PAGE CONTENTS

Therapies

Alagille syndrome therapies include supportive medications that are used to relieve pruritus and medications that supplement mineral stores and fat-soluble vitamins, such as vitamins A, D, E, and K.

Antipruritics in ALGS

Individuals with Alagille syndrome (ALGS) have fewer bile ducts than healthy individuals do. This results in reduced bile flow from the liver (cholestasis) that can cause pruritus as a result of a buildup of bile acid in the blood and skin. Pruritus is often resistant to medical therapy and monotherapy is frequently ineffective, so combination therapy is used.

The treatment of pruritus is done in a stepwise manner, beginning with the first-line therapy (choleretics and bile salt-binding agents), then second-line therapy (bile acid hydroxylation) if the initial treatment is not efficacious. If pruritus persists, third-line line therapy is initiated, followed by the fourth-line therapy if necessary. Adjunctive therapy is used in combination with the primary treatment.¹

ursodeoxycholic acid ALGS — *Ursodeoxycholic acid. Chemical molecular formula of bile acids.*

First-Line Therapy

First-line therapy for pruritus includes ursodeoxycholic acid (UDCA) and cholestyramine. UDCA is a water-soluble bile acid that acts as a choleretic; it promotes bile flow and, therefore, can help reduce itching. It works in multiple ways, including making the bile acid more hydrophilic, decreasing the cholesterol content of bile, and improving the flow of bile from the liver to the small intestine. These effects of UDCA aid in reducing some of the symptoms associated with bile acid accumulation such as pruritus or cholesterol deposits on the skin (xanthomas). It is generally safe but may cause diarrhea, abdominal pain. and vomiting.²

Cholestyramine is a bile salt-binding agent that cannot be absorbed by the body and is thus excreted. It is used to treat pruritus caused by cholestasis because it binds to the bile acids in the small intestine and forms a nonabsorbable complex, which prevents the reabsorption of bile acids, promoting their excretion, and thereby, decreasing the amount of bile acids in the body. Side effects include poor taste, constipation, and abdominal pain, in addition to interference with absorption of food, medications, and fat-soluble vitamins.³

Second-Line Therapy

The second line of therapy for pruritus is rifampin. Although the precise mechanism of action is unclear, rifampin is believed to work by hydroxylation of bile acids, making them less pruritic, and facilitating their excretion by the kidneys. Research shows that rifampin is effective in reducing pruritus in nearly half of patients.⁴ It can cause red discoloration of bodily fluids (such as urine, sweat, or tears), vomiting, and liver injury.

Third-Line Therapy

Third-line therapy includes naltrexone, an oral opioid antagonist approved for the treatment of opiate addiction and alcohol dependence in adults. It blocks mu opioid receptors that are upregulated in cholestasis. It has been shown to reduce pruritus in adults as well as children with ALGS.⁴ However, patients may experience symptoms of opioid withdrawal, such as diarrhea, abdominal pain, chills, salivation, and irritability.

Fourth-Line Therapy

The fourth line of therapy includes investigational treatments that belong to the class of intestinal bile acid transport (IBAT) inhibitors⁵ — maralixibat⁶ and odevixibat.⁷ IBAT is a transporter protein that mediates the uptake of conjugated bile acids from the small intestine and ultimately transports them to the liver. Through IBAT inhibition, maralixibat and odevixibat could reduce pruritus by preventing bile acid uptake, allowing more bile acids to be excreted and thereby decreasing their serum levels. However, there is limited data for these therapies and their side effects include vomiting, diarrhea, abdominal pain, rash, hepatitis, and fat-soluble vitamin deficiencies.

Read more about Maralixibat.

Adjunctive Therapy

Adjunctive therapy includes diphenhydramine and sertraline. Diphenhydramine⁸ is an antihistamine which is generally used for mild allergy cases and in combination with a primary medication as its effect is short-lived. It may cause side effects such as drowsiness.

Sertraline⁹ belongs to the class of selective serotonin reuptake inhibitors (SSRI).¹⁰ Although its mechanism of action for treating pruritus is not known, it has been shown to be effective in treating adults with cholestatic pruritus. Sertraline is metabolized by the liver so it should be used with caution in children with liver dysfunction. It may cause side effects such as agitation, alopecia, vomiting, and hypertension.

Fat-Soluble Vitamins

In ALGS, reduced bile acid flow to the small intestine hampers the digestion of fats and the absorption of fat-soluble vitamins A, D, E, and K. This may result in malnutrition and growth deficiencies. Thus, patients may need oral supplementation with vitamins A, D, E, and K to compensate for their deficiency.¹¹ It is recommended that supplements are given individually and not as multivitamin preparations, based on the levels of individual vitamins in the blood that should be measured periodically (2-3 times per year) so as to adjust the dose accordingly. Cholestasis-specific vitamin formulations are available for fat-soluble vitamins supplementation.¹

Vitamin K

Vitamin K is important for blood clotting because it is necessary to make clotting factors (factors II, VII, IX, and X). Vitamin K deficiency impairs normal coagulation function, causing easy bruising or bleeding.

The most sensitive method for measuring vitamin K deficiency is the protein induced by vitamin K absence (PIVKA-II) assay. Because the assay is not widely available, vitamin K status is evaluated by measuring coagulation using prothrombin time and international normalized ratio (INR).

A formulation of vitamin K compound solubilized in glycocholate and lecithin (Konakion MM) efficiently corrects vitamin K deficiency.¹²

Vitamin E

Vitamin E has antioxidant properties that prevent the oxidation of vitamins A and C and protect the cellular membranes from oxidative damage. It is needed for a healthy nervous system and the development of coordination. Vitamin E deficiency causes neurological deficits because of poor nerve conduction, poor coordination, and developmental delays.

Vitamin E status is commonly determined by measuring the serum tocopherol level.

The preferred form for vitamin E replacement therapy in patients with cholestasis is D-alpha tocopheryl PEG-1000 succinate (tocophersolan (TPGS) ),¹³ which is directly absorbed from the intestine without the need for bile acids. TPGS also improves vitamin D absorption.

Vitamin D

Vitamin D is needed for strong and healthy bones and teeth. It promotes the absorption of calcium and phosphate from the intestine. Vitamin D deficiency results in defective bone mineralization, causing rickets in children.

Vitamin D status is determined by measuring levels of the serum 25-hydroxy cholecalciferol, which is a metabolite of vitamin D that is formed in the liver.¹⁴

Vitamin A

Vitamin A is required for bone development, growth, healthy vision, and gonadal function. It is a biochemical cofactor. Vitamin A deficiency can lead to vision problems such as night blindness and xerophthalmia.

The most convenient way to assess vitamin A status is to measure the serum retinol level. Because excess levels of vitamin A can lead to fatal liver toxicity, it is important to regularly monitor levels in children receiving supplementation.¹⁴

Other Supplements

Supplements of zinc, selenium, calcium, phosphorus, and magnesium should be given if the serum levels indicate their deficiency.

Zinc is an essential cofactor for several enzymes that are important in immune function, tissue repair, normal growth, and development. Zinc deficiency may be associated with growth retardation, skin rashes, diarrhea, and loss of appetite.¹⁵

References

Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics. 2020;10(11):907. doi:10.3390/diagnostics10110907.
Ursodeoxycholic acid. PubChem. Accessed May 25, 2021.
Cholestyramine (Oral Route). Mayo Clinic. Updated June 1, 2021. Accessed June 23, 2021.
Kronsten V, Fitzpatrick E, Baker A. Management of cholestatic pruritus in paediatric patients with Alagille syndrome: The King’s College Hospital experience. J Pediatr Gastroenterol Nutr. 2013;57(2):149-154. doi:10.1097/MPG.0b013e318297e384
Kamath BM, Stein P, Houwen RHJ, Verkade HJ. Potential of ileal bile acid transporter inhibition as a therapeutic target in Alagille syndrome and progressive familial intrahepatic cholestasis. Liver Int. 2020;40(8):1812-1822. doi:10.1111/liv.14553
Shneider BL, Spino C, Kamath BM, et al. Placebo-controlled randomized trial of an intestinal bile salt transport inhibitor for pruritus in Alagille syndrome. Hepatol Commun. 2018;2(10):1184-1198. doi:10.1002/hep4.1244
Al-Dury S, Wahlström A, Wahlin S, et al. Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis. Sci Rep. 2018;8(1):6658. doi:10.1038/s41598-018-25214-0
Diphenhydramine. MedlinePlus. Updated August 15, 2018. Accessed May 25, 2021.
Thébaut A, Habes D, Gottrand F, et al. Sertraline as an additional treatment for cholestatic pruritus in children. J Pediatr Gastroenterol Nutr. 2017;64(3):431-435. doi:10.1097/MPG.0000000000001385
Selective serotonin reuptake inhibitors (SSRIs). Mayo Clinic. September 17, 2019. Accessed May 25, 2021.
Yang CH, Perumpail BJ, Yoo ER, Ahmed A, Kerner JA. Nutritional needs and support for children with chronic liver disease. Nutrients. 2017;9(10). doi:10.3390/nu9101127
Konakion MM Paediatric 2 mg/0.2 ml. Electronic medicines compendium (emc). Accessed May 25, 2021.
Tocophersolan. PubChem. Accessed May 25, 2021.
Socha P. Nutritional management of cholestatic syndromes in childhood. Ann Nestlé [Engl]. 2008;66:137-147. doi:10.1159/000147411
Alagille syndrome. Children’s Hospital of Philadelphia. Accessed May 25, 2021.

Reviewed by Kyle Habet, MD, on 7/1/2021.

Erum Naqvi, PhD

Erum Naqvi obtained her Ph.D. in Molecular Medicine from Hannover Medical School (Germany) after completing her Masters in Biomedical Science and Bachelors in Microbiology from University of Delhi (India). She has several years of experience as a science writer.

Alagille Syndrome (ALGS)