AlphaiAT deficiency not only represents a deficiency state characterized by inadequate defense against protease excess in interstitial tissue, but also constitutes an example of a previously unknown storage disease. Accumulation of an abnormally-glycosylated ajAT (which is strongly periodically acid-Schiff positive after diastase digestion) in the liver cell is a hallmark of the PiZ-gene expression. The abnormal ctjAT accumulates in the endoplasmic reticulum (ER) of the hepatocytes. One may consequently speak of an ER-storage disease in contrast to the well-known lysosomal storage diseases. AlphajAT deficiency is the first example and an excellent model of an ER-storage disease. Similar aggregations seem to occur in hereditary hypofibrinogenemia and in the recently described ax-antichymotrypsin deficiency. It is sufficient to emphasize that chest physicians taking care of o^AT deficient patients should consider their significant risk for developing liver disease later in life which may progress to cirrhosis and, not infrequently, primary liver cell cancer.
Today, o^AT deficiency has been known for almost exactly 25 years. I have had the privilege of contributing to the knowledge of its main clinical manifestations. This has been rewarding since this inborn error has served as a model disease in several respects. Progress has been rapid, and recently the feasibility of replacement therapy has been documented. Synthetic elastase inhibitors will probably be used in clinical trials in the near future. Nonetheless, the natural history of the disease is not completely delineated. All published series are based on more or less selected hospital materials. read more
We recently studied all cases known to us in the city of Malmo during 1963 through 1982. Close to 70 percent of all individuals who died in the city were autopsied, so the results can be regarded as representative of a well-defined population of almost 250,000. Figure 14 illustrates that all o^AT deficient subjects > 40 years of age will have more or less severe emphysema. The association with smoking is evident but, in addition, variability is present and very severe emphysema will sometimes develop even in nonsmokers. Identification of other unknown protective factors which may prevent the development of emphysema at the alveolar level seems urgent. An additional important task for the near future is primary intervention against smoking. Screening for axAT deficient individuals before definite smoking habits have been established seems ideal. Screening of school children perhaps would be the most effective method but, for psychological reasons, this approach has been criticized. In Sweden, screening of men at age 18 in connection with enrollment for army service has been discussed as a second best alternative to detect o^AT deficiency and present informtion about the dangers of smoking. This preventive approach seems preferable to later therapeutic administration of potentially dangerous drugs to individuals with already established lung disease.
Figure 14. Emphysema in patients with o^AT deficiency in a representative population sample. Of the PiZ cases, 17 individuals (eight women, nine men) ^ 40 years old have died. Of these individuals, all had emphysema as the major or contributing cause of death. For details see text.