Alagille syndrome (ALGS) is a multisystem autosomal disorder characterized by a variety of clinical features. In Alagille syndrome testing, patients typically present with defects in the Notch signaling pathway that result from mutations in the Jagged 1 (JAG1) gene or the Notch 2 (NOTCH2) receptor.1 The hallmark of the disease is cholestasis and bile duct paucity that can lead to severe liver disease or liver failure and death.2
In addition to hepatic abnormalities, the clinical and pathological features of ALGS include cardiac, renal, skeletal, and ophthalmic manifestations. These manifestations can range from a life-threatening to a subclinical condition, representing a challenge in the diagnostic process.3 Diagnostic Alagille syndrome testing and medical follow-up of patients with ALGS include blood work to quantify liver enzyme activity, imaging tests, and routine cardiac, renal, and ophthalmic tests that allow clinicians to examine every major organ that can be affected by the disease.
Hepatic manifestations are very frequent in patients with ALGS, with about 95% presenting with chronic cholestasis.4 Patients should be monitored for chronic hepatic damage. Liver enzymes gamma-glutamyl transpeptidase and alkaline phosphatase are typically elevated in this condition and in the presence of cholestasis exceed alanine and aspartate aminotransferase levels.5 Hyperbilirubinemia can occur when liver disease develops in the neonatal period.1
High serum bile acids (cholic and chenodeoxycholic acids) and cholesterol are also markers of cholestasis.5,6 In patients with ALGS, cholesterol levels can reach 1000 mg/dL to 2000 mg/dL, which consequently leads to the formation of xanthomas.1 A combination of total bilirubin above 6.5 mg/dL with conjugated bilirubin above 4.5 mg/dL and cholesterol above 520 mg/dL for patients younger than 5 years point toward a severe liver disease.7
Deficiencies in fat-soluble vitamins (A, D, E, and K) are found in pediatric patients with chronic cholestasis.8
Liver ultrasonography can be performed to study liver structure as well as screen for hepatoma and hepatocellular carcinoma.3 Biliary tract anatomy can be observed with an endoscopic retrograde cholangiopancreatography or cholangiography.9 An intraoperative ultrasonic cholangiography can be performed for the biliary system study.10
Cardiac disease accounts for high morbidity and mortality in patients with ALGS. Defects include branch pulmonary artery stenosis, left-sided lesions such as valvular and supravalvular aortic stenosis, and Tetralogy of Fallot.11 Invasive cardiac imaging is not often performed in patients undergoing ALGS testing, however, routine cardiac evaluation with echocardiography is recommended.
Renal ultrasonography with Doppler allows for monitoring renal structural manifestations, while ocular ultrasound allows identification of optic disc drusen in patients with ALGS.11
Vascular manifestations of the disease may be assessed through magnetic resonance imaging (MRI) of the brain performed in patients showing neurologic symptoms.11 As studies have also shown that vascular defects may occur in patients that do not show symptoms, it is recommended that they have an MRI scan as soon as the exam can be performed without sedation and to set a basis for future comparison in case the imaging is repeated throughout life.1
Skeletal defects in ALGS patients are variable and may include vertebral anomalies to severe fractures. The most commonly described anomaly is the butterfly vertebrae found in at least 33% of the patients.1,12,13 Radiography of the spine should be performed for patients with ALGS, aiding also in the follow-up of other skeletal changes that may occur, such as temporal bone abnormalities.12
Confirmation of ALGS diagnosis can be performed with genetic testing that allows study of the JAG1 gene. This test can detect a mutation leading to the disease in about 95% of symptomatic patients, however it does not identify all ALGS cases. When no mutation is found, other techniques such as fluorescence in situ hybridization (FISH) may complement the study to increase the number of mutations found.11
A study of the NOTCH2 gene should be performed if no JAG1 mutation is found. It is also possible to study mutations in both genes using commercially available next-generation sequencing (NGS) panels.11
Additional cardiac studies performed during ALGS testing include 12-lead electrocardiogram for evaluating repolarization abnormalities due to hepatic damage.14
Full-functional renal tests should be also performed, and these are particularly important in case a hepatic transplantation is considered.1
A routine ophthalmologic exam should also be performed to monitor retinal pigmentary and acuity vision changes. Even though visual prognosis is typically good, vision quality may be affected.15 An examination using a slit-lamp will allow observation of the common posterior embryotoxon.16
A liver biopsy, when performed, can reveal paucity of the intrahepatic bile ducts. However, when performed in newborns, this biopsy may show ductal proliferation and giant cell hepatitis, preventing the observation of bile duct paucity.1,3 Liver biopsies are not required for ALGS diagnosis but remain an important tool for evaluating additional hepatic changes that include ductular proliferation secondary to portal inflammation and hepatitis.11
The normal ratio for bile duct to portal tracts space is 0.9-1.8. Bile duct paucity is defined as a ratio lower than 0.9; however, this number usually decreases to lower than 0.5 along with a reduction in the number of ducts to the portal tract over time.1,11 Typically, pathologists require that 10 to 20 portal tracts are examined and recommend at least 6 to 10 be assessed through needle biopsies for the correct ratio determination.1
- Mitchell E, Gilbert M, Loomes KM. Alagille syndrome. Clin Liver Dis. 2018;22(4):625-641. doi:10.1016/j.cld.2018.06.001
- Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2018;67(2):148-156. doi:10.1097/MPG.0000000000001958
- Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420
- 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
- Kriegermeier A, Wehrman A, Kamath BM, Loomes KM. Liver disease in Alagille syndrome. In: Kamath BM, Loomes KM, eds. Alagille Syndrome. Springer; 2018:49-65. Accessed June 23, 2021.
- Huang H, Wang LF. Radiological changes of spine and liver in a case of Alagille syndrome. Quant Imaging Med Surg. 2018;8(3):368-371. doi:10.21037/qims.2018.04.06
- Kamath BM, Munoz PS, Bab N, et al. A longitudinal study to identify laboratory predictors of liver disease outcome in Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;50(5):526-530. doi:10.1097/MPG.0b013e3181cea48d
- Shen YM, Wu JF, Hsu HY, et al. Oral absorbable fat-soluble vitamin formulation in pediatric patients with cholestasis. J Pediatr Gastroenterol Nutr. 2012;55(5):587-591. doi:10.1097/MPG.0b013e31825c9732
- Liu QY, Nguyen V. Endoscopic approach to the patient with congenital anomalies of the biliary tract. Gastrointest Endosc Clin N Am. 2013;23(2):505-518. doi:10.1016/j.giec.2012.12.004
- Urade T, Fukumoto T. Intraoperative ultrasonic cholangiography for biliary system identification. Can J Surg. 2018;61(1):E1. doi:10.1503/cjs.1861011
- Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics (Basel). 2020;10(11):907. doi:10.3390/diagnostics10110907
- Subramaniam P, Knisely A, Portmann B, et al. Diagnosis of Alagille syndrome-25 years of experience at King’s College Hospital. J Pediatr Gastroenterol Nutr. 2011;52(1):84-89. doi:10.1097/MPG.0b013e3181f1572d
- Berrocal T, Gamo E, Navalón J, et al. Syndrome of Alagille: radiological and sonographic findings. A review of 37 cases. Eur Radiol. 1997;7(1):115-118. doi:10.1007/s003300050122
- Tretter, JT, McElhinney DB. Cardiac, aortic, and pulmonary vascular involvement in Alagille syndrome. In: Kamath BM, Loomes KM, eds. Alagille Syndrome. Springer; 2018:77-90. Accessed June 23, 2021.
- Narula P, Gifford J, Steggall MA, et al. Visual loss and idiopathic intracranial hypertension in children with Alagille syndrome. J Pediatr Gastroenterol Nutr. 2006;43(3):348-352. doi:10.1097/01.mpg.0000221895.51748.44
- Vitiello L, De Bernardo M, Guercio Nuzio S, Mandato C, Rosa N, Vajro P. Pediatric liver diseases and ocular changes: what hepatologists and ophthalmologists should know and share with each other. Dig Liver Dis. 2020;52(1):1-8. doi:10.1016/j.dld.2019.11.009
Reviewed by Eleni Fitsiou, PhD, on 7/1/2021.