Alagille syndrome is a complex multisystem autosomal dominant disorder with a wide variability in penetrance of clinical features. A majority of patients have pathogenic mutations in either the JAG1 gene, encoding a Notch pathway ligand, or the receptor NOTCH2. No genotype-phenotype correlations have been found in any organ system. Liver disease is a major cause of morbidity in this population, whereas cardiac and vascular involvement accounts for most of the mortality. Current therapies are supportive, but the future is promising for the development of targeted interventions to augment Notch pathway signaling in involved tissues.
Purpose of ReviewThe aim of the study is to review the liver disease caused by alpha-1 antitrypsin deficiency (A1ATD), including pathogenesis, epidemiology, diagnostic testing, and recent therapeutic developments.Recent FindingsTherapeutic approaches target several intracellular pathways to reduce the cytotoxic effects of the misfolded mutant globular protein (ATZ) on the hepatocyte. These include promoting ATZ transport out of the endoplasmic reticulum (ER), enhancing ATZ degradation, and preventing ATZ globule-aggregation.SummaryA1ATD is the leading genetic cause of liver disease among children. It is a protein-folding disorder in which toxic insoluble ATZ proteins aggregate in the ER of hepatocytes leading to inflammation, fibrosis, cirrhosis, and increased risk of hepatocellular carcinoma. The absence of the normal A1AT serum protein also predisposes patients to pan lobar emphysema as adults. At this time, the only approved therapy for A1ATD-associated liver disease is orthotopic liver transplantation, which is curative. However, there has been significant recent progress in the development of small molecule therapies with potential both to preserve the native liver and prevent hepatotoxicity.
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