Part 1 of a 3-part series

Henry Lin, MD, MBA

Alagille syndrome (ALGS) is an autosomal dominant condition that is due to mutations in the Notch signaling pathway. The majority of people with ALGS have a Jagged1 (JAG1) mutation, with 2%-3% of people having a mutation in the NOTCH2 gene. ALGS can affect multiple organ systems including the liver, heart, kidneys, vascular, skeleton, eyes, and other organs. People with ALGS may also have distinctive facial features characterized by a broad forehead with a pointed chin and deep-set eyes.

The diagnosis of ALGS has traditionally been based on the presence of bile duct paucity on liver biopsy along with at least 3 of 5 major clinical features: cholestasis, cardiac disease, ocular abnormalities, skeletal anomalies, and characteristic facial features. With the availability of molecular testing for JAG1 and NOTCH2 mutations, the diagnosis of ALGS can now be made based on genetics in the absence of meeting all the clinical criteria. In this manner, genetic testing has allowed for appreciation of the phenotypic variability in ALGS.


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As ALGS can affect various organ systems, the goal of this 3-part series of articles is to review the common clinical features of the disorder and describe the necessary screening for each organ system and consequent management. We will review liver and cardiac involvement in ALGS for this article.

Liver

Clinical Manifestations

The liver is the most common organ system involved in ALGS. Hepatic manifestations typically present in infancy, commonly as neonatal cholestasis with jaundice. Hepatomegaly is frequently observed, with splenomegaly being a later finding, indicative of portal hypertension from progression of liver disease.

Scleral icterus, pruritus, and xanthomas may also be seen. Pruritus rarely presents before 3 months of age, and assessment of pruritus can be challenging in infants with potential symptoms of irritability or difficulty sleeping. The presence of excoriations on the cutaneous surface is a common finding in more severe pruritus. Xanthomas are lipid deposits under the skin that are usually found on extensor surfaces. The formation of xanthomas is correlated with a total fasting cholesterol level >500mg/dL.

Evaluation

Hepatic lab findings in ALGS liver disease include elevations in total and conjugated bilirubin, gamma-glutamyl transferase (GGT), aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and serum bile acids. Transaminase elevations are usually relatively mild compared to the cholestatic markers. A baseline cholesterol panel should be considered as individuals with ALGS may have hypercholesterolemia and hypertriglyceridemia.

Hepatic synthetic function is preserved initially but with the progression of liver disease, abnormalities in coagulation and low protein or albumin levels may be seen. On liver biopsy, bile duct paucity is one of the hallmark features, but paucity may not be readily apparent on biopsy in infancy. In a neonate presenting with cholestasis, other etiologies of cholestatic liver disease should be considered, including biliary atresia, alpha-1 antitrypsin deficiency, or other metabolic or genetic disorders of cholestasis. As such, a thorough evaluation for other organ system involvement along with genetic testing can aid in the diagnosis of ALGS.

Read more about ALGS complications

Progression of liver disease can occur in individuals with ALGS, so identification of it with early referral to a gastroenterologist is key. Complications from end-stage liver disease include severe pruritus, fractures, growth failure, synthetic hepatic dysfunction, and sequelae from portal hypertension such as ascites or esophageal varices.

Currently, there are no predictors of liver disease severity of progression. Management of ALGS liver disease is symptom-based and has minimal impact on the natural history or disease progression. 

Management

For management of pruritus, response to treatment is varied. Skin care with use of emollients and trimming of fingernails is recommended. Ursodeoxycholic acid can be used to help stimulate bile flow. Other medications to consider for the management of pruritus include rifampin and naltrexone.  Antihistamines such as hydroxyzine or diphenhydramine can help with sleep but are not as effective as antipruritics. Ileal bile acid transporter inhibitors are now approved as a treatment option for pruritus. 

Aside from medical therapy, surgical biliary diversion has been helpful in some patients. Liver transplantation is considered in patients with end-stage liver disease, intractable pruritus, and growth failure. 

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Cholestasis can lead to fat malabsorption and subsequent fat-soluble vitamin deficiencies. Baseline levels of the fat-soluble vitamins (vitamin A, D, E, and K) should be obtained. An international normalized ratio (INR) is typically used as a surrogate marker for vitamin K. The degree of fat-soluble vitamin deficiency is variable but if levels are low, supplementation should be considered. Multivitamin preparations may not offer adequate ratios of the fat-soluble vitamins and individual supplementation may be needed. Further discussion about nutritional management will be reviewed in an article later in this series.

Cardiac

Clinical Manifestations

Cardiac involvement in ALGS is almost universal, with a predominance of right-sided heart lesions and pulmonary vasculature involvement. Peripheral pulmonary artery stenosis is the most prevalent cardiac finding, occurring in over three-quarters of individuals with ALGS. This narrowing of the peripheral pulmonary arteries manifests as a systolic ejection murmur and is usually benign. While most children with peripheral pulmonary artery stenosis are asymptomatic aside from a heart murmur, potential symptoms include fatigue and shortness of breath.

Other cardiac lesions associated with ALGS include Tetralogy of Fallot, atrial septal defects, ventricular septal defects, coarctation of the aorta, aortic stenosis, truncus arteriosus, and total anomalous pulmonary venous return. Tetralogy of Fallot is the most common complex cardiac lesion seen in ALGS and is characterized by pulmonary stenosis, ventricular septal defect, right ventricular hypertrophy, and an overriding aorta. A clinically severe variant of Tetralogy of Fallot with pulmonary atresia occurs more frequently in ALGS.

Evaluation

Cardiac disease increases mortality in ALGS and accounts for the majority of early mortality.  An echocardiogram and prompt evaluation by a cardiologist should be considered in a cholestatic individual who presents with a murmur. Additional evaluation is based on cardiac involvement.

Management

The management of cardiac disease is dependent on cardiac involvement and targeted to the specific anomaly. Nonsurgical invasive techniques such as stent placement, balloon dilation, or valvuloplasty can be used in select conditions. Mild peripheral pulmonary artery stenosis may be followed with routine echocardiogram.

References

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Ayoub MD, Kamath BM. Alagille syndrome: diagnostic challenges and advances in management. Diagnostics. 2020;10(11):907. doi:10.3390/diagnostics10110907

Emerick KM, EB Rand, E Goldmuntz, ID Krantz, NB Spinner, DA Piccoli. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology. 1999;29(3):822-829. doi:10.1002/hep.510290331

Emerick KM, Whitington PF. Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome. Hepatology. 2002;35(6):1501-1506. doi:10.1053/jhep.2002.33332

Feranchak AP, Sokol R. Medical and nutritional management of cholestasis in infants and children. Liver Dis Child. 2007;3:190-231.

Kamath BM, Bauer RC, Loomes KM, et al. NOTCH2 mutations in Alagille syndrome. J Med Genet. 2012;49(2):138-144. doi:10.1136/jmedgenet-2011-100544

Kamath BM, Loomes KM, Piccoli DA. Medical management of Alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;50(6):580-586.

Kamath BM, Spinner NB, Piccoli DA. Alagille syndrome. In: Suchy FJ, Balistreri WF, eds. Liver Disease in Children. Cambridge University Press; 2007:chap 15. Accessed October 7, 2021.

Kriegermeier A, Wehrman A, Kamath BM, Loomes KM. Liver disease in Alagille syndrome. In: Kamath BM, Loomes KM, eds. Alagille Syndrome. Springer; 2018:chap 4. Accessed October 7, 2021.

Mitchell E, Gilbert M, Loomes KM. Alagille syndrome. Clin Liver Dis. 2018;22(4):625-641. doi:10.1016/j.cld.2018.06.001

Russo P, Ruchelli ED, Piccoli DA, eds. Pathology of Pediatric Gastrointestinal and Liver Disease. Springer; 2014. Accessed October 7, 2021.