α1-Antitrypsin deficiency· 1: Epidemiology of α1-antitrypsin deficiency

M Luisetti, N Seersholm - Thorax, 2004 - ncbi.nlm.nih.gov
M Luisetti, N Seersholm
Thorax, 2004ncbi.nlm.nih.gov
In the last 40 years, following the publication of the seminal paper by Laurell and Eriksson, 1
there have been significant advances in the understanding of genetic abnormalities related
to o1-antitrypsin (AAT) deficiency and of the pathophysiology of the associated lung and
liver diseases. During the same period, data from a number of genetic epidemiology surveys
have been accumulated. As a result, we now have a fairly comprehensive picture of the
distribution of AAT deficiency, especially in developed countries, and some soundly based …
In the last 40 years, following the publication of the seminal paper by Laurell and Eriksson, 1 there have been significant advances in the understanding of genetic abnormalities related to o1-antitrypsin (AAT) deficiency and of the pathophysiology of the associated lung and liver diseases. During the same period, data from a number of genetic epidemiology surveys have been accumulated. As a result, we now have a fairly comprehensive picture of the distribution of AAT deficiency, especially in developed countries, and some soundly based hypotheses about AAT gene evolution, the origin of AAT deficiency, and its spread. This paper reviews the available data on the genetic epidemiology of AAT deficiency. A preliminary discussion on the protein and molecular characteristics of AAT variants provide a background to facilitate a better understanding of the nomenclature and epidemiology data discussed.
THE AAT PROTEIN o1-antitrypsin (AAT or o1-AT, also referred to as o1-proteinase (or protease) inhibitor (o1-PI)) is a 52 kD glycoprotein mostly secreted by hepatocytes and, to a lesser extent, by lung epithelial cells and phagocytes. It inhibits a variety of serine proteinases but its preferred target is human neutrophil elastase (HNE), for which it demonstrates the highest association rate constant. 2 The major function of AAT in the lungs is to protect the connective tissue from HNE released from triggered neutrophils, as supported by the development of pulmonary emphysema early in life in subjects affected by severe inherited deficiency of AAT. 3 In the majority of humans the lungs are defended from HNE attack by normal AAT plasma levels ranging from 100 to 200 mg/dl (as measured by nephelometry). Although AAT is a well known acute phase reactant, this wide variability in its normal plasma levels mostly reflects the marked pleomorphism of the glycoprotein. More than 100 genetic variants of AAT have been identified and these are strictly associated with specific AAT plasma levels in a co-dominantly inherited fashion4 5—in other words, plasma AAT levels
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