Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Alagille syndrome (ALGS) is a multisystemic autosomal dominant disorder with a wide range of symptoms. It occurs due to mutations in either the JAG1 or NOTCH2 gene. Although it was first thought to be a liver disease, molecular tests have revealed that people with ALGS or JAG1 or NOTCH2 mutations can present without symptoms of liver disease. ALGS is characterized by a lack of intrahepatic bile ducts in combination with at least 3 of the following 5 clinical symptoms: cholestasis, cardiac disorder, skeletal abnormalities, ocular disturbances, and distinctive facial features. Cholestasis occurs due to a lack of bile ducts.1
The prevalence of ALGS was previously reported to be 1 in 70,000 live births; however, this was found to be an underestimation, as patients were identified solely based on the presence of neonatal liver disease, excluding pediatric and adult cases without overt liver disease.1 Because of the multisystemic involvement, a multidisciplinary approach for the management of ALGS is typically effective.2 There is currently no cure for ALGS, however, there are treatments available to help patients manage their symptoms and improve their quality of life. These include medical treatments to enhance bile flow and minimize pruritus, vitamins and supplements to aid growth and development, and surgical procedures like biliary diversion and liver transplantation.3
Surgical Management of Pruritus
Biliary diversion procedures are performed to interrupt bile circulation between the intestines
and the liver.4 These are useful in cases of severe pruritus that do not respond to medical treatment.2 These operations are often less effective in patients with ALGS than in those with other types of cholestasis because bile duct hypoplasia in association with ALGS can result in less bile reaching the bowel. Partial external biliary diversion (PEBD) is the most commonly performed procedure, which involves the creation of a jejunal conduit between the gallbladder and an external abdominal stoma to interrupt enterohepatic circulation and divert bile acids away from the liver. The gallbladder is emptied externally through the jejunal conduit. In a study of 20 patients with ALGS who underwent PEBD, researchers found improvements in total serum cholesterol, pruritus severity, and xanthomas.5,6
Partial internal biliary diversion and ileal exclusion are other less common procedures. Partial internal biliary diversion is performed via cholecystocolostomy or by using an isolated jejunal loop as a conduit from the gallbladder to the mid-ascending colon.7 Some case studies have revealed that this method can relieve ALGS symptoms and improve quality of life; however, the long-term effects of this approach are not well documented. This procedure can frequently lead to intermittent diarrhea because of excessive bile salts in the colon.6 In ileal exclusion, the terminal ileum is excluded by creating an ileocolic diversion to interrupt enterohepatic circulation. Previous studies have demonstrated that this procedure can reduce refractory pruritus and xanthomatosis in cases of ALGS.8
It is estimated that 21% to 31% of patients with ALGS require a liver transplant.9 End-stage liver disease due to progressive cholestasis (involving malnutrition refractory to medical nutrition therapy, irresolvable pruritus, and bone fractures) and end-stage liver disease with portal hypertension and complications (including ascites and variceal bleeding) are the most common indications for liver transplantation in ALGS. The most critical part of the assessment for transplantation is evaluating the involvement of multiple systems, including heart, kidney, and vascular disease. Prior to transplantation, patients should undergo magnetic resonance imaging of the brain, abdominal computed tomography, and an echocardiography. Immunosuppression regimens that spare the kidneys should be employed. Liver transplantation can result in considerable morbidity and requires patients to take lifelong immunosuppressive medication.5,8
Donors with JAG1 and/or NOTCH2 mutations should not be considered when contemplating living related transplantation because they may have undiagnosed liver disease. As a result, all prospective related donors should undergo a thorough clinical examination, genetic testing for the proband’s known mutation, abdominal scanning for vascular abnormalities, and a liver biopsy.5
- Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420
- Spinner NB, Gilbert MA, Loomes KM, Krantz ID. Alagille syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 1993-2022. Accessed March 7, 2022.
- Alagille syndrome. Johns Hopkins Medicine. Accessed March 7, 2022.
- Alagille syndrome. University of California, San Francisco (UCSF) Transplant Surgery. September 2014. Accessed March 7, 2022.
- Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907
- 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
- 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
- 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
- Singh SP, Pati GK. Alagille syndrome and the liver: current insights. Euroasian J Hepatogastroenterol. 2018;8(2):140-147. doi:10.5005/jp-journals-10018-1280
Reviewed by Kyle Habet, MD, on 3/30/2022.