Is hyperbilirubinemia protective ?

Well..a mild increase in unconjugated bilirubin may be a good thing to have!. Iam talking about patients with Gilbert's syndrome(GS) and patients with a mild elevation in their indirect bilirubin in the absence of liver disease. GS is a benign syndrome cause by reduced activity of enzyme UDP Glucronyl Transferase. In one of the famous prospective cohort studies- The British Regional Heat Study(BRHS) there was a U shaped relationship between bilirubin level and heart disease. Men with low bilirubin levels were found to have low concentrations of HDL cholesterol, low FEV1, and low serum albumin. This led to a small study in Univ of Utah...which showed a similar inverse relationship between bilirubin & heart disease.Another prospective study from Europe called PRIME study involving 10,000 men also showed that a slightly elevated bilirubin is a marker of protection against Coronary Heart Disease. Another strong pointer towards this trend is the lesser incidence of heart disease in patients with Gilbert's syndrome compared to general population (Atherosclerosis 2002)


This benefit has been explained on the basis of the antioxidant property of Bilirubin. It might prevent oxygen radicals from damaging the endothelium, and it also prevents oxidation of LDL particles. Bot these effects can explain a lower incidence of Ischemic heart disease in this population. Well....if this idea is true....then it should protect against stoke as well. 


Stroke & bilirubin - A 30% risk reduction in incidence of carotid plaques was found in patients with their bilirubin the highest quartile compared to bilirubin in lowest quartile (Stoke 2001).  recent study published in Stroke 2009 ...studying nearly 80,000 healthy patients showed a 20% risk reduction in ISCHEMIC stroke in patients with high bilirubin levels.
Aaand...it doesnt stop here! Another study from Annals of Hepatology published in 2008 showed that a 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of peripheral vascular disease (PAD). The benefit was noticed more in men than women. Another article in JAMA 2007 comparing diabetic pts with Gilbert's syndrome to normal people...showed a a significantly lower prevalence of hypertension, HbA1c, LDLl, total cholesterol, and triglyceride,CRP and higher levels of HDL. They also had a lower incidence of proteinuria as well (have a look at the table). Very recently ,an article in Kidney International (Oct 2010) shows that in rats who had hereditary hyperbilirubnemia had lower incidence of diabetic nephropathy.


It may be difficult to prove whether high bilirubin is an effect of body's need for an antioxidant...or it does genuinely protect against atherosclerosis. But bilirubin seems to offer a definite protection, and could be used as a reasonably good marker of vascular events. The main hindrance to bilirubin's use is that we cannot modify its level...to attain any of these benefits. A level just around upper limit of normal( upto 2.5 x normal in GS) would be the level talked about in the studies.