Alagille Syndrome (ALGS)

Alagille syndrome (ALGS) is a hereditary disease affecting many organs and systems in the body.¹ It is caused by mutations in the Jagged 1 (JAG1) or Notch 2 (NOTCH2) genes. The severity of the symptoms varies greatly from one patient to another and even among affected members of the same family.

Factors Affecting ALGS Prognosis

The prognosis of a patient with ALGS depends on a number of factors. These include the severity of the symptoms and whether congenital heart disease, intracranial hemorrhages, or hepatic disease is present.²

Although most patients have only mild symptoms and a normal life expectancy, serious liver disease may develop in some, and many need a liver transplant.³ 

Research has shown that the prognosis of liver disease in ALGS is worse in children who have neonatal cholestatic jaundice.⁴ However, even when liver disease due to the condition develops later in life, severe liver complications may still occur. Therefore, the liver should be closely monitored in patients with ALGS throughout life.

A correlation does not appear to exist between the time of bile duct paucity development (ie, before or after the age of 6 months) and disease outcome, transplant rate, or survival.⁵ However, the mortality rate is higher in infants with bilirubin levels above 5 mg/dL before the age of 6 months). According to one study, no deaths were recorded in patients younger than 6 months with bilirubin levels below 5 mg/dL.⁵

Early diagnosis is a key prognostic factor because treatment can be started in a timely manner, before irreversible complications and damage occur.

Disease Course and Prediction of Outcome

Typically, cholestasis or decreasing bile flow worsens for several years before abating gradually.²

Similarly, xanthomas typically worsen over the first few years of life and then decrease with time.⁶ Medications to increase bile flow or partial external biliary diversion may resolve xanthomas completely. 

Children with ALGS usually have a better outcome than those of the same age who have other liver disorders.²

It is not possible to predict the risk for transplant requirement or mortality on the basis of measures of liver function in infancy, including scintiscan excretion.⁷

Main Causes of Mortality in ALGS

ALGS may cause a number of other complications that can affect prognosis. These include liver failure, portal hypertension, serious cardiac defects, and intracerebral hemorrhage or stroke due to vascular problems.⁸ 

Serious cardiac disease and liver failure are associated with early mortality.⁹ Several types of vascular anomalies can be present in patients with ALGS. These include noncardiac vascular anomalies or events, structural vascular abnormalities, arterial aneurysms, carotid artery anomalies, and cerebral artery aneurysms, which can be major causes of morbidity and mortality among these patients; in one study, they accounted for 34% of deaths.¹⁰ 

The mortality rate is usually higher in patients with congenital heart disease who require surgery than in those who do not.

Death secondary to liver transplant may also occur. In such cases, death is usually within the first 30 days following the transplant.¹¹ The risk for death following a liver transplant does not appear to be affected by the age of the patient at the time of transplant.

Management of ALGS

It is important that a patient with a diagnosis of ALGS be closely monitored by a multidisciplinary team of health care professionals: cardiologists, gastroenterologists, ophthalmologists, nephrologists, and nutritionists.¹²

Treatments that increase bile flow can relieve some of the symptoms of the disease, such as pruritus, and improve patients’ quality of life.¹³ 

Dietary changes, such as the consumption of a high-calorie diet rich in medium-chain triglycerides and vitamin supplementation, can also help manage the condition and improve the prognosis.¹⁴ 

Having patients avoid contact sports, especially those with splenomegaly, chronic liver disease, or vascular problems, can minimize the risk for secondary complications and improve the prognosis.⁹

Liver transplant may be necessary for patients with end-stage liver disease. This can be a whole liver transplant from a deceased donor or a partial liver transplant from a living donor. A liver transplant can increase life expectancy; however, only some patients are eligible, depending on whether the heart is involved. Those with heart problems are more likely to experience complications during and after a liver transplant.³ 

As treatment options increase, the life expectancy of patients with ALGS improves. Approximately 75% of patients in whom the disease is diagnosed during childhood live to at least the age of 20 years.¹³

References

1. Alagille syndrome. MedlinePlus. Updated April 7, 2021. Accessed June 14, 2021.
2. Alagille syndrome. Cincinnati Children’s. Updated June 2020. Accessed June 14, 2021.
3. Kamath BM, Schwarz KB, Hadzić N. Alagille syndrome and liver transplantation. J Pediatr Gastroenterol Nutr. 2010;50(1):11-15. doi:10.1097/MPG.0b013e3181c1601f
4. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut. 2001;49(3):431-435. doi:10.1136/gut.49.3.431
5. McBride KE. Clinical features of Alagille syndrome: frequency and relation to prognosis. J Pediatr Gastroenterol Nutr. 1998;26(5):580.
6. Alagille syndrome. Children’s Hospital of Philadelphia. Accessed June 14, 2021.
7. Emerick KM, Rand EB, Goldmuntz E, Krantz ID, Spinner NB, Piccoli DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29(3):822-829. doi:10.1002/hep.510290331
8. Alagille syndrome. UCSF Department of Surgery. Published September 2014. Accessed June 14, 2021.
9. Diaz-Frias J, Kondamudi NP. Alagille syndrome. StatPearls. Updated February 26, 2021. Accessed June 14, 2021.
10. Kamath BM, Spinner NB, Emerick KM, et al. Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation. 2004;23;109(11):1354-1358. doi:10.1161/01.CIR.0000121361.01862.A4
11. Kamath BM, Yin W, Miller H, et al, for Studies of Pediatric Liver Transplantation. Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transpl. 2012;18(8):940-948. doi:10.1002/lt.23437
12. Spinner NB, Gilbert MA, Loomes KM, et al. Alagille syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews^®. University of Washington;2000. Updated December 12, 2019. Accessed June 14, 2021.
13. Alagille syndrome. Cedars Sinai. Accessed June 14, 2021.
14. Eating, diet, & nutrition for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 14, 2021.

Reviewed by Eleni Fitsiou, PhD, on 6/14/2021.

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Ozge Ozkaya, MSc, PhD

Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.