The Nonlinear Relationship Between Total Bilirubin and Coronary Heart Disease: A Dose-Response Meta-Analysis

Li, Chaoxiu; Wang, Wenying; Song, Yumeng; Xu, Shengwen; Wu, Xiaohua

doi:10.3389/fcvm.2021.761520

Cited by 13 publications

(11 citation statements)

References 49 publications

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“… 9 Furthermore, unconjugated bilirubin functions intracellularly, as a potent inhibitor of NADPH oxidase complexes and albumin-bound bilirubin contributes significantly to the oxidant scavenging activity of plasma and may also potentially reduce endothelial dysfunction, which is strictly related to cardiovascular disease and total death. 3 , 4 , 10 Similar inverse associations have now been shown between serum total bilirubin concentrations and coronary artery disease, 11 coronary heart disease, 12 peripheral vascular disease, 13 and stroke. 14 Moreover, mildly elevated total bilirubin (TBIL) concentrations may protect against cardiovascular and total death.…”

Section: Introductionsupporting

confidence: 54%

Relationship Between Serum Indirect Bilirubin Levels and Cardiovascular Events and All-Cause Mortality in Maintenance Hemodialysis Patients

Chumakov¹,

Zhao²,

Fan³

et al. 2022

TCRM

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Purpose Unconjugated bilirubin is one of the most endogenous antioxidant substances. Mildly elevated total bilirubin concentrations may protect against cardiovascular disease and total death. However, most studies only focused on the association between serum total bilirubin and the risk of cardiovascular disease and total death. This study aimed to investigate the relationship between serum indirect bilirubin (IBIL) and the cardiovascular events in maintenance hemodialysis patients. Patients and Methods: This retrospective cohort study included 284 maintenance hemodialysis patients. Patients were divided into two groups according to the median IBIL level: high IBIL group (IBIL ≥3.0 μmol/L) and low IBIL group (IBIL <3.0 μmol/L). All demographic and laboratory data were recorded at baseline. The endpoint was cardiovascular events and all-cause mortality. Results During the median follow-up time of 62 months, 96 patients developed cardiovascular disease. There were 134 deaths. In Kaplan–Meier analysis curves, the risk of cardiovascular events in the low IBIL group was significantly higher than high IBIL group ( P < 0.001). In multivariate Cox regression analysis, the risk of cardiovascular events in high IBIL group was 0.484 times (95% CI 0.278–0.844, P = 0.010) the risk in low IBIL group. However, there was no significant association between serum IBIL level and all-cause mortality ( P = 0.269). Conclusion Our findings suggest that lower circulating IBIL levels were associated with the increased risk of cardiovascular events in maintenance hemodialysis patients.

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Section: Introductionsupporting

confidence: 54%

Relationship Between Serum Indirect Bilirubin Levels and Cardiovascular Events and All-Cause Mortality in Maintenance Hemodialysis Patients

Chumakov¹,

Zhao²,

Fan³

et al. 2022

TCRM

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“…The paradoxical conclusions may be related to the exposure levels and types of bilirubin in the studied objects. For example, a U-shaped relationship between bilirubin and CHD was reported; that is, TB levels within the range of 12–16 µmol/l had the strongest protective effect on CHD ( 9 , 28 , 29 ). Furthermore, Chen and colleagues ( 30 ) analyzed the associations of different types of bilirubin (D-BIL, I-BIL, and TB) with diabetic foot (DF) separately and discovered that serum I-BIL, but not TB and D-BIL, played a protective role in DF, and I-BIL and TB but not D-BIL were independent risk factors for the severity of DF.…”

Section: Discussionmentioning

confidence: 99%

“…Bilirubin, one of the final products of heme metabolism and long considered merely as a toxic waste, has been known for its strong antioxidant, anti-inflammatory, and neuroprotective activities in recent decades ( 1 – 5 ). As a result, many studies focused on the associations between serum bilirubin levels and chronic inflammatory diseases such as ischemic arterial diseases, especially coronary heart disease (CHD), but with controversial conclusions ( 6 – 10 ). For example, some studies found that serum bilirubin was negatively related to clinically manifested cardiovascular disease and events ( 6 – 8 ), whereas others discovered a U-shaped correlation between bilirubin levels and the risk of CHD ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

“…As a result, many studies focused on the associations between serum bilirubin levels and chronic inflammatory diseases such as ischemic arterial diseases, especially coronary heart disease (CHD), but with controversial conclusions ( 6 – 10 ). For example, some studies found that serum bilirubin was negatively related to clinically manifested cardiovascular disease and events ( 6 – 8 ), whereas others discovered a U-shaped correlation between bilirubin levels and the risk of CHD ( 9 , 10 ). Furthermore, relevant studies conducted in a diabetic population have not been sufficiently investigated.…”

Section: Introductionmentioning

confidence: 99%

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Low-normal serum unconjugated bilirubin levels are associated with late but not early carotid atherosclerotic lesions in T2DM subjects

Jin

Wang

et al. 2022

Front. Endocrinol.

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AimsWe aimed to examine the association of serum unconjugated bilirubin (UCB) within normal limits with carotid atherosclerosis in Chinese patients with type 2 diabetes mellitus (T2DM).MethodsThis cross-sectional, real-world study was performed in 8,006 hospitalized T2DM patients including 4,153 men and 3,853 women with normal UCB. The subjects were stratified into quintiles based on serum UCB levels (<6.2, 6.2–7.9, 8.0–8.9, 9.0–10.9, and >10.9 μmol/l, respectively). Carotid atherosclerotic lesions detected by ultrasonography, including carotid intima-media thickness (CIMT), carotid plaque, and stenosis, were compared among the five groups. The associations of serum UCB levels and quintiles with carotid atherosclerotic lesions were also determined by multiple logistic regression.ResultsThe prevalence of carotid plaque (55.3%, 49.5%, 47.4%, 43.8%, and 37.5%, respectively; p < 0.001 for trend) and stenosis (15.2%, 12.2%, 9.1%, 7.7%, and 5.4%, respectively; p < 0.001 for trend) was progressively lower across the UCB quintiles even after adjusting for age, sex, and duration of diabetes. Results of a fully adjusted multiple logistic regression analysis revealed that serum UCB levels and quintiles were significantly associated with carotid plaque and stenosis. Compared with the subjects in the lowest UCB quintile, the risk of carotid plaque decreased by 25.5%, 28.7%, 33.5%, and 42.8%, and that of carotid stenosis by 24.6%, 37.4%, 44.9%, and 47.3%, respectively, in those from the second to highest UCB quintiles. High serum UCB within the normal range was a protective factor against carotid plaque [odds ratio (OR) 0.810, 95% confidence interval (CI) 0.747–0.878; p < 0.001] and stenosis [OR 0.722, 95% CI 0.647–0.805; p < 0.001]. However, no significant association was observed between serum UCB and CIMT in T2DM patients. Furthermore, C-reactive protein (CRP) levels were significantly higher in the subjects with carotid atherosclerosis than in those without carotid atherosclerosis and clearly decreased across the UCB quintiles.ConclusionsSerum UCB within normal limits is inversely associated with late carotid atherosclerotic lesions including carotid plaque and stenosis but not CIMT, an early carotid atherosclerotic lesion in T2DM patients. High-normal UCB may be protective against carotid atherosclerosis by its anti-inflammation effect, which was indicated by significantly decreased CRP levels from the lowest to highest UCB quintiles.

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“…Notably, several studies have revealed a U-shaped association between total bilirubin concentration and coronary heart disease [ 39 , 40 ], telomere length [ 41 ], and all-cause mortality [ 42 ]. These findings suggest bilirubin’s threshold effect on bone health.…”

Section: Discussionmentioning

confidence: 99%

Association between total bilirubin and bone mineral density level in adolescents

Wang

et al. 2022

BMC Musculoskelet Disord

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Background Increasing bone mass accumulation in adolescence and obtaining greater peak bone mass is one of the effective methods to prevent osteoporosis in the future. We aimed to examine the association between total bilirubin and bone mineral density (BMD) level in adolescents. Methods We used the data from 2005–2010 and 2013–2014 cycles of National Health and Nutrition Examination Survey (NHANES). The BMD levels in the region of lumbar spine and femoral regions, including total femur, femoral neck, trochanter, and intertrochanter were measured. Univariable and multivariable linear regression model were used to assess the relationship between total bilirubin concentration and BMD. Results A total of 3741 participants aged 12–19 years were ultimately included in the study. There were 1997 (53.38%) males and 1744 (46.62%) females. Univariate analysis results showed that age, sex, race, education, income, body mass index, dietary calcium intake, and diabetes were correlated with BMD levels. Compared with the lowest quartile of total bilirubin concentration, the highest quartile of total bilirubin concentration was positively associated with BMD levels in the regions of total femur (β = 0.036, 95% CI = 0.021 to 0.050, P < 0.001), femur neck (β = 0.030, 95% CI = 0.016 to 0.044, P < 0.001), trochanter (β = 0.033, 95% CI = 0.019 to 0.046, P < 0.001), intertrochanter (β = 0.040, 95% CI = 0.023 to 0.056, P < 0.001), and lumbar spine (β = 0.032, 95% CI = 0.018 to 0.045, P < 0.001). We also observe the same trend in sensitivity analysis (P for trend < 0.001). Conclusion Our study demonstrated that total bilirubin concentration was positively associated with BMD levels in adolescents in United States. Total bilirubin concentration might be a protective marker against bone loss in adolescents.

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The Nonlinear Relationship Between Total Bilirubin and Coronary Heart Disease: A Dose-Response Meta-Analysis

Cited by 13 publications

References 49 publications

Relationship Between Serum Indirect Bilirubin Levels and Cardiovascular Events and All-Cause Mortality in Maintenance Hemodialysis Patients

Relationship Between Serum Indirect Bilirubin Levels and Cardiovascular Events and All-Cause Mortality in Maintenance Hemodialysis Patients

Low-normal serum unconjugated bilirubin levels are associated with late but not early carotid atherosclerotic lesions in T2DM subjects

Association between total bilirubin and bone mineral density level in adolescents

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