Physiologically increased total bilirubin is associated with reduced risk of first myocardial infarction: A meta-analysis and dose-response analysis

Nutr Metab Cardiovasc Dis. 2021 Apr 9;31(4):1016-1026. doi: 10.1016/j.numecd.2021.01.002. Epub 2021 Jan 12.


Aim: Bilirubin has potential predictive and prognostic value for myocardial infarction (MI), but the clinical evidence remains controversial. We performed this meta-analysis to systematically quantify the relationships between circulating bilirubin levels and the incidence of MI and post-MI adverse events.

Data synthesis: We searched the PubMed, Cochrane Library, Embase, and Web of Science databases for ad-hoc studies, published up to October 17, 2020, recording bilirubin before MI (predictive analyses) or adverse events (prognostic analyses). Relative risks (RR) were pooled by a random-effects model. The dose-response analysis was conducted by restricted cubic splines. In patients without previous MI, increased total bilirubin (TB) reduced the risk of long-term (>3 year) first MI by 22% (95% confidence interval [CI]: 0.69-0.88, n = 4). The dose-response analysis indicated that the RR for first MI decreased by 2.7% per each 2 μmol/L increment of TB (three studies, 95% CI: 1.3%-4.1%, P < 0.001), with a cut-off value of 12.60 μmol/L for RR > 1.00. Elevated bilirubin reduced the incidence of first and recurrent MI by 36% (95% CI: 0.42-0.98, n = 7). However, after suffering MI, higher TB concentrations could not decrease the risk of recurrent MI (RR: 1.02, 95% CI: 0.67-1.55, n = 5) and increased the incidence of short-term (<1 year) post-MI major adverse cardiovascular events, all-cause mortality, and cardiovascular mortality, but not long-term (≥1 year).

Conclusion: Higher TB levels within a physiological range reduced the incidence of long-term first MI, with a cut-off value of 12.60 μmol/L.

Keywords: Bilirubin; Dose-reponse; Meta-analysis; Myocardial infarction; Predictive; Prognostic.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Bilirubin / blood*
  • Biomarkers / blood
  • Female
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Myocardial Infarction / blood
  • Myocardial Infarction / diagnosis
  • Myocardial Infarction / epidemiology
  • Myocardial Infarction / prevention & control*
  • Prognosis
  • Protective Factors
  • Risk Assessment
  • Risk Factors
  • Up-Regulation


  • Biomarkers
  • Bilirubin