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Gilbert's syndrome (GS) is a relatively common condition, inducing a benign, non-hemolytic, unconjugated hyperbilirubinemia. Gilbert's Syndrome is associated with mutation in the Uridine Glucuronosyl Transferase 1A1 (UGT1A1) gene promoter, reducing UGT1A1 activity, which normally conjugates bilirubin allowing its elimination from the blood. Individuals with GS demonstrate mildly elevated plasma antioxidant capacity caused by elevated levels of unconjugated bilirubin (UCB), reduced thiols and glutathione. Interestingly, the development of, and risk of mortality from, cardiovascular disease is remarkably reduced in GS individuals. An explanation for this protection may be explained by bilirubin's ability to inhibit multiple processes that induce platelet hyper-reactivity and thrombosis, thus far under-appreciated in the literature. Reactive oxygen species are produced continuously via metabolic processes and have the potential to oxidatively modify proteins and lipids within cell membranes, which may encourage the development of thrombosis and CVDs. Oxidative stress induced platelet hyper-reactivity significantly increases the risk of thrombosis, which can potentially lead to tissue infarction. Here, we discuss the possible mechanisms by which increased antioxidant status might influence platelet function and link this to cardiovascular protection in GS. In summary, this is the first article to discuss the possible role of bilirubin as an anti-thrombotic agent, which inhibits platelet activation and potentially, organ infarction, which could contribute to the reduced mortality rate in mildly hyperbilirbinemic individuals., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Bilirubin is a potent antioxidant, however, uncertainty surrounds its physiological importance. Individuals with Gilbert's syndrome (GS) have increased circulating bilirubin and a reduced prevalence of cardiovascular disease (CVD). The aim of this study was to investigate mechanisms that may link bilirubin to protection from CVD seen in GS by examining markers of antioxidant and oxidative stress status and the susceptibility of serum to oxidation. Nine individuals with GS and twelve controls, matched for age, height and weight, were assessed for plasma antioxidant status, red blood cell antioxidant enzyme activities, plasma malondialdehyde, the susceptibility of serum to copper (Cu(2+)) induced oxidation and blood lipid profile. Individuals with GS had significantly elevated unconjugated bilirubin (GS: 26.0+/-6.4; control: 9.7+/-3.0 micromol/L; P<0.001), increased trolox equivalent antioxidant capacity (GS: 1.59+/-0.07; control: 1.52+/-0.07 mmol/L trolox Equ; P=0.035) and ferric reducing ability of plasma (GS: 1.09+/-0.16; control: 0.92+/-0.14 mmol/L Fe(2+) Equ; P=0.024). The lag phase of serum oxidation was significantly longer in the GS group (GS: 121.4+/-10.5; control: 106.8+/-14.6 min; P=0.020) and was positively correlated with the bilirubin concentration (r=0.451, P=0.040). A trend toward elevated HDL:LDL ratio was observed in GS (GS 0.96+/-0.31; control: 0.73+/-0.21; P=0.072). In summary, individuals with GS have an increased circulating antioxidant status and an improved resistance to serum oxidation which may partially explain their reduced prevalence of CVD.