Medical genetics / edited by Victor A. McKusick and Robert Claiborne.

Date:
[1973]
Catalogue details

Licence: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)

Credit: Medical genetics / edited by Victor A. McKusick and Robert Claiborne. Source: Wellcome Collection.

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    SHARP 30 20 With Emphysema ra О z о О Without Emphysema 30 40 50 60 70 80 Age in Years |: * I Men I I Women Severe alpha-1-antitrypsin deficiency is not necessarily evidenced as overt illness; thus comparable serum levels are seen in subjects of Pi phenotype ZZ whether they have familial emphysema (upper graph) or are free of the pulmonary disease (lower graph). may depend on interaction with other genes or perhaps exposure to some en¬ vironmental agent, or other factors. As the Swedish work on the rela¬ tion of alpha-1-antitrypsin deficiency to pulmonary emphysema became known, investigators elsewhere sought to confirm it. The first example out¬ side of Scandinavia was reported in 1966 by Friedrich Kueppers and co¬ workers while in New York; their pa¬ tient was a 53-year-old man who had been ill with pulmonary disease since age 48. He and a brother both proved markedly deficient in serum alpha-1- antitrypsin; his three sons had half the normal amount. As other workers re¬ ported additional cases, the destruc¬ tive pulmonary disease associated with severe alpha-l-antitrypsin deficiency became well characterized. An associ¬ ation between the serum protein de¬ fect and early onset panacinar emphy¬ sema was firmly established, although the question of a causal relationship remained unresolved. Also unresolved was the possibility of an association between an interme¬ diate serum protein deficiency and the lung disease. Several investigators undertook to define this relationship more clearly. For example, Martin Welch and coworkers in Oklahoma City assessed serum antitryptic activ¬ ity in 51 presumably healthy adult blood donors and 146 consecutive un- selected patients attending a chest clinic. Three in the healthy group were found to have intermediate serum levels of alpha-l-antitrypsin, as did 17 in the group with pulmonary disease, a difference not found statistically sig¬ nificant. Turning then to patients in whom the deficiency had been identi¬ fied, they studied 18 with intermedi¬ ate and 13 with severe deficiency with respect to pulmonary disease. All 18 patients with intermediate levels were men; 10 of the 13 with severe defi¬ ciency were women. In the latter group the lung disease almost always took the form of primary emphysema with minimal chronic bronchitis; in contrast, a wide assortment of pul¬ monary diseases affected the patients with intermediate antitrypsin levels. X-ray and lung scan findings also differed sharply. Characteristically, in the severely deficient group, x-rays showed diffuse loss of vascular mark¬ ings over both lower lung fields; up¬ per lobe vessels tapered and branched normally and extended to the lung periphery. These findings were con¬ firmed on lung scans, which showed greater perfusion of upper zones. In patients with intermediate antitrypsin levels, radiographic findings ranged from normal to extensive bullous dis¬ ease. None of the x-rays indicated a pattern of bilateral decrease in lower zone perfusion; none of the lung scans showed bilateral lower-zone disease. Similar differences obtained in a Boston study by Richard Talamo and coworkers of families of six patients with a combination of pulmonary dis¬ ease and alpha-l-antitrypsin deficien¬ cy. Serum antitrypsin concentration and antitryptic activity were deter¬ mined in 93 relatives and three addi¬ tional subjects. Eight of 11 genetical¬ ly homozygous relatives proved to have obstructive pulmonary disease; findings in a ninth suggested similar lung involvement. Among 34 family members with intermediate antitryp¬ sin levels only one, a 77-year-old man, was found to have pulmonary disease, and he for years had been a heavy smoker. Thus the investigators could conclude that no remarkable rate of occurrence of pulmonary dis¬ ease was noted among either genetic heterozygotes or family members with normal alpha-l-antitrypsin function and concentration. Admittedly, the question of in¬ creased risk to heterozygotes remains open. For example, Jack Lieberman and coworkers in California report¬ edly observed several heterozygous in¬ dividuals with lung disease among relatives of an afi'ected homozygote. This prompted them to survey pa¬ tients with pulmonary emphysema at a Veterans Administration hospital in reference to serum alpha-l-antitrypsin deficiency. Of the 66 patients studied, 25.8% proved deficient in the serum protein; seven of these were homo¬ zygotes and 10 heterozygotes. The average age of homozygous deficient patients was 44 years; average age of the heterozygotes was 52. When only patients below the age of 50 were considered, 47.8% proved to have some degree of antitrypsin deficiency. In support of predisposition of het¬ erozygotes to a similar type of emphy- 134