Clinical Laboratory Strategies: October 23, 2008

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Seeking a New Role for Bilirubin
Byproduct May Protect Against Strokes and Related Damage

By Deborah Levenson

Bilirubin has long been considered little more than a metabolic waste product not worth attention outside the realms of neonatal care and liver maladies in older children and adults. But in recent years, research on bilirubin’s antioxidant, anti-inflammatory, and cytoprotective properties has raised the possibility that it helps protect against cardiovascular and inflammatory diseases, plus certain vascular complications. In particular, one large new epidemiological study suggests that higher serum total bilirubin level is associated with reduced stroke prevalence and improved stroke outcomes. This issue of Strategies examines its findings.

Stroke is the third leading cause of death and a major cause of disability in the United States. Researchers have identified several risk factors for stroke, but little is known about factors that modulate stroke risk beyond lowering blood pressure and cholesterol levels. Some researchers see bilirubin as an intriguing possibility. Certain studies have found an inverse association between bilirubin and carotid atherosclerotic plaque, suggesting that higher bilirubin levels may be associated with reduced risk of stroke. Based on research indicating that bilirubin protects nerve cells from injury in acute ischemic stroke, various investigators have hypothesized that bilirubin might also limit neurological damage once a stroke has occurred.

Now an analysis of data from the National Health and Nutrition Examination Survey for 1999–2004 (NHANES) shows that serum total bilirubin level is associated with reduced stroke prevalence and improved stroke outcomes (Am J Med  2008;121: 781-788).  A research team from Brigham and Women’s Hospital and Harvard School of Public Health in Boston reports that after multivariate adjustment, a 0.1 mg/dL increment in bilirubin level is associated with a 9% reduced odds of stroke (OR 0.90, 95% CI, 0.86– 1.96) and with a 10% reduced odds of an adverse stroke outcome (OR 0.90, 95% CI, 0.80– 1.00). The highest tertile of bilirubin level was associated with a 44% reduced odds of stroke.

The researchers got these results after identifying participants with history of stroke from 13,214 adult NHANES participants who all had data on stroke history, serum total bilirubin level, and stroke risk factors. Of these, 453 reported a history of stroke. Of those who had suffered stroke, 138 participants reported an adverse stroke outcome, defined as a long-term health problem or disability resulting from stroke. To estimate odds of stroke and adverse outcomes, the researchers performed multivariable logistic regression, with adjustment for demographic characteristics and stroke risk factors. These included age, race or ethnicity, sex, smoking status, total cholesterol to HDL cholesterol ratio, and diagnosis of hypertension and diabetes.

Part of a Pathway

The Harvard researchers and other bilirubin researchers note that bilirubin concentrations in the blood are controlled by three enzymes: heme oxygenase (HO), biliverdin reductase, and uridine diphosphate-glucuronosyltransferase (UGT1A1). HO and biliverdin reductase govern bilirubin’s formation, while UGT1A1 regulates the clearance of bilirubin by the liver and the bile. If more research confirms the link between higher bilirubin levels and reduced stroke risk and improved stroke outcomes, the Harvard team believes that interventions that induce HO or inhibit UGT1A1 could be strategies for preventing or treating stroke.

But much must be done before bilirubin should be used in such a strategy, noted Todd Perlstein, MD, one of the paper’s authors and fellow in Cardiovascular Medicine at Brigham and Women’s Hospital and Harvard Medical School. “What’s first needed is prospective analysis showing that having high bilirubin levels today reduces the chance of a stroke tomorrow, as our cross-sectional analysis does not address the temporal association of bilirubin with stroke,” he explained. “Ultimately, there’s hope that bilirubin might be used therapeutically to treat or prevent stroke. There are papers that have argued for bilirubin’s use as a biomarker, but we didn’t make that point. We were more interested in pathophysiology than in risk prediction.”

Bilirubin and Variability

If prospective studies of bilirubin and different types of stroke of varying severity in men, women, and various ethnic groups confirm the link made by Perlstein and his colleagues, research should examine how to control bilirubin levels “day to day” within individuals and how they vary among different people, noted Harvey Schwertner, PhD, research chemist at Wilford Hall Medical Center at Lackland Air Force Base in Texas. Before bilirubin can ever be reliably used as a marker, laboratorians will need more accurate and sensitive measures, he added.

Schwertner was excited about the Harvard team’s findings. “Those results are in line with what we and others have shown for CVD. As bilirubin increases, there’s less chance of an event,” he explained. The research is also valuable because it showed the relationship remained very significant after adjustment for other, known risk factors.

Not There Yet

An epidemiologist who has studied bilirubin in CVD was less enthusiastic about its role in either CVD or stroke. Paul Hopkins, MD, professor of Internal Medicine and Co-Director of Cardiovascular Genetics at University of Utah School of Medicine in Salt Lake City, said that his own research has identified two genes that boost bilirubin levels throughout life, but based on another of his studies, do not seem to be associated with coronary disease. “So, we have the seeming paradox that low bilirubin is associated with an increased risk of coronary disease or other atherosclerotic disease, but the gene variants that affect the bilirubin throughout life, at least so far, do not seem to be associated,” he noted. “One possible explanation is that factors that do cause atherosclerosis, such as increases in oxidation or inflammation, also consume bilirubin, leaving the bilirubin in the plasma at a lower level. Bilirubin may be an innocent bystander or just a gauge of some other process.” He was skeptical about bilirubin’s role in protecting against stroke and its damage, explaining that noone really knows if bilirubin is an indicator of stroke or a result of it. “But it’s still a plausible hypothesis that it plays a role in stroke,” he added.

Hopkins, Perlstein, and Schwertner agreed that the most recent data on stroke should cement the idea that bilirubin is more than a waste product. But Hopkins cautioned against getting too excited about the NHANES data. “They show that at the least, higher bilirubin levels are benign and maybe even protective, but bilirubin is nowhere near ready for prime time as a strategy for prevention or treatment,” he concluded.

Schwertner holds several patents on technology used to measure bilirubin to predict risk of coronary artery disease.

Deborah Levenson is a freelance writer in College Park, Md. 

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