AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Neonatal jaundice
Breast-mild jaundice
Gilbert syndrome (see Physical)

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

No widely available simple clinical test is available to confirm diagnosis of Crigler-Najjar (CN) syndrome.

• Determination of bilirubin level
• • The unconjugated bilirubin level is elevated, with direct bilirubin less than 15% of the total serum bilirubin. High-performance liquid chromatography analysis of duodenal bile reveals that, in CN syndrome type 1, negligible bilirubin diglucuronides or monoglucoronides are present; in CN syndrome type 2, these conjugates are present but in low concentrations. DNA analysis can be very helpful in establishing the correct diagnosis.
  • Persistent unconjugated hyperbilirubinemia levels of more than 20 mg/dL after the first week of life in the absence of liver disease or hemolysis strongly suggests UGT deficiency.
• Liver function testing
• • Liver enzyme levels are usually within the reference range.
  • Occasionally, liver enzyme levels may be somewhat elevated as a result of intrahepatic cholestasis.

Procedures

Percutaneous liver biopsy: Enzymatic assay of liver tissue reveals absent UGT activity in CN syndrome type 1 and diminished activity in CN Syndrome type 2. Definitive diagnosis of CN syndrome requires high-performance liquid chromatography of bile or tissue enzyme assay of a liver biopsy sample.

Histologic Findings

Liver biopsy reveals normal histology other than the occasional bile plugs in the bile canaliculi. Bile is sometimes observed in the portal triad, in dilated bile canaliculi, in hepatocytes, and in Kupffer cells. Enzymatic assays of the biopsy specimen confirm the almost-absent UGT hepatic activity in CN syndrome type 1.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment of patients with Crigler-Najjar (CN) syndrome is not limited to phototherapy, phenobarbital therapy, or both. Response to treatment varies according to the type of CN syndrome.
 
CN syndrome type 1 does not respond to phenobarbital therapy, and patients may require repeated exchange transfusions followed by long-term phototherapy to prevent neurologic complications. Other therapies include plasmapheresis, hemoperfusion, cholestyramine, calcium phosphate, and oral agar. An approach to therapy using Sn-protoporphyrin, a heme oxygenase inhibitor, was introduced to prevent an increase in serum bilirubin levels.⁸ In patients with CN syndrome type 1, liver transplantation remains the only guaranteed form of therapy.

In contrast, CN syndrome type 2 responds favorably to phenobarbital therapy. A favorable response to phenobarbital supports the diagnosis of CN syndrome type 2. However, rarely, patients with CN syndrome type 2 may require exchange transfusions or long-term phototherapy.

• Phototherapy
• • Phototherapy has been successful in controlling bilirubin levels for years.
  • Phototherapy causes the formation of water-soluble bilirubin isomers that can be secreted in bile without conjugation.
  • Patients with CN syndrome type 1 generally need 10-16 hours of treatment per day. Monitor the intensity of light to a level of at least 4-10 µW/cm²/nm. The appropriate wave length is in the blue-green spectrum at 425-475 nm.
  • The efficacy of phototherapy is dose dependent; therefore, the response to phototherapy increases when the dose is increased. Efficacy of phototherapy can be increased by increasing the intensity of light, by increasing exposure of body surface, and by using reflecting surfaces (eg, mirrors).
  • Double-surface phototherapy has also been used in some cases to improve the outcome.
  • The effectiveness of phototherapy decreases with increasing patient age, and the need for alternative therapy increases.
  • Newer methods of delivering phototherapy, such as sit-up phototherapy units, may reduce phototherapy time by 50% while maintaining effectiveness and, thus, may allow a child to attend school.
  • Long-term phototherapy may lead to developmental delay, impaired weight gain, and possible psychological disturbances.
  • Problems associated with phototherapy include decreased effectiveness with age, restriction of activity and play, poor compliance, inability of the patient to travel or take vacations, irritation from the eye shades, difficulties in temperature maintenance, tanning of the skin, embarrassment from the need to be nearly nude during phototherapy, and difficulty in procuring phototherapy lamps.
• Exchange transfusion
• • Exchange transfusion is used in CN syndrome type 1 to lower unconjugated bilirubin levels to a safe level to prevent kernicterus.
  • Treatment with exchange transfusions and phototherapy should be intensified early to prevent kernicterus due to high levels of unconjugated bilirubin.
• Gene therapy
• • Gene therapy offers the greatest potential for cure for patients with CN syndrome. Successful cloning of the gene responsible for bilirubin glucuronosyltransferase activity offers the hope of future gene therapy to correct this deficiency.
  • Clinically significant improvement can be achieved, even with partial enzyme replacement.
  • Only about 5% of normal UGT 1A1 can significantly lower the plasma bilirubin concentration and decrease the need for phototherapy.
  • Studies of the Gunn rat (deficient in all members of the UGT 1A family) showed long-term correction of hyperbilirubinemia with one injection of helper-dependent adenoviral vectors.⁵ This effect has yet to be proven in humans.

Surgical Care

• Liver transplantation
• • Liver transplantation remains the sole definitive treatment.^{9, 10} Cadaveric orthotopic or auxiliary and living related liver transplantation has resulted in excellent survival rates and prognoses.
  • Patients with CN syndrome type 1 are ideal candidates for auxiliary liver transplantation.
  • Early liver transplantation in patients with CN syndrome type 1 decreases the incidence of neurologic deficits, especially for patients in whom reliable administration of phototherapy cannot be guaranteed.
• Hepatocyte transplantation^{11, 12}
• • Hepatocyte transplantation involves catheterization of the portal vein and an infusion of donor hepatocytes.
  • The immunosuppression regimen is similar to that administered to patients receiving whole-organ transplantation and currently includes tacrolimus and prednisolone.
  • Stem cells and stem cell–derived hepatocytes should offer the potential to overcome the current limitations of both the supply of hepatocytes and the extent of repopulation of the liver after transplantation.¹³
  • Hepatocyte transplantation has been reported to decrease the need for phototherapy and to increase the activity of UGT to 5.5% of normal.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Phenobarbital, ursodeoxycholic acid, calcium (infusions), metalloporphyrins, cholestyramine, chlorpromazine, clofibrate (no longer on US market), and alkalinization of urine have all been considered as potential therapies for patients with Crigler-Najjar syndrome type 1. Problems associated with the use of cholestyramine include taste and concern about bile salt depletion and fat malabsorption. The exact roles and adverse effects of many of these drugs are not yet defined.

Drug Category: Barbiturates

These drugs are used to induce hepatic-enzyme metabolism to decrease serum bilirubin levels.

Drug Category: Metalloporphyrins

These agents are used as a synthetic analog of heme to inhibit the heme oxygenase enzyme, the rate-limiting step in heme catabolism to bilirubin.

Drug Category: Calcium supplements

These agents bind bilirubin in the gut and, thus, enhance its fecal excretion.

Drug Category: Naturally occurring bile acids

Ursodiol partially replaces the circulating pool of endogenous bile acids with ursodeoxycholic acid, which is highly hydrophilic, and, thus, replaces toxic detergent bile acids (eg, chenodeoxycholic acid, lithocholic acid). This effect may enhance the biliary excretion of the toxic bile acids and may protect cells against liver-cell toxicity induced by detergent bile acids.

Drug Category: Phenothiazines

These drugs are used in the therapy of acute intermittent porphyria, psychotic disorders, nausea, and vomiting.

Drug Category: Antihyperlipidemic agents

Clofibrate has been used for its effect in reducing bilirubin in newborns.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Despite medical treatment, patients are at risk for sudden rises in serum bilirubin levels.
• Parents and physicians should be alert to such bilirubin crises.
• • The child usually presents with altered sensorium, incoordination, slurring of speech, and weakness. Coma may eventually occur.
  • Treatment of severe episodes of hyperbilirubinemia includes intense phototherapy, exchange transfusion, plasmapheresis, and tin mesoporphyrin.
  • During periods of illness, kernicterus may occur at a low level of bilirubin.

Deterrence/Prevention

• Use drugs that displace bilirubin, such as sulfa, salicylates, furosemide, ampicillin, and ceftriaxone, with caution (or completely avoid).
• The bilirubin level may rapidly rise to dangerous levels under certain conditions, such as fasting, infections, trauma, fever, and poor compliance with therapy.

Complications

• Complications arise from both the disease itself and the various methods of treatment.
• Most, if not all, patients with Crigler-Najjar (CN) syndrome type 1 eventually develop some neurologic deficit despite treatment.
• Phototherapy restricts the life of the child and his or her family. Phototherapy also causes insensible water loss, diarrhea, tanning of the skin, and problems in maintaining body temperature.
• Adverse effects of transplantation include rejection, bleeding, infections, hepatic-artery thrombosis, and bile-duct leaks. Long-term immunosuppressive therapy and recurrent hospitalization are recognized problems in treatment after transplantation.

Patient Education

• Educate patients and families about the chronicity of the disease and the need for life-long treatment. Instruct them to immediately report any change in the patient's mental or neurological status.
• Genetic counseling is recommended for prospective parents with a family history of CN syndrome.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Special Concerns

• Crigler-Najjar (CN) syndrome remains a potentially fatal condition unless diagnosed early and managed appropriately.¹⁴
• Early neurologic symptoms may improve if therapy is immediately intensified.
• Newly developed intragenic polymorphic probes may facilitate carrier detection as well as prenatal and presymptomatic diagnosis in the near future.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. 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].
2. 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].
3. 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].
4. 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].
5. 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].
6. Jansen PL. Diagnosis and management of Crigler-Najjar syndrome. Eur J Pediatr. Dec 1999;158 Suppl 2:S89-94. [Medline].
7. 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].
8. 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].
9. 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].
10. 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].
11. 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].
12. Fox IJ, Chowdhury JR. Hepatocyte transplantation. Am J Transplant. 2004;4 Suppl 6:7-13. [Medline].
13. 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].
14. 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].
15. 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].
16. 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].
17. 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].
18. 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].
19. 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].

Article Last Updated: Mar 24, 2008