Management of adults with Alagille syndrome

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TL;DR

Alagille syndrome (ALGS) is a rare genetic disorder with multi-organ involvement that increasingly requires adult care as over 90% of children survive past age 18. This review provides a comprehensive framework for diagnosing and managing adults with ALGS, emphasizing lifelong surveillance for hepatic, cardiac, renal, and cerebrovascular complications. Key recommendations include screening for hepatocellular carcinoma every 6 months, brain MRI/MRA for intracranial vasculopathy, and careful pre-transplant evaluation of cardiac and renal function.

Full summary

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**Background** Alagille syndrome (ALGS) is a complex, rare genetic disorder involving multiple organ systems, historically considered a childhood disease. It is inherited in an autosomal dominant manner in 40% of patients, with mutations in JAG1 (94% of cases) and NOTCH2 (2.5%). The condition is characterized by cholestatic liver disease, cardiac anomalies (up to 94% of children), renal involvement (up to 40%), skeletal abnormalities (butterfly vertebrae in 44%), ocular findings (posterior embryotoxon in 51%), and characteristic facial features. With improved survival—approximately 90% of children with ALGS survive beyond age 18—adult clinicians must be prepared to manage these patients. This review aims to provide a comprehensive overview of ALGS in adults, focusing on lifelong surveillance, diagnostic frameworks, and liver transplantation considerations.

**Methods** This is a narrative review synthesizing available literature on ALGS in adults. The authors draw on data from the Global Alagille Alliance Study Group (GALA), which includes 1184 children with ALGS and cholestasis, as well as case series, case reports, and registry data (e.g., UNOS). They also reference clinical trials of ileal bile acid transporter (IBAT) inhibitors, including phase IIb studies of maralixibat and the phase III ASSERT study of odevixibat. No systematic search strategy or meta-analysis is described; the review is expert opinion-based.

**Key Results** - **Hepatic involvement**: Neonatal cholestasis occurs in 85% of patients, with pruritus in 74%. Among 1184 children with cholestasis, 29% underwent liver transplantation (LT) at a median age of 2.8 years. Cumulative incidence of LT at 5, 10, and 18 years was 27%, 38%, and 50%, respectively. Only 40% survived with native liver to age 18, and 70% of those had clinically evident portal hypertension. - **Hepatocellular carcinoma (HCC)**: 14 adult cases of HCC in ALGS have been reported. Notably, 67% of adult HCC cases had no cirrhosis, and 38% had normal serum alpha-fetoprotein (AFP). The authors recommend screening with abdominal ultrasound and serum AFP every 6 months. - **Cardiac involvement**: Congenital heart disease is present in up to 94% of children, with peripheral pulmonary artery stenosis (PPS) in 76% and tetralogy of Fallot in 12%. No new-onset progressive cardiac disease occurs after childhood. - **Renal involvement**: Renal anomalies occur in up to 40% of children. In adults, progressive renal disease may require renal replacement therapy; median age of reported cases is 38 years (range 16–62). Annual monitoring of blood pressure, serum creatinine, electrolytes, and urinary protein/creatinine ratio is recommended. - **Cerebrovascular involvement**: Intracranial hemorrhage occurs in 12–15% of patients and is responsible for 25–50% of non-cardiac deaths in childhood. In adults, 5 cases of subarachnoid hemorrhage (SAH) have been reported (age range 21–30, median 25), with 40% mortality. Aneurysms predominantly involve the vertebrobasilar system. Screening with brain MRI/MRA is recommended at transition to adult care, prior to major surgeries, and emergently for neurological symptoms. - **Liver transplantation in adults**: Among 44 adult LT recipients (median age 30 years) from UNOS data, 1- and 5-year patient survival was 96% and 91%, and graft survival was 84% and 80%. Adults had lower rates of vascular thrombosis (8% vs 25%) and primary non-function (8% vs 21%) compared to children. - **IBAT inhibitors**: Maralixibat (Livmarli) is FDA-approved for cholestatic pruritus in ALGS patients aged 1 year and older. In clinical trials, it significantly improved pruritus, xanthomas, growth, fatigue, and quality of life. Seven adult patients (≥17 years) were included in the trials. Odevixibat (Bylvay) showed statistically significant improvement in pruritus and reduction in serum bile acids in the phase III ASSERT study.

**Clinical Implications** Adult clinicians must be aware that ALGS is not exclusively a childhood disease. Key recommendations include: (1) HCC surveillance with abdominal ultrasound and AFP every 6 months for all patients with native liver, regardless of cirrhosis status; (2) annual renal function monitoring; (3) brain MRI/MRA at transition to adult care and before major surgeries; (4) pre-conception counseling for women with ALGS, including genetic testing and high-risk pregnancy management; (5) careful cardiac and renal evaluation before liver transplantation, including stress echocardiography and renal-sparing immunosuppression; (6) living-related donor screening with JAG1/NOTCH2 mutation analysis; and (7) consideration of IBAT inhibitors (maralixibat) for refractory pruritus in adults. The review emphasizes that coordinated multidisciplinary care remains essential in adulthood.