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The existence of alpha-1 antitrypsin variants with apparently unremarkable phenotypes and serum concentrations, contrasting with a clinical picture suggestive of a severe deficiency, led us to investigate whether in these cases there was a reduction or even suppression of the capacity of alpha-1 antitrypsin to inhibit elastase. To this end, in two different laboratories, we adapted and validated a method for measuring the functional activity of alpha-1 antitrypsin. We carried out spectrophotometric kinetic analysis of the inhibition by serum alpha-1 antitrypsin of the hydrolytic activity of porcine pancreatic elastase on a chromogenic substrate. This method has proved to be robust, reproducible, and transferable, and made it possible to define, by analyzing a hospital population, a functionality index with a confidence interval of between 0.87 and 1.2. This in turn enabled us to identify subjects likely to have a functional deficiency of alpha-1 antitrypsin, be it of a genetic origin without any quantitative or phenotypic translation, or acquired under the effect of external agents (cigarette smoke or viruses).