BACKGROUND: Although bilirubin is a proven antioxidant substance and a protective factor against the development of various diseases, in emergency medicine, its increased concentration is considered solely a marker of organ damage and negative prognosis. However, clinical data on the role of bilirubin in cardiac arrest (CA) and reperfusion injury, are sparse. The presented study investigates the protective effects of increased serum bilirubin concentrations and genetic determinants (UGT1A1 promoter variations) on the outcomes of patients with refractory out-of-hospital CA (r-OHCA) in a randomized population. METHODS: Between March 1, 2013, and October 25, 2020, 256 randomized Prague OHCA patients with r-OHCA were evaluated for inclusion and categorized as having increased (>10 µmol/l) or low/normal serum bilirubin concentrations on hospital arrival and present or absent genetic variations for mild hyperbilirubinemia. The primary outcome was survival with a good neurological outcome (defined as cerebral performance category 1-2) 180 days after randomization. RESULTS: Finally, 164 patients were included in the bilirubin concentration analysis. Favorable neurological survival after 180 days occurred in 50 of 99 patients (50.5 %) in the group with higher initial serum bilirubin concentrations and 18 of 65 patients (27.7 %) in the low-bilirubin group (absolute difference 22.8 [8.1-37.5]; P = 0.006). The effect persisted also in multivariable analysis (OR for favorable outcome = 3.02 [95 % CI = 1.16-7.84]; P = 0.023). Genetic predisposition for mild hyperbilirubinemia was not associated with any patient outcomes. CONCLUSIONS: A higher initial serum bilirubin concentration predicts better outcomes in patients with refractory OHCA regardless of the treatment used. UGT1A1 gene promotor variations are not associated with refractory OHCA patient outcomes.

• Keywords
• Antioxidants, Bilirubin, Cardiac arrest, Genetic variations, Mechanical circulatory support, Oxidative stress,
• Publication type
• Journal Article MeSH

Bilirubin has potent biological beneficial effects, protecting against atherosclerosis, obesity, and metabolic syndrome. The aim of this study was to assess serum bilirubin concentrations and (TA)n and (GT)n microsatellite variations in the promoter regions of the UGT1A1 and HMOX1 genes, respectively, in patients with type 2 diabetes mellitus (T2DM). The study was carried out in 220 patients with T2DM and 231 healthy control subjects, in whom standard biochemical tests were performed. The (TA)n and (GT)n dinucleotide variations were determined by means of fragment (size-based) analysis using an automated capillary DNA sequencer. Compared to controls, both male and female patients with T2DM had lower serum bilirubin concentrations (9.9 vs. 12.9 μmol/L, and 9.0 vs. 10.6 μmol/L, in men and women, respectively, p < 0.001). Phenotypic Gilbert syndrome was much less prevalent in T2DM patients, as was the frequency of the (TA)7/7UGT1A1 genotype in male T2DM patients. (GT)nHMOX1 genetic variations did not differ between diabetic patients and controls. Our results demonstrate that the manifestation of T2DM is associated with lower serum bilirubin concentrations. Consumption of bilirubin due to increased oxidative stress associated with T2DM seems to be the main explanation, although (TA)n repeat variations in UGT1A1 partially contribute to this phenomenon.

• Keywords
• Gilbert syndrome, HMOX1, UGT1A1, benign hyperbilirubinemia, bilirubin, heme oxygenase, type 2 diabetes mellitus,
• MeSH
• Bilirubin metabolism   MeSH
• Diabetes Mellitus, Type 2 * genetics   MeSH
• Genotype MeSH
• Glucuronosyltransferase genetics   metabolism   MeSH
• Heme Oxygenase-1 genetics   metabolism   MeSH
• Humans MeSH
• Polymorphism, Genetic * MeSH
• Promoter Regions, Genetic MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic epidemiology   MeSH
• Names of Substances
• Bilirubin MeSH
• Glucuronosyltransferase MeSH
• Heme Oxygenase-1 MeSH
• HMOX1 protein, human MeSH Browser

Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent immunosuppressive effects associated with long-term pathophysiological sequelae. It has been recently recognized as a hormone with endocrine actions and interconnected effects on various cellular signaling pathways. Current studies show that bilirubin also decreases adiposity and prevents metabolic and cardiovascular diseases. All in all, the physiological importance of bilirubin is only now coming to light, and strategies for increasing plasma bilirubin levels to combat chronic diseases are starting to be considered. This review discusses the beneficial effects of increasing plasma bilirubin, incorporates emerging areas of bilirubin biology, and provides key concepts to advance the field.

• Keywords
• BVRA, Blvra, HO-1, Hmox1, bilirubin, cardiovascular disease, cell signaling, heme oxygenase, metabolism, nuclear receptors,
• MeSH
• Bilirubin * metabolism   pharmacology   MeSH
• Heme Oxygenase-1 metabolism   MeSH
• Cardiovascular Diseases * MeSH
• Humans MeSH
• Reactive Oxygen Species metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Bilirubin * MeSH
• Heme Oxygenase-1 MeSH
• Reactive Oxygen Species MeSH

OBJECTIVES: Bilirubin is a potent endogenous antioxidant and immunomodulating substance, which is also implicated in both cell signalling and various metabolic pathways. Mild elevation of systemic bilirubin concentrations provides substantial protection against many diseases of civilization. Rare published reports have suggested that serum bilirubin might also be relevant to sports performance. The purpose of the current study was to evaluate serum bilirubin concentrations and the prevalence of Gilbert syndrome (GS) in elite athletes. METHODS: The study was carried out in 536 consecutive healthy elite athletes and in 2594 individuals of the Czech post-MONICA study representing the general Czech population. Serum bilirubin concentrations, the prevalence of benign hyperbilirubinemia > 17 µmol/L (1 mg/dL, a phenotypic sign of GS), and a variant of the UGT1A1 gene promoter responsible for GS manifestation in Caucasians (rs81753472) were evaluated in study subjects. RESULTS: Compared to the general Czech population, significantly higher serum bilirubin concentrations were found in elite athletes (9.6 vs. 11.6 µmol/L, p < 0.001), both in men (11.3 vs. 12.6 µmol/L, p < 0.001) and women (8.3 vs. 10.5 µmol/L, p < 0.001). Furthermore, the prevalence of GS was also significantly higher in elite athletes (9.6 vs. 22%, p < 0.001) together with the tendency to higher frequencies of the genotypes (TA)7/7 and (TA)6/7 UGT1A1. CONCLUSION: Elite athletes have significantly higher concentrations of serum bilirubin, the most potent endogenous antioxidant substance known. Simultaneously, the prevalence of GS syndrome is also much higher in elite athletes, suggesting that a mild elevation of serum bilirubin might predispose to better sports performance.

• Keywords
• Bilirubin, Elite athletes, Gene predisposition, Gilbert syndrome, Sports performance, UGT1A1 gene promoter,
• Publication type
• Journal Article MeSH