KEGG   DISEASE: HyperbilirubinemiaHelp
Entry
H00208                      Disease                                

Name
Hyperbilirubinemia, including:
Crigler-Najjar syndrome, type I (CN1);
Crigler-Najjar syndrome, type II (CN2);
Gilbert Syndrome;
Dubin-Johnson syndrome (DJS);
Roter syndrome (RS)
Description
Gilbert disease and Crigler-Najjar syndromes result in unconjugated hyperbilirubinemia caused by deficiency of bilirubin-UDP-glucuronosyltransferase which is involved in the detoxification of bilirubin by conjugation with glucuronic acid. Gilbert disease is a benign familial disorder characterized by low-grade chronic hyperbilirubinemia, while Crigler-Najjar syndromes are more severe by kernicterus and jaundice. Dubin-Johnson syndrome (DJS) is caused by mutations in ABCC2, a canalicular bilirubin glucuronide and xenobiotic export pump. Roter syndrome (RS) is caused by mutations in the SLCO1B1 and SLCO1B3 genes that encode organic anion transporters. In both DJS and RS, mild jaundice begins shortly after birth or in childhood. There are no signs of hemolysis, and routine hematologic and clinical-biochemistry test results are normal, aside from the primarily conjugated hyperbilirubinemia. The hepatocyte pigment deposits is typical of DJS. Total urinary excretion of coproporphyrins is greatly increased in RS.
Category
Inherited metabolic disease; Liver disease
Brite
Human diseases [BR:br08402]
 Congenital disorders of metabolism
  Congenital disorders of cofactor/vitamin metabolism
   H00208  Hyperbilirubinemia
Human diseases in ICD-10 classification [BR:br08403]
 4. Endocrine, nutritional and metabolic diseases (E00-E90)
  E70-E90  Metabolic disorders
   E80  Disorders of porphyrin and bilirubin metabolism
    H00208  Hyperbilirubinemia
BRITE hierarchy
Pathway
Porphyrin and chlorophyll metabolism
ABC transporters
Bile secretion
Gene
UGT1A1; UDP glucuronosyltransferase [HSA:54658] [KO:K00699]
(DJS) ABCC2 [HSA:1244] [KO:K05666]
(RS) SLCO1B1 [HSA:10599] [KO:K05043]
(RS) SLCO1B3 [HSA:28234] [KO:K05043]
Marker
Bilirubin [CPD:C00486]
Coproporphyrin [CPD:C05769]
Drug
(CN2) Phenobarbital [DG:DG00845]
Other DBs
Reference
  Authors
Costa E
  Title
Hematologically important mutations: bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler-Najjar syndromes.
  Journal
Blood Cells Mol Dis 36:77-80 (2006)
DOI:10.1016/j.bcmd.2005.10.006
Reference
  Authors
Bosma PJ
  Title
Inherited disorders of bilirubin metabolism.
  Journal
J Hepatol 38:107-17 (2003)
DOI:10.1016/S0168-8278(02)00359-8
Reference
  Authors
Kadakol A, Ghosh SS, Sappal BS, Sharma G, Chowdhury JR, Chowdhury NR
  Title
Genetic lesions of bilirubin uridine-diphosphoglucuronate glucuronosyltransferase (UGT1A1) causing Crigler-Najjar and Gilbert syndromes: correlation of genotype to phenotype.
  Journal
Reference
  Authors
Sampietro M, Iolascon A
  Title
Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes.
  Journal
Haematologica 84:150-7 (1999)
Reference
  Authors
Keitel V, Nies AT, Brom M, Hummel-Eisenbeiss J, Spring H, Keppler D
  Title
A common Dubin-Johnson syndrome mutation impairs protein maturation and transport activity of MRP2 (ABCC2).
  Journal
Am J Physiol Gastrointest Liver Physiol 284:G165-74 (2003)
DOI:10.1152/ajpgi.00362.2002
Reference
  Authors
van de Steeg E, Stranecky V, Hartmannova H, Noskova L, Hrebicek M, Wagenaar E, van Esch A, de Waart DR, Oude Elferink RP, Kenworthy KE, Sticova E, al-Edreesi M, Knisely AS, Kmoch S, Jirsa M, Schinkel AH
  Title
Complete OATP1B1 and OATP1B3 deficiency causes human Rotor syndrome by interrupting conjugated bilirubin reuptake into the liver.
  Journal
J Clin Invest 122:519-28 (2012)
DOI:10.1172/JCI59526

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