Glucuronyl Transferase Deficiency Clinical Presentation

  • Author: Dena Nazer, MD; Chief Editor: Carmen Cuffari, MD   more...
 
Updated: Jan 11, 2010
 

History

Crigler-Najjar (CN) syndrome type 1 is the more serious of the 2 forms of Crigler-Najjar syndrome, with an almost complete absence of uridinediphosphoglucuronate glucuronosyltransferase (UGT) activity in the liver. Apart from jaundice, the affected infant usually appears healthy at birth. Jaundice develops in the first few days of life and rapidly progresses by the second week; therefore, exchange transfusion is warranted despite phototherapy. A family history the includes consanguinity, relatives with severe jaundice without hemolysis, or relatives with evidence of liver disease and a history of exchange transfusion further supports the diagnosis.

Patients with Crigler-Najjar syndrome type 2 appear healthy at birth with no signs of liver disease. Because UGT activity is deficient but not absent, patients have a form of disease milder than that of type 1. Jaundice, usually mild, develops late in early infancy. Kernicterus has also been reported.

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Physical

Apart from jaundice, physical findings are usually normal, with no signs of hemolysis or liver disease.

Findings in Gilbert syndrome include the following:

  • Gilbert syndrome, first described in 1901 by Gilbert and Lereboullet, is a benign inherited condition usually diagnosed during adolescence. It affects around 6% of the adult population and is characterized by mild unconjugated hyperbilirubinemia with otherwise normal liver function tests. Jaundice may fluctuate and may be accompanied by unexplained vague symptoms such as upper abdominal discomfort, lethargy, and general malaise.
  • Family studies suggest an autosomal recessive mode of inheritance.
  • The age of onset is usually late childhood, at approximately age 10 years, although the diagnosis may be delayed even further.
  • Diagnosis is made in patients who have no past history of liver disease and manifest only jaundice on clinical examination.
  • Laboratory investigations reveal normal liver function test findings but a persistent mild hyperbilirubinemia and normal serum bile acids. However, at least 4 subtypes of Gilbert syndrome have been identified. Hepatic UGT activity in Gilbert syndrome is generally higher than that seen in Crigler-Najjar syndrome type 1; however, significant overlap is observed.
  • Duodenal bile from patients with Gilbert syndrome contains a decreased amount of bilirubin diglucuronides and an increased amount of bilirubin monoglucuronides.
  • A recognized test used to support the diagnosis of Gilbert syndrome involves the intravenous administration of nicotinic acid with assessment of the subsequent rise in serum bilirubin concentration.
  • The most common genetic polymorphism encountered in whites with Gilbert syndrome is an additional TA insertion in the TATAA box of the UGT 1A1 gene promoter.[7] Gilbert syndrome appears to result from missense mutations in the coding area of the UGT 1A1 gene. The most common of these is a G→A transition at nucleotide 211, which causes arginine to replace glycine at position 71 of the corresponding protein product.
  • Gilbert syndrome is a fairly benign condition that warrants medical therapy if jaundice is distressing to the patient. Oral phenobarbitone in a dose of 6-8 mg/kg body weight may alleviate symptoms in most patients.
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Causes

Bilirubin UGT activity arises from a gene complex of unusual structure found on human chromosome 2. In the complete absence of its activity, as in Crigler-Najjar syndrome type 1, the mode of inheritance is autosomal recessive.

The mode of inheritance of Crigler-Najjar syndrome type 2 is still not clear. Both autosomal dominant transmission with variable penetrance and autosomal recessive transmission have been reported.

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Contributor Information and Disclosures
Author

Dena Nazer, MD  Medical Director, Child Protection Center, Children's Hospital of Michigan; Assistant Professor, Wayne State University

Dena Nazer, MD is a member of the following medical societies: Ambulatory Pediatric Association, American Academy of Pediatrics, American Professional Society on the Abuse of Children, and Helfer Society

Disclosure: Nothing to disclose.

Coauthor(s)

Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H  Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, University of Jordan

Hisham Nazer, MB, BCh, FRCP, DCh, DTM&H is a member of the following medical societies: Royal College of Paediatrics and Child Health, Royal College of Physicians, Royal College of Surgeons in Ireland, Royal College of Surgeons of Edinburgh, and Royal Society of Tropical Medicine and Hygiene

Disclosure: Nothing to disclose.

Specialty Editor Board

Jayant Deodhar, MD  Associate Professor in Pediatrics, BJ Medical College, India; Honorary Consultant, Departments of Pediatrics and Neonatology, King Edward Memorial Hospital, India

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine

Disclosure: Nothing to disclose.

David A Piccoli, MD  Chief of Pediatric Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia; Professor, University of Pennsylvania School of Medicine

David A Piccoli, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American Gastroenterological Association, and North American Society for Pediatric Gastroenterology and Nutrition

Disclosure: Nothing to disclose.

Steven M Schwarz, MD, FAAP, FACN, AGAF  Professor of Pediatrics, Children's Hospital at Downstate, SUNY-Downstate Medical Center

Steven M Schwarz, MD, FAAP, FACN, AGAF is a member of the following medical societies: American Academy of Pediatrics, American College of Nutrition, American College of Physician Executives, American Gastroenterological Association, American Pediatric Society, Gastroenterology Research Group, New York Academy of Medicine, North American Society for Pediatric Gastroenterology and Nutrition, and Society for Pediatric Research

Disclosure: TAP Pharmaceuticals Honoraria Speaking and teaching; Curemark, LLC Consulting fee Board membership; Centocor, Inc. Grant/research funds Independent contractor

Chief Editor

Carmen Cuffari, MD  Associate Professor, Department of Pediatrics, Division of Gastroenterology/Nutrition, Johns Hopkins University School of Medicine

Carmen Cuffari, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and Royal College of Physicians and Surgeons of Canada

Disclosure: Nothing to disclose.

References

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  17. Ciotti M, Werlin SL, Owens IS. Delayed response to phenobarbital treatment of a Crigler-Najjar type II patient with partially inactivating missense mutations in the bilirubin UDP-glucuronosyltransferase gene. J Pediatr Gastroenterol Nutr. Feb 1999;28(2):210-3. [Medline].

  18. Costa E, Vieira E, Martins M, Saraiva J, Cancela E, Costa M. Analysis of the UDP-glucuronosyltransferase gene in Portuguese patients with a clinical diagnosis of Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis. Jan-Feb 2006;36(1):91-7. [Medline].

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  21. Strauss KA, Robinson DL, Vreman HJ, Puffenberger EG, Hart G, Morton DH. Management of hyperbilirubinemia and prevention of kernicterus in 20 patients with Crigler-Najjar disease. Eur J Pediatr. May 2006;165(5):306-19. [Medline].

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Conjugation of bilirubin.
 
 
 
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