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Comorbidities
Alagille syndrome (ALGS) is an inherited multisystem disorder characterized by abnormalities in the heart, face, skeleton, eyes, and liver.1 Most cases of the disorder are due to mutations in Jagged1 (JAG1) gene (ALGS type 1), while a small proportion of cases are a result of NOTCH2 gene mutation (ALGS type 2).2
ALGS is often associated with cholestatic liver disease, potentially leading to end-stage liver disease and death, pulmonary valve stenosis or atresia, vasculopathy, and renal disease.3 In addition to cholestasis, which is the major cause of mortality and morbidity during the life span of ALGS patients, it is now known that a large number of individuals may suffer from significant comorbidities, which will require multidisciplinary care and surveillance.4–6
Liver Disease
ALGS is the most common cholestatic liver disorder of childhood, with a frequency of 1:30,000 to 1:50,000.7,8 Cholestasis in ALGS typically manifests as cholestasis with unremitting pruritus,8 and it appears during the neonatal period or in the first 3 months of life, together with jaundice due to conjugated hyperbilirubinaemia.2
The effect of ALGS on the liver varies from minimal biochemical abnormalities to profound cholestasis, portal hypertension, and end-stage liver disease,7 requiring liver transplantation in 20% to 50% of cases.9–12 When liver transplantation occurs, reports demonstrate that the majority of deaths occur within the first 30 days and are due to postoperative complications,8 with 20.9% from vascular complications, 15.4% from biliary tract complications, and 9.9% from renal complications.7,8
With no reliable way to predict which individuals are at high risk for hepatic complications, those who indeed develop liver disease have been shown to have chronic higher levels of total bilirubin, conjugated bilirubin, and cholesterol.13 Although only a small percentage of ALGS patients do not present with liver disease,14,15 hepatic complications are responsible for a significant amount of later deaths in ALGS.2
Cardiac Disease
The most common type of cardiac anomaly in ALGS patients involves the pulmonary outflow tract, leading to some form of peripheral pulmonary stenosis (PPS), and affects about two-thirds of ALGS subjects. The most common complex structural anomaly observed is the tetralogy of Fallot (TOF), occurring in up to 16% of patients.2,9,16 The presence of congenital heart disease, one of the diagnostic criteria for ALGS, appears to be a powerful indicator of early mortality, particularly because it is associated with PPS.2 In that sense, routine assessment for cardiac lesions should be performed with echocardiography, with a low threshold for cardiac catheterization to determine cardiac health and the need for any kind of intervention and/or surgery.17
Intracranial Bleeding
Intracranial bleeding is a recognized complication and a cause of mortality in ALGS that remains inexplicable3 and may occur due to minor head trauma.2 Such vascular events have been reported to occur in up to 15% of cases9 and were a cause of death in 34% of the cohort in a study led by Kamath and colleagues,3 including subarachnoid hemorrhage, subdural hematoma, epidural hemorrhage, and cerebrovascular accident.8 Vascular abnormalities of the central nervous system have been described in some ALGS individuals, which could explain the intracranial events, and demonstrates the need for more preventive evaluation of ALGS individuals who show symptoms such as neurological deficits, persistent headaches, and hypertension.3 The presence of these vascular anomalies could be potentiated by the deterioration of the liver function, which will affect coagulation, and therefore should be also monitored.2
Malnutrition
A high proportion of ALGS patients show significant growth deficits, which have been associated with malabsorption and malnutrition,2,9,18 as a result of the inability to absorb fat-soluble vitamins such as vitamin D, A, E, and K.19 This imbalance in nutrients and vitamins predisposes ALGS patients to a higher risk for secondary osteoporosis, rickets/osteomalacia, and ultimately fractures.19
In addition, studies have recently demonstrated that the failure to thrive characteristic — including delayed puberty and short stature of some ALGS patients — might be due to hypothyroidism.2
Metabolic Bone Disease
The majority of ALGS individuals suffer from chronic cholestasis, which can seriously affect bone metabolism.19 Therefore, it is not surprising that AGLS subjects can develop metabolic bone disease, characterized by the osteoporosis and fractures that result from the malnutrition status and a consequence of multi-organ involvement of the disorder.2 In fact, a recent survey on ALGS families reported fractures in 28% of 42 subjects, with 70% affecting long-bones in the lower limbs, resulting in pathologic fractures.20
References
1. Yang WH, Zhang L, Xue FS, Riaz A, Zhu ZJ. Pediatric liver transplantation for alagille syndrome: anesthetic evaluation and perioperative management. Ann Transplant. Published online October 13, 2020. doi:10.12659/AOT.924282
2. Turnpenny PD, Ellard S. Alagille syndrome: pathogenesis, diagnosis and management. Eur J Hum Genet. 2012;20(3):251-257. doi:10.1038/ejhg.2011.181
3. Kamath B, Spinner N, Emerick K, et al. Vascular anomalies in alagille syndrome: a significant cause of morbidity and mortality. Circulation. 2004;109(11):1354-1358. doi:10.1161/01.CIR.0000121361.01862.A4
4. Luong R, Feinstein JA, Ma M, et al. Outcomes in patients with alagille syndrome and complex pulmonary artery disease. J Pediatr. 2021;229:86-94.e4. doi:https://doi.org/10.1016/j.jpeds.2020.09.053
5. May L, Hanley FL, Connolly AJ, Reddy S. Atherosclerosis causing recurrent catastrophic aortopulmonary shunt dehiscence in a patient with Alagille syndrome. Pediatr Cardiol. 2013;34(8):1945-1948. doi:10.1007/s00246-012-0484-4
6. Mouzaki M, Kamath BM. Alagille syndrome. In: Dawan A, ed. Pediatric and Adolescent Medicine, Vol 16. Karger; 2012:50-63.
7. Kamath B, Yin W, Miller H, et al. Outcomes of liver transplantation for patients with alagille syndrome: the studies of pediatric liver transplantation experience. Liver Transplant. 2012;18(8):940-948. doi:10.1002/lt.23437
8. 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
9. 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
10. Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of interlobular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr. 1995;127(2):220-224. doi:10.1016/s0022-3476(95)70298-9
11. Lykavieris P, Hadchouel M, Chardot C, Bernard O. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut. 2001;49(3):431-435. doi:10.1136/gut.49.3.431
12. Quiros-Tejeira R, Ament M, Heyman M, et al. Variable morbidity in alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr. 1999;29(4):431-437. doi:10.1097/00005176-199910000-00011
13. Kamath B, Munoz P, 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
14. Krantz I, Smith R, Colliton R, et al. Jagged1 mutations in patients ascertained with isolated congenital heart defects. Am J Med Genet. 1999;84(1):56-60. doi:10.1002/(SICI)1096-8628(19990507)84:1<56::AID-AJMG11>3.0.CO;2-W
15. Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet. 2003;40(12):891-895. doi:10.1136/jmg.40.12.891
16. McElhinney D, Krantz I, Bason L, et al. Analysis of cardiovascular phenotype and genotype-phenotype correlation in individuals with a JAG1 mutation and/or Alagille syndrome. Circulation. 2002;106(20):2567-2574. doi:10.1161/01.cir.0000037221.45902.69
17. Ruth ND, Drury NE, Bennett J, Kelly DA. Cardiac and liver disease in children: implications for management before and after liver transplantation. Liver Transplant. 2020;26(3):437-449. doi:https://doi.org/10.1002/lt.25666
18. Arvay J, Zemel B, Gallagher P, et al. Body composition of children aged 1 to 12 years with biliary atresia or alagille syndrome. J Pediatr Gastroenterol Nutr. 2005;40(2):146-150. doi:10.1097/00005176-200502000-00012
19. Maharjana MA, Suyasa IK, Kawiyana IKS, Nugraha HK. Pathological fracture of the femur in alagille syndrome: a case report. J Clin Orthop Trauma. 2020;11(2):298-301. doi:10.1016/j.jcot.2019.12.00920.
Bales CB, Kamath BM, Munoz PS, et al. Pathologic lower extremity fractures in children with alagille syndrome. J Pediatr Gastroenterol Nutr. 2010;51(1):66-70. doi:10.1097/MPG.0b013e3181cb9629
Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.
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