Ronald J. Knudson

Relation of Protease Inhibitor Phenotypes to Obstructive Lung Diseases in a Community

To examine the relative risk for the development of obstructive lung disease in persons heterozygous for alpha1-antitrypsin deficiency, we determined protease inhibitor phenotypes in 2944 subjects in a general community population. Phenotype M was found in 89.5 per cent, MS in 7.1 per cent, and MZ in 3.0 per cent of the population. There were two persons of phenotype Z and six of phenotype SZ. The study also included respiratory questionnaires and spirometry. There were no statistically significant differences in the prevalence of respiratory symptoms and diagnoses or of ventilatory impairment among the three major phenotype groups (M, MS and MZ), nor were there differences in the rates of deterioration of function with age or smoking. Consequently, we do not consider population screening for heterozygous alpha1-antitrypsin deficiency to be worthwhile.

A Community Study of the Relation of Alpha1-Antitrypsin Levels to Obstructive Lung Diseases

Since it is still uncertain whether moderate degrees of alpha1-antitrypsin deficiency predispose to the development of lung disease, data obtained from a stratified random sample of white households in Tucson, Arizona, consisting of 2586 subjects over five years of age, were analyzed. No relation was found between serum alpha1-antitrypsin levels, measured as trypsin inhibitory capacity, and ventilatory function, respiratory symptomatology, or frequency of diagnosed pulmonary diseases even among cigarette smokers. The data indicate that an intermediate level of alpha1-antitrypsin deficiency (i.e., inhibitory capacity between 20 and 62 per cent of the populations mean value) is not an important risk factor for the development of chronic obstructive lung diseases. The data militate strongly against the use of any quantitative determination of alpha1-antitrypsin as a test to identify subjects with moderate deficiency for the purpose of predicting later development of chronic respiratory disorders. The rate of severe deficiency is so low as to make population screening for such subjects impractical.

Evaluation of lung elastic recoil by exponential curve analysis

Static deflation pressure-volume curves for the lungs of 104 subjects were satisfactorily fitted to an exponential function, V = Vmax - Ae-kP (where Vmax is volume V extrapolated to infinite transpulmonary pressure P, and A and k are constants). Subjects included 48 who met rigorous criteria defining normal, 35 were PiM phenotype for alpha-1-antitrypsin deficiency and 21 were PiMZ phenotype. The shape constant k was significantly related to age, whereas an index of curve position was not. Values for k corresponded closely to the data of other investigators suggesting that it was independent of size and insensitive to differences in experimental technique. Elevated values of k, indicative of emphysema, were no more prevalent among PiMZ subjects than among subjects with no alpha-1-anti-trypsin deficiency. The natural logarithm (1n) of k, rather than k itself, appears to provide a useful, normally distributed, expression of lung distensibility.

The effect of passive smoking on pulmonary function in children

Abstract A study of ventilatory function was conducted in 344 nuclear families in a representative community population sample in Tucson, AZ. Household aggregation of pulmonary function, which is dependent on household aggregation of body mass, might affect the relationship of childrens pulmonary function to parental smoking. When household aggregation of body mass was taken into account, there was no relationship of childrens pulmonary function values to parental smoking. The trend, in the opposite direction, was similar to that found by Speizer et al. (1980a), but was not significant in this study. It must be concluded that passive smoking in the family, usually due to parental smoking habits, does not seriously affect permanent markers of respiratory disease such as pulmonary function.

Assessment of alpha-1-antitrypsin deficiency heterozygosity as a risk factor in the etiology of emphysema. Physiological comparison of adult normal and heterozygous protease inhibitor phenotype subjects from a random population.

For plethysmographic studies of lung mechanics and measurement of pulmonary diffusing capacity, 62 subjects were drawn from a randomly selected population sample. Data obtained from the 24 subjects of heterozygous phenotype for alpha-1-antitrypsin deficiency (PiMZ) were compared by age group with data from 38 normal (PiM) subjects matched for sex, age, and smoking history. Comparison of mean values by age group for lung volumes, diffusing capacity, lung elastic recoil, maximum expiratory flow, and the occurrence of frequency dependence of dynamic compliance revealed no differences between phenotype groups. There was no evidence of an accelerated effect of aging among PiMZ subjects when compared with normal counterparts nor was there evidence of an increased effect of smoking. From these data it appears that the PiMZ phenotype per se is not a risk factor in the development of emphysema.

Influence of airway geometry on expiratory flow limitation and density dependence

In a study of individuals of the same sex and similar age and size, between subject variability was noted in lung recoil, lung size, density dependence of maximum expiratory flow, tracheal cross-sectional area, and anatomic dead space. No significance was observed in the relationships to one another of lung size or either estimate of airway size, nor did the magnitude of the change in flow with changes in gas density show a consistent relationship to any of the size variables. The results indicate that there is a dissociation between tracheal dimensions and anatomic dead space as well as between airway size and lung size, suggesting that dysanapsis is a general phenomenon. This introduces additional sources of interindividual variability of maximum expiratory flow and measurements of density dependence of flow.

A consideration of density dependence of maximum expiratory flow

Density dependence of maximum expiratory flow was considered in terms of equal pressure point and wave speed theories of flow limitation. It appears likely that the sites of flow-limitation, patterns of flow, and airway geometry differ with the density of the gas being expired. Because the conditions which determine maximum expiratory flow for helium-oxygen and for air differ, measurement of density dependence is of questionable value as a test for peripheral airways dysfunction.

Extrathoracic Manifestations of Bronchogenic Carcinoma

The experimental manifestations of bronchogenic carcinoma are widely varied and often bizarre. Most of them, however, occur in association with malignant disease of other organs, so that they cannot be considered pathognomonic of bronchogenic carcinoma. Since these manifestations may be the initial clue to the presence of cancer of the lung, instead of the classical symptoms of cough, hemoptysis, and pain in the chest, it is important to be familiar with them if this highly fatal disease is to be diagnosed in its early stages when surgical excision is possible. Knowles and Smith4 classified the extrathoracic manifestations of bronchogenic carcinoma into five groups: metabolic, neuromuscular, connective-tissue and osseous, vascular, and hematologic. For purposes of this discussion their excellent classification will be used. Five hundred and thirty cases of bronchogenic carcinoma encountered at the Ochsner Clinic from 1950 to 1959 were reviewed in an effort to determine the incidence and types of extrapulmonary symptoms in these patients. This series has the usual age and sex distribution for cancer of the lung. There were 474 male and 56 female patients, 417 of whom were between 50 and 89 years of age, and 113 between 30 and 49 years. This discussion includes all extrathoracic manifestations in the series. In many patients symptoms originated in more than one site. For comparative purposes only the local and metastatic manifestations will be discussed.