ATLANTA—For most people, mention of bilirubin, which is formed after the breakdown of red blood cells and is eliminated by the liver, elicits thoughts of jaundice—which occurs when the compound is too high. Or, maybe, they think of yellowing skin associated with bruising.

But what if bilirubin had a more beneficial effect? That’s the suggestion of a new study in the Journal of the American Heart Association.

A team led by researchers from the Atlanta VAMC, Emory University School of Medicine and Emory’s Rollins School of Public Health found indication that it might be positive for cardiovascular (CV) health.

Their large-scale epidemiological analysis of health data from nearly 100,000 veterans—with and without HIV infection—suggested that, when in normal ranges, higher levels of bilirubin in the blood were associated with lower rates of heart failure, heart attack and stroke.

Past studies have hinted that bilirubin could have beneficial effects by acting as an antioxidant or interfering with atherosclerosis, but study authors said this was the first report of the relationship between bilirubin levels and incident CVD events for HIV patients.

A focus on HIV was important, according to lead author Vincent Marconi, MD, because the infectious disease has a negative effect on heart health even if well-controlled by antiretroviral drugs.

“We initially wanted to see if bilirubin and cardiovascular disease had a different relationship in people who were HIV positive, compared to HIV negative,” explained Marconi, director of infectious disease research at the Atlanta VAMC.

The data came from the Veterans Aging Cohort Study, a nationwide look at HIV infection, supported by the National Institutes of Health. Included in the VACS data is information on 31,418 HIV-positive and 66,987 HIV-negative veterans. Almost all of those patients, averaging 48-years-old, are male, and 48% of them are African American.

Based on bilirubin levels, the participants were divided into four groups, while acute myocardial infarction, heart failure, ischemic stroke events and other cardiovascular disease were assessed.

Researchers analyzed the data to determine hazard ratios of outcomes associated with quartiles of total bilirubin. With 6,603 total incident CVD events over a mean of 5.7 years, adjusted models indicated that increasing quartiles of baseline total bilirubin were associated with decreased hazards of all outcomes (hazard ratio, 0.86; 95% confidence interval, 0.80–0.91), according to the report.

The study team pointed out that, among HIV-positive participants, results persisted for heart failure, ischemic stroke and total CVD, but nonsignificant associations were observed for acute myocardial infarction.

Overall, the group with the highest level of bilirubin was determined to have 76% of the risk for combined cardiovascular events vs. the group with the lowest level; those effects even were documented in patients without liver disease.

“Large increases in bilirubin were not required to see an effect on CVD risk reduction,” added Marconi, who also is professor of medicine and global health at Emory University School of Medicine and Rollins School of Public Health. “Most of the change happened well within the normal physiologic range and specifically from the first to the second quartile.”

Study authors pointed out that their study, for the first time, associated levels of bilirubin with cardiovascular disease risk for HIV patients. Those findings were confirmed among age‐, sex‐ and ethnicity‐matched HIV negative controls from the same healthcare system.

One focus of the research was on the anti-HIV drug, atazanavir, known to elevate bilirubin, but the study was unable to document an independent effect of atazanavir on cardiovascular risk. Atazanavir, a protease inhibitor designed to stop HIV from processing itself, has a side effect on an enzyme in human cells that is necessary for the recycling of bilirubin. Marconi noted in an Emory Health Sciences press release that there are some indications that the drug itself has negative effects, balancing out the benefits of bilirubin.

“This work provides epidemiologic rationale for future studies to investigate how the antioxidant effect of bilirubin could be harnessed to reduce chronic disease morbidity risk,” study authors concluded. “Future studies should explore the use of bilirubin as a biomarker for other inflammation-mediated conditions and all-cause mortality.”

The goal, according to the researchers, is for future studies to investigate how the antioxidant effect of bilirubin could be employed to reduce chronic disease morbidity risk.

With inflammation suspected as a mediator in increased cardiovascular risk with HIV, additional trials could explore the use of bilirubin as a biomarker for other inflammation‐mediated conditions and all‐cause mortality among HIV patients, as well as provide additional prognostic information on morbidity and mortality risk calculators.

1. Marconi VC, Duncan MS, So-Armah K, Re VL 3rd, Lim JK, Butt AA, Goetz MB, Rodriguez-Barradas MC, Alcorn CW, Lennox J, Beckman JA, Justice A, Freiberg M. Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV-Positive and HIV-Negative Individuals in VACS (Veterans Aging Cohort Study). J Am Heart Assoc. 2018 May 2;7(10). pii: e007792. doi: 10.1161/JAHA.117.007792. PubMed PMID: 29720501; PubMed Central PMCID: PMC6015337.