16th ed. Contrary to the evidence presented above, several studies have negated the protective effect of bilirubin on CAD. Diagnosis. British Regional Health Study (BRHS) was a prospective study designed to examine the relationship between the level of bilirubin and risk of ischemic CAD. They observed a statistically significant inverse association between bilirubin and CAD. This site needs JavaScript to work properly. National Library of Medicine Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Laboratory tests in liver disease. Heme oxygenase (the rate-limiting enzyme in bilirubin production) also functions as a vasodilatory and anti- proliferative agent during vascular injury[15]. Ayaz et al[43] reported an independent positive association between bilirubin and left ventricular mass/hypertrophy in a population with untreated hypertension (n = 114). WebJaundice can cause other symptoms such as: Nausea and diarrhea. However, the association between the incidence of myocardial infarction (MI) and gene polymorphism was not significant although the trend was similar. Before They compared 619 subjects in training set (complete data on all risk factors considered was available) vs 258 subjects in test set (some risk factor data was not available). Erdogan T, Ciek Y, Kocaman SA, Canga A, Cetin M, Durakoglugil E, Satiroglu O, Temiz A, Ergl E, Sahin I, et al. Liver function. Mahabadi AA, Lehmann N, Mhlenkamp S, Klsch H, Bauer M, Schulz R, Moebus S, Jckel KH, Erbel R, Heusch G. Association of bilirubin with coronary artery calcification and cardiovascular events in the general population without known liver disease: the Heinz Nixdorf Recall study. 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. These findings suggest a possible protective effect of elevated serum bilirubin levels against myocardial ischemia in patients with chronic total coronary occlusion with collaterals limiting infarct size and providing additional blood flow to the ischemic area[29]. They hypothesized the role of liver growth factor inhibition by bilirubin. Meta-analysis of existing studies has also confirmed that serum bilirubin concentrations are inversely related to CVD. Subsequently, in another study by Erdogan et al[29] in 2012, 179 patients undergoing angiography were analyzed to evaluate for CAD. 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. Eleven relevant studies were used for analysis and the subjects involved were males. But its worse in babies born 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). Impaired Bilirubin Conjugation - StatPearls - NCBI Bookshelf Cecil textbook of medicine. 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). Out of them, 110 patients had good collateral formation and 69 had poor collateral development. Thus, preservation of nitric oxide offers a significant protection against atherosclerosis[12]; (3) Bilirubin has also been seen to reduce platelet aggregation. A similar U-shaped relationship between serum bilirubin level and risk of developing CAD was observed in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. Correspondence to: Nancy Gupta, MD, Department of Medicine, Westchester Medical Center, New York Medical College, 40 Sunshine Cottage Rd, Valhalla, NY 10595, United States. Bilirubin is produced by the breakdown of red blood The https:// ensures that you are connecting to the After performing a linear and logistical regression, total bilirubin (P = 0.011) was shown to be an independent risk factor for CAD. Vtek L, Jirsa M, Brodanov M, Kalab M, Marecek Z, Danzig V, Novotn L, Kotal P. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Bilirubin and coronary heart disease risk in the Prospective Epidemiological Study of Myocardial Infarction (PRIME). 2012 Mar 15;48(3):166-72. doi: 10.1016/j.bcmd.2012.01.004. This, in turn, yields bilirubin (orange) after enzymatic reduction of biliverdin. Gilbert syndrome - UpToDate the contents by NLM or the National Institutes of Health. Hsieh et al[38] sought to explore the association of UGTA1A polymorphisms with risk of CAD development. Role of heme oxygenase in preserving vascular bioactive NO. 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). Routh JI. Kundur AR, Singh I, Bulmer AC. In a retrospective cross-sectional study, they included 1501 patients who underwent coronary angiography. This leads to deficiency of the enzyme that leads to accumulation of unconjugated bilirubin within the blood[4]. 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). 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 WebGilbert (zheel-BAYR) syndrome is a common, harmless liver condition in which the liver doesn't properly process bilirubin. Grosser N, Erdmann K, Hemmerle A, Berndt G, Hinkelmann U, Smith G, Schrder H. Rosuvastatin upregulates the antioxidant defense protein heme oxygenase-1. Epub 2007 Sep 6. This recycling of bilirubin amplifies its anti-oxidant potential up to 10000 times; (2) Bilirubin has been shown to be inversely associated with increased arterial stiffness[12,13]. Int J Mol Sci. Hence, indicating that increased bilirubin levels and not genetic polymorphisms are associated with reduced risk of CAD. Gilbert syndrome, also known as constitutional hepatic dysfunction or familial nonhemolytic jaundice, is an inherited disorder of the liver that results in an overabundance Epub 2012 Feb 9. Song YS, Koo BK, Cho NH, Moon MK. To understand the true role of bilirubin it is prudent to look into the association between UGT1A1*28 and CAD. Please enable it to take advantage of the complete set of features! Individuals with bilirubin levels < 0.33 mg/dL and > 0.8 mg/dL were seen to have higher incidence of development of CAD, even after adjustment of other risk factors. Relton CL, Davey Smith G. Two-step epigenetic Mendelian randomization: a strategy for establishing the causal role of epigenetic processes in pathways to disease. Several studies have suggested a cardioprotective role of bilirubin. Low bilirubin levels were shown to further increase the risk of CAD development six fold in patients with metabolic syndrome with HR of 2.016 (95%CI: 1.069-3.800, P = 0.030). 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. Association of serum total bilirubin level with severity of coronary atherosclerosis is linked to systemic inflammation. Med Hypotheses. Capillary Blood Recovery Variables in Young Swimmers: An Observational Case Study. This genetic variation involves insertion of an additional thymine-adenine base pair in the TATA box of the UGT1A1 gene instead of the normal 6 pairs[4,6] (Figure (Figure1).1). Later, Song et al[32] designed a prospective cohort study with 8593 subjects followed over a period of 4 years. Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). 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]. However, another condition called Crigler-Najjar syndrome with unconjugated hyperbilirubinemia stems from complete or near complete loss of UGT1A1 activity. In fact, recent literature reports an inverse relationship between serum concentration of bilirubin and the presence of CAD. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. ''Iatrogenic Gilbert syndrome''--a strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin. Kang SJ, Lee C, Kruzliak P. Effects of serum bilirubin on atherosclerotic processes. Gilbert's syndrome is a benign hereditary disease that affects the way bilirubin is processed in the liver and causes jaundice. Thus, a conclusion can be safely inferred that if at all bilirubin is protective in CAD, it is likely that bilirubin production (by induction of heme oxygenase and accompanied by production of carbon monoxide) and not just its excretion indirectly confers the protective effect observed with CAD. Unauthorized use of these marks is strictly prohibited. Before In a meta-analysis published in 2003 by Novotny et al[28] a significant inverse relationship was shown between serum bilirubin levels and the severity of atherosclerosis. By virtue of these properties, bilirubin was hypothesized to have a protective effect in coronary artery disease (CAD)[4]. Other symptoms The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Inclusion in an NLM database does not imply endorsement of, or agreement with, This condition is called Dubin-Johnson syndrome[8]. Disclaimer. Rodrigues C, Vieira E, Santos R, de Carvalho J, Santos-Silva A, Costa E, Bronze-da-Rocha E. Blood Cells Mol Dis. 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. Suppressing Hepatic UGT1A1 Increases Plasma Bilirubin, Lowers Plasma Urobilin, Reorganizes Kinase Signaling Pathways and Lipid Species and Improves Fatty Liver Disease. Common genetic disorder linked to increased death rate from 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. Heme oxygenase modulates selectin expression in different regional vascular beds. Hepatic uptake of organic anions affects the plasma bilirubin level in subjects with Gilbert's syndrome mutations in UGT1A1. 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). Fatigue. While the available evidence regarding the effects of bilirubin are not definitive and different studies provide contradictory findings, some useful conclusions can be drawn. Wei S, Gao C, Wei G, Chen Y, Zhong L, Li X. Yellowing of the 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. The benefits of elevated bilirubin were seen to be comparable to those of HDL. 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]. Tannd A, Erkan AF, Alhan A, Tre HF. Biliverdin modulates the expression of C5aR in response to endotoxin in part via mTOR signaling. Moreover, it also points out towards incomplete penetrance of the UGT1A1 gene. Fundamentals of clinical chemistry; pp. Features of an altered AMPK metabolic pathway in Gilberts eCollection 2023. 1n: Tietz NW (eds.). Bethesda, MD 20894, Web Policies 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. In another study, 221 patients who were evaluated for CAD by coronary angiography showed a moderate but significant positive correlation between direct bilirubin levels and the Gensini score (r = 0.158, P = 0.019). The https:// ensures that you are connecting to the and transmitted securely. 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]. Shortly after that study, Canpolat et al[18] used computed tomographic angiography (CTA) to evaluate the relationship between bilirubin levels and nature of coronary plaques. Impact of UGT1A1 gene variants on total bilirubin levels in Gilbert syndrome patients and in healthy subjects. Gilbert Syndrome - Disease Symptoms, Causes, Treatment Author contributions: All authors contributed to the manuscript; Gupta N, Singh T and Chaudhary R have contributed equally for the paper. Federal government websites often end in .gov or .mil. 2022 Jul 14;19(14):8580. doi: 10.3390/ijerph19148580. Genetically determined serum bilirubin level and the risk of heart failure: A mendelian randomization study. Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Breimer LH, Wannamethee G, Ebrahim S, Shaper AG. Heme oxygenase-1: unleashing the protective properties of heme. sharing sensitive information, make sure youre on a federal Akboga MK, Canpolat U, Sahinarslan A, Alsancak Y, Nurkoc S, Aras D, Aydogdu S, Abaci A. Authors interpreted that the relationship between bilirubin and CAD was unlikely causal. 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. Hsieh CJ, Chen MJ, Liao YL, Liao TN. 2023 Jun 25;24(13):10614. doi: 10.3390/ijms241310614. UGT1A1 polymorphism was strongly associated with bilirubin concentration in both patients and controls. Nowak R, Rj K, Ciechanowicz A, Lewandowska K, Kostrzewa-Nowak D. Int J Environ Res Public Health. In the present study, low prevalence of IHD in GS subjects was detected. 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. Schwertner et al[26] was the first to report this protective effect of high level of bilirubin in CAD. 2023 Jan 13;14:1067146. doi: 10.3389/fgene.2023.1067146. Epub 2005 Dec 28. The .gov means its official. Serum bilirubin has been shown to be inversely related to cardiovascular disease (CVD) in both retrospective and prospective studies. 2001 Mar;33(3):627-32. doi: 10.1053/jhep.2001.22499. Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Patient education: Gilbert syndrome (Beyond the Basics) Neuzil J, Stocker R. Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. Philadelphia: WB Saunders; 1982. pp. Gilbert Nancy Gupta, Sachin Sule, Department of Medicine, Westchester Medical Center, New York Medical College, Valhalla, NY 10595, United States, Tavankit Singh, Department of Medicine, Cleveland Clinic, Cleveland, OH 44195, United States, Rahul Chaudhary, Department of Medicine, Sinai Hospital of Baltimore, Johns Hopkins University, Baltimore, MD 21218, United States, Sushil K Garg, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, United States, Gurprataap Singh Sandhu, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, United States, Varun Mittal, Einstein Healthcare Network, Philadelphia, PA 19141, United States, Rahul Gupta, Government Medical College, Amritsar, Punjab 143001, India, Roxana Bodin, Division of Gastroenterology and Hepatobiliary Disease, New York Medical College, Valhalla, NY 10595, United States. WebWhat is Gilbert's syndrome? Strassburg CP. 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]. Clipboard, Search History, and several other advanced features are temporarily unavailable. Following its uptake by the hepatocytes, unconjugated bilirubin is converted to conjugated bilirubin by the action of uridine-diphosphoglucuronate glucuronosyltransferase (UDP-GT). Lingenhel et al[37] studied two polymorphisms in the promoter region of UGT1A1 gene to analyze whether UGTA1A gene polymorphisms or bilirubin levels are independently associated with risk of CAD development. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels - ScienceDirect Atherosclerosis Volume 160, Issue 2, February 2002, Pages Also, Grosser et al[47-49] have reported induction of heme oxygenase with statin and aspirin therapy. Bilirubin is produced by the breakdown of red This case-control study enlisted 477 patients with premature, familial CAD and 619 controls that were matched for age and gender. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. Common variants of four bilirubin metabolism genes and their association with serum bilirubin and coronary artery disease in Chinese Han population. Bilirubin is yellow liquid waste that occurs naturally as the body breaks
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