Risk of Ischemic Stroke and Decreased Serum Bilirubin Levels

Bilirubin, often thought to be a toxic end product of heme, is a potent antioxidant compound in vivo.1,2As shown in the schematic Figure, degraded red blood cells release heme, which is broken down by heme oxygenase to biliverdin, which is reduced by biliverdin reductase into the hydrophobic compound bilirubin. Unconjugated bilirubin is a lipid-soluble molecule that must be made water soluble to be excreted. Unconjugated bilirubin is carried by albumin to the liver, where it is conjugated into a water-soluble form by hepatic glucuronyl transferase. The hepatic enzyme UDP-glucuronyl transferase 1A1 (UGT1A1) converts bilirubin to a soluble (conjugated) form suitable for renal and biliary elimination.1,2 Importantly, in healthy European populations, common genetic variation of the UGT1A1 promoter region explains ≈50% of the variability in serum total (TB) and conjugated bilirubin levels.3 UGT1A1 is also responsible for the glucuronidation of many other small lipophilic molecules, such as steroid hormones and drugs that affect the vasculature.1,2Figure. Schematic representation of the bilirubin metabolism and the putative biological mechanisms by which higher levels of serum bilirubin might exert vasoprotective effects on the development of silent brain infarcts and other cardiovascular complications. HO-1 indicates heme oxygenase-1.See accompanying article on page 946Currently, ample evidence suggests that lower levels of TB are associated with increased risk of cardiovascular disease (CVD), independently of traditional risk factors.4–9 In 2012, further evidence for a possible beneficial role of bilirubin protecting against CVD was provided from a large UK primary care database (n=130 052 patients) with the measurement of TB levels recorded 3 months before first statin treatment. After a median of …