From the Guidelines
The management of Alagille syndrome should focus on treating specific symptoms, with liver transplantation remaining the standard of care for progressive cholestasis, and the use of IBAT inhibitors like maralixibat or odevixibat for the treatment of cholestatic pruritus, as supported by recent studies 1.
Overview of Alagille Syndrome
Alagille syndrome is a rare genetic disorder characterized by bile duct abnormalities leading to cholestasis, which can cause jaundice, itching, and poor absorption of fat-soluble vitamins. It affects multiple organ systems, primarily the liver, heart, eyes, skeleton, and face, due to mutations in the JAG1 or NOTCH2 genes.
Management of Cholestasis
For the management of cholestasis, medications like ursodeoxycholic acid can improve bile flow. However, the routine use of liver biopsy for determining prognosis or management of liver disease in ALGS is not recommended due to insufficient data supporting its use in prognosis or management, as stated in the EASL clinical practice guidelines 1.
Treatment of Cholestatic Pruritus
Recent data from studies such as the ITCH and ICONIC trials support the use of maralixibat to treat cholestatic pruritus in children with ALGS, showing statistically significant reductions in serum bile acid levels and improvements in pruritus and quality of life 1. Additionally, odevixibat, another IBAT inhibitor, has shown positive results in the ASSERT study, further supporting the use of IBAT inhibitors for this condition.
Liver Transplantation
Liver transplantation remains the standard of care for progressive cholestasis in ALGS, with referral to a liver transplant centre strongly encouraged for patients with substantial liver involvement. Initial data have shown that reductions in serum bile acids are linked to improved outcomes such as transplant-free survival in ALGS 1.
Multidisciplinary Care
The syndrome's multisystem nature requires coordinated care from gastroenterologists, cardiologists, ophthalmologists, and geneticists. Early diagnosis and intervention are crucial for managing complications and improving quality of life, as the severity varies widely among affected individuals.
From the Research
Definition and Characteristics of Alagille Syndrome
- Alagille syndrome (ALGS) is a rare, cholestatic multiorgan disease associated with bile duct paucity, leading to cholestasis 2.
- It is characterized by a wide array of clinical manifestations, including cardiac anomalies, impaired growth, renal disease, poor health-related quality of life (HRQoL), fat-soluble vitamin deficiencies, and debilitating pruritus 2, 3.
- The syndrome involves multiple organ systems, including the liver, heart, eyes, skeleton, face, kidneys, and vasculature 4.
Clinical Features and Diagnosis
- Clinical features of ALGS span multiple organ systems, including hepatic, cardiac, vascular, renal, skeletal, craniofacial, and ocular, and occur with variable phenotypic penetrance 5.
- The identification of JAG1 and NOTCH2 as disease-causing genes has deepened our understanding of the molecular mechanisms underlying ALGS 4.
- Diagnosis of ALGS can be challenging due to the variable expressivity of the clinical phenotype and the lack of genotype-phenotype relationships 4, 6.
Management and Treatment
- Medical management of ALGS is supportive, focusing on clinical manifestations of disease, with liver transplant indicated for severe pruritus, liver synthetic dysfunction, portal hypertension, bone fractures, and/or growth failure 5.
- Recent therapeutic advancements in cholestasis treatment, including ileal bile acid transporter (IBAT) inhibitors, have shown potential in improving cholestatic pruritus symptoms, HRQoL, and native liver survival 2.
- Liver transplantation (LT) is curative for liver disease secondary to ALGS, but complications secondary to extrahepatic involvement remain problematic lifelong 6.