eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology
Glucuronyl Transferase Deficiency: Treatment & Medication
Updated: Mar 24, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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 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 transplantation11,12
- 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
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.
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.
Adult
Pediatric
5-10 mg/kg/d PO
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).
Adult
Pediatric
Not established
None reported
Documented hypersensitivity
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
Documented hypersensitivity
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#150;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 |
| References |
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References
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Further Reading
Keywords
glucuronyl transferase deficiency, Crigler-Najjar disease type 1, Crigler-Najjar syndrome type 2, CN syndrome, Arias syndrome, congenital nonhemolytic jaundice, inherited unconjugated hyperbilirubinemias , Gilbert syndrome, phototherapy, kernicterus, bilirubin metabolism, uridine 5 diphosphate glucuronyl transferase activity, UDPG-T, Gilbert syndrome
