Medical Management of Alagille Syndrome
Alagille syndrome is a highly variable, autosomal dominant disorder that affects the liver, heart, eyes, face, skeleton, kidneys, and vascular system. Much has been learned about the genetics of this disorder, which is caused primarily by mutations in the Notch signaling pathway ligand JAGGED1; however, the medical management of this condition is complex and continues to generate controversy. The significant variability of organ involvement requires the managing physician to have an understanding of the breadth and interplay of the variable manifestations. Furthermore, the liver disease in particular requires an appreciation of the natural history and evolution of the profound cholestasis.
Available from: Benjamín Antonio Rodríguez-Espino
- "Alagille syndrome (ALGS (MIM 118450), OMIM) is a multisystem disorder with an autosomic dominant pattern of inheritance that affects the liver (particularly presenting bile duct paucity diagnosed by liver biopsy), heart (peripheral pulmonary artery stenosis), eyes (posterior embriotoxon), kidneys (renal dysplasia, renal tubular acidosis, among others), and skeletal system (butterfly vertebrae), and presents characteristic facial features (broad forehead, deep-set eyes, pointed chin and a triangular face) (Kamath et al., 2010, 2011). ALGS shows a variable expression that complicates the diagnosis, which is established with the identification of at least three out of five main clinical characteristics (Emerick et al., 1999; Kamath et al., 2003). "
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ABSTRACT: Alagille syndrome is a multisystem disorder with an autosomic dominant pattern of inheritance that affects the liver, heart, eyes, kidneys, skeletal system and presents characteristic facial features. Mutations of the JAG1 gene have been identified in 20–89% of the patients with Alagille syndrome, this gene encodes for a ligand that activates the Notch signaling pathway. In the present study we analyzed 9 Mexican patients with Alagille syndrome who presented the clinical criteria for the classical presentation of the disease. By using the denaturing high performance liquid chromatography mutation analysis we were able to identify different mutations in 7 of the patients (77.77%), importantly, we found 5 novel mutations in JAG1 gene. The allelic frequency distribution of 13 polymorphisms in Mexican population is also reported. The overall results demonstrated an expanding mutational spectrum of JAG1 gene in the Mexican population.
Available from: Gideon Hirschfield
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ABSTRACT: Cholestatic liver disorders are caused by genetic defects, mechanical aberrations, toxins, or dysregulations in the immune system that damage the bile ducts and cause accumulation of bile and liver tissue damage. They have common clinical manifestations and pathogenic features that include the responses of cholangiocytes and hepatocytes to injury. We review the features of bile acid transport, tissue repair and regulation, apoptosis, vascular supply, immune regulation, and cholangiocytes that are associated with cholestatic liver disorders. We now have a greater understanding of the physiology of cholangiocytes at the cellular and molecular levels, as well as genetic factors, repair pathways, and autoimmunity mechanisms involved in the pathogenesis of disease. These discoveries will hopefully lead to new therapeutic approaches for patients with cholestatic liver disease.
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