183. Elucidation of Alpha-1 Antitrypsin Levels in Human Infant Blood Samples

Abstract

Alpha-1 antitrypsin (AAT) is a serum anti-protease that is produced in the liver and secreted into the circulation to function in the lung, protecting the alveolar interstitium from degradation by neutrophil elastase. AAT deficiency is a monogenic disease that results from mutations to the AAT gene. In the case of the PiZ mutation, the mutant Z-AAT produced in the liver undergoes loop-sheet polymerization inhibiting the secretion of AAT from the hepatocytes into the blood stream. Since AAT is sequestered in the liver, the protein is incapable of inhibiting neutrophil elastase's destruction of the alveolar epithelium, resulting in progressive lung disease. Accumulation of Z-AAT within the hepatocyte endoplasmic reticulum leads to hepatocellular stress, which can result in acute or chronic liver disease. About 5% of children afflicted with AAT deficiency develop acute liver failure within the first year of life. The cause for this acute liver failure in young patients has not yet been elucidated. Previous analysis of AAT levels in a mouse model expressing human Z-AAT from the endogenous AAT promoter has shown a considerable increase in hAAT concentration within the first few weeks of life, peaking at about 8.0*106 ng/mL at eight weeks, followed by a decrease in AAT concentration leveling out at 4.0*106 ng/mL at eighteen weeks of age. If the AAT promoter is regulated in a similar fashion in humans, one might predict that higher AAT expression in the early neonatal period may lead to increased accumulation of mutant AAT within the hepatocytes and precipitate fulminant liver disease early in life. In order to investigate this possibility, AAT levels were measured in healthy human infants over the course of the first two years of life. AAT levels were determined using a modified sandwich enzyme-linked immunosorbent assay (ELISA). Infant AAT levels demonstrate a biphasic trend with an initial increase to a maximum mean level of 2.8*106 ng/mL at five months, followed by a gradual decreasing trend. Mean levels remain higher than mean adult levels (1.3*106 ng/mL) up to twenty-four months of age and higher than previously reported infant levels (0.93*106 - 2.51*106 ng/mL) up to thirteen months of age.