eMedicine Specialties > Pediatrics: General Medicine > Gastroenterology
Alagille Syndrome: Treatment & Medication
Updated: Oct 22, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
- Correction of vitamin deficiencies with appropriate vitamin dosage is important for optimal growth and development in patients with Alagille syndrome (AS). Water miscible forms of vitamins A, D, E, and K frequently are poorly absorbed. Complexes of vitamins A, D, E, and K with polyethylene glycol compounds (TPGS) are generally well tolerated by patients and are better absorbed. Zinc deficiency is sometimes observed; zinc is easily replaced via oral compounds.
- Some decreases in the degree of hyperlipidemia have been treated with cholestyramine.
- Pruritus is often recalcitrant to medical therapy and significantly impacts on the quality of life. Trials of antihistamine agents, such as hydroxyzine and diphenhydramine, are helpful to some patients. Several studies have noted beneficial effects of either cholestyramine (12-15 g/d) or rifampin in management of bile acid-induced pruritus found in patients with Alagille syndrome.12
- A cardiologist should manage cases of clinically significant cardiac disease.
- All patients, except those with peripheral pulmonic stenosis, require subacute bacterial endocarditis (SBE) prophylaxis.
- Screening for other vascular anomalies, such as aneurysms or stenoses, such be considered.
- Administer standard immunizations along with the hepatitis A vaccine to patients with liver manifestations. Also administer the multivalent pneumococcal vaccine to these patients, particularly if ascites is present due to the risk for spontaneous bacterial peritonitis.
Surgical Care
- The exclusion of the diagnosis of extrahepatic biliary atresia (EHBA) via exploratory laparotomy and intraoperative cholangiography is not infrequent in patients with Alagille syndrome. Some studies have noted that 3-5% of patients undergoing the Kasai procedure for EHBA are eventually diagnosed with nonsyndromic bile duct paucity or Alagille syndrome.
- Surgical management for bile acid–induced pruritus includes biliary diversion and eventual orthotopic liver transplantation for those with refractory disease.13 Whitington et al reported a series of patients treated with partial external biliary diversion for pruritus associated with Alagille syndrome.14 They noted a decrease in bile salt concentrations and some abatement of pruritus and xanthomas; however, the results for the patients with Alagille syndrome were less striking than with other preoperative diagnoses, including progressive familial intrahepatic cholestasis.
- Indications for consideration of liver transplantation include the following:15
- Progressive hepatic dysfunction
- Severe portal hypertension
- Failure to thrive
- Intractable pruritus and osteodystrophy
- Estimated 20-year survival rates are 80% for those not requiring liver transplantation and 60% for those requiring transplantation.
- Patients with more serious cardiovascular anomalies, including tetralogy of Fallot, ventricular septal defect (VSD) with pulmonary atresia (PA), atrial septal defect (ASD) and VSD, and patent ductus arteriosus (PDA), are likely to eventually require cardiac surgery. The 20-year predicted survival by Kaplan-Meier plots for those with significant intracardiac lesions is 40%; the 20-year predicted survival for those without intracardiac lesions is 80%.
Consultations
- Subspecialty consultation may facilitate diagnosis and provide long-term care.
- Consultation with an ophthalmologist may provide the diagnosis.
- A pediatric hepatologist can assist with management of chronic cholestatic liver disease.
- Consultation with a cardiologist can assist with the diagnosis of Alagille syndrome and therapy for intracardiac disease, as well as other vascular abnormalities.
- Consultation with a nephrologist is indicated if significant structural renal disease is present or if suspicions of evolving renal insufficiency arise.
Diet
- Diets higher in carbohydrates and medium chain triglycerides are generally absorbed better in patients with Alagille syndrome.
- Consider drip feeds via nasogastric tube or gastrostomy in patients with poor weight gain and increased caloric requirements secondary to malabsorption and cholestasis or cardiac disease.
- Patients with Alagille syndrome and cholestasis may develop essential fatty acid deficiency if not appropriately supplemented.
- Supplementation of fat-soluble vitamins is necessary.
Activity
- Activity is not limited unless patient also has significant intracardiac disease.
- Patients with evidence of hypersplenism should avoid contact sports.
Medication
Medications are used to manage bile acid-induced pruritus and supplement fat-soluble vitamin stores.
Antipruritics
Pruritus is often recalcitrant to medical therapy and significantly impacts on the quality of life.
Hydroxyzine (Atarax, Vistaril)
Useful adjunct in the management of pruritus with histamine-mediated triggers. Antagonizes H1-receptors in periphery. May suppress histamine activity in subcortical region of CNS.
Adult
25 mg PO tid/qid
Pediatric
0.6 mg/kg/dose PO q6h
CNS depression may increase with alcohol or other CNS depressants
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
Associated with clinical exacerbations of porphyria (may not be safe for porphyric patients); ECG abnormalities (alterations in T waves) may occur; may cause drowsiness; caution in early pregnancy (when given in substantial doses to pregnant mice, it induced fetal abnormalities); not to be administered IV/SC/IA (thrombosis and digital gangrene can occur); caution in angle-closure glaucoma, peptic ulcer, urinary tract obstruction, and hyperthyroidism
Cholestyramine (Questran)
Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts. Take other medications at least 1 h before or 4-6 h after cholestyramine.
Not to be administered in dry powder form. Mix with plenty of water or applesauce.
Adult
3-4 g PO tid/qid; not to exceed 16-32 g/d PO divided bid/qid
Pediatric
240 mg/kg/d PO divided tid
Inhibits absorption of numerous drugs including warfarin, fat-soluble vitamins, thyroid hormone, phenylbutazone, amiodarone, NSAIDs, methotrexate, digitalis glycosides, glipizide, phenytoin, imipramine, niacin, methyldopa, tetracyclines, clofibrate, hydrocortisone, penicillin G, hormonal replacements
Documented hypersensitivity; complete biliary obstruction
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 patients with constipation and phenylketonuria; may result in fat-soluble vitamin deficiencies (hypoprothrombinemia), hyperchloremic acidosis (chloride form of anion exchange resin), and intestinal obstruction
Rifampin (Rifadin, Rimactane)
Precise mechanism of action is unclear. May involve inhibition of bile acid uptake into hepatocytes and facilitation of excretion of dihydroxy and monohydroxy bile acids and toxic bile acids.
Adult
300 mg/d PO qd or divided bid
Pediatric
10 mg/kg/d PO qd or divided bid; not to exceed adult dose
Induces microsomal enzymes, which may decrease effects of acetaminophen, PO anticoagulants, barbiturates, benzodiazepines, beta-blockers, chloramphenicol, PO contraceptives, corticosteroids, mexiletine, cyclosporine, digitoxin, disopyramide, estrogens, hydantoins, methadone, clofibrate, quinidine, dapsone, tazobactam, sulfonylureas, theophyllines, tocainide, and digoxin; blood pressure may increase with coadministration of enalapril; coadministration with isoniazid may result in higher rate of hepatotoxicity than with either agent alone (discontinue one or both agents if alterations in LFT results occur); cotrimoxazole and probenecid may increase blood level
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
Obtain CBC counts and baseline clinical chemistries prior to and throughout therapy; in liver disease, weigh benefits against risk of further liver damage; interruption of therapy and high-dose intermittent therapy are associated with thrombocytopenia that is reversible if therapy is discontinued as soon as purpura occurs; if treatment is continued or resumed after appearance of purpura, cerebral hemorrhage or death may occur; may cause reddish-orange discoloration to tears, saliva, urine, and sweat; may permanently stain soft contact lenses
Fat-soluble vitamins
These vitamins are used for supplementation of vitamin A, D, E, and K losses.
Phytonadione (AquaMEPHYTON)
Vitamin K-1 is necessary for the production of factors II, VII, IX, and X by serving as a cofactor during carboxylation of glutamic acid residues.
Adult
Correction of coagulopathy: up to 10 mg IV qd for 3-5 d, then switch to PO
Chronic supplementation: 10 mg PO qd or divided bid
Pediatric
Correction of coagulopathy: 2.5-10 mg IV qd for 3-5 d, then switch to PO
Chronic supplementation: 2.5-10 mg PO qd
Effects of warfarin sodium and dicumarol are antagonized by phytonadione
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
Transient flushing sensations and taste abnormalities have been noted during parenteral administration, as well as rare occurrences of dizziness, brief hypotension, and cyanosis; hyperbilirubinemia reported in infants given parenteral phytonadione at doses above standard guidelines; patients with elevated PT/PTT may bleed into muscle following IM injection; rate of infusion not to exceed 1 mg/min
Vitamin E (Nutr-E-Sol)
Antioxidant that prevents the oxidation of vitamins A and C. Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects RBCs against hemolysis. Nutr-E-Sol is a specially formulated vitamin E complex with polyethylene glycol 1000 succinate to allow direct absorption without biliary emulsification. Formulation of choice for vitamin E replacement therapy in patients with cholestasis. The formulation contains 400 IU vitamin E/15 mL.
Adult
400-1200 IU (15-45 mL) PO qd; based on monitoring of levels
Pediatric
15-25 IU/kg/d; based on monitoring of levels
Mineral oil decreases absorption of vitamin E; vitamin E delays absorption of iron and increases effects of anticoagulants
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Pregnancy factor with large doses of vitamin E is C; vitamin E may induce vitamin K deficiency; NEC may occur when large doses of vitamin E are given; in neonates, increased intraventricular hemorrhage, NEC, sepsis, and hepatic toxicity may occur if administered in large IV doses
Ergocalciferol (Calciferol, Drisdol)
Also referred to as vitamin D-2. Undergoes metabolic activation in vivo to the biologically active form 1,25-dihydroxyergocalciferol (1,25[OH]2 -D2). Stimulates absorption of calcium and phosphate from the intestines and promotes release of calcium from bone into blood. Ergocalciferol 1 mg provides 40,000 IU of vitamin D activity. Available as liquid drops (8000 IU/mL) and 50,000 IU capsules.
Adult
10,000-80,000 IU/d PO plus 1-2 g/d PO of elemental phosphorus
Pediatric
Infants and healthy children: 10 mcg/d PO (400 IU)
Vitamin D-dependent rickets: 75-125 mcg/d PO (3000-4000 IU); not to exceed 1500 mcg/d
Nutritional rickets and osteomalacia: 25-125 mcg/d PO (1000-5000 IU) in normal absorption; 250-650 mcg/d PO (10,000-25,000 IU/d) if malabsorption present
Cholestyramine and colestipol decrease absorption; magnesium-containing antacids and thiazide diuretics can increase effects
Documented hypersensitivity; hypercalcemia; malabsorption syndrome
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
Maintain adequate fluid intake; can cause hypercalcemia, hypercalciuria, and pseudotumor cerebri; caution in impaired renal function and heart disease
Vitamin A (Palmitate-A 5000, Aquasol-A)
This vitamin is required for bone development, growth, night vision, and gonadal function. It is a biochemical cofactor. In the past, vitamin A has been expressed in units. It is now expressed as retinol equivalents (RE) or mcg of retinol; 1 RE = 1 mcg retinol, and 1 RE of vitamin A = 3.33 units of retinol and 10 u of beta-carotene.
Adult
Dietary supplement: 4000-5000 IU/d PO
RDI: 2670 IU/d (females) and 3330 IU/d (males)
Pediatric
Use water miscible products
Dietary supplement:
<6 months: 1500 IU/d PO
6 months to 3 years: 1500-2000 IU/d PO
4-6 years: 2500 IU/d PO
7-10 years: 3300-3500 IU/d PO
>10 years: Administer as in adults
Deficiency (serum retinol: RBP molar ratio <0.8):
<1 year: 10,000 IU/kg/d IM for 5 d, then 7,500-15,000 IU/d for 10 d
1-8 years: 5,000-10,000 IU/kg/d IM for 5 d, then 17,000-35,000 IU/d for 10 d
>8 years: 100,000 IU/d IM for 3 d, then 50,000 IU/d for 14 d
Mineral oil and cholestyramine decrease absorption; oral contraceptives increase plasma levels
Documented hypersensitivity
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Pregnancy category X if dose exceeds RDA (ie, 1000 RE or 3300 IU from supplement); can result in hypervitaminosis A syndrome (eg, fever, malaise, anorexia, vomiting, slow growth, migratory arthralgia, premature epiphyseal closure, tender cortical thickening over the radius and tibia, headache, ICP, lip fissures, dry/cracked skin, alopecia, desquamation, hyperpigmentation, hepatosplenomegaly, jaundice, leukopenia, hypomenorrhea); caution in renal or hepatic impairment
Trace Element
Zinc deficiency is sometimes seen; zinc is easily replaced via oral compounds.
Zinc (Galzin, Orazinc, Verazinc, Zincate)
Zinc is an essential cofactor for more than 70 enzymes that are important in immune function and cell replication. Dosing guidelines are based on monitoring of levels. The elemental zinc content depends on the particular salt form. Zinc acetate liquid has 5 mg of elemental zinc per mL. Zinc sulfate suspension has 10 mg elemental zinc per mL and zinc sulfate tablets contain 23% elemental zinc.
Adult
25-50 mg elemental zinc PO qd or divided bid/tid
Pediatric
<10 years: 0.5-1 mg/kg/d elemental
>10 years: 15-25 mg elemental zinc PO qd
May reduce penicillamine and tetracycline effects; iron decreases uptake; bran and dairy products decrease absorption
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Caution in renal impairment; nausea, vomiting, dyspepsia, and pancreatitis reported; administer with food to minimize GI upset
Bile Acid
This agent promotes bile salt excretion via direct stimulation of bile flow and via indirect alterations in composition of bile.
Ursodeoxycholic acid (Actigall)
Decreases cholesterol content of bile.
Adult
3 mg/kg/dose PO bid
Pediatric
10-15 mg/kg/dose PO bid/tid
Bile acid sequestering agents (eg, cholestyramine, colestipol) and aluminum-containing antacids may adsorb bile acids and reduce absorption; estrogens, oral contraceptives, and clofibrate increase secretion of cholesterol from liver and may counteract effectiveness of ursodeoxycholic acid
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Overdosage may result in diarrhea
More on Alagille Syndrome |
| Overview: Alagille Syndrome |
| Differential Diagnoses & Workup: Alagille Syndrome |
 Treatment & Medication: Alagille Syndrome |
| Follow-up: Alagille Syndrome |
| Multimedia: Alagille Syndrome |
| References |
| « Previous Page | Next Page » |
References
Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet. Feb 1997;34(2):152-7. [Medline].
Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. Jun 1973;48(6):459-66. [Medline].
Alagille D, Odievre M, Gautier M, Dommergues JP. Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur. J Pediatr. Jan 1975;86(1):63-71. [Medline].
McDaniell R, Warthen DM, Sanchez-Lara PA, et al. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway. Am J Hum Genet. Jul 2006;79(1):169-73. [Medline].
Li L, Krantz ID, Deng Y, et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nat Genet. Jul 1997;16(3):243-51. [Medline].
Krantz ID, Colliton RP, Genin A, et al. Spectrum and frequency of jagged1 (JAG1) mutations in Alagille syndrome patients and their families. Am J Hum Genet. Jun 1998;62(6):1361-9. [Medline].
Bucuvalas JC, Horn JA, Carlsson L, et al. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature. J Clin Endocrinol Metab. Jun 1993;76(6):1477-82. [Medline].
Hingorani M, Nischal KK, Davies A, et al. Ocular abnormalities in Alagille syndrome. Ophthalmology. Feb 1999;106(2):330-7. [Medline].
Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. Mar 1999;29(3):822-9. [Medline].
Lalani SR, Thakuria JV, Cox GF, Wang X, Bi W, Bray MS. 20p12.3 microdeletion predisposes to Wolff-Parkinson-White syndrome with variable neurocognitive deficits. J Med Genet. Mar 2009;46(3):168-75. [Medline].
Kamath BM, Spinner NB, Emmerich KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation. 2004;110:1354-8. [Medline]. [Full Text].
Cynamon HA, Andres JM, Iafrate RP. Rifampin relieves pruritus in children with cholestatic liver disease. Gastroenterology. Apr 1990;98(4):1013-6. [Medline].
Kasahara M, Kiuchi T, Inomata Y, et al. Living-related liver transplantation for Alagille syndrome. Transplantation. Jun 27 2003;75(12):2147-50. [Medline].
Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. Jul 1988;95(1):130-6. [Medline].
[Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. Jun 2005;41(6):1407-32. [Medline]. [Full Text].
Bekassy AN, Garwicz S, Wiebe T, et al. Hepatocellular carcinoma associated with arteriohepatic dysplasia in a 4-year-old girl. Med Pediatr Oncol. 1992;20(1):78-83. [Medline].
Danks DM, Campbell PE, Jack I, et al. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch Dis Child. May 1977;52(5):360-7. [Medline].
Gottrand F, Clavey V, Fruchart JC, Farriaux JP. Lipoprotein pattern and plasma lecithin cholesterol acyl transferase activity in children with Alagille syndrome. Atherosclerosis. Jun 1995;115(2):233-41. [Medline].
Hoffenberg EJ, Narkewicz MR, Sondheimer JM, et al. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr. Aug 1995;127(2):220-4. [Medline].
Kay MH, Wyllie R, Steffen RM. Use of ursodeoxycholic acid in the treatment of arteriohepatic dysplasia. Clin Pediatr (Phila). Nov 1996;35(11):593-6. [Medline].
Martin SR, Garel L, Alvarez F. Alagille's syndrome associated with cystic renal disease. Arch Dis Child. Mar 1996;74(3):232-5. [Medline].
Miguet JP, Mavier P, Soussy CJ, Dhumeaux D. Induction of hepatic microsomal enzymes after brief administration of rifampicin in man. Gastroenterology. May 1977;72(5 Pt 1):924-6. [Medline].
Oestreich AE, Sokol RJ, Suchy FJ, Heubi JE. Renal abnormalities in arteriohepatic dysplasia and nonsyndromic intrahepatic biliary hypoplasia. Ann Radiol (Paris). Feb-Mar 1983;26(2-3):203-9. [Medline].
Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Variable morbidity in alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr. Oct 1999;29(4):431-7. [Medline].
Rabinovitz M, Imperial JC, Schade RR, Van Thiel DH. Hepatocellular carcinoma in Alagille's syndrome: a family study. J Pediatr Gastroenterol Nutr. Jan 1989;8(1):26-30. [Medline].
Russo PA, Ellis D, Hashida Y. Renal histopathology in Alagille's syndrome. Pediatr Pathol. 1987;7(5-6):557-68. [Medline].
Shulman SA, Hyams JS, Gunta R. Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Genet. Oct 1984;19(2):325-32. [Medline].
Further Reading
Keywords
Alagille syndrome, AS, Alagille's syndrome, Alagille-Watson syndrome, arteriohepatic dysplasia, syndromic bile duct paucity, pulmonary valvular stenosis, hypoplasia of the hepatic ducts, mental retardation, treatment, diagnosis
