Crigler-Najjar Syndrome 

  • Author: Praveen K Roy, MD, AGAF; Chief Editor: Julian Katz, MD   more...
 
Updated: Jan 6, 2010
 

Background

Crigler-Najjar syndrome (CNS) is a rare autosomal recessive disorder of bilirubin metabolism. Two distinct forms have been described, as follows: type 1 and type 2. Type 1 Crigler-Najjar syndrome, first described in 1952 by Crigler and Najjar, is associated with neonatal unconjugated hyperbilirubinemia (high levels) and kernicterus. Type 2 Crigler-Najjar syndrome (also called Arias syndrome), first described in 1962 by Arias, presents with a lower serum bilirubin level and responds to phenobarbital treatment.

The differential diagnosis of hyperbilirubinemia can be divided into 3 broad groups: (1) disorders of excessive bilirubin production (eg, hemolysis, ineffective erythropoiesis), (2) impaired hepatic handling of bilirubin (eg, hepatitis, cirrhosis, inherited syndromes), and (3) defective bile outflow (eg, intrahepatic or extrahepatic biliary obstruction).

A markedly elevated unconjugated (indirect) hyperbilirubinemia is observed in inherited disorders such as Gilbert syndrome and Crigler-Najjar syndrome. Among the inherited unconjugated hyperbilirubinemias, Gilbert syndrome is believed to affect approximately 3-7% of the adult population. Crigler-Najjar syndrome is a much rarer disorder, with only a few hundred cases described in the literature.

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Pathophysiology

Effective elimination of bilirubin requires its conversion to polar derivatives. In humans, conjugation of bilirubin with the sugar molecule glucuronic acid accomplishes this conversion in a process called glucuronidation.

Crigler-Najjar syndrome is elicited by a lack or deficiency of the enzyme uridine diphosphate glycosyltransferase (UGT). Type 1 Crigler-Najjar syndrome is associated with an almost complete absence of the enzyme, which results in very high levels of unconjugated hyperbilirubinemia (up to 50 mg/dL) at birth. Lower levels of serum bilirubin (up to 20 mg/dL) and markedly depressed activity of hepatic UGT are characteristic of type 2 Crigler-Najjar syndrome (Arias syndrome). Importantly, treatment with phenobarbital can induce the expression of UGT in patients with type 2 Crigler-Najjar syndrome, with a decrease in the serum bilirubin level of approximately 25%.

Crigler-Najjar syndrome is caused by alterations in the coding sequence of UGT. This results in complete absence of UGT or the presence of abnormal UGT with reduced or no enzyme activity. In contrast, in Gilbert syndrome, the defect is in the promoter region of UGT, and reduced amounts of the normal protein are produced.

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Epidemiology

Frequency

United States

Crigler-Najjar syndrome is an extremely rare disorder that follows an autosomal recessive pattern of inheritance. Incidence is less than 1 case per 1,000,000 births. Only a few hundred cases have been described in the world literature, and the real prevalence is unknown.

Mortality/Morbidity

If left untreated, type 1 Crigler-Najjar syndrome is uniformly lethal secondary to the development of kernicterus by age 2 years. Although much rarer, bilirubin encephalopathy can also occur in type 2 Crigler-Najjar syndrome, usually when patients experience a superimposed infection or stress.

Race

Crigler-Najjar syndrome is thought to affect all races equally.

Sex

Crigler-Najjar syndrome occurs in both sexes equally.

Age

If left untreated, type 1 Crigler-Najjar syndrome is uniformly lethal secondary to the development of kernicterus by age 2 years. Although much rarer, bilirubin encephalopathy can also occur in type 2 Crigler-Najjar syndrome, usually when patients experience a superimposed infection or stress.

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Contributor Information and Disclosures
Author

Praveen K Roy, MD, AGAF  Gastroenterologist, Oschner Clinic Foundation; Clinical Assistant Professor of Medicine, University of New Mexico School of Medicine; Comments and Criticisms Editor, Cochrane Colorectal Cancer Group; Adjunct Associate Research Scientist, Lovelace Respiratory Research Institute; Editor-in-Chief, The Internet Journal of Gasteroenterology; Editorial Board, Signal Transduction Insights; Editorial Board, The Internet Journal of Epidemiology; Editorial Board, Gastrointestinal Endoscopy Review Letter

Praveen K Roy, MD, AGAF is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Coauthor(s)

Mohamed Othman, MD  Resident Physician, Department of Internal Medicine, University of New Mexico School of Medicine

Disclosure: Nothing to disclose.

Alessio Pigazzi, MD  PhD, Head, Minimally Invasive Surgery Program, Division of Surgery, Department of General Oncologic Surgery, City of Hope National Medical Center

Disclosure: Nothing to disclose.

Jack Bragg, DO  Associate Professor, Department of Clinical Medicine, University of Missouri School of Medicine

Jack Bragg, DO is a member of the following medical societies: American College of Osteopathic Internists and American Osteopathic Association

Disclosure: Nothing to disclose.

Gautam Dehadrai, MD  Department Chair, Section Chief, Department of Interventional Radiology, Norman Regional Hospital

Gautam Dehadrai, MD is a member of the following medical societies: American College of Radiology, Medical Council of India, and Radiological Society of North America

Disclosure: Nothing to disclose.

Showkat Bashir, MD  Assistant Professor, Department of Medicine, Division of Gastroenterology, George Washington University, Washington, DC

Showkat Bashir, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Tushar Patel, MB, ChB  Professor of Medicine, Ohio State University Medical Center

Tushar Patel, MB, ChB is a member of the following medical societies: American Association for the Study of Liver Diseases and American Gastroenterological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

BS Anand, MD  Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD  Clinical Professor of Medicine, Drexel University College of Medicine; Consulting Staff, Department of Medicine, Section of Gastroenterology and Hepatology, Hospital of the Medical College of Pennsylvania

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

References

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