Charles Mittman

Alpha1 Antitrypsin in the Livers of Patients with Emphysema

Parenchymal liver cells from emphysema patients with an inherited deficiency of α1-antitrypsin contain globules of glycoprotein that bind fluorescent antibody to α1-antitrypsin. The globules can be seen after hematoxylin and eosinstaining or on electron microscopy, but are more readily demonstrated by PAS stain of amylase-treated liver sections. It appears that an inappropriately large amount of α1-antitrypsin is found in the liver even when there is a deficiency in the serum. Genetic variants of the normal antitrypsin molecule may be unable to leave their site of synthesis in the liver cell because of some molecular aberration.

Alpha1-antitrypsin (A1AT) accumulation in livers of emphysematous patients with A1AT deficiency*

Abstract An inherited deficiency of alpha 1 -antitrypsin (A 1 AT) in human serum predisposes to the development of pulmonary emphysema. A 1 AT is synthesized primarily by the liver, but no specific liver abnormality has been described in deficient subjects with lung disease. Fourteen of 17 livers from emphysematous patients with a Pi z variant of A 1 AT (nine homozygotes and five heterozygotes) showed discrete, rounded, membrane enclosed cytoplasmic globules 1 to 20 microns in diameter and strongly PAS positive after diastase digestion. Three livers from patients with a Pi s variant of A 1 AT did not have the globules. A battery of histochemical tests indicated a nonlipid, glycoprotein, globular composition. Electron microscopic study showed the globules to be single membrane bound, roughly oval, and occasionally irregular, containing a homogeneous, moderately electron dense substance. Application of fluorescein conjugated antisera to human A 1 AT to the liver tissues in five patients revealed positively staining structures corresponding to the globules. Use of fluorescein conjugated antisera to human albumin, fibrinogen, and gamma globulin revealed no globular fluorescence. These observations document the presence of an intracellular hepatic accumulation of A 1 AT in patients with the serum deficiency and emphysema and complement the findings of Sharp, who has described similar globules in inherited infantile cirrhosis and A 1 AT deficiency. No similar structures were observed in the livers of the emphysematous patients with a normal or elevated A 1 AT level. The cause of this accumulation may be an anomalous organelle, an allelic variant that is unable to escape, or a third unidentified factor.

Antitrypsin Deficiency and Abnormal Protease Inhibitor Phenotypes

Protease inhibitor phenotypes associated with severe and intermediate antitrypsin deficiency were observed more frequently than expected in 164 patients with chronic, obstructive lung disease. The risk associated with any phenotype appears related to the severity of the deficiency. An association between the intermediate deficiency and chronic, obstructive lung disease would have been obscured if only the serum concentration of antitrypsin had been measured. When compared with patients with normal protease inhibitor types, those with the intermediate deficiency generally developed overt disease after relativeiy little exposure to cigarette smoke. It is suggested that antitrypsin deficiency is one inherited abnormality that is predisposing to the development of lung disease by rendering individuals more susceptible to the harmful effects of environmental factors, in this circumstance, lung disease in these individuals is preventable.

Respiratory impairment in coke oven workers: relationship to work exposure and bronchial inflammation detected by sputum cytology.

Coke oven workers are at excess risk of developing lung cancer and may be at risk for chronic obstructive lung disease (COLD). We have studied 3799 male workers to assess the relationship between the two diseases. Repeated lung function and sputum cytology tests were obtained over a 3-year period. Sputum samples were assessed using standardized methods; in addition to metaplastic and neoplastic changes, we reproducibly assessed the presence and extent of acute and chronic inflammatory changes. Spirometric flow rates (FEV1) were significantly reduced in workers most exposed to coke oven emissions, particularly in those with excessive inflammatory cells and regular metaplasia in sputum. The presence of reactive bronchial epithelial cells and metaplasia were potent predictors of an abnormal FEV1/FVC. Studies like these may offer a means to investigate the relationship between COLD and lung cancer. Such changes in sputum may identify individuals at risk of developing both diseases.

Medullary carcinoma of the lung with amyloid stroma: A counterpart of medullary carcinoma of the thyroid

Abstract A patient surviving five years with an amyloid producing pulmonary neoplasm died of bronchopneumonia. At necropsy it was found that the amyloid was present only in association with the neoplastic cells, both within the lung and at the sites of metastases. To our knowledge this is a unique association. Our evidence suggests that this tumor might be a medullary carcinoma of the lung, a counterpart to medullary carcinoma of the thyroid.

James Jackson, Jr., and emphysema.

Excerpt To the editor: Dr. William B. Spauldings review of the life of James Jackson, Jr., in the March 1973 issue (pp. 429-435) reminded me of an earlier encounter with the work of this remarkabl...

More on Antitrypsin Activity in Lung Disease

Excerpt To the editor: Welch and associates (Ann Intern Med71:533-542, 1969) present data that suggest to them that individuals with intermediate levels of antitrypsin activity (heterozygotes) are ...

Familial temperature sensitive alpha 1 protease inhibitor (m1anaheim)

An alpha 1 protease inhibitor which is sensitive to increased temperatures and which migrates in the same position as the normal M1 phenotype, has been identified. The sensitivity of the trypsin inhibitory capacity is an inherited characteristic, which is enhanced by acid conditions, as well as conditions during isoelectric focusing. Loss of the serum trypsin inhibitory capacity is not parallel to that of the serum elastase capacity, suggesting that the inhibitory sites for these proteases are oriented differently within the alpha 1 protease inhibitor molecule.

Aids in Screening for Heterozygous Alpha1-Antitrypsin Deficiency.

Excerpt Detection of the carrier state for alpha1-antitrypsin deficiency is valuable for studying the genetic predisposition to chronic obstructive lung disease and as a screening test in preventiv...