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Bilirubin as a Biomarker in Liver Disease

Reference work entry
First Online:
Part of the Biomarkers in Disease: Methods, Discoveries and Applications book series (BDMDA)

Abstract

Bilirubin had been studied since the eighteenth century because assessment of serum bilirubin concentration is important in the diagnosis and prognosis of patients with liver disorders. All prognostic scores for liver diseases include bilirubin in their calculations, and some studies have shown that bilirubin is an independent biomarker of mortality risk. We know that a high total bilirubin level is an indicator of disease, but nowadays there is evidence indicating the association of a low level with increased risk of diseases, for example, cancer or cardiovascular disorders. Bilirubin is a potential biomarker because its concentration is associated with mortality and may also be associated with the prevention of disease. This chapter will review the usefulness of bilirubin as a marker in liver diseases and their possible use to assess outcomes and risk of other non-liver diseases.

Keywords

Chronic liver diseases Acute liver failure Gilbert syndrome Cardiovascular diseases Cancer Autoimmune diseases Prognosis Mortality 

List of Abbreviations

ABIC

Age–bilirubin–INR–creatinine

ACLF

Acute-on-chronic liver failure

AH

Alcoholic hepatitis

ALF

Acute liver failure

ALFIHMS

ALF in-hospital mortality score

APACHE II score

Acute Physiology and Chronic Health Evaluation II score

BLVR

Biliverdin reductase

CB

Conjugated bilirubin

CO

Carbon monoxide

CTP score

Child–Turcotte–Pugh score

ECBL

Early change in bilirubin level

GAHS

Glasgow alcoholic hepatitis score

HCl

Hydrochloric acid

HELLP

Hemolysis, elevated liver enzyme levels, and low platelet count

HIV

Human immunodeficiency virus

HMOX

Heme oxygenase

HPLC

High-performance liquid chromatography

INR

International normalized ratio

KCH

King’s College Hospital

LT

Liver transplantation

mDF

Maddrey discriminant function

MELD

Model for End-Stage Liver Disease

NHANES

National Health and Nutrition Examination Survey

OATP

Organic anion-transporting protein

TcBm

Transcutaneous bilirubin measurement

UCB

Unconjugated bilirubin

UGT1A1

Bilirubin UDP-glucuronosyltransferase

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Notes

Acknowledgements

This work was supported by the Medica Sur Clinic and Foundation (NMS) and by the following grants: PRVOUK 4102280002 from the Czech Ministry of Education and RVO VFN64165 from the Czech Ministry of Health (LV).

References

  1. Adachi Y, Inufusa H, Yamashita M, et al. Clinical application of serum bilirubin fractionation by simplified liquid chromatography. Clin Chem. 1988;34:385–8.PubMedGoogle Scholar
  2. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297–316.CrossRefGoogle Scholar
  3. Arroyo V, Moreau R, Jalan R, et al. Acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis. J Hepatol. 2015;62:S131–43.PubMedCrossRefGoogle Scholar
  4. 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;15:137–42.PubMedCrossRefGoogle Scholar
  5. Baranano DE, Rao M, Ferris CD, et al. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci U S A. 2002;99:16093–8.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Basiglio CL, Arriaga SM, Pelusa F, et al. Complement activation and disease: protective effects of hyperbilirubinaemia. Clin Sci (Lond). 2009;118:99–113.CrossRefGoogle Scholar
  7. Berk PD, Rodkey FL, Blaschke TF, et al. Comparison of plasma bilirubin turnover and carbon monoxide production in man. J Lab Clin Med. 1974;83:29–37.PubMedGoogle Scholar
  8. Bernal W, Lee WM, Wendon J, et al. Acute liver failure: a curable disease by 2024? J Hepatol. 2015;62:S112–20.PubMedCrossRefGoogle Scholar
  9. Boon AC, Hawkins CL, Bisht K, et al. Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert syndrome. Free Radic Biol Med. 2012;52:2120–7.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bosma PJ. Inherited disorders of bilirubin metabolism. J Hepatol. 2003;38:107–17.PubMedCrossRefGoogle Scholar
  11. Bosschaart N, Kok JH, Newsum AM, et al. Limitations and opportunities of transcutaneous bilirubin measurements. Pediatrics. 2012;129:689–94.PubMedCrossRefGoogle Scholar
  12. Brites D. The evolving landscape of neurotoxicity by unconjugated bilirubin: role of glial cells and inflammation. Front Pharmacol. 2012;3:88.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Brodersen R. Competitive binding of bilirubin and other substances to plasma albumin: equilibrium studies in vitro. Birth Defects Orig Artic Ser. 1976;12:179–83.PubMedGoogle Scholar
  14. Busbee PB, Rouse M, Nagarkatti M, et al. Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders. Nutr Rev. 2013;71:353–69.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Chalasani N, Chowdhury NR, Chowdhury JR, et al. Kernicterus in an adult who is heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic defect. Gastroenterology. 1997;112:2099–103.PubMedCrossRefGoogle Scholar
  16. Chang JH, Plise E, Cheong J, et al. Evaluating the in vitro inhibition of UGT1A1, OATP1B1, OATP1B3, MRP2, and BSEP in predicting drug-induced hyperbilirubinemia. Mol Pharm. 2013;10:3067–75.PubMedCrossRefGoogle Scholar
  17. Chen XM, O’hara SP, Larusso NF. The immunobiology of cholangiocytes. Immunol Cell Biol. 2008;86:497–505.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Cui Y, Konig J, Leier I, et al. Hepatic uptake of bilirubin and its conjugates by the human organic anion transporter SLC21A6. J Biol Chem. 2001;276:9626–30.PubMedCrossRefGoogle Scholar
  19. Deng J, Liang XM, Zhang XL, et al. Relationship between serum bilirubin levels and optic neuritis. Chin Med J (Engl). 2013;126:3307–10.Google Scholar
  20. Dhaliwal G, Cornett PA, Tierney LM Jr. Hemolytic anemia. Am Fam Physician. 2004;69:2599–606.PubMedGoogle Scholar
  21. Dominguez M, Rincon D, Abraldes JG, et al. A new scoring system for prognostic stratification of patients with alcoholic. Am J Gastroenterol. 2008;103:2747–56.PubMedCrossRefGoogle Scholar
  22. Du WB, Pan XP, Li LJ. Prognostic models for acute liver failure. Hepatobiliary Pancreat Dis Int. 2010;9:122–8.PubMedGoogle Scholar
  23. Ehrlich P. Sulfadiazobensol, ein Reagens auf Bilirubin. Centr Klin Med. 1883;4:721–3.Google Scholar
  24. 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;2:256–60.PubMedPubMedCentralGoogle Scholar
  25. Forrest EH, Morris AJ, Stewart S, et al. The glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids. Gut. 2007;56:1743–6.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Fouassier L, Beaussier M, Schiffer E, et al. Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes. Am J Physiol Gastrointest Liver Physiol. 2007;293:G25–35.PubMedCrossRefGoogle Scholar
  27. Fuhua P, Xuhui D, Zhiyang Z, et al. Antioxidant status of bilirubin and uric acid in patients with myasthenia gravis. Neuroimmunomodulation. 2012;19:43–9.PubMedCrossRefGoogle Scholar
  28. Gärtner U, Goeser T, Wolkoff AW. Effect of fasting on the uptake of bilirubin and sulfobromophthalein by the isolated perfused rat liver. Gastroenterology. 1997;113:1707–13.PubMedCrossRefGoogle Scholar
  29. Geier A, Dietrich CG, Voigt S, et al. Effects of proinflammatory cytokines on rat organic anion transporters during toxic liver injury and cholestasis. Hepatology. 2003;38:345–54.PubMedCrossRefGoogle Scholar
  30. Gollan JL, Zucker SD. A new voyage of discovery: transport through the hepatocyte. Trans Am Clin Climatol Assoc. 1996;107:48–55.PubMedPubMedCentralGoogle Scholar
  31. Goyal SK, Dixit VK, Jain AK, et al. Assessment of the Model for End-stage Liver Disease (MELD) score in predicting prognosis of patients with alcoholic hepatitis. J Clin Exp Hepatol. 2014;4:19–24.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Harada K, Ohira S, Isse K, et al. Lipopolysaccharide activates nuclear factor-kappaB through toll-like receptors and related molecules in cultured biliary epithelial cells. Lab Invest. 2003;83:1657–67.PubMedCrossRefGoogle Scholar
  33. Hatano T, Saiki S, Okuzumi A, et al. Identification of novel biomarkers for Parkinson’s disease by metabolomic technologies. J Neurol Neurosurg Psychiatry. 2016;87:295–301.PubMedCrossRefGoogle Scholar
  34. Higashijima H, Yamashita H, Makino I, et al. Significance of serum delta bilirubin during obstructive jaundice in dogs. J Surg Res. 1996;66:119–24.PubMedCrossRefGoogle Scholar
  35. Horsfall LJ, Rait G, Walters K, et al. Serum bilirubin and risk of respiratory disease and death. JAMA. 2011;305:691–7.PubMedCrossRefGoogle Scholar
  36. Iłzecka J, Stelmasiak Z. Serum bilirubin concentration in patients with amyotrophic lateral sclerosis. Clin Neurol Neurosurg. 2003;105:237–40.PubMedCrossRefGoogle Scholar
  37. Jangi S, Otterbein L, Robson S. The molecular basis for the immunomodulatory activities of unconjugated bilirubin. Int J Biochem Cell Biol. 2013;45:2843–51.PubMedCrossRefGoogle Scholar
  38. Jirásková A, Novotný J, Novotný L, et al. Association of serum bilirubin and promoter variations in HMOX1 and UGT1A1 genes with sporadic colorectal cancer. Int J Cancer. 2012;131:1549–55.PubMedCrossRefGoogle Scholar
  39. Kazmierczak SC, Robertson AF, Catrou PG, et al. Direct spectrophotometric method for measurement of bilirubin in newborns: comparison with HPLC and an automated diazo method. Clin Chem. 2002;48:1096–7.PubMedGoogle Scholar
  40. Kim W, Kim DJ. Severe alcoholic hepatitis-current concepts, diagnosis and treatment options. World J Hepatol. 2014;6:688–95.PubMedPubMedCentralCrossRefGoogle Scholar
  41. Kim TS, Pae CU, Yoon SJ, et al. Decreased plasma antioxidants in patients with Alzheimer’s disease. Int J Geriatr Psychiatry. 2006;21:344–8.PubMedCrossRefGoogle Scholar
  42. Kosters A, Karpen SJ. The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis. 2010;30:186–94.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Kufer W, Scheer H. The diazo reaction of bilirubin: structure of the yellow products: studies on plant bile pigments-14. Tetrahedron. 1983;39:1887–92.CrossRefGoogle Scholar
  44. Lankisch TO, Moebius U, Wehmeier M, et al. Gilbert’s disease and atazanavir: from phenotype to UDP-glucuronosyltransferase haplotype. Hepatology. 2006;44:1324–32.PubMedCrossRefGoogle Scholar
  45. Lankisch TO, Behrens G, Ehmer U, et al. Gilbert’s syndrome and hyperbilirubinemia in protease inhibitor therapy – an extended haplotype of genetic variants increases risk in indinavir treatment. J Hepatol. 2009;50:1010–8.PubMedCrossRefGoogle Scholar
  46. Lauff JJ, Kasper ME, Ambrose RT. Separation of bilirubin species in serum and bile by high-performance reversed-phase liquid chromatography. J Chromatogr. 1981;226:391–402.PubMedCrossRefGoogle Scholar
  47. Lee JP, do Kim H, Yang SH, et al. Serum bilirubin affects graft outcomes through UDP-glucuronosyltransferase sequence variation in kidney transplantation. PLoS One. 2014;9:e93633.PubMedPubMedCentralCrossRefGoogle Scholar
  48. Leníček M, Duricová D, Hradsky O, et al. The relationship between serum bilirubin and Crohn’s disease. Inflamm Bowel Dis. 2014;20:481–7.PubMedCrossRefGoogle Scholar
  49. Li RY, Cao ZG, Zhang JR, et al. Decreased serum bilirubin is associated with silent cerebral infarction. Arterioscler Thromb Vasc Biol. 2014;34:946–51.PubMedCrossRefGoogle Scholar
  50. Lidofsky SD. Liver transplantation for fulminant hepatic failure. Gastroenterol Clin North Am. 1993;22:257–69.PubMedGoogle Scholar
  51. Lim JE, Kimm H, Jee SH. Combined effects of smoking and bilirubin levels on the risk of lung cancer in Korea: the severance cohort study. PLoS One. 2014;9, e103972.PubMedPubMedCentralCrossRefGoogle Scholar
  52. Lin JP, Vitek L, Schwertner HA. Serum bilirubin and genes controlling bilirubin concentrations as biomarkers for cardiovascular disease. Clin Chem. 2010;56:1535–43.PubMedCrossRefGoogle Scholar
  53. Liu Y, Li P, Lu J, et al. Bilirubin possesses powerful immunomodulatory activity and suppresses experimental autoimmune encephalomyelitis. J Immunol. 2008;181:1887–97.PubMedCrossRefGoogle Scholar
  54. López-Velázquez JA, Chávez-Tapia NC, Ponciano-Rodríguez G, et al. Bilirubin alone as a biomarker for short-term mortality in acute-on-chronic liver failure: an important prognostic indicator. Ann Hepatol. 2013;13:98–104.PubMedGoogle Scholar
  55. Lott JA, Doumas BT. “Direct” and total bilirubin tests: contemporary problems. Clin Chem. 1993;39:641–7.PubMedGoogle Scholar
  56. Louvet A, Naveau S, Abdelnour M, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007;45:1348–54.PubMedCrossRefGoogle Scholar
  57. Mathurin P, Abdelnour M, Ramond MJ, et al. Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone. Hepatology. 2003;38:1363–9.PubMedCrossRefGoogle Scholar
  58. McDonagh AF, Palma LA, Schmid R. Reduction of biliverdin and placental transfer of bilirubin and biliverdin in the pregnant guinea pig. Biochem J. 1981;194:273–82.PubMedPubMedCentralCrossRefGoogle Scholar
  59. Méndez-Sánchez N, Uribe M. Intestinal motility and bacterial overgrowth in patients with gallstones. Gastroenterology. 2001;120:1310–1.PubMedCrossRefGoogle Scholar
  60. Misso NL, Brooks-Wildhaber J, Ray S, et al. Plasma concentrations of dietary and nondietary antioxidants are low in severe asthma. Eur Respir J. 2005;26:257–64.PubMedCrossRefGoogle Scholar
  61. Moseley RH. Sepsis and cholestasis. Clin Liver Dis. 2004;8:83–94.PubMedCrossRefGoogle Scholar
  62. Nakayama K. Differences between enzymatic and diazo methods for measuring direct bilirubin. Eur J Clin Chem Clin Biochem. 1995;33:513–7.PubMedGoogle Scholar
  63. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354:731–9.PubMedCrossRefGoogle Scholar
  64. Nejedlá Z. The development of immunological factors in infants with hyperbilirubinemia. Pediatrics. 1970;45:102–4.PubMedGoogle Scholar
  65. Novotný L, Vítek L. Inverse relationship between serum bilirubin and atherosclerosis in men: a meta-analysis of published studies. Exp Biol Med (Maywood). 2003;22:568–71.CrossRefGoogle Scholar
  66. Oren DA, Desan PH, Boutros N, et al. Effects of light on low nocturnal bilirubin in winter depression: a preliminary report. Biol Psychiatry. 2002;51:422–5.PubMedCrossRefGoogle Scholar
  67. Ostrow JD, Pascolo L, Shapiro SM, et al. New concepts in bilirubin encephalopathy. Eur J Clin Invest. 2003;33:988–97.PubMedCrossRefGoogle Scholar
  68. Palomaki GE, Bradley LA, Douglas MP, et al. Can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? An evidence-based review. Genet Med. 2009;11:21–34.PubMedPubMedCentralCrossRefGoogle Scholar
  69. Papastergiou V, Tsochatzis EA, Pieri G, et al. Nine scoring models for short-term mortality in alcoholic hepatitis: cross-validation in a biopsy-proven cohort. Aliment Pharmacol Ther. 2014;39:721–32.PubMedPubMedCentralCrossRefGoogle Scholar
  70. Papatheodoridis GV, Hamilton M, Mistry PK, et al. Ulcerative colitis has an aggressive course after orthotopic liver transplantation for primary sclerosing cholangitis. Gut. 1998;43:639–44.PubMedPubMedCentralCrossRefGoogle Scholar
  71. Park BJ, Shim JY, Lee HR, et al. Association between serum total bilirubin level and leukoaraiosis in Korean adults. Clin Biochem. 2012;45:289–92.PubMedCrossRefGoogle Scholar
  72. Peng F, Deng X, Yu Y, et al. Serum bilirubin concentrations and multiple sclerosis. J Clin Neurosci. 2011;18:1355–9.PubMedCrossRefGoogle Scholar
  73. Phelan D, Winter GM, Rogers WJ, et al. Activation of the Ah receptor signal transduction pathway by bilirubin and biliverdin. Arch Biochem Biophys. 1998;357:155–63.PubMedCrossRefGoogle Scholar
  74. Ramond MJ, Poynard T, Rueff B, et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med. 1992;326:507–12.PubMedCrossRefGoogle Scholar
  75. Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev. 2006;86:583–650.PubMedCrossRefGoogle Scholar
  76. Said A, Williams J, Holden J, et al. Model for end stage liver disease score predicts mortality across a broad spectrum of liver disease. J Hepatol. 2004;40:897–903.PubMedCrossRefGoogle Scholar
  77. Sane RS, Steinmann GG, Huang Q, et al. Mechanisms underlying benign and reversible unconjugated hyperbilirubinemia observed with faldaprevir administration in hepatitis C virus patients. J Pharmacol Exp Ther. 2014;351:403–12.PubMedCrossRefGoogle Scholar
  78. Schieving JH, de Vries M, van Vugt JM, et al. Alpha-fetoprotein, a fascinating protein and biomarker in neurology. Eur J Paediatr Neurol. 2014;18:243–8.PubMedCrossRefGoogle Scholar
  79. Schluchter WM, Glazer AN. Characterization of cyanobacterial biliverdin reductase. Conversion of biliverdin to bilirubin is important for normal phycobiliprotein biosynthesis. J Biol Chem. 1997;272:13562–9.PubMedCrossRefGoogle Scholar
  80. Schwertner HA, Fischer Jr JR. Comparison of various lipid, lipoprotein, and bilirubin combinations as risk factors for predicting coronary artery disease. Atherosclerosis. 2000;150:381–7.PubMedCrossRefGoogle Scholar
  81. Schwertner HA, Vítek L. Gilbert syndrome, UGT1A1*28 allele, and cardiovascular disease risk: possible protective effects and therapeutic applications of bilirubin. Atherosclerosis. 2008;198:1–11.PubMedCrossRefGoogle Scholar
  82. Serrano MA, Bayón JE, Pascolo L, et al. Evidence for carrier-mediated transport of unconjugated bilirubin across plasma membrane vesicles from human placental trophoblast. Placenta. 2002;23:527–35.PubMedCrossRefGoogle Scholar
  83. Taylor JA, Burgos AE, Flaherman V, et al. Discrepancies between transcutaneous and serum bilirubin measurements. Pediatrics. 2015;135:224–31.PubMedPubMedCentralCrossRefGoogle Scholar
  84. van de Steeg E, Stránecký V, Hartmannová H, et al. Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver. J Clin Invest. 2012;122:519–28.PubMedPubMedCentralCrossRefGoogle Scholar
  85. Vander Jagt DL, Dean VL, Wilson SP, et al. Regulation of the glutathione S-transferase activity of bilirubin transport protein (ligandin) from human liver. Enzymic memory involving protein-protein interactions. J Biol Chem. 1983;258:5689–94.Google Scholar
  86. Virchow R. Die pathologischen Pigmente. Arch Pathol Anat Physiol Klin Med. 1847;1:379.CrossRefGoogle Scholar
  87. Vítek L, Carey MC. Enterohepatic cycling of bilirubin as a cause of ‘black’ pigment gallstones in adult life. Eur J Clin Invest. 2003;33:799–810.PubMedCrossRefGoogle Scholar
  88. Vítek L, Ostrow JD. Bilirubin chemistry and metabolism; harmful and protective aspects. Curr Pharm Des. 2009;15:2869–83.PubMedCrossRefGoogle Scholar
  89. Vítek L, Schwertner HA. The heme catabolic pathway and its protective effects on oxidative stress-mediated diseases. Adv Clin Chem. 2007;43:1–57.PubMedCrossRefGoogle Scholar
  90. Vítek L, Kotal P, Jirsa M, et al. Intestinal colonization leading to fecal urobilinoid excretion may play a role in the pathogenesis of neonatal jaundice. J Pediatr Gastroenterol Nutr. 2000;30:294–8.PubMedCrossRefGoogle Scholar
  91. Vítek L, Jirsa M, Brodanová M, et al. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis. 2002;160:449–56.PubMedCrossRefGoogle Scholar
  92. Vítek L, Zelenka J, Zadinová M, et al. The impact of intestinal microflora on serum bilirubin levels. J Hepatol. 2005;42:238–43.PubMedCrossRefGoogle Scholar
  93. Vítek L, Novotný L, Sperl M, et al. The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis. Cerebrovasc Dis. 2006;21:408–14.PubMedCrossRefGoogle Scholar
  94. Vítek L, Muchová L, Jančová E, et al. Association of systemic lupus erythematosus with low serum bilirubin levels. Scand J Rheumatol. 2010a;39:480–4.PubMedCrossRefGoogle Scholar
  95. Vítek L, Novotná M, Lenícek M, et al. Serum bilirubin levels and UGT1A1 promoter variations in patients with schizophrenia. Psychiatry Res. 2010b;178:449–50.PubMedCrossRefGoogle Scholar
  96. Wagner KH, Wallner M, Mölzer C, et al. Looking to the horizon: the role of bilirubin in the development and prevention of age-related chronic diseases. Clin Sci (Lond). 2015;129:1–25.CrossRefGoogle Scholar
  97. Weisiger RA, Ostrow JD, Koehler RK, et al. Affinity of human serum albumin for bilirubin varies with albumin concentration and buffer composition: results of a novel ultrafiltration method. J Biol Chem. 2001;276:29953–60.PubMedCrossRefGoogle Scholar
  98. Wlodzimirow KA, Eslami S, Abu-Hanna A, et al. A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality. Liver Int. 2013;33:40–52.PubMedCrossRefGoogle Scholar
  99. Zelenka J, Muchova L, Zelenkova M, et al. Intracellular accumulation of bilirubin as a defense mechanism against increased oxidative stress. Biochimie. 2012;94:1821–7.PubMedCrossRefGoogle Scholar
  100. Zucker SD, Horn PS, Sherman KE. Serum bilirubin levels in the U.S. population: gender effect and inverse correlation with colorectal cancer. Hepatology. 2004;40:827–35.PubMedCrossRefGoogle Scholar
  101. Zieve L, Hill E, Hanson M, et al. Normal and abnormal variations and clinical significance of the one-minute and total serum bilirubin determinations. J Lab Clin Med. 1951;38:446–69.PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Liver Research UnitMedica Sur Clinic & FoundationMexico CityMexico
  2. 2.4th Department of Internal Medicine, and Institute of Medical Biochemistry and Laboratory Diagnostics, 1st Faculty of MedicineCharles University in PraguePragueCzech Republic

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