Alagille Syndrome (ALGS)


Alagille syndrome is a rare genetic disease caused by mutations in the Jagged 1 (JAG1) or Notch 2 (NOTCH2) genes.1 This impairs the Notch signaling pathway, which is involved in many developmental processes.2 As a result, the disease affects many organs and systems in the body. The hallmark of the disease is intrahepatic bile duct paucity leading to chronic cholestasis. 

There is currently no cure for Alagille syndrome but there are treatment options aimed at alleviating disease symptoms and enhancing patients’ quality of life. These include medical treatments that increase bile flow and reduce pruritus, vitamins and supplements to support growth and development, and surgical care such as biliary diversion and liver transplantation.3

Pharmacologic Treatments

Intrahepatic bile duct paucity causes bile acids to accumulate inside the liver. This can cause symptoms such as pruritus, jaundice, and xanthomas.4

These symptoms can be managed in some patients using bile acid sequestrants, ursodeoxycholic acid, rifampin, antihistamines, and opioid antagonists such as naltrexone.5 Bile acid sequestrants such as cholestyramine bind to bile acids in the intestines and prevent their reabsorption, promoting their excretion in the feces instead.6

Ursodeoxycholic acid.
Chemical molecular formula of bile acids.

Read more about ALGS therapies.

Ursodeoxycholic acid has many mechanisms of action, including the protection of injured cholangiocytes against toxic effects of bile acids, the stimulation of impaired biliary secretion and detoxification of hydrophobic bile acids, and the inhibition of apoptosis of hepatocytes. The medication may help reduce some of the symptoms associated with bile acid accumulation in some patients.7

Rifampin is an agent that hydroxylates bile acid, making it less pruritic. It can reduce pruritus in about half of patients with ALGS.8 Antihistamines and naltrexone may also be prescribed to reduce pruritus.9

Diet and Activity

The reduced bile flow to the small intestines due to intrahepatic bile duct paucity can cause issues with fat digestion and the absorption of fat-soluble vitamins, leading to malnutrition. This, in turn, can cause bone weakness, growth problems, delayed puberty, and failure to thrive.10

A high-calorie diet containing carbohydrates and medium-chain triglycerides, which are easier to digest, is therefore recommended. Infants with the disease should be fed a special formula containing medium-chain triglycerides.11

Patients may also need vitamin A, D, E, and K supplements. This should be decided based on the results of blood tests, which should be done regularly. Because multivitamin preparations may not provide the correct ratio of fat-soluble vitamins, these should be administered as individual supplements. The hepatic toxicity of vitamin A should be taken into account when administering this vitamin.12

Some patients with ALGS may have splenomegaly. These patients should avoid contact sports and should wear a spleen guard during physical activity.12

Surgical Care

Biliary diversion procedures can be performed to interrupt bile circulation between the intestines and the liver.9 These include partial external biliary diversion, partial internal biliary diversion, and ileal exclusion.

Partial external biliary diversion involves the creation of a jejunal conduit between the gallbladder and an external abdominal stoma to interrupt the enterohepatic circulation and divert bile acids away from the liver.13 Research has shown the procedure can reduce disease progression in patients with Alagille syndrome. Risks associated with partial external biliary diversion include dehydration following surgery, electrolyte imbalances, surgical complications, and the presence of a lifelong stoma substantially affecting the patient’s quality of life.

For patients not willing to receive an ostomy, partial internal biliary diversion or ileal exclusion can be an option. 

Partial internal biliary diversion is performed by cholecystocolostomy or using an isolated jejunal loop as a conduit from the gallbladder to the mid ascending colon.14 A few case studies have shown that the procedure has the potential to relieve the symptoms of Alagille syndrome and improve patients’ quality of life, but the long-term effects of this approach are not well known. Partial internal biliary diversion also often causes intermittent diarrhea due to the high concentration of bile salts in the colon.13

In ileal exclusion, the terminal ileum is excluded by ileocolic diversion to interrupt the enterohepatic circulation. Research has shown that this approach can effectively decrease refractory pruritus and xanthomatosis in ALGS patients.15 

Liver transplantation.
Segmental anatomy of the liver and blood supply.
Human anatomy

Patients with ALGS who develop liver failure need a liver transplant. It is estimated that 21% to 31% of patients with the disease require a liver transplant.16 The most important part of the transplant assessment is the evaluation of heart and kidney involvement. Liver transplantation can also cause significant morbidity and means that patients must be on lifelong immunosuppressive therapy.15

References

  1. Alagille syndrome. MedlinePlus. Updated April 7, 2021. Accessed June 18, 2021.
  2. Lasky JL, Wu H. Notch signaling, brain development, and human disease. Pediatr Res. 2005;57(5 Pt 2):104R-109R. doi:10.1203/01.PDR.0000159632.70510.3D
  3. Alagille syndrome. Johns Hopkins Medicine. Accessed June 18, 2021.
  4. El-Darouti MA, Al-Ali FM. Jaundice, pruritus, and xanthomas with intrahepatic ductal atresia. In: El-Darouti MA, Al-Ali FM, eds. Challenging Cases in Dermatology Volume 2. Springer; 2019:509-514. Accessed June 23, 2021.
  5. Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11): 907. doi:10.3390/diagnostics10110907
  6. Bile acid sequestrants for cholesterol. MedlinePlus. Updated June 9, 2021. Accessed June 18, 2021.
  7. Paumgartner G, Beuers U. Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis. 2004;8(1):67-81, vi. doi:10.1016/S1089-3261(03)00135-1
  8. Kronsten V, Fitzpatrick E, Baker A. Management of cholestatic pruritus in paediatric patients with Alagille syndrome: the King’s College Hospital experience. J Pediatr Gastroenterol Nutr. 2013;57(2):149-154. doi:10.1097/MPG.0b013e318297e384
  9. Alagille syndrome. UCSF Transplant Surgery. September 2014. Accessed June 18, 2021.
  10. Definition & facts for Alagille syndrome. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed June 18, 2021.
  11. Alagille syndrome. Cincinnati Children’s. Updated June 2020. Accessed June 18, 2021.
  12. Kamath BM, Piccoli DA. Chapter 26 – Alagille syndrome. In: Liacouras CA, Piccoli DA, eds. Pediatric Gastroenterology: The Requisites in Pediatrics. Maryland Heights, MO: Mosby; 2008:227-232. Accessed June 23, 2021.
  13. Slavetinsky C, Sturm E. Odevixibat and partial external biliary diversion showed equal improvement of cholestasis in a patient with progressive familial intrahepatic cholestasis. BMJ Case Rep. 2020;13(6):e234185. doi:10.1136/bcr-2019-234185
  14. Sheflin-Findling S, Arnon R, Lee S, et al. Partial internal biliary diversion for Alagille syndrome: case report and review of the literature. J Pediatr Surg. 2012;47(7):1453-1456. doi:10.1016/j.jpedsurg.2012.04.008
  15. Modi BP, Suh MY, Jonas MM, Lillehei C, Kim HB. Ileal exclusion for refractory symptomatic cholestasis in Alagille syndrome. J Pediatr Surg. 2007;42(5):800-805. doi:10.1016/j.jpedsurg.2006.12.032
  16. Kamath BM, Schwarz KB, Hadžić N. Alagille syndrome and liver transplantation. J Pediatr Gastroenterol Nutr. 2010;50(1):11-15. doi:10.1097/MPG.0b013e3181c1601f

Reviewed by Kyle Habet, MD, on 7/1/2021.