease (PAD). All relevant data were collected from studies meeting the inclusion criteria.

          A total of 20 published studies (323,891 cases) met the inclusion criteria. The meta-analysis revealed that, in studies excluding heterogeneity, STBL was significantly positively related to in-hospital cardiovascular mortality (odds ratio [OR] 2.82, 95% confidence interval [CI] 1.83–4.36, Z = 4.69, P < .001) and major adverse cardiac events (OR 1.88, 95% CI 1.414–2.491, Z = 4.36, P < .001), also negatively associated with prognosis of acute myocardial infarction, pooled hazard ratio (HR) = 0.804 (95% CI 0.700–0.923, Z = 3.08, P = .002). The correlation similarity was also reflected in terms of patients with stroke (HR 0.78, 95% CI 0.70–0.88, Z = 4.24, P = .003). Combined analysis revealed that lower STBL was significantly associated with PAD, pooled OR = 0.91 (95% CI 0.85–0.98, Z = 2.39, P = .017). In general analysis, a conclusion can be drawn, that higher STBL was significantly negative correlated with cardiovascular disease, pooled HR = 0.83 (95% CI 0.73–0.94, Z = 3.02, P = .003).

          Higher STBL significantly improved the prognosis of ASCVD; furthermore, STBL was an important factor in the long-term prognosis of vascular-related disease prevention and can be used as a predictor in vascular-related disease risk prediction.

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          Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women.

          Heejin Kimm, Jaeseong Jo, Sun Jee … (2009)
          Bilirubin is not only a waste end-product but also an antioxidant. Bilirubin is known to be associated with decrease in cardiovascular risk in men, but its relationship to stroke was not clearly understood. Serum bilirubin concentrations were measured in 78 724 health examinees (41 054 men, aged 30-89 years) from 1994 to 2001. The subjects with potential hepatobiliary diseases or Gilbert syndrome were excluded from analysis. Stroke incidence outcome was collected from hospital records of admission attributable to stroke from 1994 to 2007. Serum bilirubin measurements were divided into 4 levels: 0 to 10.2, 10.3 to 15.3, 15.4 to 22.1, and 22.2 to 34.2 micromol/L. The number of stroke cases was 1137 in men and 827 in women. In Cox proportional hazard models, participants with a higher level of bilirubin showed lower hazard ratios in men with ischemic stroke after adjustment for multiple confounding factors compared to the lowest level of bilirubin (hazard ratio [HR], 0.72; 95% CI, 0.58-0.90 in level 3; HR, 0.66; 95% CI, 0.49-0.89 in level 4; P for trend=0.016). The risk of all stroke types also decreased as bilirubin levels increased (HR, 0.81; 95% CI, 0.68-0.97 in level 3; HR, 0.74; 95% CI, 0.58-0.94 in level 4; P for trend=0.0071). However, these associations were not seen in hemorrhagic stroke or in women. These findings suggest that serum bilirubin might have some protective function against stroke risk in men.
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            Serum bilirubin and risk of ischemic heart disease in middle-aged British men.

            Abdul Ebrahim, G Wannamethee, A. Gerald Shaper … (1995)
            The possibility that low concentrations of serum bilirubin may be associated with increased risk of ischemic heart disease has been examined in a prospective study of 7685 middle-aged British men. During 11.5 years there were 737 major ischemic heart disease (IHD) events. A U-shaped relationship was observed between serum bilirubin and risk of IHD. Low bilirubin was associated with several cardiovascular risk factors, in particular smoking, low concentrations of high-density lipoprotein cholesterol, low forced expiratory volume in 1 s, and low serum albumin. The U-shaped relationship persisted even after adjusting for several risk factors. Compared with men in the lowest fifth of the distribution (bilirubin 12 mumol/L) showed similar risk to the lowest fifth [RR = 0.99 (95% confidence intervals 0.73-1.34)], which persisted after exclusion of men with bilirubin > 17 mumol/L. The significance of this U-shaped relationship is unclear, but it could be interpreted as support for the role of endogenous antioxidants in the etiology of IHD.
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              Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert's syndrome.

              Daniel Doberer, Marlies Wallner, A C Bulmer … (2013)
              Recent epidemiological and clinical data show protection from CVD (cardiovascular disease), all-cause mortality and cancer in subjects with GS (Gilbert's syndrome), which is characterized by a mildly elevated blood bilirubin concentration. The established antioxidant effect of bilirubin, however, contributes only in part to this protection. Therefore we investigated whether mildly elevated circulating UCB (unconjugated bilirubin) is associated with altered lipid metabolism. The study was performed on GS and age- and gender-matched healthy subjects (n=59 per group). Full lipoprotein profile, TAG (triacylglycerols), Apo (apolipoprotein)-A1, Apo-B, lipoprotein(a), the subfractions of LDL (low-density lipoprotein) and selected pro-inflammatory mediators were analysed. A hyperbilirubinaemic rodent model (Gunn rats, n=40) was investigated to further support the presented human data. GS subjects had significantly (P<0.05) improved lipid profile with reduced total cholesterol, LDL-C (LDL-cholesterol), TAG, low- and pro-atherogenic LDL subfractions (LDL-1+LDL-2), Apo-B, Apo-B/Apo-A1 ratio and lower IL-6 (interleukin 6) and SAA (serum amyloid A) concentrations (P=0.094). When the control and GS groups were subdivided into younger and older cohorts, older GS subjects demonstrated reduced lipid variables (total cholesterol and LDL-C, TAG and LDL-C subfractions, Apo-B/Apo-A1 ratio; P<0.05; Apo-B: P<0.1) compared with controls. These data were supported by lipid analyses in the rodent model showing that Gunn rat serum had lower total cholesterol (2.29±0.38 compared with 1.27±0.72 mM; P<0.001) and TAG (1.66±0.67 compared with 0.99±0.52 mM; P<0.001) concentrations compared with controls. These findings indicate that the altered lipid profile and the reduced pro-inflammatory status in hyperbilirubinaemic subjects, particularly in the older individuals, probably contribute additionally to the commonly accepted beneficial antioxidant effects of bilirubin in humans.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Medicine (Baltimore)
                Journal ID (iso-abbrev): Medicine (Baltimore)
                Journal ID (publisher-id): MEDI
                Title: Medicine
                Publisher: Wolters Kluwer Health
                ISSN (Print): 0025-7974
                ISSN (Electronic): 1536-5964
                Publication date Collection: October 2019
                Publication date (Electronic): 18 October 2019
                Volume: 98
                Issue: 42
                Electronic Location Identifier: e17544
                Affiliations
                Vascular Medicine Center, Peking University Shougang Hospital, Beijing, China.
                Author notes
                [∗ ]Correspondence: Hongyu Wang, No 9, Jinyuanzhuang Road, Shijingshan District, Beijing, China (e-mail: hongyuwang@ 123456188.com ).
                Article
                Publisher ID: MD-D-19-01785 Accession ID: 17544
                DOI: 10.1097/MD.0000000000017544
                PMC ID: 6824698
                PubMed ID: 31626117
                SO-VID: f1b1b62e-844a-48d9-8c4d-d209e55482d7
                Copyright © Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
                License:

                This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

                History
                Date received : 6 March 2019
                Date revision received : 24 August 2019
                Date accepted : 1 September 2019
                Categories
                Subject: 3400
                Subject: Research Article
                Subject: Meta-Analysis of Observational Studies in Epidemiology
                Custom metadata
                OPEN-ACCESS TRUE

                Keywords: coronary artery disease,meta-analysis,peripheral arterial disease,serum total bilirubin level,stroke
                Data availability:
                Keywords: coronary artery disease, meta-analysis, peripheral arterial disease, serum total bilirubin level, stroke

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