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Minerva Pediatrica Apr 2005Jaundice in an infant or older child may reflect accumulation of either unconjugated or conjugated bilirubin and could be related to inherited bilirubin disorders. Three... (Review)
Review
Jaundice in an infant or older child may reflect accumulation of either unconjugated or conjugated bilirubin and could be related to inherited bilirubin disorders. Three grades of inherited unconjugated hyperbilirubinemia are recognised in humans. This spectrum of disorders is distinguished primarily on the basis of the plasma bilirubin level, the response to phenobarbital administration, and the presence or absence of bilirubin glucoronides in bile. The enzyme responsible for the conjugation of bilirubin is the bilirubin uridine-diphosphate-glucuronosyltransferase (UGT). Mutations in the gene encoding bilirubin-UGT (UGT1A1), lead to complete or partial inactivation of the enzyme causing the rare autosomal recessively inherited conditions, Crigler-Najjar syndrome type 1 (CN-1) and type 2 (CN-2). Gilbert syndrome (GS) is due to an insertional mutation at homozygous state of the TATAA element (seven TA repeats) of UGT1A1 producing a reduced level of expression of the gene. The association of GS with haemolytic anemias, e.g., Hereditary Spherocytosis (HS) or Congenital Dyserythropoietic Anemia type 2 (CDA 2), increase the hyperbilirubinemia level and the risk of cholelithiasis. Forms of chronic conjugated hyperbilirubinemia are Dubin-Johnson syndrome, Rotor syndrome, Alagille syndrome or arteriohepatic dysplasia, Wilson disease or hepatolenticular degeneration. Liver or liver cell transplantation is the therapy in some cases.
Topics: Bilirubin; Crigler-Najjar Syndrome; Genotype; Gilbert Disease; Glucuronosyltransferase; Humans; Hyperbilirubinemia, Hereditary; Point Mutation
PubMed: 15985997
DOI: No ID Found -
Pharmacogenetics Jun 1992At least three types of congenital nonhemolytic unconjugated hyperbilirubinemias, including the rare Crigler-Najjar (CN) diseases (Types I or II) and Gilbert's syndrome... (Review)
Review
At least three types of congenital nonhemolytic unconjugated hyperbilirubinemias, including the rare Crigler-Najjar (CN) diseases (Types I or II) and Gilbert's syndrome (affecting 6% of the population) are associated with either absent or reduced hepatic UDP-glucuronosyltransferase (transferase) activity towards the potentially toxic endogenous acceptor, bilirubin. Here, we review the biochemical studies associated with these deficiencies. Accumulated evidence from studies with an animal model of CN Type I syndrome, the Gunn strain of hyperbilirubinemic rats, suggested that multiple isozymes are absent. These confounding observations have been clarified by a flurry of reports which have revealed the molecular basis for the complex disease phenotype in the Gunn rat and by the isolation and description of a novel human gene complex, UGT1, which encodes multiple and independently-regulated transferase isozymes that contain identical carboxyl terminal regions (246 amino acids). Finally, we discuss the implications of the gene organization and genetic defects determined for four different CN Type I individuals as a basis for a model which explains the inheritance pattern and genotypes of other familial unconjugated hyperbilirubinemias.
Topics: Animals; Cloning, Molecular; Crigler-Najjar Syndrome; DNA; Female; Gilbert Disease; Glucuronosyltransferase; Humans; Hyperbilirubinemia, Hereditary; Male; Multigene Family; Pedigree; Phenotype; Rats; Rats, Gunn
PubMed: 1306114
DOI: 10.1097/00008571-199206000-00001 -
Seminars in Liver Disease Feb 1983
Review
Topics: Adult; Animals; Bilirubin; Crigler-Najjar Syndrome; Diagnosis, Differential; Energy Intake; Fasting; Gilbert Disease; Humans; Hyperbilirubinemia; Hyperbilirubinemia, Hereditary; Infant, Newborn; Jaundice; Kinetics; Liver; Liver Diseases; Rats; Rats, Gunn
PubMed: 6340207
DOI: 10.1055/s-2008-1040670 -
Naika. Internal Medicine May 1971
Topics: Adult; Cytoplasmic Granules; Humans; Hyperbilirubinemia, Hereditary; Indocyanine Green; Liver; Male; Microscopy, Electron; Sulfobromophthalein
PubMed: 5572501
DOI: No ID Found -
The American Journal of Pathology Nov 1972
Topics: Animals; Disease Models, Animal; Female; Hexosyltransferases; Hyperbilirubinemia, Hereditary; Liver; Male; Mutation; Rats
PubMed: 4634741
DOI: No ID Found -
World Journal of Gastroenterology Oct 2013Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding... (Review)
Review
Bilirubin, a major end product of heme breakdown, is an important constituent of bile, responsible for its characteristic colour. Over recent decades, our understanding of bilirubin metabolism has expanded along with the processes of elimination of other endogenous and exogenous anionic substrates, mediated by the action of multiple transport systems at the sinusoidal and canalicular membrane of hepatocytes. Several inherited disorders characterised by impaired bilirubin conjugation (Crigler-Najjar syndrome type I and type II, Gilbert syndrome) or transport (Dubin-Johnson and Rotor syndrome) result in various degrees of hyperbilirubinemia of either the predominantly unconjugated or predominantly conjugated type. Moreover, disrupted regulation of hepatobiliary transport systems can explain jaundice in many acquired liver disorders. In this review, we discuss the recent data on liver bilirubin handling based on the discovery of the molecular basis of Rotor syndrome. The data show that a substantial fraction of bilirubin conjugates is primarily secreted by MRP3 at the sinusoidal membrane into the blood, from where they are subsequently reuptaken by sinusoidal membrane-bound organic anion transporting polypeptides OATP1B1 and OATP1B3. OATP1B proteins are also responsible for liver clearance of bilirubin conjugated in splanchnic organs, such as the intestine and kidney, and for a number of endogenous compounds, xenobiotics and drugs. Absence of one or both OATP1B proteins thus may have serious impact on toxicity of commonly used drugs cleared by this system such as statins, sartans, methotrexate or rifampicin. The liver-blood cycling of conjugated bilirubin is impaired in cholestatic and parenchymal liver diseases and this impairment most likely contributes to jaundice accompanying these disorders.
Topics: Animals; Bilirubin; Biomarkers; Cholestasis; Genetic Predisposition to Disease; Humans; Hyperbilirubinemia, Hereditary; Jaundice; Liver; Liver-Specific Organic Anion Transporter 1; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Phenotype; Risk Factors; Solute Carrier Organic Anion Transporter Family Member 1B3
PubMed: 24151358
DOI: 10.3748/wjg.v19.i38.6398 -
Biochimica Et Biophysica Acta Sep 1998Bilirubin, the oxidative product of heme in mammals, is excreted into the bile after its esterification with glucuronic acid to polar mono- and diconjugated derivatives.... (Review)
Review
Bilirubin, the oxidative product of heme in mammals, is excreted into the bile after its esterification with glucuronic acid to polar mono- and diconjugated derivatives. The accumulation of unconjugated and conjugated bilirubin in the serum is caused by several types of hereditary disorder. The Crigler-Najjar syndrome is caused by a defect in the gene which encodes bilirubin UDP-glucuronosyltransferase (UGT), whereas the Dubin-Johnson syndrome is characterized by a defect in the gene which encodes the canalicular bilirubin conjugate export pump of hepatocytes. Animal models such as the unconjugated hyperbilirubinemic Gunn rat, the conjugated hyperbilirubinemic GY/TR-, and the Eisai hyperbilirubinemic rat, have contributed to the understanding of the molecular basis of hyperbilirubinemia in humans. Elucidation of both the structure of the UGT1 gene complex, and the Mrp2 (cMoat) gene which encodes the canalicular conjugate export pump, has led to a greater understanding of the genetic basis of hyperbilirubinemia.
Topics: Animals; Anion Transport Proteins; Bile; Bilirubin; Carrier Proteins; Disease Models, Animal; Glucuronosyltransferase; Heme; Humans; Hyperbilirubinemia, Hereditary; Rats; Rats, Gunn
PubMed: 9748558
DOI: 10.1016/s0925-4439(98)00044-1 -
Ergebnisse Der Inneren Medizin Und... 1969
Review
Topics: Adolescent; Adult; Bilirubin; Blood Chemical Analysis; Child; Child, Preschool; Cholestasis; Diagnosis, Differential; Female; Humans; Hyperbilirubinemia, Hereditary; Infant; Infant, Newborn; Jaundice, Chronic Idiopathic; Liver; Liver Function Tests; Male; Middle Aged; Pedigree
PubMed: 4896115
DOI: No ID Found -
Gazette Medicale de France May 1965
Topics: Adolescent; Child; Child, Preschool; Classification; Humans; Hyperbilirubinemia, Hereditary; Infant; Infant, Newborn
PubMed: 5839759
DOI: No ID Found -
Nihon Rinsho. Japanese Journal of... Jan 2002
Review
Topics: Age Factors; Databases, Factual; Diagnosis, Differential; Female; Glucuronosyltransferase; Humans; Hyperbilirubinemia, Hereditary; Internet; Japan; Male; Mitochondrial Proteins; Mutation; Prognosis; Reference Standards; Ribosomal Proteins; Saccharomyces cerevisiae Proteins; Sex Factors
PubMed: 11838126
DOI: No ID Found