eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology

Glucuronyl Transferase Deficiency: Treatment & Medication

Author: Dena Nazer, MD, Medical Director, Child Protection Center, Children's Hospital of Michigan; Assistant Professor, Wayne State University
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
Contributor Information and Disclosures

Updated: Jan 11, 2010

Treatment

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 Crigler-Najjar syndrome.

Crigler-Najjar 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 Crigler-Najjar syndrome type 1, liver transplantation remains the only guaranteed form of therapy.

In contrast, Crigler-Najjar syndrome type 2 responds favorably to phenobarbital therapy. A favorable response to phenobarbital supports the diagnosis of Crigler-Najjar syndrome type 2. However, rarely, patients with Crigler-Najjar 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 Crigler-Najjar 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 Crigler-Najjar 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 therapy9
    • Gene therapy offers the greatest potential for cure for patients with Crigler-Najjar 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 uridinediphosphoglucuronate glucuronosyltransferase (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.10,11 Cadaveric orthotopic or auxiliary and living related liver transplantation has resulted in excellent survival rates and prognoses.
    • Patients with Crigler-Najjar syndrome type 1 are ideal candidates for auxiliary liver transplantation.
    • Early liver transplantation in patients with Crigler-Najjar syndrome type 1 decreases the incidence of neurologic deficits, especially for patients in whom reliable administration of phototherapy cannot be guaranteed.
  • Hepatocyte transplantation12,13,14
    • 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.15
    • Hepatocyte transplantation has been reported to decrease the need for phototherapy and to increase the activity of UGT to 5.5% of normal.

Medication

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 (CN) 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.

Barbiturates

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


Phenobarbital (Solfoton)

Functions by means of phenobarbital-responsive enhancer module that stimulates gene for UGT 1A1 to induce production of bilirubin-conjugating enzyme; does not directly act on UGT enzyme as previously thought. Used to treat CN syndrome type 2 and as adjunct to phototherapy in some cases of CN syndrome type 1. Considered effective when bilirubinemia decreases by two thirds after 2-3 wk of therapy.

May decrease effects of chloramphenicol, digitoxin, corticosteroids, carbamazepine, theophylline, verapamil, metronidazole, and anticoagulants (patients whose conditions are stabilized with anticoagulants may require dose adjustments if added to or withdrawn from regimen); coadministration with alcohol may produce additive CNS effects and death; chloramphenicol, valproic acid, and MAOIs may increase toxicity; rifampin may decrease effects; induction of microsomal enzymes may result in decreased effects of PO contraceptives in women (must use additional contraception to prevent unwanted pregnancy; menstrual irregularities may occur)

Documented hypersensitivity; porphyria; marked impairment of liver; respiratory disease when dyspnea or obstruction present

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

In prolonged therapy, evaluate hematopoietic, renal, hepatic, and other organ systems; caution in fever, hyperthyroidism, diabetes mellitus, and severe anemia (adverse reactions can occur); caution in myasthenia gravis and myxedema

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.


Tin mesoporphyrin (SnMp)

DOC for clinical use because of its increased potency, stability, and photophysical properties. In animal studies, more stable and potent than tin protoporphyrin, another heme oxygenase inhibitor (enzyme involved in converting heme to bile pigments).

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Reversible photosensitivity, iron deficiency anemia

Calcium supplements

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


Calcium phosphate (Posture)

May reduce plasma bilirubin concentration in CN syndrome type 1 and may be a useful adjunct to phototherapy in reducing serum bilirubin level.

Adult

Pediatric

100 mmol (elemental calcium) PO qd administered as mixture of calcium salts containing half calcium carbonate and half calcium phosphate

May decrease effects of tetracyclines, atenolol, salicylates, iron salts, and fluoroquinolones; large intakes of dietary fiber may decrease calcium absorption and levels

Documented hypersensitivity; renal calculi; hypercalcemia; hypophosphatemia; renal or cardiac disease; digitalis toxicity

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Constipation, GI upset, hypertension, cardiac arrhythmias, venous thrombosis

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.


Ursodeoxycholic acid (Actigall, Urso)

Also called ursodiol. Decreases liver enzymes (by decreasing liver-cell toxicity) and, therefore, recommended in chronic liver disease. Routine administration in CN syndrome not universally adopted.

Adult

Pediatric

10-15 mg/kg/d PO divided tid/qid

Antacids, charcoal, cholestyramine, and colestipol interfere with absorption

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Diarrhea, pruritus, transient rise in liver function results, and hypercholesterolemia; caution in chronic liver disease, peptic ulcer, and inflammatory bowel disease

Phenothiazines

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


Chlorpromazine (Thorazine)

Usually used to treat acute intermittent porphyria, psychotic disorders, nausea, and vomiting. Recommended as adjunct to phototherapy to treat CN syndrome type 1.

Adult

Pediatric

<6 months: Contraindicated
>6 months: 0.5-1 mg/kg/dose PO tid/qid; not to exceed 25 mg/dose

Other CNS depressants, anticholinergics, or anticonvulsants; antihypertensives may cause additive effect; coadministration with epinephrine may cause hypotension

Documented hypersensitivity; bone-marrow suppression; narrow-angle glaucoma; severe liver or cardiac disease; age <6 mo

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in epilepsy, chronic respiratory disease, cardiovascular disorders, glaucoma, and hepatic encephalopathy

Antihyperlipidemic agents

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


Clofibrate (Atromid-S)

No longer on US market. Used as adjunct to phototherapy. Antihyperlipidemic agent that decreases serum lipids by reducing levels of very low–density lipoprotein, LDL, and triglycerides.

Adult

Pediatric

Not established; data limited; 50 mg/kg/d PO; may increase to 100-150 mg/kg/d if necessary

Increases hypoglycemic effect, adjust dose of insulin or PO hypoglycemic agents; increases warfarin effect; coadministration with HMG-CoA reductase inhibitors (eg, simvastatin, pravastatin) increases the risk of rhabdomyolysis

Documented hypersensitivity; primary biliary cirrhosis; hepatic or renal dysfunction

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use for short duration because may increased risk of malignancy and cholelithiasis; may cause myalgia, myositis, myopathy, or rhabdomyolysis (with or without CK elevation); caution in history of MI or peptic ulcer disease; monitor blood glucose levels

More on Glucuronyl Transferase Deficiency

Overview: Glucuronyl Transferase Deficiency
Differential Diagnoses & Workup: Glucuronyl Transferase Deficiency
Treatment & Medication: Glucuronyl Transferase Deficiency
Follow-up: Glucuronyl Transferase Deficiency
Multimedia: Glucuronyl Transferase Deficiency
References
[ CLOSE WINDOW ]

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. 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].

  10. 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].

  11. 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].

  12. 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].

  13. Fox IJ, Chowdhury JR. Hepatocyte transplantation. Am J Transplant. 2004;4 Suppl 6:7-13. [Medline].

  14. 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].

  15. 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].

  16. 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].

  17. 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].

  18. 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].

  19. Miranda PS, Bosma PJ. Towards liver-directed gene therapy for crigler-najjar syndrome. Curr Gene Ther. Apr 2009;9(2):72-82. [Medline].

  20. 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].

  21. 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].

  22. 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].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

glucuronyl transferase deficiency, Crigler-Najjar disease type 1, Crigler-Najjar syndrome type 2, CN syndrome, Arias syndrome, congenital nonhemolytic jaundice, inherited unconjugated hyperbilirubinemias, treatment, diagnosis, symptoms

[ CLOSE WINDOW ]

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.

Medical Editor

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.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

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.

CME Editor

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.

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.