Neonatal hyperbilirubinemia and molecular mechanisms of jaundice

Authors: M. Jirsa;  E. Sticová
Authors‘ workplace: Centrum experimentální medicíny IKEM Praha, přednosta prof. MU Dr. Luděk Červenka, CSc., MBA
Published in: Vnitř Lék 2013; 59(7): 566-571


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.

Key words:
heme –  bilirubin –  Gilbert’s syndrome –  Dubin‑Johnson syndrome –  Rotor syndrome –  OATP1B1 –  OATP1B3


1. Owens IS, Basu NK, Banerjee R. UDP‑ glucuronosyltransferases: gene structures of UGT1 and UGT2 families. Methods Enzymol 2005; 400: 1– 22.

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.

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.

6. Jansen PL. Dia­gnosis and management of Crigler‑ Najjar syndrome. Eur J Pediatr 1999; 158 (Suppl 2): S89– S94.

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.

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.

10. Owens D, Evans J. Population studies on Gilbert’s syndrome. J Med Genet 1975; 12: 152– 156.

11. Sieg A, Arab L, Schlierf G et al. Prevalence of Gilbert’s syndrome in Germany. Dtsch Med Wochenschr 1987; 112: 1206– 1208.

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.

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.

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.

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.

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.

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.

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.

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.

20. Dubin IN. Chronic idiopathic jaundice; a review of fifty cases. Am J Med 1958; 24: 268– 292.

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.

23. Erlinger S, Dhumeaux D, Desjeux JF et al. Hepatic handling of unconjugated dyes in the Dubin‑Johnson syndrome. Gastroenterology 1973; 64: 106– 110.

24. Bar‑ Meir S, Baron J, Seligson U et al. 99mTc‑ HIDA cholescintigraphy in Dubin‑Johnson and Rotor syndromes. Radiology 1982; 142: 743– 746.

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.

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.

28. Shieh CC, Chang MH, Chen CL. Dubin‑Johnson syndrome presenting with neonatal cholestasis. Arch Dis Child 1990; 65: 898– 899.

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.

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.

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.

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.

33. Wolkoff AW, Wolpert E, Pascasio FN et al. Rotor’s syndrome. A distinct inheritable pathophysiologic entity. Am J Med 1976; 60: 173– 179.

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.

35. Fretzayas AM, Garoufi AI, Moutsouris CX et al. Cholescintigraphy in the dia­gnosis of Rotor syndrome. J Nucl Med 1994; 35: 1048– 1050.

36. Fretzayas AM, Stavrinadis CS, Koukoutsakis PM et al. Dia­gnostic approach of Rotor syndrome with cholescintigraphy. Clin Nucl Med 1997; 22: 635– 636.

37. van de Steeg E, Stranecky V, Hartmannova Het 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.

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.

39. Lee J, Boyer JL. Molecular alterations in hepatocyte transport mechanisms in acquired cholestatic liver disorders. Semin Liver Dis 2000; 20: 373– 384.

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.

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.

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.

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.

44. Karlson P, Gerok W, Gross W. Patobiochemie. Praha: Academia 1987.

Diabetology Endocrinology Internal medicine
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

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


Don‘t have an account?  Create new account