High serum bilirubin can be used as a prognostic marker for cardiovascular disease in patients starting statin therapy

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Key study points:

1. High levels of serum bilirubin decrease the rates of cardiovascular events in both men and women who are about to start statin therapy.

Primer: Cardiovascular disease is one of the major causes of mortality in the world. There are several markers that used clinically to determine whether a person is at risk for a cardiovascular event. The main marker used is the concentration of plasma low-density lipoprotein cholesterol, but we can also monitor c-reactive protein (CRP) levels and b-type natriuretic protein (BNP). Unconjugated serum bilirubin is a protein that has shown some promise as well. Bilirubin is the breakdown product of heme in red blood cells in the liver. Usually, bilirubin is glucoronidated by the enzyme UGT1A1 so that it can be excreted into the bile duct and pass out of the body through stool. This is important because high levels of serum bilirubin are toxic to the body. However, patients who have Gilbert syndrome which have a polymorphism in the UGT1A1 promoter and thus have higher than normal serum bilirubin levels, have a decreased risk for cardiovascular disease. The purpose of this study was to determine whether serum bilirubin levels are associated with cardiovascular disease in patients who are about to start statin therapy.

Background reading: 

1. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study
2. Bilirubin and glutathione have complementary antioxidant and cytoprotective roles

This [retrospective cohort] study evaluated the use of serum unconjugated bilirubin as a prognostic marker for cardiovascular disease before the use of statin therapy. Data (69,000 men and 61,000 women) were collected from The Health Improvement Network (THIN) in the United Kingdom. Subjects were required to have a serum bilirubin, alkaline phosphatase and 1 transaminase measurement within 3 months of starting a statin therapy. Major outcomes were myocardial infarction, ischemic heart disease, angina, or cerebrovascular accident

This study found that increased bilirubin levels were significantly associated with decreases in all the major outcomes. This was true for both men and women. Compared to a level of 10 μmol/L, patients who had a serum bilirubin level of 5 μmol/L had an 18% higher chance of having a cardiovascular event and a 33% increased risk of death.

In sum: This cohort study evaluated the use of serum unconjugated bilirubin as a marker for cardiovascular risk in patients who have yet to begin statin therapy. They found that an increased serum bilirubin level was associated with a decreased risk of death and cardiovascular event. The supposed mechanism of action is that serum bilirubin is a potent antioxidant within the serum and thus may decrease the rate of oxidation of low density lipoproteins which are necessary for the formation of atherosclerosis. The main strength of this study is the number of men and women included and that it uses a diagnostic test routinely used in patients prior to statin therapy initiation.

Click to read the study in Circulation

Click to read an accompanying editorial in Circulation

By [JC] and [MP]

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