Alpha1-antitrypsin Deficiency: Lessons Learned from the Bedside to the Gene and Back Again: Early Support for the Proteolytic Theory

Alpha1-antitrypsin Deficiency: Lessons Learned from the Bedside to the Gene and Back Again: Early Support for the Proteolytic TheoryThey emphasized a possible role of elastase in the development of emphysema. In agreement with earlier findings by Hamburger and Haupt,15 they showed that ajAT was an effective inhibitor of pancreatic elastase. Several independent groups should be given credit for focusing interest on the role of leukocyte elastase in the pathogenesis of emphysema. Janoff and Scherer first demonstrated elastase activity in the human leukocyte granules, Olsson showed its high affinity for otjAT, and Lieberman demonstrated lung digestion by leukoproteases which could be inhibited by o^AT. We and others emphasized the early loss of elastic recoil force in these patients19 and Senior et al used purified human leukocyte elastase to produce experimental emphysema in animals. The key role of neutrophilic elastase in human emphysema has gradually been accepted. Today, synthetic elastase inhibitors begin to appear in phase 1 clinical trials.
What We Did Not Understand
I had observed a number of deficient subjects, mainly women, who lived to an advanced age without developing clinical evidence of emphysema. I did not realize at that time the enormous prognostic importance of cigarette smoking in deficient individuals, a fact first emphasized by investigators at the Mayo Clinic. In a classic paper from 1978 my coworker, Dr. C. Larsson, convincingly demonstrated the importance of cigarette smoking as a prognostic factor in deficient individuals (Fig 12). canadian good neighbor pharmacy

We realized that axAT was an acute phase reactant synthesized mainly in the liver. I was disappointed to find normal liver function tests in a number of deficient patients.6 In 1962 we had a patient on our ward with cryptogenic, decompensated cirrhosis and absence of a visible o^-band in the electrophoretic strip (Fig 13). Unfortunately, we misinterpreted this patient as having an aquired form of o^AT deficiency secondary to a severely impaired hepatocellular function. No relatives were available for study. If we had performed an immunoelectrophoretic analysis on his serum, we would have found the retarded electrophoretic mobility previously discussed (Fig 3) and would probably have understood that the patient had cirrhosis based on hereditary otjAT deficiency. As it was, this aspect was not documented until 1969 when Sharp and coworkers22 recognized the association of liver disease with otxAT deficiency in children.

Figure 12. Influence of smoking on survival in a, AT deficiency. Reproduced from Larsson by permission.

Figure 12. Influence of smoking on survival in a, AT deficiency. Reproduced from Larsson by permission.

Figure 13. a, AT deficiency and cirrhosis of the liver. Electrophoresis in agar gel. Note hypoalbumine-mia, absence of an a,-band and pronounced hypergammaglobulinemia.

Figure 13. a, AT deficiency and cirrhosis of the liver. Electrophoresis in agar gel. Note hypoalbumine-mia, absence of an a,-band and pronounced hypergammaglobulinemia.

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