Guan B, Yang M, Shen X, Wang Y, Liu Y, Liu R, Li S, Cao J. 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]. Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects. A similar effect has been seen in pre-clinical studies in rats, which showed a protective effect of elevated bilirubin on left ventricular hypertrophy in spontaneously hypertensive rats. However, the association between bilirubin levels > 0.8 mg/dL and the incidence of CAD was not statistically significant (OR = 0.68, CI: 0.34-1.39, P = 0.29). Heme oxygenase-1 inhibits angiotensin II-induced cardiac hypertrophy in vitro and in vivo. WebBackground and aims: Gilbert's syndrome is a common familial hyperbilirubinemia that may reduce the risk of various age-related diseases because of the antioxidant properties of Canpolat U, Aytemir K, Yorgun H, Hazrolan T, Kaya EB, ahiner L, Sunman H, Tokgzolu L, Kabakc G, Oto A. Heme oxygenase-1: unleashing the protective properties of heme. Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Despite its inconvenient nature, Gilbert syndrome may have a protective effect regarding cardiovascular disease, given that bilirubin is a potent antioxidant. Although few studies have reported an inverse association between bilirubin and the risk of CAD, no such association was seen with UGT1A1 gene polymorphism and the risk of CAD. Li Volti G. Letter regarding article by Hu et al, heme oxygenase-1 inhibits angiotensin II-induced cardiac hypertrophy in vitro and in vivo. Gilbert syndrome (Meulengracht disease, constitutional hepatic dysfunction, and familial nonhemolytic jaundice) is a benign condition characterized by recurrent Patients with critical stenosis (> 50% obstruction) had lower bilirubin levels compared to non-critical stenosis (0.57 0.18 mg/dL vs 0.70 0.24 mg/dL, P < 0.001). MeSH Bilirubin, Cytotoxic, Protective, Anti-oxidant, Anti-inflammatory, Anti coronary artery disease, Lipid peroxidation, Gilbert. WebGilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin Serum bilirubin has been shown to be Bilirubin and coronary heart disease risk in the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. ''Iatrogenic Gilbert syndrome''--a strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin. Liver function. Bilirubin increases in response to the oxidative stress and acts as a scavenger of the reactive oxygen species[9,10]. Hemoglobin is broken down into heme pigment and globin chains. Lin R, Wang Y, Wang Y, Fu W, Zhang D, Zheng H, Yu T, Wang Y, Shen M, Lei R, et al. 2006 Jan-Feb;36(1):77-80. doi: 10.1016/j.bcmd.2005.10.006. World Journal of Gastrointestinal Pharmacology and Therapeutics. 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]. Gilbert (zheel-BAYR) syndrome is a common, harmless liver condition in which the liver doesn't properly process bilirubin. In this article, we review the current literature exploring the association between levels of bilirubin and risk of CAD. 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. Clin Sci 125 , Hemoglobin is cleaved to yield globin and heme (red). As a library, NLM provides access to scientific literature. Also, Grosser et al[47-49] have reported induction of heme oxygenase with statin and aspirin therapy. The relation between serum bilirubin levels and severity of atherosclerosis had a spearman rank coefficient of r = -0.31 (P < 0.0001). Biliverdin is further degraded by biliverdin reductase into unconjugated bilirubin. Patients with any coronary plaque were observed to have statistically significant lower levels of serum bilirubin (P = 0.002). government site. Decreased levels of nitric oxide impair the ability of the coronary vessels to dilate during exercise or stress, thus, provoking myocardial ischemia in patients with CAD[14]. In the PRIME study, 216 individuals who had developed CAD at 5-year follow up were designated as cases, and 434 individuals as matched controls. Meta-analysis of existing studies has also confirmed that serum bilirubin concentrations are inversely related to CVD. An official website of the United States government. and transmitted securely. Subsequently, in another study by Erdogan et al[29] in 2012, 179 patients undergoing angiography were analyzed to evaluate for CAD. Lin JP, ODonnell CJ, Schwaiger JP, Cupples LA, Lingenhel A, Hunt SC, Yang S, Kronenberg F. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. They found that the relative risk of myocardial infarction (MI) for heterozygous genotype was 0.9 (95%CI: 0.7-1.3) and with homozygous UGT1A1*28 was 1.3 (95%CI: 0.8-2.2). moc.liamg@78atpugycnanrd, Telephone: +1-914-5361563 Fax: +1-914-4935827. 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]. Yellowing of the Author contributions: All authors contributed to the manuscript; Gupta N, Singh T and Chaudhary R have contributed equally for the paper. These properties potentially confer bilirubin a new role of protection especially in coronary artery disease (CAD), which is a low grade inflammatory process exacerbated by oxidative stress. Heme is enzymatically converted to biliverdin (green) by liberating iron, via oxidation with loss of a carbon atom (CO). Novotn L, Vtek L. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Mutations in the gene that affects this transport protein leads to conjugated hyperbilirubinemia. Thus, patients with UGT1A1*28 allele have shown to have higher levels of bilirubin[35]. Heme pigment is oxidatively metabolized by heme oxygenase into biliverdin, carbon monoxide and free iron. This anti-oxidative effect of bilirubin is amplified by the recycling of bilirubin to biliverdin and so forth via redox reactions (Figure (Figure11)[3]. Breimer LH, Wannamethee G, Ebrahim S, Shaper AG. British Regional Health Study (BRHS) was a prospective study designed to examine the relationship between the level of bilirubin and risk of ischemic CAD. Less information is known about the protective effects of slightly elevated serum bilirubin concentrations. Such individuals have decreased hepatic bilirubin UDP-glucuronosyltransferase activity, decreased bilirubin clearance, and increased serum bilirubin concentrations. Arterial stiffness and central arterial wave reflection are associated with serum uric acid, total bilirubin, and neutrophil-to-lymphocyte ratio in patients with coronary artery disease. In animal models, bilirubin has also been seen to exhibit anti-complement effect in vitro, thus, conferring protection against increased thrombogenicity and clot formation[3,17-19]. Bates EA, Kipp ZA, Martinez GJ, Badmus OO, Soundarapandian MM, Foster D, Xu M, Creeden JF, Greer JR, Morris AJ, Stec DE, Hinds TD Jr. Biomolecules. Patients with Gilbert have otherwise normal serum liver chemistries[6]. 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). In fact, recent literature reports an inverse relationship between serum concentration of bilirubin and the presence of CAD. Wei S, Gao C, Wei G, Chen Y, Zhong L, Li X. Vachharajani TJ, Work J, Issekutz AC, Granger DN. As mentioned above, a lack of significant association between the gene polymorphisms of UGT1A1 and risk for CAD goes in favor of bilirubin being a marker than a primary mediator for the cardioprotective effects observed with CAD. HHS Vulnerability Disclosure, Help sharing sensitive information, make sure youre on a federal However, no association was seen between low serum bilirubin and the risk for CAD[36]. It has also been suggested to have a lipid lowering effect by reducing plasma and low-density lipid peroxidation[3]. First, it is possible that the protective effects seen with higher bilirubin levels are possibly mediated through heme oxygenase or by other substrates involved in the pathway of bilirubin production, namely, biliverdin and carbon monoxide. and transmitted securely. eCollection 2023. Cecil textbook of medicine. the contents by NLM or the National Institutes of Health. Neuzil J, Stocker R. Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. doi: 10.1136/bmjopen-2022-064433. Abdominal discomfort. Biliverdin reductase: a major physiologic cytoprotectant. Schwertner et al[26] was the first to report this protective effect of high level of bilirubin in CAD. Would you like email updates of new search results? In fact, recent literature reports an inverse relationship between serum concentration of bilirubin and the presence of CAD. doi: 10.1016/j.atherosclerosis.2008.01.001. Hepatology. Song YS, Koo BK, Cho NH, Moon MK. It may be Hunt SC, Kronenberg F, Eckfeldt JH, Hopkins PN, Myers RH, Heiss G. Association of plasma bilirubin with coronary heart disease and segregation of bilirubin as a major gene trait: the NHLBI family heart study. Kang SJ, Lee C, Kruzliak P. Effects of serum bilirubin on atherosclerotic processes. The site is secure. 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. Of note, unconjugated bilirubin in concentrations as low as 10 nmol/L has been reported to protect neuronal cultures from the oxidative stress generated by 10000 times higher concentrations of hydrogen peroxide[11]. This case-control study enlisted 477 patients with premature, familial CAD and 619 controls that were matched for age and gender. Gilbert syndrome, also known as constitutional hepatic dysfunction or familial nonhemolytic jaundice, is an inherited disorder of the liver that results in an overabundance Bilirubin levels were found to be significantly lower in the familial CAD group as compared to the controls (P = 1.2 10-10 in men and 1.9 10-9 in women). 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. HHS Vulnerability Disclosure, Help 775778. Contrary to the evidence presented above, several studies have negated the protective effect of bilirubin on CAD. 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. This, in turn, yields bilirubin (orange) after enzymatic reduction of biliverdin. Acet et al[42] investigated patients (n = 360) undergoing percutaneous coronary intervention (PCI) within 12 h of symptom onset with the aim to establish a relation between bilirubin levels and infarct-related artery patency in the setting of ST-segment elevation myocardial infarction (STEMI). FOIA Careers, Unable to load your collection due to an error. 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. Tannd A, Erkan AF, Alhan A, Tre HF. The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). To understand the true role of bilirubin it is prudent to look into the association between UGT1A1*28 and CAD. Establishing an inverse association between the two would strengthen the hypothesis of bilirubin being protective in CAD. Association between bilirubin levels and risk of stroke: a systematic review and meta-analysis. The group with elevated total bilirubin was seen to have higher impaired flow (defined as pre-PCI TIMI 2 flow) than normal flow (Pre-PCI TIMI > 3) (P < 0.001).
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