Unconjugated bilirubin functions physiologically to inhibit NADPH oxidase complexes

Gilbert syndrome (GS) is a common genetic variant in which plasma unconjugated bilirubin levels are elevated throughout life, in the absence of hepatic pathology.1 This typically reflects decreased hepatic capacity for conjugation of bilirubin coupled with an upregulation of bilirubin generation. Typically, subjects with GS are homozygous for promoter mutations compromising transcriptional efficiency in the gene coding for uridine-diphosphoglucuronate glucuronosyltransferase 1A1 (UGT1A1), which links bilirubin to glucuronic acid; as a result, hepatic expression of this enzyme is decreased, although the enzyme itself is functionally normal. However, plasma bilirubin levels in many people homozygous for such mutations fail to exceed the level (defined as either 17.1 or 20 µmol/L) considered diagnostic for GS. Hence, subjects with GS also are characterised by an increased rate of bilirubin generation, ultimately traceable to increased heme synthesis. In some cases, this may reflect upregulated heme oxygenase activity, which would reflexly boost heme production.1 2

Epidemiological studies have found that GS confers potent and versatile health protection.2–5 Notably, an analysis of the Health Improvement Network primary care database in the UK found that, after adjustment for pertinent covariants, a diagnosis of GS was associated with a relative risk for all-cause mortality of 0.5 (95% CI 0.4 to 0.7; p<0.001).6

This remarkable health benefit appears likely to stem largely from the fact that physiological intracellular levels of unconjugated bilirubin inhibit certain common isoforms of NADPH oxidase.7–11 These membrane-bound superoxide-generating complexes are a major source of the oxidants that drive or exacerbate a high proportion of health disorders. Bilirubin’s inhibitory impact on NADPH oxidase activity presumably explains much of the profound antioxidant activity of heme oxygenase, which cleaves heme to yield biliverdin, carbon monoxide and free iron; biliverdin is then rapidly reduced by the ubiquitously expressed enzyme biliverdin reductase to yield bilirubin. Expression …