Alagille syndrome (ALGS) is a multi-organ disorder characterized by intrahepatic bile duct paucity with a wide range of symptoms including pruritus, jaundice, congenital heart defects, ocular defects, and vertebral anomalies.1
The disease is caused by mutations in the Jagged 1 (JAG1) or Notch 2 (NOTCH2) genes, impairing the Notch signaling pathway.2 It is inherited in an autosomal dominant manner and is thought to affect 1 in 70,000 newborns. However, this figure is based on the diagnosis of liver disease in infants and may be an underestimate as not all patients with Alagille syndrome have liver disease in infancy.3
The disease can cause a number of complications, including liver failure, portal hypertension, mental and physical growth delays, chronic diarrhea, and intracerebral hemorrhages. Patients can have one or a combination of these complications, and not all patients will have every complication.4
ALGS and Liver Failure
The low number of bile ducts, which is a hallmark of the disease, can lead to liver failure or end-stage liver disease with time due to bile buildup inside the liver. Bile buildup can also cause cirrhosis.5 Liver failure can develop over many years.
Both pediatric and adult patients with Alagille syndrome may also have a higher risk of hepatocellular carcinoma. However, the incidence and etiology of liver cancer in patients with Alagille syndrome are not known.6
Portal Hypertension in ALGS
In patients with advanced liver disease, the blood flow from the spleen to the liver can back up into the spleen and blood vessels, causing portal hypertension.4 This can lead to splenomegaly.
Portal hypertension can also lead to the formation of varices in and around the esophagus, spleen, stomach, and colon. Advanced portal hypertension can cause serious bleeding complications.
Other ALGS Complications
Alagille syndrome can lead to poor growth and delayed puberty.4 This is caused by malabsorption due to liver disease. Congenital heart defects can also have a negative impact on growth in patients with Alagille syndrome. Malabsorption can also cause frequent fractures, rickets, and learning disability.
Malabsorption results in protein, calorie, and vitamin deficiencies. This can lead to chronic diarrhea.
Intracerebral hemorrhage can be caused by vascular anomalies in the brain and accounts for a significant percentage of mortality and morbidity in Alagille syndrome.5 Some patients with the disease may also develop moyamoya syndrome due to stenosis or occlusion of the carotid artery.
Management of ALGS Complications
Patients with Alagille syndrome should be followed closely by a multidisciplinary team of health care professionals to monitor growth, development, diet and nutritional status, renal tubular function, and pancreatic function to prevent the worsening of complications.7
The condition can be managed with good nutrition. Good nutrition can also help prevent the development of other health problems. Dietary supplements and vitamins may be prescribed based on a particular patient’s symptoms and complications.4 The consumption of alcohol should be minimized.
Pruritus can be treated with a choleretic agent such as ursodeoxycholic acid or cholestyramine, rifampin, or naltrexone.7 Ursodeoxycholic acid also increases the flow of bile out of the liver and may relieve pruritus, however, most cases of pruritus are refractory to medical treatment.
Surgical biliary diversion methods, such as cholecystojejunocolonic anastomosis, cholecystoappendicocolonic anastomosis, cholecystoileocolonic anastomosis, and cholecystocolostomy may also be used to resolve pruritus and delay the progression of the disease.8
Patients with end-stage liver disease may be candidates for a liver transplant unless they have congenital cardiopulmonary defects. Around 21% to 33% of Alagille syndrome patients are eligible for a liver transplant.9 Other clinical indications for a liver transplant include portal hypertension and impaired quality of life with growth failure due to severe cholestasis, xanthomatosis, and refractory pruritus.
The 5-year survival rate following a liver transplant is approximately 80% in patients with Alagille syndrome, and transplant leads to improvements in liver function and growth in 90% of cases.7 If the liver donor is a relative of the patient, they should undergo genetic testing before the transplant to ensure they are not carrying the same genetic mutation as the patient, since in some cases of Alagille syndrome, symptoms are so mild that the patient may not be aware of their condition.
According to a case study published in the International Journal of Cardiology, a transcatheter therapeutic approach may be used to optimize the cardiopulmonary system prior to liver transplantation.9
Contact sports must be avoided in patients with splenomegaly to minimize the risk of injury and bleeding.7
- Jesina D. Alagille syndrome: an overview. Neonatal Netw. 2017;36(6):343-347. doi:10.1891/0730-08126.96.36.1993
- Symptoms & causes for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 17, 2021.
- Alagille syndrome. MedlinePlus. Updated April 7, 2021. Accessed June 17, 2021.
- Alagille syndrome. UCSF Department of Surgery. September 2014. Accessed June 17, 2021.
- Alagille syndrome. National Organization for Rare Disorders. Accessed June 17, 2021.
- Schindler EA, Gilbert MA, Piccoli DA, Spinner NB, Krantz ID, Loomes KM. Alagille syndrome and risk for hepatocellular carcinoma: need for increased surveillance in adults with mild liver phenotypes. Am J Med Genet A. 2021;185(3):719-731. doi:10.1002/ajmg.a.62028
- Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3):251-257. doi:10.1038/ejhg.2011.181
- Gunaydin M, Tander B, Demirel D, et al. Different techniques for biliary diversion in progressive familial intrahepatic cholestasis. J Pediatr Surg. 2016;51(3):386-389. doi:10.1016/j.jpedsurg.2015.08.011
- Smithson S, Hall D, Trachtenberg B, et al. Treatment of cardiovascular complications of Alagille syndrome in clinical optimization for liver transplantation. Int J Cardiol. 2014;20;176(2):e37-40. doi:10.1016/j.ijcard.2014.04.187
Reviewed by Kyle Habet, MD, on 7/1/2021.