AUTHOR INFORMATION

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Authored by Praveen K Roy, MD, Assistant Professor of Medicine, Associate Director of Research, Division of Gastroenterology, Department of Internal Medicine, University of Missouri at Columbia; Chief of Gastroenterology, Harry Truman Veteran Affairs Memorial Hospital

Coauthored by Mohamed Othman, MD, Staff Physician, Department of Internal Medicine, University of New Mexico School of Medicine; Alessio Pigazzi, MD, PhD, Head, Minimally Invasive Surgery Program, Division of Surgery, Department of General Oncologic Surgery, City of Hope National Medical Center

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

Edited by Tushar Patel, MD, Associate Professor, Department of Internal Medicine, Texas A&M College of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; BS Anand, MD, Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor University College of Medicine; Alex J Mechaber, MD, FACP, Assistant Dean for Medical Curriculum, Associate Professor of Medicine, Division of General Internal Medicine, University of Miami Miller School of Medicine; and 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

Author's Email:	Praveen K Roy, MD
Editor's Email:	Tushar Patel, MD

eMedicine Journal, August 8 2006, VOLUME 7, Number 8

INTRODUCTION

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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 CNS, first described in 1952 by Crigler and Najjar, is associated with neonatal unconjugated hyperbilirubinemia (high levels) and kernicterus. Type 2 CNS (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 CNS. Among the inherited unconjugated hyperbilirubinemias, Gilbert syndrome is believed to affect approximately 3-7% of the adult population. CNS is a much rarer disorder, with only a few hundred cases described in the literature.

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.

CNS is elicited by a lack or deficiency of the enzyme uridine diphosphate glycosyltransferase (UGT). Type 1 CNS 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 CNS (Arias syndrome). Importantly, treatment with phenobarbital can induce the expression of UGT in patients with type 2 CNS, with a decrease in the serum bilirubin level of approximately 25%.

CNS 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.

Frequency:

• In the US: CNS 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 CNS is uniformly lethal secondary to the development of kernicterus by age 2 years. Although much rarer, bilirubin encephalopathy can also occur in type 2 CNS, usually when patients experience a superimposed infection or stress.

Race: CNS is thought to affect all races equally.

Sex: CNS occurs in both sexes equally.

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

CLINICAL

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History: Because of its autosomal recessive transmission, consanguinity is a risk factor for CNS, especially type 1 CNS.

Physical: Persistent jaundice is present at or soon after birth in type 1 CNS. Jaundice may not manifest until later in infancy or childhood in type 2 CNS. Kernicterus is the most worrisome consequence of hyperbilirubinemia and occurs in virtually all patients with untreated type 1 CNS, especially in the first few days of life. Bilirubin encephalopathy is rare in patients with type 2 CNS, but it can be induced by factors such as infection, anesthesia, or drug use. Clinical manifestations of kernicterus are hypotonia, deafness, oculomotor palsy, lethargy, and, ultimately, death.

Causes: Both type 1 CNS and type 2 CNS are transmitted by autosomal recessive inheritance. Alterations in the coding sequence of the UGT1 gene result in absent or reduced UGT activity, with marked impairment of bilirubin conjugation. The UGT1 gene is located on 2q37. Several isoforms of UGT1 enzyme exist based on the variability in the amino-terminal region of the final protein. These differences are the result of alternative splicing among 10 different types of exon 1 at the 5' end of the UGT1 gene and constant exons 2-5 at the 3' end. Thus, the different UGT1 isoforms are distinguished according to the type of exon 1 they contain.

DIFFERENTIALS

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Gilbert Syndrome

Other Problems to be Considered:

Hemolytic disorders
Neonatal jaundice
Breast milk jaundice

WORKUP

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Lab Studies:

• Unconjugated hyperbilirubinemia in the presence of normal liver function test findings is characteristic of CNS. The usual bilirubin level is 17-50 mg/dL in type 1 CNS and 6-22 mg/dL in type 2. Higher bilirubin levels may be seen in type 2 CNS if coexisting hemolysis or intercurrent illness is present.



• Transferase activity measurements and the response to phenobarbital treatment distinguish type 1 CNS from type 2. Phenobarbital has no effect in type 1 CNS but causes an approximately 25% reduction in plasma bilirubin level in most patients with type 2 CNS.

Imaging Studies:

• Findings on abdominal imaging studies, such as plain x-rays, CT scan, or ultrasound, are normal in CNS.

TREATMENT

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Medical Care: Patients with type 2 CNS may not require any treatment or can be managed with phenobarbital. By contrast, prompt treatment of kernicterus is required in patients with type 1 CNS to avoid the potentially devastating neurological sequelae.

• Emergent management of bilirubin encephalopathy involves plasma exchange transfusion, which acts by removing the bilirubin-saturated albumin and provides free protein, which draws bilirubin from the tissues.



• Plasma exchange should be accompanied by long-term phototherapy, which helps in the conversion of bilirubin to more soluble isoforms that can be excreted in the urine. Oral calcium phosphate may be a useful adjuvant to phototherapy in type 1 CNS.



• Therapies based on gene and cell transfer techniques, although largely experimental at the present time, are likely to play an important role in the management of CNS in the future.



• Inhibitors of heme oxygenase, such as tin protoporphyrin or tin-mesoporphyrin, may be helpful in reducing bilirubin levels emergently, but the effect is short-lived.

Surgical Care: Liver transplantation has been attempted in select patients with type 1 CNS and has achieved good success rates.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Barbiturates -- Used to avoid potentially devastating neurological sequelae in type 1 CNS and for the management of neurological symptoms in type 2 CNS.

Drug Name	Phenobarbital (Luminal, Barbita) -- Interferes with the transmission of impulses from the thalamus to the cerebral cortex.
Adult Dose	30-120 mg PO/IV bid/tid
Pediatric Dose	3-6 mg/kg/d PO/IV
Contraindications	Documented hypersensitivity, severe respiratory disease, marked impairment of liver function, patients with nephritis
Interactions	Coadministration with alcohol may produce additive central nervous system effects and death; chloramphenicol and MAOIs may increase its effect; MAOIs may enhance sedative effects of barbiturates; may decrease chloramphenicol effects; rifampin may decrease its effect; valproic acid appears to decrease barbiturate metabolism and increase toxicity; barbiturates can decrease effects of anticoagulants, and patients stabilized on anticoagulants may require dose adjustments if barbiturates are added to or withdrawn from their regimen; may decrease serum carbamazepine levels; decreased effect of contraceptives may occur because of induction of microsomal enzymes; in women, menstrual irregularities and pregnancy may occur; barbiturates may decrease corticosteroid effects by inducing hepatic microsomal enzymes; barbiturates may increase digitoxin metabolism; may decrease antimicrobial effects of metronidazole; barbiturates decrease theophylline levels possibly resulting in decreased effectiveness; may decrease bioavailability of verapamil
Pregnancy	D - Unsafe in pregnancy
Precautions	During prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; exercise caution in the presence of fever, hyperthyroidism, diabetes mellitus, and severe anemia because adverse reactions can occur; caution in myasthenia gravis, myxedema, and depression; may be habit forming

FOLLOW-UP

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Complications:

• Prompt treatment of kernicterus in patients with type 1 CNS is required to prevent development of potentially devastating neurological sequelae.

Prognosis:

• Untreated type 1 CNS is uniformly lethal by age 2 years, secondary to the development of kernicterus.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Failure to make the diagnosis



• Failure to promptly and properly treat the condition



• Failure to consider concomitant illnesses

TEST QUESTIONS

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CME Question 1: Currently, which of the following is not a commonly accepted treatment for Crigler-Najjar syndrome (CNS)?

A: Phenobarbital
B: Long-term phototherapy
C: Plasma exchange transfusion
D: Therapies based on gene and cell transfer techniques
E: Liver transplantation

The correct answer is D: Therapies based on gene and cell transfer techniques are experimental at the present time but are likely to play an important role in the management of CNS in the future.

CME Question 2: Which of the following is a clinical manifestation of kernicterus?

A: Hypotonia
B: Deafness
C: Oculomotor palsy
D: Death
E: All of the above

The correct answer is E: Clinical manifestations of kernicterus are hypotonia, deafness, oculomotor palsy, lethargy, and, ultimately, death.

Pearl Question 1 (T/F): Crigler-Najjar syndrome (CNS) is an extremely rare disorder that follows an autosomal recessive pattern of inheritance.

The correct answer is True: Only a few hundred cases of CNS have been described in the world literature, and the real prevalence is unknown.

Pearl Question 2 (T/F): Findings of abdominal imaging by plain x-rays, CT scan, and ultrasound are abnormal in patients with Crigler-Najjar syndrome (CNS).

The correct answer is False: Plain x-rays, CT scan, and ultrasound findings are normal in CNS.

Pearl Question 3 (T/F): Unconjugated hyperbilirubinemia with normal liver function test results is characteristic of Crigler-Najjar syndrome (CNS).

The correct answer is True: The bilirubin level is 17-50 mg/dL in type 1 CNS and 6-22 mg/dL in type 2.

Pearl Question 4 (T/F): Liver histology findings are abnormal in Crigler-Najjar syndrome (CNS).

The correct answer is False: Liver histology findings are characteristically normal in CNS.

BIBLIOGRAPHY

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• Arias IM, Gartner LM, Cohen M: Chronic nonhemolytic unconjugated hyperbilirubinemia with glucuronyl transferase deficiency. Clinical, biochemical, pharmacologic and genetic evidence for heterogeneity. Am J Med 1969 Sep; 47(3): 395-409[Medline].
• Costa E: Hematologically important mutations: bilirubin UDP-glucuronosyltransferase gene mutations in Gilbert and Crigler-Najjar syndromes. Blood Cells Mol Dis 2006 Jan-Feb; 36(1): 77-80[Medline].
• Gupta R, Parashar Y: Crigler-najjar syndrome type II. Indian J Pediatr 2004 Nov; 71(11): 1043[Medline].
• Jansen PL: Genetic diseases of bilirubin metabolism: the inherited unconjugated hyperbilirubinemias. J Hepatol 1996 Sep; 25(3): 398-404[Medline].
• Jansen PL: Diagnosis and management of Crigler-Najjar syndrome. Eur J Pediatr 1999 Dec; 158 Suppl 2: S89-94[Medline].
• 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 2000 May; 105(5): 1152-3[Medline].
• Nowicki MJ, Poley JR: The hereditary hyperbilirubinaemias. Baillieres Clin Gastroenterol 1998 Jun; 12(2): 355-67[Medline].
• Owens IS, Basu NK, Banerjee R: UDP-glucuronosyltransferases: gene structures of UGT1 and UGT2 families. Methods Enzymol 2005; 400: 1-22[Medline].
• Petit FM, Gajdos V, Francoual J: Allelic heterogeneity of Crigler-Najjar type I syndrome: a study of 24 cases. Clin Genet 2004 Dec; 66(6): 571-2[Medline].
• Sampietro M, Iolascon A: Molecular pathology of Crigler-Najjar type I and II and Gilbert's syndromes. Haematologica 1999 Feb; 84(2): 150-7[Medline].
• Servedio V, d'Apolito M, Maiorano N: Spectrum of UGT1A1 mutations in Crigler-Najjar (CN) syndrome patients: identification of twelve novel alleles and genotype-phenotype correlation. Hum Mutat 2005 Mar; 25(3): 325[Medline].
• Shevell MI, Majnemer A, Schiff D: Neurologic perspectives of Crigler-Najjar syndrome type I. J Child Neurol 1998 Jun; 13(6): 265-9[Medline].
• Sleisenger MH, Fordtran JS: Gastrointestinal Disease. Philadelphia, Pa: WB Sanders Company; 1993: Chapter 85.
• Takeuchi K, Kobayashi Y, Tamaki S: Genetic polymorphisms of bilirubin uridine diphosphate-glucuronosyltransferase gene in Japanese patients with Crigler-Najjar syndrome or Gilbert's syndrome as well as in healthy Japanese subjects. J Gastroenterol Hepatol 2004 Sep; 19(9): 1023-8[Medline].

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