Glucuronyl Transferase Deficiency

Author: Dena Nazer, MD; Chief Editor: Carmen Cuffari, MD more...

Updated: Jan 11, 2010

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Background
Pathophysiology
Epidemiology
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Background

First recognized by Crigler and Najjar in 1952, Crigler-Najjar (CN) syndrome is a congenital familial nonhemolytic jaundice associated with high levels of unconjugated bilirubin. The original report described 6 infants from 3 related families with severe unconjugated hyper bilirubinemia, which was recognized shortly after birth; 5 children died of kernicterus by age 15 months, and the remaining patient died at age 15 years, several months after suffering a devastating brain injury.^[1]

The etiology was later recognized later recognized as a familial disorder of bilirubin metabolism caused by deficiency or complete absence of hepatic microsomal bilirubin uridine 5 diphosphate glucuronyl transferase (UDPG-T) activity.

Over the past decades, progress has been made in the diagnosis and treatment of this rare disease. Phototherapy was long recognized as a form of treatment,^[2]and, in 1986, liver transplantation was shown to be curative.^[3]In 1992, the locus of the missing gene was identified, making Crigler-Najjar syndrome a potential disease for gene therapy.^[4]In 2005, new advances in gene therapy were established in Gunn rats, an animal model of Crigler-Najjar syndrome.^[5]

Pathophysiology

Unconjugated bilirubin must be conjugated with glucuronic acid in the hepatocyte to form water-soluble bilirubin glucuronides to be excreted from the body. A specific hepatic enzyme isoform (1A1) that belongs to the uridinediphosphoglucuronate glucuronosyltransferase (UGT) family of enzymes catalyzes this process. UGT is a group of enzymes that mediate the conjugation of many substances to glucuronic acid. This group of enzymes is normally concentrated in the lipid bilayer of the endoplasmic reticulum of hepatocytes, intestinal cells, kidneys, and other tissues.

Although the UGT1 family contains several isoforms, only UGT 1A1 participates in the conjugation of bilirubin. A large gene complex located on chromosome 2 controls the synthesis of these enzymes. One or more mutations in any one or more of the 5 exons of the gene that codes for UGT 1A1 can cause Crigler-Najjar syndrome.^[6]More than 50 mutations that cause Gilbert syndrome and Crigler-Najjar syndrome have been identified, most of which are missense or nonsense mutations.

An illustration of bilirubin conjugation is shown in the image below.

Conjugation of bilirubin.

Depending on the severity of its effect on the enzymatic activity, Crigler-Najjar syndrome type 1 (a complete absence of enzymatic activity) or Crigler-Najjar syndrome type 2 (UGT level < 10% of normal) may result. The differentiation between type 1 and 2 is not always easy, and both types are quite possibly different expressions of one disease.

Frequency

United States

Crigler-Najjar syndrome is a very rare disease, with less than 50 known cases in the United States.

International

Crigler-Najjar syndrome is a rare disease. The estimated incidence is 1 case per 1,000,000 births, with only several hundred people reported to have this disease. The disease is mostly encountered in communities where high rates of consanguineous marriages prevail.

Mortality/Morbidity

With early and appropriate treatment, prolonged survival free of neurologic deficits is possible. However, the risk of sudden decompensation remains with a steep rise in bilirubin levels.

Kernicterus in infancy or later in life is the main cause of death. With early and proper treatment, the life expectancy of patients with Crigler-Najjar syndrome type 1 has been extended from death in early childhood to survival to age 30 years or older.

Morbidity results from adverse effects of various methods of treatment, such as phototherapy and liver transplantation.

Sex

No sex predilection is reported.

Age

Patients with Crigler-Najjar syndrome type 1 usually present by the second to third week of life. Those with Crigler-Najjar syndrome type 2 may present later.

Proceed to Clinical Presentation

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

Lucey JF, Suresh GK, Kappas A. Crigler-Najjar syndrome, 1952-2000: learning from parents and patients about a very rare disease and using the internet to recruit patients for studies. Pediatrics. May 2000;105(5):1152-3. [Medline]. [Full Text].
Nydegger A, Bednarz A, Hardikar W. Use of daytime phototherapy for Crigler-Najjar disease. J Paediatr Child Health. Jul 2005;41(7):387-9. [Medline].
Morioka D, Kasahara M, Takada Y, et al. Living donor liver transplantation for pediatric patients with inheritable metabolic disorders. Am J Transplant. Nov 2005;5(11):2754-63. [Medline].
Bosma PJ, Chowdhury NR, Goldhoorn BG, et al. Sequence of exons and the flanking regions of human bilirubin-UDP- glucuronosyltransferase gene complex and identification of a genetic mutation in a patient with Crigler-Najjar syndrome, type I. Hepatology. May 1992;15(5):941-7. [Medline].
Toietta G, Mane VP, Norona WS, et al. Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector. Proc Natl Acad Sci U S A. Mar 15 2005;102(11):3930-5. [Medline].
Jansen PL. Diagnosis and management of Crigler-Najjar syndrome. Eur J Pediatr. Dec 1999;158 Suppl 2:S89-94. [Medline].
Kaplan M, Hammerman C, Maisels MJ. Bilirubin genetics for the nongeneticist: hereditary defects of neonatal bilirubin conjugation. Pediatrics. Apr 2003;111(4 Pt 1):886-93. [Medline].
Sisson TR, Drummond GS, Samonte D, Calabio R, Kappas A. Sn-protoporphyrin blocks the increase in serum bilirubin levels that develops postnatally in homozygous Gunn rats. J Exp Med. Mar 1 1988;167(3):1247-52. [Medline].
Birraux J, Menzel O, Wildhaber B, Jond C, Nguyen TH, Chardot C. A step toward liver gene therapy: efficient correction of the genetic defect of hepatocytes isolated from a patient with Crigler-Najjar syndrome type 1 with lentiviral vectors. Transplantation. Apr 15 2009;87(7):1006-12. [Medline].
Schauer R, Stangl M, Lang T, et al. Treatment of Crigler-Najjar type 1 disease: relevance of early liver transplantation. J Pediatr Surg. Aug 2003;38(8):1227-31. [Medline].
van der Veere CN, Sinaasappel M, McDonagh AF, et al. Current therapy for Crigler-Najjar syndrome type 1: report of a world registry. Hepatology. Aug 1996;24(2):311-5. [Medline].
Ambrosino G, Varotto S, Strom SC, et al. Isolated hepatocyte transplantation for Crigler-Najjar syndrome type 1. Cell Transplant. 2005;14(2-3):151-7. [Medline].
Fox IJ, Chowdhury JR. Hepatocyte transplantation. Am J Transplant. 2004;4 Suppl 6:7-13. [Medline].
Lysy PA, Najimi M, Stephenne X, Bourgois A, Smets F, Sokal EM. Liver cell transplantation for Crigler-Najjar syndrome type I: update and perspectives. World J Gastroenterol. Jun 14 2008;14(22):3464-70. [Medline].
Dhawan A, Mitry RR, Hughes RD. Hepatocyte transplantation for liver-based metabolic disorders. J Inherit Metab Dis. Apr-Jun 2006;29(2-3):431-5. [Medline].
Nazer H, Al-Mehaidib A, Shabib S, Ali MA. Crigler-Najjar syndrome in Saudi Arabia. Am J Med Genet. Aug 27 1998;79(1):12-5. [Medline].
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].
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].
Miranda PS, Bosma PJ. Towards liver-directed gene therapy for crigler-najjar syndrome. Curr Gene Ther. Apr 2009;9(2):72-82. [Medline].
Nazer H, Gunasekaran TS, Sakati NA, Nyhan WL. Concurrence of Robinow syndrome and Crigler-Najar syndrome in two offspring of first cousins. Am J Med Genet. Dec 1990;37(4):516-8. [Medline].
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].
Vitek L, Muchova L, Zelenka J, et al. The effect of zinc salts on serum bilirubin levels in hyperbilirubinemic rats. J Pediatr Gastroenterol Nutr. Feb 2005;40(2):135-40. [Medline].