Protease inhibitors in patients with chronic obstructive pulmonary disease: the alpha-antitrypsin heterozygote controversy.

A group of 163 patients with chronic obstructive pulmonary disease, from the pulmonary service of a large urban hospital, were evaluated for their protease inhibitor (Pi) type by starch gel and crossed immunoelectrophoresis, for serum concentrations of alpha1-antitrypsin and alpha1-antichymotrypsin, and for pulmonary function. Of the patients with emphysema, 17.8% were of Pi type Z; 50% of these were less than 45 years of age, compared to 13% of those of Pi type M. Of all patients with chronic obstructive pulmonary disease, 4.9% were of Pi type Z; 4.9% of patients were of Pi type MZ (heterozygotes) compared with 1.9% of the control population. There was an increased incidence of chronic obstructive pulmonary disease in persons of Pi type MZ, but no increase in persons of Pi type MS. Concentrations of both alpha1-antitrypsin and alpha1-antichymotrypsin were increased and were correlated. No patient had a deficiency of alpha1-antichymotrypsin.     

The flaccid lung syndrome and alpha 1-protease inhibitor deficiency

We examined breathing mechanics and alpha 1PI deficiency in 1,850 unrelated male subjects with various lung complaints. The loss in lung elasticity appeared to be significantly more pronounced in ZZ individuals as compared to MM, MS and also MZ individuals. The MZ group did not differ significantly in this respect from MM individuals. This implies that the excess risk of developing a flaccid lung (C greater than 1 kPa-1) due to the partial alpha 1-antitrypsin deficiency is negligible. PI MZ and PI ZZ frequencies are significantly higher in the population with flaccid lung compared to control subjects. Furthermore, it was found that the increase in residual volume in smokers is independent of the PI type.     

Alpha1-antitrypsin deficiency: genetic, clinical and functional correlations in a three generation family.

alpha1-antitrypsin (alpha1-AT) deficiency is a hereditary condition transmitted as an autosomal codominant trait. Fully deficient homozygotes develop chronic obstructive pulmonary disease at an early age. It remains controversial whether heterozygotes develop some degree of airway disease at an early age which results in severe obstructive disease later in life. We studied 12 alpha1-AT-deficient members of a family spanning three generations by extensive pulmonary function tests, clinical history and genetic determinations. 3 of the subjects were homozygotes and showed important clinical and lung function abnormalities by the age of 30. Two out of 9 heterozygotes, a female and a male, had decreased dynamic compliance, elevated closing volume and low PaO2. 3 showed clinical and physiological abnormalities (elevation in functional residual capacity and residual volume, low FEV1/FVC and elevated closing volume); however, these alterations could be attributed to their smoking habits or concomitant medical condition. The remaining 4 subjects were normal. None of the heterozygotes showed alterations in the static elastic recoil of the lung or static compliance.     

Emphysema of early onset associated with a complete deficiency of alpha-1-antitrypsin (null homozygotes)

We have compared lung function in 3 subjects with no alpha 1-antitrypsin (alpha 1-protease inhibitor) (null homozygotes) with subjects having the typical deficiency, PIZZ. We identified a 31-yr-old woman, presenting with severe obstructive lung disease, who had no detectable plasma alpha 1-antitrypsin, indicating homozygosity for a "null" (or PI*QO) allele of alpha 1-antitrypsin. Two of her sisters have a similar deficiency, one with an onset of symptoms at 17 yr of age. Because of the likelihood that there are a number of different PI*QO alleles, the type in this family has been named null Mattawa (QOmattawa). All 3 homozygotes have shown a marked deterioration of lung function over a 7-yr period of follow-up. In contrast, lung function tests of 6 age-matched nonsmoking subjects with alpha 1-antitrypsin deficiency, PI type ZZ, showed no abnormalities of lung function. The 15 to 20% of the normal plasma concentration of alpha 1-antitrypsin associated with the PI*Z allele appears to provide some protection to the lung in comparison with a complete deficiency state.     

Chronic 'cryptogenic' liver disease and malignant hepatoma in intermediate alpha 1-antitrypsin deficiency identified by a Pi Z-specific monoclonal antibody

Using a monoclonal antibody against the Pi Z genetic variant of alpha 1-antitrypsin in an enzyme-linked immunosorbent assay, we have screened plasma samples from 857 consecutive patients with liver disease for the presence of Pi Z alpha 1-antitrypsin. Intermediate alpha 1-antitrypsin deficiency (Pi MZ and SZ) was found in 64 cases, or 7.6%, compared with an expected 4.8% (p less than 0.001). The plasma alpha 1-antitrypsin level was subnormal in only 50% of them. Forty-three of the 64 heterozygotes were men, compared with 494 of 857 (58%) in the total study population (p less than 0.001). At least 14 heterozygotes had cryptogenic liver disease, compared with 3 of 128 sex- and age-matched controls from the same study population (p less than 0.001). Malignant hepatoma occurred in 6 heterozygotes compared with 1 control (p less than 0.01), and in 13 of all 793 non-Pi Z patients (p less than 0.001).     

Collaborative study to assess risk of lung disease in Pi MZ phenotype subjects

We studied 143 Pi MZ heterozygous (MZ) subjects from random populations that had been examined previously for alpha 1-antitrypsin phenotype. Each Pi MZ subject was closely matched with a Pi M control subject from the same population at each of 6 centers. An expanded National Heart, Lung and Blood Institute (NHLBI) respiratory symptom questionnaire was completed by each subject. Pulmonary function tests designed to detect established as well as early obstructive airway abnormalities were administered. Multivariate analysis of the variance of data from the questionnaire and pulmonary function tests corrected for age, race, sex, and smoking history showed no significant difference (p less than 0.05) between subjects of Pi MZ and Pi M phenotype. The size of the populations studied and number of observations made for each variable were sufficient to assure that small differences could be detected with 95% power. We conclude that MZ phenotype alone carries no greater risk of developing lung disease than M phenotype.     

Alpha 1-antitrypsin Pi-types in 965 COPD patients

To study further the role of intermediate alpha 1-antitrypsin (AAT) deficiency in chronic obstructive pulmonary disease (COPD), AAT Pi-types and serum-trypsin-inhibitory-capacity (STIC) were measured in 965 patients with COPD. Heterozygosity of the Z variant was the major cause of intermediate AAT deficiency (primarily the MZ phenotype), accounting for 8.0 percent of the patients compared to 2.9 percent of control subjects (p less than .0005). ZZ homozygosity was detected in 1.9 percent of the patients, compared to 0.04 percent of control studies performed by others (none was present in our own control group of 1,380 subjects). The mean age for MS or MZ patients did not differ from that of the COPD patients as a whole, whereas the ZZ homozygotes were younger (55.9 +/- 9.8 vs 65.3 +/- 7.5 years). These results resemble those of a previous study in 66 male veterans with pulmonary emphysema suggesting that the MZ phenotype, or intermediate AAT deficiency in general, probably does predispose to the development of COPD. However, the prevalence of AAT deficiency in COPD patients is small (approximately 10 percent). The number with an MS phenotype was not increased in this group of COPD patients.     

Susceptibility genes for rapid decline of lung function in the lung health study

The genes that contribute to the genetic susceptibility to chronic obstructive pulmonary disease (COPD) remain largely unknown. We hypothesized that widely divergent rates of decline in lung function in smokers would be a robust phenotype for detection of genes that contribute to COPD severity. We selected 283 rapid decliners (deltaFEV1 = -154 +/- 3 ml/yr) and 308 nondecliners (deltaFEV1 = +15 +/- 2 ml/yr) from among smokers followed for 5 yr in the NHLBI Lung Health Study. Rapid decline of FEV1 was associated with the MZ genotype of the alpha1-antitrypsin gene (odds ratio [OR] = 2.8, p = 0.03). This association was stronger for a combination of a family history of COPD with MZ (OR = 9.7, p = 0.03). These data suggest that the MZ genotype results in an increased rate of decline in lung function and interacts with other familial factors. Haplotype frequencies of the microsomal epoxide hydrolase (mEH) gene were significantly different between rapid decliners and nondecliners (p = 0.03). A combination of a family history of COPD with homozygosity for the His113/His139 mEH haplotype was also associated with rapid decline of lung function (OR = 4.9, p = 0.04). The alpha1-antitrypsin S and 3' polymorphisms, vitamin D-binding protein isoforms, and tumor necrosis factor (TNF-alpha G-308A and TNF-beta A252G) polymorphisms were not associated with rate of decline of lung function.     

Risk of hospital admission for obstructive pulmonary disease in alpha(1)-antitrypsin heterozygotes of phenotype PiMZ

Whether subjects heterozygous for alpha(1)-antitrypsin (alpha(1)-AT) deficiency are at risk for development of obstructive pulmonary disease (OPD) has been discussed for the past three decades. Both cohort and case-control studies have reached different conclusions, with the major problems being small sample sizes. A cohort of heterozygotes with the phenotype PiMZ was retrieved from the Danish Alpha(1)-Antitrypsin Deficiency Registry. Ten matched controls for each PiMZ subject were identified from the files of the Danish Central Population Registry. Cases and controls were subsequently linked to the files of the Danish Hospital Discharge Registry, and relative risk for OPD was calculated. In the cohort of 1,551 PiMZ subjects (11,678 person-years), we identified 47 subjects with a discharge diagnosis of OPD, as compared with 206 subjects with this diagnosis in the control group (109,748 person-years), yielding a relative risk (RR) of 2.2 (95% confidence interval [CI]: 1.5 to 3.0). This increased risk was present in both men and women and in all age groups; however, it was significant only in the age group from 40 to 79 yr. Of the 1,551 PiMZ subjects, 565 (36%) were first-degree relatives of PiZ index cases, and it appeared that only this group was at increased risk of hospital admission for OPD (RR: 3.4, 95% CI: 2.2 to 5.3). We conclude that alpha(1)-AT heterozygotes of phenotype PiMZ are at increased risk of hospital admission for OPD if they are first-degree relatives of PiZ index cases only, and that other, yet unknown genetic or environmental factors contribute to the development of lung disease.     

A study of antielastase activity in the development of pulmonary emphysema in a family with alpha 1-antitrypsin deficiency

The five siblings of a family with alpha 1-antitrypsin deficiency including three of Pi- and two of PiM- phenotypes, were studied for the development of pulmonary emphysema during nine years. The changes of pulmonary function showed significant decrease in FEV1.0 and V50, and increase in RV/TLC. Clinical diagnoses for each patient were assessed by pulmonary function, inhalation and perfusion lung scintigram. Two case of Pi- phenotypes were diagnosed definite pulmonary emphysema 9 years previously, in one case of Pi- emphysema was suspected and two PiM- cases were also suspected of emphysema. alpha 1-antitrypsin and elastase inhibitory capacity (EIC) were investigated in serum and bronchoalveolar lavage fluids (BALF) from four patients with alpha 1-antitrypsin deficiency, healthy non-smokers and smokers. alpha 1-Antitrypsin and EIC in BALF in patients with alpha 1-antitrypsin deficiency were markedly decreased. There were no differences between non-smokers and smokers in alpha 1-antitrypsin and EIC, but EIC in BALF showed a significant correlation with DLCO or %DLCO. These findings suggest that a deficiency of alpha 1-antitrypsin results in insufficient antielastase protection in the lower respiratory tract, and EIC in BALF may be useful for detecting early changes of emphysema.     

Study of familial alpha-1-proteinase inhibitor deficiency including a rare proteinase inhibitor phenotype (IZ). I. Alpha-1-phenotyping and clinical investigations

Proteinase inhibitor (PI) phenotyping and clinical investigations were performed on 20 persons in three generations of a family with alpha 1-antitrypsin deficiency. Two persons were homozygotes and 9 were heterozygotes for the Z allele; one is the first reported IZ phenotype; 11 were common M-types. Both homozygotes and 5 of the heterozygotes, including the IZ individual, had suffered from recurring or chronic respiratory diseases. However, only mild to moderate impairment in lung function tests was observed in some of these patients (DLCO steady state, 3 subjects; FEV1, 3 subjects; FEF25-75, 2 subject; elevation of RV, 2 subjects). The rare IZ type, a 35-year-old female, smoker, showed normal lung function except for an elevated RV. Our results indicate that PI deficiency is not necessarily associated with severe lung destruction if noxious inhalants are absent.     

The prevalence of alpha-antitrypsin heterozygotes (Pi MZ) in patients with obstructive pulmonary disease.

An increased incidence of intermediate deficiency of serum alpha1-antitrypsin resulting from Pi phenotype MZ has been reported in patients with chronic obstructive pulmonary disease (COPD) by some laboratories but not confirmed by others. Prevalence of Pi MZ was determined in patients with COPD among 502 subjects referred to a pulmonary function testing laboratory in a region with low concentrations of air pollutants. Control prevalences were obtained from 930 randomly selected subjects in the same community as well as from patients without COPD referred to the laboratory. Depending on criteria used to define COPD, 155 to 306 subjects had COPD. Pi MZ prevalence in subjects with COPD varied from 1.5 to 4 times the prevalence in the community control group and in the patients without COPD. This difference approached significance or was significant. Because Pi MZ was present in only 3.5 to 4.5 per cent of patients with COPD, Pi MZ is not a major factor in the etiology of COPD in this community. The higher incidence of Pi MZ inpatients with COPD reported by other investigators may be explained by small sample size, bias in selection of study or control population groups, or the development of COPD from interaction between Pi MZ and air pollutants or other factors not present in this community.     

Variability of pulmonary function in alpha-1-antitrypsin deficiency: clinical correlates

STUDY OBJECTIVE: To determine the range of pulmonary function variability in alpha-1-antitrypsin-deficient persons and to identify epidemiologic factors and pulmonary symptoms and conditions associated with this variability. DESIGN: Case series ascertained through investigation of extant obstructive lung disease (index cases, 22 subjects) or by other means (non-index cases, 30 subjects). SETTING: Referral-based pulmonary division at a tertiary care medical center. PARTICIPANTS: Fifty-two alpha-1-antitrypsin-deficient persons of type Pi Z ascertained by: extant chronic obstructive pulmonary disease (22 cases), family studies (20 cases), liver disease (4 cases), population screening (4 cases), and other pulmonary problems (2 cases). MEASUREMENTS and MAIN RESULTS: Pulmonary function tests and a version of the American Thoracic Society 1978 standard respiratory epidemiology questionnaire were used. Persons of type Pi Z who were not specifically ascertained with chronic obstructive pulmonary disease had values of forced expiratory volume in 1 second over 65% of predicted in 20 out of 30 cases and frequently had normal lung function. Univariate and multivariate analyses of possible causes of lung disease showed that the following factors were significant (P less than 0.05): pulmonary symptoms (effects associated with chronic obstructive pulmonary disease), including dyspnea and chronic cough; age and pack-years of smoking (epidemiologic correlates); and other pulmonary conditions (potential causes or effects) including asthma, pneumonia, and episodes of increased cough and phlegm. Finally, we found a striking excess of questionnaire-reported parental emphysema in families of type Pi Z persons with chronic obstructive pulmonary disease compared with families of type Pi Z persons without disease. CONCLUSIONS: Many persons with alpha-1-antitrypsin deficiency do not have clinically significant lung function impairment: the perceived natural history of antitrypsin deficiency has been distorted by ascertainment bias. In addition to cigarette smoking, it appears that asthma, lower respiratory infections, and possibly some familial factors contribute to a severe clinical course. Follow-up of our cohort with widely varying lung function will provide insights into the natural history of the emphysema associated with alpha-1-antitrypsin deficiency.     

Clinical, epidemiologic, and pulmonary function studies in alpha,-antitrypsin-deficient subjects of Pi Z type.

The results of pulmonary function testing and systematic medical history and epidemiologic data collection are reported for 20 persons with alpha 1-antitrypsin deficiency of Pi Z phenotype. The most common symptom, reported in 19 subjects (95 per cent), was dyspnea on exertion; 16 subjects (80 per cent) gave a history of wheezing, and 8 (40 percent) reported chronic cough and sputum production. The 8 women who had been pregnant reported a miscarriage rate of 29 per cent for all pregnancies. Respiratory symptoms and disease were commonly reported in the children of study subjects. Pulmonary function testing revealed abnormalities for 18 of 20 subjects, all of those 26 or more years of age. The test that was most frequently abnormal was the 1-sec forced expiratory volume expressed as a per cent of the forced vital capacity. All pulmonary function studies demonstrated a trend toward increased impairment with increased age, which was evident by the fourth decade. Within this group of persons having severe alpha1-antitrypsin deficiency, there was no correlation between serum concentrations of antitrypsin and subjective or objective indices of pulmonary disease. A group of 7 subjects who were incidentally found to have Pi Z alpha1-antitrypsin deficiency exhibited symptoms and pulmonary function abnormalities comparable to those of 13 subjects who were originally referred for known or suspected pulmonary disease. These data suggest that if interventions such as smoking cessation and occupational counseling are to be effective, they should be initiated before the fourth decade of life.     

Alpha 1-antitrypsin phenotypes and obstructive lung disease in the city of Oslo.

In a community survey in Oslo, Norway, comprising 1268 persons, alpha 1-antitrypsin concentration in serum (AT) and protease-inhibitor (Pi) phenotypes were examined in 1258 subjects. Estimated percentage distribution of Pi-phenotypes in the target population aged 15--70 years was M 87.30%, MS 4.65%, MZ 4.73%, FM 2.69%, SZ 0.13%, IM 0.20%, FZ 0.07%, S 0.06%, FS 0.07% and Z 0.06%. The distribution curve of AT had a normal (Gaussian) shape and the ranges of AT demonstrated great overlap of types MS and MZ with type M. In subjects with phenotype MZ neither respiratory symptoms nor physicians' diagnoses of chronic obstructive lung disease (COLD) were more frequent than in M subjects. Physicians' diagnoses of COLD were slightly more frequent (0.06 greater than P greater than 0.01) in subjects with phenotype MS than M, probably due to there being more smokers in the MS group. Spirometric variables given as per-cent of predicted values yielded large differences between smokers and non-smokers but no differences among phenotypes M, MS and MZ. Radiologic signs of hypertransradiancy and/or emphysema were evently distributed in M, MS and MZ subjects. The only subject observed with Pi-type Z and one out of three subjects with type SZ had COLD. In neither smokers nor non-smokers is phenotype MZ a risk factor of clinical importance for development of obstructive lung disease.     

Pulmonary function associated with the Mmalton deficient variant of alpha 1-antitrypsin

We have studied 78 members of a large family in which the Mmalton deficiency allele of alpha 1-antitrypsin (alpha 1AT) is present. Four patients of PI type MmaltonZ (alpha 1AT concentration, 16.4% of normal) had severe emphysema and marked depression in all flow and gas exchange parameters, significantly different from other members of the same family who were normal or had intermediate concentrations of alpha 1AT. Fourteen subjects with PI type MMmalton (alpha 1AT concentration, 63.3% of normal) were compared with 46 PI MM relatives (alpha 1AT, 103.8% of normal) and 14 relatives of PI type MZ (alpha 1AT concentration, 66.5% of normal). Spirometry, flow-volume loops, plethysmography, gas exchange at rest and exercise, and xenon 133 regional lung function were similar in those partially deficient when compared with the normal subjects. There was a trend for impairment of tests of lung function between smoking partially deficient (PI MZ, PI Mmalton) and normal (PI MM) relatives.     

Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms

Alpha-1-antitrypsin (alpha 1AT) deficiency is a hereditary disorder characterized in adults by a high risk for the development of severe destructive lung disease at an early age. The present study was designed to draw conclusions concerning the characteristics of a referral population of 124 patients with alpha 1AT deficiency and symptomatic emphysema. Typically, the alpha 1AT level was 30 mg/dl, and the alpha 1AT phenotype was almost always PiZZ. The individuals in this population were most often male, caucasian, and ex-smokers, and they had become dyspneic between 25 and 40 yr of age. Most routine blood tests were normal. The chest radiographs and ventilation-perfusion studies typically showed abnormalities with a lower zone distribution, and about one third of the study population had evidence suggestive of pulmonary hypertension. Lung function tests were typical for emphysema; the FEV1 and DLCO were the parameters most dramatically reduced, and the annual rate of decline of those parameters was greater than that of the general population. The cumulative probability of survival of this population indicated a significantly shortened lifespan with a mean survival of 16% at 60 yr of age compared with 85% for normal persons.     

Serum angiotensin converting enzyme levels in patients with alpha 1-antitrypsin variants

Serum angiotensin converting enzyme levels were measured in 184 subjects having either MM, MZ, ZZ, or MS Pi-types of alpha 1-antitrypsin. Elevated angiotensin converting enzyme levels were detected in 31 percent of the patients with the MZ Pi-type, 20 percent of the patients with the ZZ Pi-type, and 20 percent of the patients with the MS Pi-type compared with 1.33 percent of those with normal MM Pi-type. The mean serum angiotensin converting enzyme levels were also significantly higher in those with the MZ, ZZ, and MS Pi-types. Multiple family members of two families were found to have both the Z variant and angiotensin converting enzyme elevations, suggesting the possibility of a genetic linkage. Alpha 1-antitrypsin deficiency must be added to the list of disease states potentially associated with elevated serum angiotensin converting enzyme levels.     

Pi phenotypes and the prevalence of chest symptoms and lung function abnormalities in workers employed in dusty industris.

Epidemiologic surveys were carried out on 1,138 white men employed in sawmills and grain elevator terminals in British Columbia. In addition to the administration of an occupational-health questionnaire and spirometry, Pi phenotype and the concentration of serum alpha1-antitrypsin were determined. Most of the workers (88.8 per cent) had the Pi M phenotype, whereas 8.0 per cent had the MS phenotype, and 2.7 per cent had the MZ phenotype. Very few workers (0.4 per cent) had other phenotypes. No differences were found among the 3 major phenotypes in the prevalence of chest symptoms and lung function abnormalities, even among cigarette smokers. These findings did not indicate that workers have the MZ phenotype with intermediate alpha-1-antitrypsin deficiency are particularly susceptible to the development of chronic obstructive lung disease under the conditions prevailing in these industries.     

Changes of volume of trapped gas after bronchodilation in subjects with suspected subclinical emphysema

We studied the volume of trapped gas (VTG), using a nitrogen washout method, before and after bronchodilation in four groups with theoretically increasing risk of developing pulmonary emphysema: (1) nonsmoking healthy controls (PiMn), (2) nonsmoking subjects with an intermediate alpha 1-antitrypsin deficiency (PiMZn), (3) smoking subjects with normal concentration of alpha 1-antitrypsin, and (4) smoking PiMZ subjects. VTG was the only lung function variable that showed a significant difference between PiMZn and PiMn subjects but only after bronchodilation. Some conventional lung function tests also distinguished smokers from nonsmokers of both genotypes but VTG was the most sensitive test. VTG decreased after salbutamol inhalation in the control group but showed a consecutively larger increase with more risk factors of developing emphysema. An increase in VTG after bronchodilation may be a sign of alveolar abnormality preceding development of clinical lung emphysema.