#PAGE_PARAMS# #ADS_HEAD_SCRIPTS# #MICRODATA#

Role of bilirubin in the prevention of cardiovascular diseases and cancer


Authors: prof. MUDr. Libor Vítek, Ph.D.;  Mba
Authors‘ workplace: Ústav lékařské biochemie a laboratorní diagnostiky 1. LF UK a VFN, U Nemocnice, Praha 2;  IV. interní klinika 1. LF UK a VFN : U Nemocnice, Praha 2
Published in: Čas. Lék. čes. 2016; 155: 64-68
Category: Review Articles

Overview

Oxidative stress contributes importantly to pathogenesis of numerous civilization diseases, including cardiovascular diseases, cancer, as well as autoimmune and neurodegenerative conditions. Bilirubin is the major product of the heme catabolic pathway in the intravascular compartment. For long time, bilirubin was considered to be only a waste product, however, recent data from the last two decades have proved its important protective properties, which contributes to defense against development of civilization diseases. Numerous experimental as well as clinical studies have demonstrated association between low bilirubin concentrations and cardiovascular diseases, as well as certain cancers. On the other hand, subjects with mildly elevated blood bilirubin levels, typical for Gilbert syndrome, have decreased risk of these diseases.

Keywords:
antioxidant, bilirubin, cancer, cardiovascular diseases, Gilbert syndrome, oxidative stress


Sources

1. Watchko JF, Tiribelli C. Bilirubin-induced neurologic damage-mechanisms and management approaches. N Engl J Med 2013; 369: 2021−2030.

2. Wagner KH, Wallner M., Molzer C et al. Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases. Clin Sci 2015; 129: 1−25.

3. Novotny L, Vitek L. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med 2003; 228: 568−571.

4. Jiraskova A, Novotny J, Novotny L et al. Association of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancer. Int J Cancer 2012; 131: 1549−1555.

5. Lenicek M, Duricova D, Hradsky O et al. The relationship between serum bilirubin and Crohn's disease. Inflamm Bowel Dis 2014; 20: 481−487.

6. Vitek L, Muchova L, Jancova E et al. Association of systemic lupus erythematosus with low serum bilirubin levels. Scand J Rheumatol 2010; 39: 480−484.

7. Vitek L, Novotna M, Lenicek M et al. Serum bilirubin levels and UGT1A1 promoter variations in patients with schizophrenia. Psychiatry Res 2010; 178: 449−450.

8. Lin JP, Vitek L, Schwertner HA. Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease. Clin Chem 2010; 56: 1535−1543.

9. Zucker SD, Horn PS, Sherman KE. Serum bilirubin levels in the US population: Gender effect and inverse correlation with colorectal cancer. Hepatology 2004; 40: 827−835.

10. Stocker R, Keaney JF. Role of oxidative modifications in atherosclerosis. Phys Rev 2004; 84: 1381−1478.

11. Wu TW, Fung KP, Yang CC. Unconjugated bilirubin inhibits the oxidation of human low density lipoprotein better than Trolox. Life Sci 1994; 54: 477−481.

12. Frei B, Stocker R, Ames BN. Antioxidant defenses and lipid peroxidation in human blood plasma. Proc Natl Acad Sci USA 1988; 85: 9748−9752.

13. Jangi S, Otterbein L, Robson S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin. Int J Biochem Cell Biol 2013; 45: 2843−2851.

14. Basiglio CL, Arriaga SM, Pelusa F et al. Complement activation and disease: protective effects of hyperbilirubinaemia. Clin Sci 2010; 118: 99−113.

15. Vitek L, Malikova I, Kvasnicka J et al. Relationship between serum bilirubin and markers of inflammation and oxidative stress. J Gastroenterol Hepatol 2007; 22: A235.

16. Nejedla Z. The development of immunological factors in infants with hyperbilirubinemia. Pediatrics 1970; 45: 102−104.

17. Rocuts F, Zhang X, Yan J et al. Bilirubin promotes de novo generation of T regulatory cells. Cell Transplant 2010; 19: 443−451.

18. Mazzone GL, Rigato I, Ostrow JD et al. Bilirubin inhibits the TNF alpha-related induction of three endothelial adhesion molecules. Biochem Biophys Res Commun 2009; 386: 338−344.

19. Hansen TW, Mathiesen SB, Walaas SI. Bilirubin has widespread inhibitory effects on protein phosphorylation. Pediatr Res 1996; 39: 1072−1077.

20. Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem 1994; 40: 18−23.

21. Schwertner HA, Fischer JR jr. Comparison of various lipid, lipoprotein, and bilirubin combinations as risk factors for predicting coronary artery disease. Atherosclerosis 2000; 150: 381−387.

22. Schwertner HA, Fischer JR. Combined cholesterol and bilirubin tests as risk predictors for coronary artery disease. USA Patent č. 6869802. 2005.

23. Vitek L, Jirsa M, Brodanova M et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 2002; 160: 449−456.

24. Vitek L, Novotny L, Sperl M et al. The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis. Cerebrovasc Dis 2006; 21: 408−414.

25. Wang HY, Han P, Zhang WH et al. Serum bilirubin level is negatively correlated with disease progression of peripheral arterial disease: an observational cohort study. Angiology 2012; 63: 248−253.

26. Cure E, Yuce S, Cicek Y, Cure MC. The effect of Gilbert's syndrome on the dispersions of QT interval and P-wave: an observational study. Anadolu Kardiyol Derg 2013; 13: 559−565.

27. Horsfall LJ, Rait G, Walters K et al. Serum bilirubin and risk of respiratory disease and death. J Am Med Assoc 2011; 305: 691−697.

28. Ghoorah K, De Soyza A, Kunadian V. Increased cardiovascular risk in patients with chronic obstructive pulmonary disease and the potential mechanisms linking the two conditions: a review. Cardiol Rev 2013; 21: 196−202.

29. Kayahan H, Sari I, Cullu N et al. Evaluation of early atherosclerosis in patients with inflammatory bowel disease. Dig Dis Sci 2012; 57: 2137−2143.

30. Scalzi LV, Ballou SP, Park JY et al. Cardiovascular disease risk awareness in systemic lupus erythematosus patients. Arthritis Rheum 2008; 58: 1458−1464.

31. Fischman D, Valluri A, Gorrepati VS et al. Bilirubin as a protective factor for rheumatoid arthritis: An NHANES study of 2003−2006 data. J Clin Med Res 2010; 2: 256−260.

32. Garcia-Gomez C, Bianchi M, de la Fuente D et al. Inflammation, lipid metabolism and cardiovascular risk in rheumatoid arthritis: A qualitative relationship? World J Orthop 2014; 5: 304−311.

33. Balta S, Balta I, Mikhailidis DP et al. Bilirubin levels and their association with carotid intima media thickness and high-sensitivity C-reactive protein in patients with psoriasis vulgaris. Am J Clin Dermatol 2014; 15: 137−142.

34. Coumbe AG, Pritzker MR, Duprez DA. Cardiovascular risk and psoriasis: beyond the traditional risk factors. Am J Med 2014; 127: 12−18.

35. Unsal C, Oran M, Tureli HO et al. Detection of subclinical atherosclerosis and diastolic dysfunction in patients with schizophrenia. Neuropsychiatr Dis Treat 2013; 9: 1531−1537.

36. Peng F, Deng X, Yu Y et al. Serum bilirubin concentrations and multiple sclerosis. J Clin Neurosci 2011; 18: 1355−1359.

37. Christiansen CF, Christensen S, Farkas DK et al. Risk of arterial cardiovascular diseases in patients with multiple sclerosis: a population-based cohort study. Neuroepidemiology 2010; 35: 267−274.

38. Bian LQ, Li RZ, Zhang ZY et al. Effects of total bilirubin on the prevalence of osteoporosis in postmenopausal women without potential liver disease. J Bone Miner Metab 2013; 31: 637−643.

39. Anagnostis P, Karagiannis A, Kakafika AI et al. Atherosclerosis and osteoporosis: age-dependent degenerative processes or related entities? Osteoporosis Int 2009; 20: 197−207.

40. Breslin E, Kaufmann A, Quenby S. Bilirubin influences the clinical presentation of pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 2013; 170: 111−113.

41. McDonald SD, Ray J, Teo K et al. Measures of cardiovascular risk and subclinical atherosclerosis in a cohort of women with a remote history of preeclampsia. Atherosclerosis 2013; 229: 234−239.

42. Bulmer AC, Ried K, Blanchfield JT, Wagner KH. The anti-mutagenic properties of bile pigments. Mutat Res 2008; 658: 28−41.

43. Wallner M, Antl N, Rittmannsberger B et al. Anti-genotoxic potential of bilirubin in vivo: damage to DNA in hyperbilirubinemic human and animal models. Cancer Prev Res (Phila) 2013; 6: 1056−1063.

44. Molzer C, Huber H, Steyrer A et al. Interaction between TNFone and tetrapyrroles may account for their anti-genotoxic effects – a novel mechanism for DNA-protection. J Porph Phthalocyan 2013; 17: 1157−1166.

45. Temme EHM, Zhang J, Schouten EG, Kesteloot H. Serun bilirubin and 10-year mortality risk in a Belgian population. Cancer Causes Control 2001; 12: 887−894.

46. Shatalova EG, Walther SE, Favorova OO et al. Genetic polymorphisms in human SULT1A1 and UGT1A1 genes associate with breast tumor characteristics: a case-series study. Breast Cancer Res 2005; 7: R909−R921.

47. Ajja R, Lee DC, Sui X et al. Usefulness of serum bilirubin and cardiorespiratory fitness as predictors of mortality in men. Am.J Cardiol 2011; 108: 1438−1442.

48. Fulks M, Stout RL, Dolan VF. Mortality associated with bilirubin levels in insurance applicants. J Insur Med 2009; 41: 49−53.

49. Horsfall LJ, Nazareth I, Pereira SP, Petersen I. Gilbert's syndrome and the risk of death: a population-based cohort study. J Gastroenterol Hepatol 2013; 28: 1643−1647.

50. McCarty MF. ''Iatrogenic Gilbert syndrome''- a strategy for reducing vascular and cancer risk by increasing plasma unconjugated bilirubin. Med Hypotheses 2007; 69: 974−994.

51. McCallum L, Panniyammakal J, Hastie CE et al. Longitudinal Blood Pressure Control, Long-Term Mortality, and Predictive Utility of Serum Liver Enzymes and Bilirubin in Hypertensive Patients. Hypertension 2015; 66: 37−43.

52. Li Y, Meng SY, Meng CC et al. Decreased serum bilirubin is associated with arterial stiffness in men. Nutr Metab Cardiovasc Dis 2013; 23: 375−381.

53. Yoshino S, Hamasaki S, Ishida S et al. Relationship between bilirubin concentration, coronary endothelial function, and inflammatory stress in overweight patients. J Atheroscler Thromb 2011; 18: 403−412.

54. Andersson C, Weeke P, Fosbol EL et al. Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: an analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial. Metabolism 2009; 58: 1109−1115.

55. Bulmer AC, Verkade HJ, Wagner KH. Bilirubin and beyond: a review of lipid status in Gilbert's syndrome and its relevance to cardiovascular disease protection. Prog Lipid Res 2013; 52: 193−205.

56. Dong H, Huang H, Yun X et al. Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation. Endocrinology 2014; 155: 818−828.

57. Guzek M, Jakubowski Z, Bandosz P et al. Inverse association of serum bilirubin with metabolic syndrome and insulin resistance in Polish population. Przegl Epidemiol 2012; 66: 495−501.

58. Vitek L. The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front Pharmacol 2012; 3: 55.

59. Kundur AR, Bulmer AC, Singh I. Unconjugated bilirubin inhibits collagen induced platelet activation. Platelets 2014; 25: 45−50.

60. Cure MC, Cure E, Kirbas A et al. The effects of Gilbert's syndrome on the mean platelet volume and other hematological parameters. Blood Coagul Fibrinolysis 2013; 24: 484−488.

61. Tiker F, Gurakan B, Tarcan A. Relationship between serum bilirubin and coagulation test results in 1-month-old infants. Indian J Pediatr 2005; 72: 205−207.

62. Kalousova M, Novotny L, Zima T et al. Decreased levels of advanced glycation end-products in patients with Gilbert syndrome. Cell Mol Biol 2005; 51: 387−392.

63. Lanone S, Bloc S, Foresti R et al. Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: implications for protection against endotoxic shock in rats. FASEB J 2005; 19: 1890−1892.

64. Wallner M, Marculescu R, Doberer D et al. Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert's syndrome. Clin Sci 2013; 125: 257−264.

65. Mazzone GL, Rigato I, Tiribelli C. Unconjugated bilirubin modulates nitric oxide production via iNOS regulation. Biosci Trends 2010; 4: 244−248.

66. Keshavan P, Deem TL, Schwemberger SJ et al. Unconjugated bilirubin inhibits VCAM-1-mediated transendothelial leukocyte migration. J Immunol 2005; 174: 3709−3718.

67. Stoeckius M, Erat A, Fujikawa T et al. Essential roles of Raf/Extracellular signal-Regulated Kinase/Mitogen-activated Protein Kinase pathway, YY1, and Ca2+ influx in growth arrest of human vascular smooth muscle cells by bilirubin. J Biol Chem 2012; 287: 15418−15426.

68. Cesaratto L, Calligaris SD, Vascotto C et al. Bilirubin-induced cell toxicity involves PTEN activation through an APE1/Ref-1-dependent pathway. J Mol Med 2007; 85: 1099−1112.

69. Mazzone GL, Rigato I, Ostrow JD, Tiribelli C. Bilirubin effect on endothelial adhesion molecules expression is mediated by the NF-kappaB signaling pathway. Biosci Trends 2009; 3: 151−157.

Labels
Addictology Allergology and clinical immunology Angiology Audiology Clinical biochemistry Dermatology & STDs Paediatric gastroenterology Paediatric surgery Paediatric cardiology Paediatric neurology Paediatric ENT Paediatric psychiatry Paediatric rheumatology Diabetology Pharmacy Vascular surgery Pain management Dental Hygienist
Topics Journals
Login
Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.

Login

Don‘t have an account?  Create new account

#ADS_BOTTOM_SCRIPTS#