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 achieved with cholestyramine therapy.
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, should 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, owing to the risk of spontaneous bacterial peritonitis.
Treatment of cholestatic pruritus
Pruritus is often recalcitrant to medical therapy and significantly affects 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 the management of bile acid–induced pruritus found in patients with Alagille syndrome. [17]
Maralixibat
The ileal bile acid transport (IBAT) inhibitor maralixibat (Livmarli) was approved in September 2021 for treatment of cholestatic pruritus in patients with Alagille syndrome aged 1 year and older. The indication was expanded to include children aged 3 months and older in March 2023. Approval was based on the ICONIC study and 5 years of data from supportive studies in 86 patients with Alagille syndrome. On average, patients administered maralixibat for 22 weeks maintained pruritus reduction, whereas those in the placebo group who were withdrawn from maralixibat after week 18 returned to baseline pruritus scores by week 22. [18]
Odevixibat
A second iBAT inhibitor, odevixibat (Bylvay) was also approved by the FDA in June 2023 for treatment of cholestatic pruritus in patients with Alagille syndrome aged 1 year and older. Approval was based on the phase 3 ASSERT trial that showed the scratching score decreased significantly from baseline with odevixibat treatment compared with placebo (-1.7 vs -0.8; P = 0.002). [19, 20]
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. [21] Whitington et al reported a series of patients treated with partial external biliary diversion for pruritus associated with Alagille syndrome. [22] 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: [23]
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Progressive hepatic dysfunction
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Severe portal hypertension
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Failure to thrive
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Intractable pruritus and osteodystrophy
Estimated 20-year survival rates are 80% for those not requiring liver transplantation and 60% for those requiring transplantation. Among children with cholestatic liver disease, 1-year and 5-year survival after liver transplantation is significantly lower in children with Alagille syndrome than in children with biliary atresia. [24]
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 and Activity
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 the patient also has significant intracardiac disease. Patients with evidence of hypersplenism should avoid contact sports.
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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/).
