eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Glucuronyl Transferase Deficiency

Author: Dena Nazer, MD, Fellow, Child Protection Center, Children's Hospital of Michigan
Coauthor(s): Hisham Nazer, MBBCh, FRCP, Professor of Pediatrics, Consultant in Pediatric Gastroenterology, Hepatology and Clinical Nutrition, Bushnaq Medical Centre, University of Jordan
Contributor Information and Disclosures

Updated: Mar 24, 2008

Introduction

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 CN syndrome a potential disease for gene therapy.⁴ In 2005, new advances in gene therapy were established in Gunn rats, an animal model of CN 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 CN syndrome.⁶ More than 50 mutations that cause Gilbert Syndrome and CN Syndrome have been identified, most of which are missense or nonsense mutations.

Depending on the severity of its effect on the enzymatic activity, CN syndrome type 1 (a complete absence of enzymatic activity) or CN 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

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

International

CN 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 CN 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 CN syndrome type 1 usually present by the second to third week of life. Those with CN syndrome type 2 may present later.

Clinical

History

Crigler-Najjar (CN) syndrome type 1 is the more serious of the 2 forms of CN syndrome, with an almost complete absence of 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 CN 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.

Physical

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

Gilbert syndrome

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 CN 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.

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 CN syndrome type 1, the mode of inheritance is autosomal recessive.
• The mode of inheritance of CN 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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