Part 3 of a 3-part series

Henry Lin, MD, MBA
Henry Lin, MD, MBA

Alagille syndrome (ALGS) is a multisystem genetic condition that typically manifests as cholestasis in childhood and is defined by a paucity of bile ducts. There is variable phenotypic penetrance which can involve the following systems: liver, heart, kidney, skeletal, eyes, and vascular. Management of ALGS is supportive and primarily focused on the associated organ system involvement. In addition, there are growth, nutritional, and psychosocial considerations when managing ALGS.

Etiology and Impacts

Impairment of growth is well-established in ALGS, with over half of children being below the 5th percentile for age in weight or height. The etiology of poor growth in ALGS is unclear, but there are likely multiple potential contributing factors. Growth failure is a common sequela in chronic diseases, whether secondary to inadequate caloric intake or increased metabolic demand.  In those with cholestatic liver disease, malabsorption of fat can also contribute to poor weight gain and these patients may have protein calorie malnutrition.


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Furthermore, some studies have reported a negative correlation between total bilirubin and height and weight z-scores. Poor weight gain is observed in those without severe liver involvement and could also be secondary to other organ system manifestations such as cardiac disease.

Read Part 1 of the series: Managing the Clinical Manifestations of ALGS: Hepatic and Cardiac Considerations

Low birth weight is present in over half of newborns with ALGS. While there is a growth catch-up period, the overall weight and linear growth of children with ALGS typically remain below the reference ranges for age, especially in individuals with more severe liver involvement. Poor linear growth also appears to be present even in those without malnutrition, suggesting a potential role of skeletal involvement or underlying endocrine disturbances. For instance, animal models have also suggested a role of growth hormone insensitivity with decreased expression of insulin-like growth factor 1. 

Poor growth can impact quality of life and highlight the need for ALGS-specific growth charts to help with clinical assessments. Longitudinal studies on the natural history of ALGS report lower health-related quality of life (HRQOL) scores in children with ALGS, with an association between the HRQOL scores and growth failure.

Evaluation

The evaluation of growth and nutrition in patients with ALGS includes routine screening of growth parameters such as height and weight z-score and percentile for age. For individuals with malnutrition or poor growth, anthropometrics such as mid-arm circumference and triceps skinfold should be followed.

Read Part 2 of the series: Kidney, Skeletal, Eye, and Vascular Considerations in Managing Alagille Syndrome

Fat-soluble vitamin levels should be checked in cholestatic liver disease, as the absorption of vitamins A, D, E, and K is dependent on bile acids to facilitate intestinal uptake. Vitamin A, D, and E levels should be checked along with an INR, which is a surrogate for vitamin K deficiency as vitamin K is required for clotting factor synthesis. A baseline bone density scan—such as a dual-energy x-ray absorptiometry (DEXA) scan—should also be considered, as cholestasis can interfere with the absorption of calcium and vitamin D, which are important in bone health and development.

Management

Management of poor growth in patients with ALGS depends on its underlying etiology. In most instances, inadequate caloric intake contributes to poor growth and, consequently, supplementing calories can help with growth.

Breastfeeding is encouraged and milk can be fortified to increase caloric density. For individuals with cholestatic liver disease, a formula with medium chain triglycerides (MCT) should be considered, as MCTs are more readily absorbed in cholestasis. MCT oil can be supplemented individually and commercially available oils such as coconut oil are high in MCT. If there is poor oral intake, supplemental enteral feeds via a nasogastric or gastrostomy tube may be indicated to help achieve calorie intake goals.

Vitamin supplementation may be needed for individuals with cholestatic liver disease. Fixed-ratio fat-soluble vitamin preparations such as ADEK can be used, but separate supplementation of individual vitamins A, D, E, and K may be needed. A risk of night blindness or retinal degenerative changes is associated with vitamin A deficiency. Vitamin D deficiency can increase the risk of rickets or osteoporosis; as such, routine screening of bone density and vitamin D levels should be performed. Neuropathies are associated with vitamin E deficiency. Hypovitaminosis K can lead to coagulopathy and increase the risk of bleeding. Coagulopathy can also be an indication of hepatic synthetic dysfunction and for individuals with coagulopathy, vitamin K deficiency should be ruled out.

References

Andersson ER, Chivukula IV, Hankeova S, et al. Mouse model of Alagille syndrome and mechanisms of Jagged1 missense mutations. Gastroenterology. 2018;154(04):1080-1095. doi:10.1053/j.gastro.2017.11.002.

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

Bales CB, Kamath BM, Munoz PS, et al. Pathologic lower extremity fractures in children with Alagille syndromeJ Pediatr Gastroenterol Nutr. 2010;51(1):66-70. doi:10.1097/MPG.0b013e3181cb9629

Bucuvalas JC, Horn JA, Carlsson L, Balistreri WF, Chernausek SD. Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature. J Clin Endocrinol Metab. 1993;76(6):1477-1482. doi:10.1210/jcem.76.6.8501153

Francavilla R, Miniello VL, Brunetti L, Lionetti ME, Armenio L. Hepatitis and cholestasis in infancy: clinical and nutritional aspects. Acta Paediatr. 2003; Suppl 441:101-104. doi:10.1080/08035320310018600

Kamath BM, Chen Z, Romero R, et al; Childhood Liver Disease Research Network (ChiLDReN). Quality of life and its determinants in a multicenter cohort of children with Alagille syndrome. J Pediatr. 2015;167(2):390-396.e3. doi:10.1016/j.jpeds.2015.04.077

Kamath BM, Baker A, Houwen R, Todorova L, Kerkar N. Systematic review: the epidemiology, natural history, and burden of Alagille syndromeJ Pediatr Gastroenterol Nutr. 2018;67(2):148-156. doi:10.1097/MPG.0000000000001958

Kamath BM, Ye W, Goodrich NP, et al; Childhood Liver Disease Research Network (ChiLDReN). Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study. Hepatol Commun. 2020;4(3):387-398. doi:10.1002/hep4.1468

Kohut TJ, Gilbert MA, Loomes KM. Alagille syndrome: a focused review on clinical features, genetics, and treatment. Semin Liver Dis. 2021;41:525-537. doi:10.1055/s-0041-1730951

Rovner AJ, Schall JI, Jawad AF, et al. Rethinking growth failure in Alagille syndrome: the role of dietary intake and steatorrhea. J Pediatr Gastroenterol Nutr. 2002;35(4):495-502. doi:10.1097/00005176-200210000-00007