Alagille syndrome is a rare disease that typically presents in infants within the first three months of life.[1,2] Patients may present a wide spectrum of signs and symptoms.[1,2] The first recognized cases were reported in 1969 by Daniel Alagille in France.[3,4] It is an autosomal dominant genetic disorder, meaning that only one parent needs to have a copy of the gene mutations to transmit the disease.[5] In the case of Alagille syndrome, mutations or deletions in either of two key genes account for virtually all of the cases.[1,6] In more than half the cases, the genetic anomalies are not inherited but occur spontaneously (called de novo mutations).[4,6] Alagille syndrome occurs once in every 30,000 to 50,000 live births.[1] The clinical features of the disease involve the liver, heart, skeleton, eyes, kidneys, central nervous system, and facial appearance.[1]
Common early clues to diagnosis are related to liver function: lack of bile ducts and chronic cholestasis (reduced or obstructed bile flow from the liver).[1] This may cause pruritus or itching, which can be unremitting and severe.[2] However, the clinical presentation is highly variable, and may be difficult to diagnose in patients without genetic confirmation.[1] Patients with severe cholestasis and/or its associated complications (e.g., persistent pruritus) may require liver transplantation.[4] Liver transplantation may also be indicated for patients with cirrhosis and complications related to portal hypertension.[4]
Etiology
Mutations to JAG1 gene are responsible for around 94% of recorded cases, and mutations to the NOTCH2 gene account for 2% to 4% of recorded cases.[4] These genes are located on chromosomes 20 and 1, respectively.[7] Of 892 patients with Alagille syndrome who underwent genetic testing, 2% of patients were found to not have mutations in either gene but otherwise met clinical criteria for having Alagille syndrome.[6]
Both genes affect NOTCH2 signaling, which is implicated in the development of intrahepatic bile ducts.[1,4] In patients with Alagille syndrome, bile-duct paucity (an abnormal deficiency in bile ducts throughout the liver [8]) results in cholestasis, or impaired bile flow from the liver. Cholestasis is associated with progressive liver damage.[4-6]
Signs and Symptoms
The symptoms and severity among patients with Alagille syndrome vary widely.[4] Some individuals will have mild symptoms.[2]. In some patients, the problems with NOTCH2 signaling may impact multiple organs (Table).[4,6]
TABLE: COMMON CLINICAL SIGNS AND ORGAN INVOLVEMENT IN ALAGILLE SYNDROME (N = 1433) [6] |
|
Clinical Feature | Percentage of Patients |
Characteristic Facial Features | 90% |
Cardiac Anomalies | 91% |
Any Liver Involvement | 95% |
Renal Anomalies | 39% |
Posterior Embryotoxon | 51% |
Butterfly Vertebrae | 44% |
Vascular Findings | 36% |
Several of the key clinical features are described below.
Liver Problems. Lack of bile ducts is a common sign of the disease and is reported in at least 75% of patients with Alagille syndrome; this can occur within the first few months of life but is more common in infants 6 months and older.[1,4] The inadequate bile drainage from the liver results in cholestasis; in one study of 1184 patients with Alagille syndrome, 29% of patients with a history of neonatal cholestasis required liver transplantation.[6] The median age of liver transplantation in those who received it was 2.8 years.[6]
Cholestasis is often associated with moderate-to-severe pruritus.[1,2] Cholestasis also leads to the emergence of xanthomas (or fatty bumps) under the skin’s surface, which may appear nearly anywhere on the body.[1,2,4]
The incidence of portal hypertension (or high blood pressure in the major vein leading to the liver and its branches) rises as patients age, with 69% having clinically evident portal hypertension by the time they reach 16 years old.[4] The incidence of splenomegaly (an enlarged spleen) and ascites (the accumulation of fluid in the abdomen, causing swelling) also increases with age.[6]
Characteristic Facial Features. Approximately 90% of patients with Alagille syndrome display several facial features (isolated or in combination), including a broad forehead, straight nose with a bulbous tip, triangular face with pointed chin, and deep-set eyes that are spaced widely apart.[3,6] These features may be less noticeable in infants but seem to develop as they age.[4]
Cardiac Anomalies. Cardiac issues are also commonly seen in patients with Alagille syndrome (91%, n = 1231/1347, in one international retrospective cohort of patients with Alagille syndrome born between 1997 and 2019).[6]These include structural heart defects (e.g., atrial or ventricular septal defects or valvular disease), congenital heart disease, and cardiac murmurs (without positive echocardiographic findings). Peripheral pulmonary artery stenosis or hyperplasia occurs in up to three-quarters of patients.[1,4] Patients can experience mild or severe anomalies, with a few presenting a combination of cardiovascular issues, consisting of valvular problems, coarctation of the aorta (a narrowing of the aorta[9]), and tetralogy of Fallot.[1,10]
Vascular Features. Patients with Alagille syndrome may also present with intracranial or systemic vascular abnormalities. Arterial stenosis, aneurysms, and intracranial bleeding have been reported, along with vascular malformations in the brain.[4] Screening with brain magnetic resonance imaging and angiography is recommended for children with Alagille syndrome at age 8 or for those undergoing major surgery.[4]
Ocular Signs. A wide range of ocular findings may be present, and posterior embryotoxon is most common.[4] Posterior embryotoxon is a thickening of a ring of corneal tissue. Though this thickening does not significantly affect vision,[3] it is present in up to 51% of patients.[6,10]
Another ocular feature that is sometimes seen in Alagille syndrome is “Axenfeld anomaly” comprising a prominent Schwalbe’s ring with attached iris strands.[3,7]
Skeletal Conditions. The most common skeletal abnormality is “butterfly vertebrae,” which are apparent in 30% to 90% of patients with Alagille syndrome.[4,10] This condition is characterized by misshapen bones in the spinal column.[3]
Renal Issues. Dysplastic kidneys or a single kidney, renal tubular acidosis, and other structural and functional anomalies have been noted in approximately 40% of patients.[4,6,11]
Additional Clinical Considerations. Other potential signs and symptoms include the following:
- Vitamin deficiencies—Likely owing to cholestasis, deficiencies in vitamins A, D, E, and K are possible[11]
- Growth deficiency/failure to thrive—A common finding in patients with Alagille syndrome,[10] which may largely result from the reduced absorption of fats and vitamins and malnutrition[3]
- Hearing loss—In one series of 110 patients, some degree of hearing loss was found in 38% and affected one or both ears[10]
- Xanthomas—Associated with very high serum cholesterol levels and occur in multiple skin areas, are found in 30% to 40% of patients, and first develop at a median 20-48 months of age.[1,2] These bumps can be yellow in color and may interfere with motor development and negatively affect the patients’ self-image.[4]
Diagnosis
The diagnosis of Alagille syndrome can be challenging, owing to the highly variable presentation. [1] Bile-duct paucity, which is found in a high percentage of patients, is also not specific to Alagille syndrome. It has also been seen in healthy preterm infants, those who are small for their gestational age, and in patients with biliary atresia. Histologic evidence of biliary atresia has been reported in infants with Alagille syndrome, further complicating the diagnosis.[4]
A careful examination of the patient should include a detailed medical history and several tests or specific investigations to detect the five common signs of Alagille syndrome: (1) cholestasis, (2) characteristic facies, (3) congenital heart disease, (4) skeletal anomalies (especially butterfly vertebrae), or (5) ocular anomalies. A clinical diagnosis of Alagille syndrome can be made if patients have bile duct paucity and 3 of the 5 classic signs.[3] Based on its potential manifestations and multiple organ involvement, a multidisciplinary approach to patient care may be required,[3,12] including a care team of specialists (e.g., hepatologists [liver specialists], cardiologists [heart specialists], nephrologists [kidney specialists], and/or ophthalmologists [eye specialists]).
Additionally, liver biopsy is not required but may be performed to differentiate Alagille syndrome from biliary atresia.[4,12,13] Diagnosis can be supported with genetic testing.[4] Molecular testing reveals a mutation causing Alagille syndrome in 98% of cases.[6]
Patients with suspected Alagille syndrome may not meet three of these classic criteria because of the variability in presentation. Early genetic testing may be advisable in patients with neonatal cholestasis but few other obvious signs.[3,14] When evaluating cholestatic infants, this “sequence-early” approach emphasizes genetic screening to clarify the diagnostic picture if a genetic mutation–based disorder is suspected.[4]
Prognosis
A retrospective study by the Global Alagille Alliance (GALA) Study Group of patients with clinically and/or genetically confirmed Alagille syndrome across 29 countries found that 85% (n = 1184/1387) presented with neonatal cholestasis, and 74% (n = 761/1028) had some degree of pruritus (first reported at a median age of 12 months).[6]
Xanthomas were recorded in approximately one-quarter of the patients, first appearing at a median of 25 months of age.[6] Twenty-nine percent of the patients in the GALA registry required liver transplant, and an additional four patients underwent combined liver and kidney transplantation.[6] The principal reasons for liver transplantation were related to complications of persistent cholestasis (e.g., intractable pruritus, xanthomas, metabolic bone disease, growth failure, or fat-soluble vitamin deficiency) in 72%; complications of portal hypertension were cited in 30% of cases. Almost three-quarters of all transplants were performed by age 5. Graft survival rates exceeded 80% through 20 years post-transplant.[6]
The risk of death for patients not undergoing transplantation was 6% at 5 years, 8% at 10 years, and 9% at 18 years of age.[6] Overall patient survival was 93% at age 5, 91% at age 10, and 88% at age 18, though this may vary by country. Of the 108 patients who died over the follow-up period, median age of death was 2.6 years, with liver-related (including complications of liver transplant) or cardiac-related complications accounting for 40% of all deaths.[6] Vascular accidents may play a significant role in the remainder.[3,6] Eighteen-year survival was somewhat greater in patients who did not present with neonatal cholestasis compared with those who did (86% vs. 97%, respectively).[6] After 10 and 18 years, the rate of native liver survival was 54% and 40%, respectively.[6]
Patients with Alagille syndrome may experience severe pruritis, which reduces their quality of life.[1] In addition, caregiver burden, especially in light of the pruritus experienced by young patients, can be considerable. This serious pruritus can result in sleep disturbances for patients and their caregivers.[1,2,15,16]
Treatments and Disease Management
Unfortunately, there is no treatment to address the JAG1 or NOTCH2 mutations causing Alagille syndrome.[17] Healthcare providers focus on managing the conditions based on the extent of symptoms and liver dysfunction: (1) vitamin and nutrient supplementation for malabsorption, (2) medicine to alleviate symptoms (e.g., pruritus), and (3) surgical interventions or treatments to ease cholestasis and pruritus.[4]
In addition to administering vitamins A, D, E, and K supplements, patients may be given medium-chain triglyceride–rich foods and other caloric dense foods. [5,11,18] For children who are failing to thrive, nutrients given via nasogastric or gastrostomy tube may be helpful.[3]
Several older, conventional medicines may help treat the symptoms of pruritus, such as antihistamines, bile-acid resins like cholestyramine, opioid antagonists such as naloxone or naltrexone, phenobarbital, rifampin, sertraline, and ursodeoxycholic acid.[2,4] None of these medications are specifically indicated for the treatment of patients with Allagille syndrome.
The surgical procedure partial biliary diversion can help redirect the flow of bile to reduce the bile pool and improve quality of life in patients with severe, refractory pruritus.[2,19] The terminal ileum absorbs nearly all of the bile acid from the intestinal contents and recirculates it back to the liver.[20] Therefore, surgical bypass of the terminal ileum can prevent bile reabsorption and lower bile acid levels.[4,20] Ileal exclusion is another option, which bypasses the distal 15% of the ileum and avoids the need for a stoma.[20,21]
Liver transplantation may be indicated as a last resort in patients with severe, refractory pruritus in patients with severe cholestasis and or its associated complications, including intractable pruritus, and patients with cirrhosis and complications of portal hypertension.[4] It may also be necessary in patients with progressive liver damage, resulting in fibrosis, cirrhosis, or liver failure.[4,6]
Bile-Acid Transporter Inhibitors. A relatively recent class of drugs, ileal bile-acid transporter inhibitors, may play a role in the treatment of pruritis in patients with Alagille syndrome and progressive familial intrahepatic cholestasis.[2,4,17] Like the ileal bypass surgical procedure, ileal bile-acid transporters decrease the reabsorption of bile acids, directing them out to the colon, with the fecal waste.[17,19]
Most recently approved (in June 2023) is Bylvay® (odevixibat) for the treatment of cholestatic pruritus in patients 12 months of age or older with Alagille syndrome. The treatment is also indicated for treating pruritus in patients 3 months or older with progressive familial intrahepatic cholestasis. Bylvay may not be effective in a subgroup of patients with progressive familial intrahepatic cholestasis type 2, with specific ABCB11 variants resulting in non-functional or complete absence of the bile-salt export pump protein.[22]
In a Phase 3, double-blind, placebo-controlled trial of Bylvay comprising 52 patients with Alagille syndrome, the once-daily oral medication was found to result in statistically significant improvement in pruritus symptoms at 6 months, primary endpoint was change in pruritus from baseline to month 6 (weeks 21 – 24). [21]. Bylvay was not associated with any drug discontinuations among the 35 patients randomized to receive Bylvay. Of adverse reactions occurring in at least 5% of the 35 patients receiving Byvay, diarrhea was most common (29% in the treatment group vs. 6% in the placebo group), abdominal pain (14% vs. 6%, respectively), hematoma (9% vs. 0%, respectively), and weight loss (6% vs. 0%, respectively).[22]
Please see Important Safety Information below and full Prescribing Information.
Conclusion
Alagille syndrome is a rare genetic disorder that causes cholestasis and liver damage, but with highly variable clinical signs, symptoms, and prognosis. Beyond liver complications, Alagille syndrome may affect several other organs.
Although treatments do not exist to address the underlying mutations affecting the NOTCH2 signaling pathway, progress is being made to help improve cholestatic pruritus in patients 12 months and older with Alagille Syndrome.
IMPORTANT SAFETY INFORMATION for BYLVAY (odevixibat)
- Speak with your healthcare provider if you experience: abdominal pain, vomiting, diarrhea, and dehydration as these have been reported with the use of Bylvay. Patients should contact their healthcare provider if they experience new onset or worsening of diarrhea.
- Elevations in liver tests (for example, AST, ALT, TB) have been observed with use of Bylvay. The patient’s health care provider will obtain liver tests before starting Bylvay and periodically during treatment with Bylvay. Patients should report to their healthcare provider any symptoms of liver problems (for example, nausea, vomiting, skin or the whites of eyes turn yellow, dark or brown urine, pain on the right side of the abdomen, loss of appetite).
- Bylvay may impair absorption of fat-soluble vitamins (FSV), which include vitamins A, D, E and K (vitamin K is assessed by measuring INR). The patient’s health care provider will obtain serum levels of vitamins A, D, E, and INR (for vitamin K) at baseline and periodically during treatment to assess for worsening of FSV deficiency.
- Do not swallow the 200 mcg or 600 mcg capsule(s) containing Oral Pellets whole. These are intended to be opened and the contents mixed into soft food or liquid. Take Bylvay in the morning with a meal.
- For patients taking bile acid binding resins, take Bylvay at least 4 hours before or 4 hours after taking a bile acid binding resin.
INDICATIONS AND USAGE
Limitation of Use
REFERENCES
- Kamath BM, Baker A, Houwen R, et al. Systematic review: The epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67:148-156.
- Ben Ameur S, Chabchoub I, Telmoudi J, et al. Management of cholestatic pruritus in children with Alagille syndrome: Case report and literature review. Arch Pediatr. 2016;23:1247-1250.
- Turnpenny PD, Ellard S. Alagille syndrome: Pathogenesis, diagnosis and management. Eur J Human Genetics. 2012;20:251-257.
- Ayoub MD, Kamath BM. Alagille syndrome: Current understanding of pathogenesis, and challenges in diagnosis and management. Clin Liver Dis. 2022;26:355-370.
- Autosomal dominant disorder. National Human Genome Research Institute August 17, 2023. https://www.genome.gov/genetics-glossary/Autosomal-Dominant-Disorder.
- Vandriel SM, Li L-T, She H, et al. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study. Hepatology. 2023;77:512-529.
- Leonard LD, Chao G, Baker A, et al. Clinical utility gene card for: Alagille syndrome (ALGS). Eur J Human Genetics. 2014;22:e1-e4.
- Zahmatakeshan M, Geramizadeh B, Haghighat M, et al. Paucity of intrahepatic bile ducts in neonates: The first case series from Iran. Iran J Pediatr 2013;23:65-70.
- Coarctation of the aorta. Mayo Clinic June 25, 2022. https://www.mayoclinic.org/diseases-conditions/coarctation-of-the-aorta/symptoms-causes/syc-20352529.
- Kamath BM, Ye W, Goodrich NP, et al. Outcomes of childhood cholestasis in Alagille syndrome: Results of a multicenter observational study. Hepatol Communications. 2020;4:387-398.
- Maharjana MA, Suyasa IK, Kawiyana IKS, et al. Pathologic fracture of the femur in Alagille syndrome: A case report. J Clin Orthop Trauma. 202:11:298-301.
- Singh SP, Pati GK. Alagille syndrome and the liver: Current insights. Euroasian J Hepatogastroenterol. 2018;8:140-147.
- Feldman AG, Sokol RJ. Neonatal cholestasis. Neoreviews. 2013;14(2). doi:10.1542/neo.14-2-e63.
- Li J, Wu H, Chen S, et al. Clinical and genetic characteristics of Alagille syndrome in adults. J Clin Translational Hepatol. 2023;11:156-162.
- Patel SP, Vasavda C, Ho B, et al. Cholestatic pruritus: Emerging mechanisms and therapeutics. J Am Acad Dermatol. 2019;81:1371–1378. doi:10.1016/j.jaad.2019.04.035.
- Quadrado L, Mogul D, Gurevich A, et al. Caregiver burden associated with caring for a child with Alagille syndrome: A multi=national, quantitative analysis (abstract). Presented at the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting; October 12–15, 2022, Orlando, FL.
- Gonzales E, Hardikar W, Stormon M, et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): A randomised phase 2 trial. Lancet 2021;398:1581-1592. doi: 10.1016/S0140-6736(21)01256-3.
- Karpen S. Pediatric cholestasis: Epidemiology, genetics, diagnosis, and current management. Clin Liver Dis. 2020;15:115-119.
- Sanchez P, Farkhondeh A, Pavlinov I, et al. Therapeutics development for Alagille syndrome. Front Pharmacol. 2021;12:704586.
- Henkel SAF, Squires JH, Ayers M, et al. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019;11:450-463.
- Modi BP, Suh My, Jonas MM, et al. Ileal exclusion for refractory symptomatic cholestasis in Alagille syndrome. J Pediatr Surg. 2007;42:800-805.
- Bylvay prescribing information. Albireo Pharma. February 2023. https://bylvay.com/pdf/Bylvay_PI.pdf.
- Kamath BM, Baker A, Houwen R, et al. Systematic review: The epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67:148-156.
- Ben Ameur S, Chabchoub I, Telmoudi J, et al. Management of cholestatic pruritus in children with Alagille syndrome: Case report and literature review. Arch Pediatr. 2016;23:1247-1250.
- Turnpenny PD, Ellard S. Alagille syndrome: Pathogenesis, diagnosis and management. Eur J Human Genetics. 2012;20:251-257.
- Ayoub MD, Kamath BM. Alagille syndrome: Current understanding of pathogenesis, and challenges in diagnosis and management. Clin Liver Dis. 2022;26:355-370.
- Autosomal dominant disorder. National Human Genome Research Institute August 17, 2023. https://www.genome.gov/genetics-glossary/Autosomal-Dominant-Disorder.
- Vandriel SM, Li L-T, She H, et al. Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study. Hepatology. 2023;77:512-529.
- Leonard LD, Chao G, Baker A, et al. Clinical utility gene card for: Alagille syndrome (ALGS). Eur J Human Genetics. 2014;22:e1-e4.
- Zahmatakeshan M, Geramizadeh B, Haghighat M, et al. Paucity of intrahepatic bile ducts in neonates: The first case series from Iran. Iran J Pediatr 2013;23:65-70.
- Coarctation of the aorta. Mayo Clinic June 25, 2022. https://www.mayoclinic.org/diseases-conditions/coarctation-of-the-aorta/symptoms-causes/syc-20352529.
- Kamath BM, Ye W, Goodrich NP, et al. Outcomes of childhood cholestasis in Alagille syndrome: Results of a multicenter observational study. Hepatol Communications. 2020;4:387-398.
- Maharjana MA, Suyasa IK, Kawiyana IKS, et al. Pathologic fracture of the femur in Alagille syndrome: A case report. J Clin Orthop Trauma. 202:11:298-301.
- Singh SP, Pati GK. Alagille syndrome and the liver: Current insights. Euroasian J Hepatogastroenterol. 2018;8:140-147.
- Feldman AG, Sokol RJ. Neonatal cholestasis. Neoreviews. 2013;14(2). doi:10.1542/neo.14-2-e63.
- Li J, Wu H, Chen S, et al. Clinical and genetic characteristics of Alagille syndrome in adults. J Clin Translational Hepatol. 2023;11:156-162.
- Patel SP, Vasavda C, Ho B, et al. Cholestatic pruritus: Emerging mechanisms and therapeutics. J Am Acad Dermatol. 2019;81:1371–1378. doi:10.1016/j.jaad.2019.04.035.
- Quadrado L, Mogul D, Gurevich A, et al. Caregiver burden associated with caring for a child with Alagille syndrome: A multi=national, quantitative analysis (abstract). Presented at the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Annual Meeting; October 12–15, 2022, Orlando, FL.
- Gonzales E, Hardikar W, Stormon M, et al. Efficacy and safety of maralixibat treatment in patients with Alagille syndrome and cholestatic pruritus (ICONIC): A randomised phase 2 trial. Lancet 2021;398:1581-1592. doi: 10.1016/S0140-6736(21)01256-3.
- Karpen S. Pediatric cholestasis: Epidemiology, genetics, diagnosis, and current management. Clin Liver Dis. 2020;15:115-119.
- Sanchez P, Farkhondeh A, Pavlinov I, et al. Therapeutics development for Alagille syndrome. Front Pharmacol. 2021;12:704586.
- Henkel SAF, Squires JH, Ayers M, et al. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019;11:450-463.
- Modi BP, Suh My, Jonas MM, et al. Ileal exclusion for refractory symptomatic cholestasis in Alagille syndrome. J Pediatr Surg. 2007;42:800-805.
- Bylvay prescribing information. Albireo Pharma. February 2023. https://bylvay.com/pdf/Bylvay_PI.pdf.