Alagille Syndrome Medication: Antipruritics, Fat-soluble vitamins, Trace Element, Bile Acid

Medication Summary

Medications are used to manage bile acid-induced pruritus and supplement fat-soluble vitamin stores.

Antipruritics

Class Summary

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.

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.

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.

Fat-soluble vitamins

Class Summary

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.

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.

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.

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.

Trace Element

Class Summary

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.

Bile Acid

Class Summary

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.

Follow-up



Ann Scheimann, MD, MBA Associate Professor, Department of Pediatrics, Section of Nutrition and Gastroenterology, Baylor College of Medicine and Johns Hopkins Medical Institution

Ann Scheimann, MD, MBA is a member of the following medical societies: North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

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, Royal College of Physicians and Surgeons of Canada

Disclosure: Received honoraria from Prometheus Laboratories for speaking and teaching; Received honoraria from Abbott Nutritionals for speaking and teaching.



Robert Baldassano, MD Director, Center for Pediatric Inflammatory Bowel Disease, Children's Hospital of Philadelphia; Professor, Department of Pediatrics, Division of Gastroenterology and Nutrition, University of Pennsylvania School of Medicine

Robert Baldassano, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Gastroenterological Association, North American Society for Pediatric Gastroenterology, Hepatology and Nutrition

Disclosure: Received consulting fee from Abbott, Inc for consulting.

References

1. Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet. 1997 Feb. 34(2):152-7. [Medline].
2. Watson GH, Miller V. Arteriohepatic dysplasia: familial pulmonary arterial stenosis with neonatal liver disease. Arch Dis Child. 1973 Jun. 48(6):459-66. [Medline].
3. 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. 1975 Jan. 86(1):63-71. [Medline].
4. 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. 2006 Jul. 79(1):169-73. [Medline].
5. 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. 1997 Jul. 16(3):243-51. [Medline].
6. 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. 1998 Jun. 62(6):1361-9. [Medline].
7. Sparks EE, Huppert KA, Brown MA, Washington MK, Huppert SS. Notch Signaling Regulates Formation of the Three-Dimensional Architecture of Intrahepatic Bile Ducts in Mice. Hepatology. 2009. [Medline].
8. 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. 1993 Jun. 76(6):1477-82. [Medline].
9. Hingorani M, Nischal KK, Davies A, et al. Ocular abnormalities in Alagille syndrome. Ophthalmology. 1999 Feb. 106(2):330-7. [Medline].
10. Emerick KM, Rand EB, Goldmuntz E, et al. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999 Mar. 29(3):822-9. [Medline].
11. 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. 2009 Mar. 46(3):168-75. [Medline]. [Full Text].
12. Kamath BM, Podkameni G, Hutchinson AL, et al. Renal anomalies in Alagille syndrome: A disease-defining feature. Am J Med Genet A. 2011 Nov 21. [Medline].
13. Kamath BM, Spinner NB, Rosenblum ND. Renal involvement and the role of Notch signalling in Alagille syndrome. Nat Rev Nephrol. 2013. 9:409-18. [Medline].
14. 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].
15. Cynamon HA, Andres JM, Iafrate RP. Rifampin relieves pruritus in children with cholestatic liver disease. Gastroenterology. 1990 Apr. 98(4):1013-6. [Medline].
16. Kasahara M, Kiuchi T, Inomata Y, et al. Living-related liver transplantation for Alagille syndrome. Transplantation. 2003 Jun 27. 75(12):2147-50. [Medline].
17. Whitington PF, Whitington GL. Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology. 1988 Jul. 95(1):130-6. [Medline].
18. [Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. 2005 Jun. 41(6):1407-32. [Medline]. [Full Text].
19. Arnon R, Annunziato R, Miloh T, et al. Orthotopic liver transplantation for children with Alagille syndrome. Pediatr Transplant. 2010 Jan 11. [Medline].
20. 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].
21. Danks DM, Campbell PE, Jack I, et al. Studies of the aetiology of neonatal hepatitis and biliary atresia. Arch Dis Child. 1977 May. 52(5):360-7. [Medline].
22. Gottrand F, Clavey V, Fruchart JC, Farriaux JP. Lipoprotein pattern and plasma lecithin cholesterol acyl transferase activity in children with Alagille syndrome. Atherosclerosis. 1995 Jun. 115(2):233-41. [Medline].
23. 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. 1995 Aug. 127(2):220-4. [Medline].
24. Kay MH, Wyllie R, Steffen RM. Use of ursodeoxycholic acid in the treatment of arteriohepatic dysplasia. Clin Pediatr (Phila). 1996 Nov. 35(11):593-6. [Medline].
25. Martin SR, Garel L, Alvarez F. Alagille's syndrome associated with cystic renal disease. Arch Dis Child. 1996 Mar. 74(3):232-5. [Medline].
26. Miguet JP, Mavier P, Soussy CJ, Dhumeaux D. Induction of hepatic microsomal enzymes after brief administration of rifampicin in man. Gastroenterology. 1977 May. 72(5 Pt 1):924-6. [Medline].
27. Oestreich AE, Sokol RJ, Suchy FJ, Heubi JE. Renal abnormalities in arteriohepatic dysplasia and nonsyndromic intrahepatic biliary hypoplasia. Ann Radiol (Paris). 1983 Feb-Mar. 26(2-3):203-9. [Medline].
28. Quiros-Tejeira RE, Ament ME, Heyman MB, et al. Variable morbidity in alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr. 1999 Oct. 29(4):431-7. [Medline].
29. Rabinovitz M, Imperial JC, Schade RR, Van Thiel DH. Hepatocellular carcinoma in Alagille's syndrome: a family study. J Pediatr Gastroenterol Nutr. 1989 Jan. 8(1):26-30. [Medline].
30. Russo PA, Ellis D, Hashida Y. Renal histopathology in Alagille's syndrome. Pediatr Pathol. 1987. 7(5-6):557-68. [Medline].
31. Shulman SA, Hyams JS, Gunta R. Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Genet. 1984 Oct. 19(2):325-32. [Medline].

Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes and pointed chin. Courtesy of University of Washington, Seattle (Pagon RA, Adam MP, Ardinger HH, et al, Eds. Seattle (WA): University of Washington, Seattle; 1993-2014. Available at: www.ncbi.nlm.nih.gov/books/NBK1116/).