Vnitr Lek 2013, 59(7):566-571

Neonatal hyperbilirubinemia and molecular mechanisms of jaundice

M. Jirsa*, E. Sticová
Centrum experimentální medicíny IKEM Praha, přednosta prof. MUDr. Luděk Červenka, CSc., MBA

The introductory summarises the classical path of heme degradation and classification of jaundice. Subsequently, a description of neonatal types of jaundice is given, known as Crigler-Najjar, Gilbert's, Dubin-Johnson and Rotor syndromes, emphasising the explanation of the molecular mechanisms of these metabolic disorders. Special attention is given to a recently discovered molecular mechanism of the Rotor syndrome. The mechanism is based on the inability of the liver to retrospectively uptake the conjugated bilirubin fraction primarily excreted into the blood, not bile. A reduced ability of the liver to uptake the conjugated bilirubin contributes to the development of hyperbilirubinemia in common disorders of the liver and bile ducts and to the toxicity of xenobiotics and drugs using transport proteins for conjugated bilirubin.

Keywords: heme; bilirubin; Gilbert's syndrome; Dubin-Johnson syndrome; Rotor syndrome; OATP1B1; OATP1B3

Received: March 20, 2013; Published: July 1, 2013  Show citation

ACS AIP APA ASA Harvard Chicago Chicago Notes IEEE ISO690 MLA NLM Turabian Vancouver
Jirsa M, Sticová E. Neonatal hyperbilirubinemia and molecular mechanisms of jaundice. Vnitr Lek. 2013;59(7):566-571.
Share...
Download citation
  • BibTeX (.bib)
  • Bookends (.ris)
  • EasyBib (.ris)
  • EndNote (.enw)
  • EndNote 8 (.xml)
  • ISI WoS (.isi)
  • Medlars (.medlars)
  • Mendeley (.ris)
  • MODS (.xml)
  • Papers (.ris)
  • RefWorks (.txt)
  • RefManager (.ris)
  • RIS (.ris)
  • MS Word (.xml)
  • Zotero (.ris)
    • Open full article

    References

    1. Owens IS, Basu NK, Banerjee R. UDP-glucuronosyltransferases: gene structures of UGT1 and UGT2 families. Methods Enzymol 2005; 400: 1-22. Go to original source... Go to PubMed...
    2. Vlaming ML, Pala Z, van Esch A et al. Functionally overlapping roles of Abcg2 (Bcrp1) and Abcc2 (Mrp2) in the elimination of methotrexate and its main toxic metabolite 7-hydroxymethotrexate in vivo. Clin Cancer Res 2009; 15: 3084-3093. Go to original source... Go to PubMed...
    3. Crigler JF Jr, Najjar VA. Congenital familial nonhemolytic jaundice with kernicterus; a new clinical entity. AMA Am J Dis Child 1952; 83: 259-260.
    4. Chowdhury JR, Wolkoff AW, Chowdhury NR et al. Hereditary jaundice and disorders of bilirubin metabolism. In: Scriver CR, Beaudet AL, Sly WS et al (eds). The metabolic & molecular bases of inherited disease. New York: McGraw Hill 2001: 3063-3101.
    5. Kadakol A, Ghosh SS, Sappal BS et al. Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype. Hum Mutat 2000; 16: 297-306. Go to original source... Go to PubMed...
    6. Jansen PL. Diagnosis and management of Crigler-Najjar syndrome. Eur J Pediatr 1999; 158 (Suppl 2): S89-S94. Go to original source... Go to PubMed...
    7. Gilbert A, Lereboulet P. La cholemie simple familiale. Sem Med 1901; 21: 241-243.
    8. Arias IM, London IM. Bilirubin glucuronide formation in vitro; demonstration of a defect in Gilbert's disease. Science 1957; 126: 563-564. Go to original source... Go to PubMed...
    9. Black M, Billing BH. Hepatic bilirubin udp-glucuronyl transferase activity in liver disease and gilbert's syndrome. N Engl J Med 1969; 280: 1266-1271. Go to original source... Go to PubMed...
    10. Owens D, Evans J. Population studies on Gilbert's syndrome. J Med Genet 1975; 12: 152-156. Go to original source... Go to PubMed...
    11. Sieg A, Arab L, Schlierf G et al. Prevalence of Gilbert's syndrome in Germany. Dtsch Med Wochenschr 1987; 112: 1206-1208. Go to original source... Go to PubMed...
    12. Bosma PJ, Chowdhury JR, Bakker C et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333: 1171-1175. Go to original source... Go to PubMed...
    13. Sugatani J, Kojima H, Ueda A et al. The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 2001; 33: 1232-1238. Go to original source... Go to PubMed...
    14. Sugatani J, Yamakawa K, Yoshinari K et al. Identification of a defect in the UGT1A1 gene promoter and its association with hyperbilirubinemia. Biochem Biophys Res Commun 2002; 292: 492-497. Go to original source... Go to PubMed...
    15. Koiwai O, Nishizawa M, Hasada K et al. Gilbert's syndrome is caused by a heterozygous missense mutation in the gene for bilirubin UDP-glucuronosyltransferase. Hum Mol Genet 1995; 4: 1183-1186. Go to original source... Go to PubMed...
    16. Aono S, Yamada Y, Keino H et al. Identification of defect in the genes for bilirubin UDP-glucuronosyl-transferase in a patient with Crigler-Najjar syndrome type II. Biochem Biophys Res Commun 1993; 197: 1239-1244. Go to original source... Go to PubMed...
    17. Aono S, Adachi Y, Uyama E et al. Analysis of genes for bilirubin UDP-glucuronosyltransferase in Gilbert's syndrome. Lancet 1995; 345: 958-959. Go to original source... Go to PubMed...
    18. 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. Go to original source... Go to PubMed...
    19. Paulusma CC, Oude Elferink RP. The canalicular multispecific organic anion transporter and conjugated hyperbilirubinemia in rat and man. J Mol Med 1997; 75: 420-428. Go to original source... Go to PubMed...
    20. Dubin IN. Chronic idiopathic jaundice; a review of fifty cases. Am J Med 1958; 24: 268-292. Go to original source... Go to PubMed...
    21. Shani M, Seligsohn U, Gilon E et al. Dubin-Johnson syndrome in Israel. I. Clinical, laboratory, and genetic aspects of 101 cases. Q J Med 1970; 39: 549-567.
    22. Wolkoff AW, Cohen LE, Arias IM. Inheritance of the Dubin-Johnson syndrome. N Engl J Med 1973; 288: 113-117. Go to original source... Go to PubMed...
    23. Erlinger S, Dhumeaux D, Desjeux JF et al. Hepatic handling of unconjugated dyes in the Dubin-Johnson syndrome. Gastroenterology 1973; 64: 106-110. Go to original source...
    24. Bar-Meir S, Baron J, Seligson U et al. 99mTc-HIDA cholescintigraphy in Dubin-Johnson and Rotor syndromes. Radiology 1982; 142: 743-746. Go to original source... Go to PubMed...
    25. Bujanover Y, Bar-Meir S, Hayman I et al. 99mTc-HIDA cholescintigraphy in children with Dubin-Johnson syndrome. J Pediatr Gastroenterol Nutr 1983; 2: 311-312. Go to original source... Go to PubMed...
    26. Artiko V, Obradovic VV, Kostic K et al. Cholescintigraphy in Dubin-Johnson syndrome. Nucl Med Rev Cent East Eur 1999; 2: 83-84.
    27. Arias IM. Studies of chronic familial non-hemolytic jaundice with conjugated bilirubin in the serum with and without an unidentified pigment in the liver cells. Am J Med 1961; 31: 510-518. Go to original source... Go to PubMed...
    28. Shieh CC, Chang MH, Chen CL. Dubin-Johnson syndrome presenting with neonatal cholestasis. Arch Dis Child 1990; 65: 898-899. Go to original source... Go to PubMed...
    29. Kartenbeck J, Leuschner U, Mayer R et al. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin-Johnson syndrome. Hepatology 1996; 23: 1061-1066. Go to original source... Go to PubMed...
    30. Mor-Cohen R, Zivelin A, Rosenberg N et al. Identification and functional analysis of two novel mutations in the multidrug resistance protein 2 gene in Israeli patients with Dubin-Johnson syndrome. J Biol Chem 2001; 276: 36923-36930. Go to original source... Go to PubMed...
    31. Cebecauerova D, Jirasek T, Budisova L et al. Dual hereditary jaundice: simultaneous occurrence of mutations causing Gilbert's and Dubin-Johnson syndrome. Gastroenterology 2005; 129: 315-320. Go to original source... Go to PubMed...
    32. Sticova E, Elleder M, Hulkova H et al. Dubin-Johnson syndrome coinciding with colon cancer and atherosclerosis. World J Gastroenterol 2013; 19: 946-950. Go to original source... Go to PubMed...
    33. Wolkoff AW, Wolpert E, Pascasio FN et al. Rotor's syndrome. A distinct inheritable pathophysiologic entity. Am J Med 1976; 60: 173-179. Go to original source... Go to PubMed...
    34. Wolpert E, Pascasio FM, Wolkoff AW et al. Abnormal sulfobromophthalein metabolism in Rotor's syndrome and obligate heterozygotes. N Engl J Med 1977; 296: 1099-1101. Go to original source... Go to PubMed...
    35. Fretzayas AM, Garoufi AI, Moutsouris CX et al. Cholescintigraphy in the diagnosis of Rotor syndrome. J Nucl Med 1994; 35: 1048-1050. Go to PubMed...
    36. Fretzayas AM, Stavrinadis CS, Koukoutsakis PM et al. Diagnostic approach of Rotor syndrome with cholescintigraphy. Clin Nucl Med 1997; 22: 635-636. Go to original source... Go to PubMed...
    37. van de Steeg E, Stranecky V, Hartmannova 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: 519-528. Go to original source... Go to PubMed...
    38. König J, Rost D, Cui Y et al. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology 1999; 29: 1156-1163. Go to original source... Go to PubMed...
    39. Lee J, Boyer JL. Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders. Semin Liver Dis 2000; 20: 373-384. Go to original source... Go to PubMed...
    40. Iusuf D, van de Steeg E, Schinkel AH. Hepatocyte hopping of OATP1B substrates contributes to efficient hepatic detoxification. Clin Pharmacol Ther 2012; 92: 559-562. Go to original source... Go to PubMed...
    41. Keitel V, Burdelski M, Warskulat U et al. Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology 2005; 41: 1160-1172. Go to original source... Go to PubMed...
    42. Niemi M, Pasanen MK, Neuvonen PJ. Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake. Pharmacol Rev 2011; 63: 157-181. Go to original source... Go to PubMed...
    43. Link E, Parish S, Armitage J et al. SLCO1B1 variants and statin-induced myopathy - a genomewide study. N Engl J Med 2008; 359: 789-799. Go to original source... Go to PubMed...
    44. Karlson P, Gerok W, Gross W. Patobiochemie. Praha: Academia 1987.

    Return to the content


    Vnitřní lékařství

    Madam, Sir,
    please be aware that the website on which you intend to enter, not the general public because it contains technical information about medicines, including advertisements relating to medicinal products. This information and communication professionals are solely under §2 of the Act n.40/1995 Coll. Is active persons authorized to prescribe or supply (hereinafter expert).
    Take note that if you are not an expert, you run the risk of danger to their health or the health of other persons, if you the obtained information improperly understood or interpreted, and especially advertising which may be part of this site, or whether you used it for self-diagnosis or medical treatment, whether in relation to each other in person or in relation to others.

    I declare:

    1. that I have met the above instruction
    2. I'm an expert within the meaning of the Act n.40/1995 Coll. the regulation of advertising, as amended, and I am aware of the risks that would be a person other than the expert input to these sites exhibited

    No
    Yes

    If your statement is not true, please be aware
    that brings the risk of danger to their health or the health of others.