A protective association between bilirubin and atherosclerosis/ischemic heart disease clearly exists in vivo. However, the relationship between bilirubin and in vivo oxidative stress parameters in a clinical population remains poorly described. The aim of this study was to assess whether persons expressing Gilbert syndrome (GS; i.e., unconjugated hyperbilirubinemia) are protected from thiol oxidation and to determine if this, in addition to their improved lipoprotein profile, could explain reduced oxidized low-density lipoprotein (oxLDL) status in them. Forty-four matched GS and control subjects were recruited and blood was prepared for the analysis of lipid profile and multiple plasma antioxidants and measures of oxidative stress. GS subjects possessed elevated plasma reduced thiol (8.03±1.09 versus 6.75±1.39 nmol/mg protein; P <0.01) and glutathione concentrations (12.7±2.39 versus 9.44±2.45 μM; P <0.001). Oxidative stress status (reduced:oxidized glutathione; GSH:GSSG) was significantly improved in GS (0.49±0.16 versus 0.32±0.12; P <0.001). Protein carbonyl concentrations were negatively associated with bilirubin concentrations and were significantly lower in persons with >40 μM bilirubin versus controls (<17.1 μmol/L; P <0.05). Furthermore, absolute oxLDL concentrations were significantly lower in GS subjects ( P <0.05). Forward stepwise regression analysis revealed that bilirubin was associated with increased GSH:GSSG ratio and reduced thiol concentrations, which, in addition to reduced circulating LDL, probably decreased oxLDL concentrations within the cohort. In addition, a marked reduction in total cholesterol concentrations in hyperbilirubinemic Gunn rats is presented (Gunn 0.57±0.09 versus control 1.69±0.40 mmol/L; P <0.001), arguing for a novel role for bilirubin in modulating lipid status in vivo. These findings implicate the physiological importance of bilirubin in protecting from atherosclerosis by reducing thiol and subsequent lipoprotein oxidation, in addition to reducing circulating LDL concentrations.

Background: Fluid resuscitation is widely considered a life saving intervention in septic

Unconjugated bilirubin is an endogenous circulating antioxidant, bound to albumin, and therefore is retained in the vascular compartment. Bilirubin has well-documented neurotoxic effects in infants; however, current evidence indicates mildly elevated bilirubin is associated with protection from cardiovascular disease and all-cause mortality in adults. Recent clinical studies show mildly elevated bilirubin is associated with protection from kidney damage and dysfunction, in addition to cardiovascular events and all-cause mortality in patients undergoing hemodialysis. This is the first review to examine the clinical evidence and summarize the potential mechanisms of action that link bilirubin to protection from kidney damage, subsequent kidney failure, and dialysis-related mortality. With this understanding, it is hoped that new therapies will be developed to prevent renal dysfunction and mortality from cardiovascular disease in at-risk individuals.