Stojanov M, Stefanovic A, Dzingalasevic G, Ivanisevic J, Miljkovic M, Mandic-Radic S, Prostran M. Total bilirubin in young men and women: association with risk markers for cardiovascular diseases. They also re-confirmed the inverse association of bilirubin with CAD severity [spearmans rank correlation coefficient (r) = -0.173, P < 0.001]. Wallner, M. et al. Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Schwertner et al[26] was the first to report this protective effect of high level of bilirubin in CAD. In this article, we review the current literature exploring the association between levels of bilirubin and risk of CAD. This anti-inflammatory effect has been hypothesized to antagonize the process of atherosclerosis, which is a low-grade chronic inflammatory state; (5) preclinical studies on mice have demonstrated a protective effect of bilirubin on angiotensin-II induced hypertension. Bethesda, MD 20894, Web Policies Heme oxygenase modulates selectin expression in different regional vascular beds. After adjustment for other risk factors, bilirubin was found to be an independent protective factor with an odds ratio of 0.25 (P = 0.001) for an increase of 1 mg/dL. A causal relationship between low serum bilirubin level and increased risk of CAD is not currently established. The low bilirubin levels were found to be significantly associated to CAD whereas UGTA1A polymorphisms were not, with odds ratio of 0.9 (CI: 0.86-0.94, P = 2.6 10-6) for men and 0.77 (CI: 0.68-0.87, P = 3.2 10-5) for women respectively for each 0.1mg/dl increase in bilirubin levels[37]. Dark urine. Second, low bilirubin levels can be indicative of decreased heme oxygenase activity (a powerful anti-oxidant) or could be indicative of high oxidative stress in patients leading to consumption of the natural anti-oxidants including bilirubin. This anti-oxidative effect of bilirubin is amplified by the recycling of bilirubin to biliverdin and so forth via redox reactions (Figure (Figure11)[3]. 2000 Oct;16(4):297-306. doi: 10.1002/1098-1004(200010)16:4<297::AID-HUMU2>3.0.CO;2-Z. Hematologically important mutations: bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler-Najjar syndromes. Received 2016 Apr 2; Revised 2016 Jun 7; Accepted 2016 Aug 27. Fifty percent reduction in total bilirubin was associated with 47% increased odds of CAD, both univariate and multivariate after adjustment for other risk factors[26]. Hsieh CJ, Chen MJ, Liao YL, Liao TN. This protective effect, in conjunction with carbon monoxide, by inhibition of angiotensin-II has also been suggested and extrapolated in the cardiomyocytes preventing left ventricular hypertrophy[21-23]; and (6) Bilirubin has also been described to solubilize cholesterol and promotes its clearance through the bile[24,25]. Wei S, Gao C, Wei G, Chen Y, Zhong L, Li X. Another autosomal recessive disorder, in which patients have multiple defects in hepatocyte uptake and excretion of bilirubin, leads to increase in conjugated bilirubin and is called Rotor syndrome. A case-control design was set up (n = 135; cases = 61, controls = 74) and although bilirubin levels in the control group were found to be significantly higher than CAD group, no significant differences were observed in the polymorphism of UGTA1A between the two groups. Gilbert syndrome - Symptoms & causes - Mayo Clinic UGT1A1*28 allele and coronary heart disease: the Rotterdam Study. Epub 2012 Feb 9. government site. WebGilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin Serum bilirubin has been shown to be 8600 Rockville Pike Patients with Gilbert have otherwise normal serum liver chemistries[6]. In this review, we will focus primarily on the association of serum bilirubin and CVD and the possible protective roles of bilirubin, heme oxygenase (HO), and bilirubin UDP-glucuronosyltransferase (UGT1A1). official website and that any information you provide is encrypted Gilbert's syndrome - Wikipedia Liao SL. The study included 1115 subjects who underwent CTA for evaluation of CAD. Patients with familial CAD had significantly lower bilirubin concentration as compared to controls (8.9 6.1 micromol/L vs 12.4 8.1 micromol/L, P = 0.0001). Before Patients with Criggler Najjar Type 1 develop severe neurological impairment and carry a high early mortality unless they receive liver transplantation. Hence, indicating that increased bilirubin levels and not genetic polymorphisms are associated with reduced risk of CAD. Acet H, Ert F, Akl MA, Polat N, Aydn M, Akyz A, Ayiek H, Alan S. A novel predictor of infarct-related artery patency before percutaneous intervention and in-hospital outcomes for ST-segment elevation myocardial infarction patients: serum bilirubin level. Clipboard, Search History, and several other advanced features are temporarily unavailable. Lingenhel A, Kollerits B, Schwaiger JP, Hunt SC, Gress R, Hopkins PN, Schoenborn V, Heid IM, Kronenberg F. Serum bilirubin levels, UGT1A1 polymorphisms and risk for coronary artery disease. Bethesda, MD 20894, Web Policies UGT1A1 polymorphism was strongly associated with bilirubin concentration in both patients and controls. They hypothesized the role of liver growth factor inhibition by bilirubin. 2001 Mar;33(3):627-32. doi: 10.1053/jhep.2001.22499. In that case, bilirubin might be looked upon as a marker of the drug activity. In 2013, Stojanov et al[31] reported cardioprotective effects of increased levels of bilirubin in 628 healthy subjects. WebWhat is Gilbert's syndrome? Bookshelf Besides vaso-relaxation, nitric oxide also inhibits leukocyte adhesion to endothelium, vascular smooth muscle cell migration and proliferation, platelet aggregation and neointimal formation[2,15]. Bilirubin is yellow liquid waste that occurs naturally as the body breaks Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. They predominantly mediate adhesion of platelets and inflammatory cells to endothelium and facilitate the formation of large stable platelet-leukocyte aggregates that can lead to thrombus formation. Association of Low Serum Bilirubin Concentrations and Promoter Variations in the. They observed a statistically significant inverse association between bilirubin and CAD. Less information is known about the protective effects of slightly elevated serum bilirubin concentrations. Routh JI. WebGilbert syndrome is associated with decreased cardiovascular health risks. Lin R, Wang Y, Wang Y, Fu W, Zhang D, Zheng H, Yu T, Wang Y, Shen M, Lei R, et al. Federal government websites often end in .gov or .mil. By virtue of these properties, bilirubin was hypothesized to have a protective effect in coronary artery disease (CAD)[4]. FOIA Heme oxygenase-1: unleashing the protective properties of heme. Type 1 Crigler Najjar is a rare and lethal recessive disorder compared to type 2 Crigler Najjar where the UGT1A1 activity is still maintained, albeit at a minimal level[7]. Disclaimer. Role of heme oxygenase in preserving vascular bioactive NO. Ndisang JF, Jadhav A. Upregulating the heme oxygenase system suppresses left ventricular hypertrophy in adult spontaneously hypertensive rats for 3 months. This site needs JavaScript to work properly. Authors interpreted that the relationship between bilirubin and CAD was unlikely causal. Song YS, Koo BK, Cho NH, Moon MK. Eleven relevant studies were used for analysis and the subjects involved were males. WebGilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Furthermore, the in-hospital mortality and major adverse cardiac events were significantly higher in the high total bilirubin group (P = 0.002, P < 0.001 respectively). Kundur et al[3] showed that when unconjugated bilirubin is added to platelet rich plasma at concentrations seen in Gilbert syndrome (0.99-5.85 mg/dL), it inhibits both - collagen induced and adenosine diphosphate induced platelet aggregation, in a dose dependent fashion for the latter. Whereas, patients with wild type allele, i.e., normal genotype have normal levels of bilirubin. Inconsistent results further support the need for further exploration of the underlying mechanisms and a prospective study with a high power to establish a definite causal relationship between bilirubin levels and CAD. Increased serum bilirubin level is related to good collateral development in patients with chronic total coronary occlusion. Contrary to the evidence presented above, several studies have negated the protective effect of bilirubin on CAD. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Gilbert An inverse association has been demonstrated between total bilirubin levels and the markers of inflammation, namely, C-reactive protein (direct marker); neutrophil to lymphocyte ratio and red cell distribution width (indirect markers)[17]. moc.liamg@78atpugycnanrd, Telephone: +1-914-5361563 Fax: +1-914-4935827. Akboga et al[17] conducted another study evaluating anti-inflammatory properties of bilirubin. Inclusion in an NLM database does not imply endorsement of, or agreement with, Int J Mol Sci. Because of the health and therapeutic implications of slightly elevated serum bilirubin concentrations, we will discuss the recent prospective studies on cardiovascular risk in individuals with Gilbert syndrome (GS) as well as those with the UGT1A1*28 allele. However, no such significant correlation was demonstrated between total bilirubin and the Gensini score. Fundamentals of clinical chemistry; pp. This reaction leads to production of bilirubin and carbon monoxide; hence an increased bilirubin level is associated with increased attenuation of superoxide production[20]. Polymorphisms of the uridine-diphosphoglucuronosyltransferase 1A1 gene and coronary artery disease. This U-shaped association was suggested as being due to reduced endogenous antioxidants with insufficient dietary intake[41]. These findings support the evidence of an anti-oxidant effect of bilirubin secondary to inverse association with ox-LDL and anti-inflammatory effect secondary to direct correlation with albumin, which is a negative acute phase reactant in inflammatory response[31]. Wei et al[30] also showed similar results with a significant inverse correlation between CAD and total bilirubin (n = 1260) in patients who underwent coronary angiography. Rantner B, Kollerits B, Anderwald-Stadler M, Klein-Weigel P, Gruber I, Gehringer A, Haak M, Schnapka-Kpf M, Fraedrich G, Kronenberg F. Association between the UGT1A1 TA-repeat polymorphism and bilirubin concentration in patients with intermittent claudication: results from the CAVASIC study. Higher serum bilirubin levels were associated with good collateral development as compared to poor collateral development (0.80 0.27 mg/dL vs 0.53 0.19 mg/dL, P < 0.001). However, an important point to note is that the study did not exclude patients with elevated markers of hepatocellular injury thus making the true relationship between isolated elevated bilirubin levels and CAD difficult to interpret. They divided them into 3 groups based on Gensini scores: No CAD (control group, n = 380), mild CAD (n = 497) and severe CAD (n = 624), with the objective of establishing anti-inflammatory effects of bilirubin in addition to its anti-oxidant effects.

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