The clinical presentation of liver disease is highly variable in homozygous ZZ alpha-1 antitrypsin (AAT) deficiency, and not all patients with the homozygous ZZ genotype develop liver disease. Although not fully identified, there is likely a strong influence of genetic and environmental modifiers of the intracellular injury cascade and fibrotic response. Most ZZ children are well and remain undiagnosed. Of those who come to medical attention, the most common pediatric presentation is neonatal cholestatic hepatitis, sometimes referred to as "neonatal hepatitis syndrome". The gold standard for diagnosis of AAT deficiency is analysis of the AAT protein phenotype in the patient serum or the genotype of their DNA genome. Careful follow up of all diagnosed children is important. Heterozygotes for S and Z alleles of AAT (SZ) may develop progressive liver disease similar to ZZ patients and also require close monitoring. There is no specific treatment for AAT deficiency induced liver disease and current therapy remains supportive with management of complications. Rarely, patients require liver transplant and typically the patient outcomes are excellent. With improved understanding of liver injury mechanisms, new strategies for treatment are now being explored, including siRNA technology, molecules to modulate secretion, and enhancers of proteolysis.
Keywords: Autophagy; ER-associated degradation (ERAD); protein polymer; proteolysis; siRNA.
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