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THE ROLE OF ALPHA-1-ANTITRYPSIN IN GENERATING CHRONIC OBSTRUCTIVE PULMONARY DISORDER

Muhammad Amin

Department of  national Education, Airlangga University, Indonesia


Introduction
The prevalence of COPD in Indonesia is not available. Wijaja (1993) reported, based on a population survey, that the prevalence of COPD in East Java is 13% of 6144 respondents.1 In the future, this will increase due to the emphasis on industrialization as part of Indonesia's second long term development plan (1994-2019). The three well-known risk factors of COPD,2 alpha-1-antitrypsin (a1AT) deficiency, cigarette smoking and air pollution, which contribute to the pathogenesis of COPD, either individually or through interaction, have never been studied before in Indonesia. Using findings from international studies may not be relevant to the situation in Indonesian because of the different ethnic and environmental conditions.3
Most of the evidence concerning risk factors for COPD is obtained from cross-sectional studies that identify association rather than a causal relationship. This study was conducted to determine the cause and effect relationship between a1AT concentration in serum and COPD; and the interaction of serum a1AT concentration, smoking and pollution in the pathogenesis of COPD. The study revealed that 81.8%  of respondents had normal a1AT concentrations in serum, 14.35% showed mildly diminished, 3.15% moderately diminished and 0.7% severely diminished a1AT concentrations in serum. The risk of developing pulmonary emphysema in subjects with diminished serum a1AT is 4.37 times the risk is normal subjects, for chronic bronchitis it is 3.09, while in asthma it is of no consequence. Diminished serum a1AT combined with smoking, increased the risk of developing pulmonary emphysema to 10.67 times, and bronchitis to 9.59 times. Smoking-related risk in chronic bronchitis was 1.06 and in emphysema 1.64, but was of no consequence in asthma. Air pollution-related risk was 44.86 in chronic bronchitis, but together with smoking it was 31.90.
MATERIALS AND METHODS
Study design
A preliminary study was carried out to determine the normal level of a1AT as a reference value, since a1AT has never been measured in Indonesia. The study protocol mandates four designs : case control, cohort, retrospective cohort and prospective analysis. Case control was used to access the role of risk factors in emphysema, chronic bronchitis and bronchial asthma, as the relatively low prevalence and long latency of these disease make populations based surveys impractical and costly. Retrospective cohort was used to obtain cases exposed to pollution risk, while the cohort method was used to enhance the validity of cause-effect relations. Moreover prospective analysis was employed to prove  the active reactant component of a1AT, by monitoring a1AT during the acute phase and 2 weeks after recovery.
Subjects
Subjects were recruited from Dr. Soetomo General Hospital for the case control and prospective study, and a cement factory and non-polluting plants in Surabaya for retrospective cohort and cohort studies. The examination included questionnaire, interview, physical examination, chest X-ray, pulmonary function test, skin test, measurement of serum a1AT level, liver and renal  function tests, and blood sugar.
Definition

Chronic bronchitis is defined by the presence of chronic of cough and expectoration on most days for  at least 3 months in a year for two consecutive years. Emphysema is diagnosed clinically by physical examination, lung function and thorax roentogenogram, indicating hyperinflation of the lung. Bronchial asthma is defined by the reversibility of airflow obstruction both spontaneously and with treatment by bronchodilator. The control group consisted healthy respondents without a history of exposure of dust. The odds ratio is defined in the term of odds of disease in exposed individuals relative to the odds of disease in the unexposed. Relative risk is how many times likely disease occurs in the exposed group as compared with the unexposed.4

Pulmonary Functions Test
The procedures were based on the standard of the American Thoracic Society and reference values for lung function using standard normal values from Pneumobile Project Indonesia.5-7
Sample Size
Assuming that equal numbers of cases and controls would be selected, the required sample size for each group (n per group) was calculated as follows :

Statistic Analysis
Analysis design used matched analysis, while for the association Odds ratio was used and for significance X2 was used. In the absence of experimentation, several lines of reasoning have been advocated to asses causality (e.g. temporal sequence, consistency, dose response, strength of association, etc.) Extension of the two by two tables to dose-response effect and temporal sequence trend analysis was used to prove the cause-effect relationship.
RESULTS
Determination of Normal Value of  a1AT  Level in Serum as Reference Value.
The total sample analysed was 418 respondents : 327 males and 91 females. The lower limit of the normal  value is determined by the tenth percentile, because the distribution does not meet the gaussian curve (skewed to the left). The percentile is the level of the measurement below which a specified proportion of the distribution fall. The tenth per centile means that 10% of the distribution is bellow the level measurement. Thus the tenth percentile was defined to indicate the lower limit of the normal value of serum a1AT in this study. a1AT level in serum was a measured using the immunoturbidimetry method and the lower limit of a1AT was determined to be 180 mg/dL for males and 194 mg/dL for females. Serum a1AT concentration was arbitrarily classified in this study as follows : mildly diminished if the level of a1AT  > 60% of the lower limit, moderately diminished if the level of a1AT < 20-60% of the lower limit, severely diminished if the level of a1AT <20% of the lower limit.
Case and Control Study
The sample size was 92 for cases 92 controls. The number of cases of chronic bronchitis was 140, bronchial asthma was 51 and pulmonary emphysema was 133. Chronic bronchitis risk for respondents with diminished a1AT in serum was 3.09 bronchial asthma was 0,35 and pulmonary emphysema was 4.37 times higher than the risk for respondents with normal a1AT (Table 1). The Mantel Haenzel technique is applied in order to adjust the disease Odds ratio because sex is a confounding factor. Table 2 shows the adjusted Odds ratio for chronic bronchitis was  3.21, while Table 1 shows the Odds ratio was 3.09. As for the  combination of diminished serum a1AT and smoking, the risk of developing chronic bronchitis was 9,59, bronchial asthma was 0.28 (not significant) and pulmonary emphysema was 10.67 times higher than respondents with normal a1AT and those who did not smoke (Table 3). The risk of chronic bronchitis for smokers was 1.06, bronchial asthma was 0.01 and pulmonary emphysema was 1.64 times higher than the risk for normal a1AT (Table 4). The Xtrend analysis is use to prove  the cause-effect relationship of the exposure and the outcome. Diminished serum a1AT concentration is significantly proven as the casual factors of pulmonary emphysema.
Table 1   The association between chronic bronchitis (CB), bronchial asthma (BA), pulmonary emphysema (EM), and serum a1AT level.

a1AT

CB

Control Total BA Control Total EM Control Total
Diminished 39 21 60 4 72 76 45 29 74
Normal 101 168 269 47 295 342 88 248 336
Total 140 189 329 51 367 418 133 277 410

Odds ratio for chronic bronchitis = 3.09 (*) P = 0.000, X2 = 15.08.
Odds ratio for bronchial asthma = 0.35 (*) P = 0.4, X2 = 4.17.
Odds ratio for pulmonary emphysema = 4.37 (*) P = 0.000, X2 = 33.17.
Table 2   The association  between chronic bronchitis (CB), bronchial asthma (BA), pulmonary emphysema (EM), and serum a1AT level based on sex

a1AT level   

Male Female
CB Co To BA Co To EM Co To CB Co To BA Co To EM Co To
Diminished 32 17 49 4 59 63 37 25 62 7 4 11 0 13 13 8 4 12
Normal 67 129 196 14 250 264 70 191 261 34 39 73 33 45 78 18 57 75
Total 99 146 245 18 309 327 107 216 323 41 43 84 33 58 91 26 61 87

Co, control; To, total
CB: Adjusted Odds ratio = 3.21(8), P = 0.000.
BA: Adjusted Odds ratio = 0.35 (not significant).
EM: Adjusted Odds ration = 4.34 (*), P = 0.000
Table 3   The association  between chronic bronchitis (CB), bronchial asthma (BA), pulmonary emphysema (EM), and serum a1AT level based on smoking habit

a1AT level   

Smoker Non-smoker
CB Co To BA Co To EM Co To CB Co To BA Co To EM Co To
Diminished 27 6 33 1 38 39 30 8 38 12 15 27 3 34 37 15 21 36
Normal 46 98 144 5 196 201 52 148 200 55 70 125 42 99 141 36 100 136
Total 73 104 177 6 234 240 82 156 238 67 85 152 45 133 178 51 121 172

Co, control; To, total
CB (SM): Odds ratio (OR) = 9.59 (3.42 < OR < 28.25), P < 0.01 (*).
BA: Adjusted Odds ratio (OR) = 0.28 (0.10 < OR < 0.82), P  0.02 (*).
EM (SM): Odds ratio (OR) = 10.67 (4.30 < OR < 27.37), P  <0.01 (*).
Table 4   The association  between chronic bronchitis (CB), bronchial asthma (BA), pulmonary emphysema (EM), and smoking habit

Smoker CB Control Total BA Control Total EM Control Total
Yes 73 124 197 6 266 272 82 188 270
No 67 121 188 45 204 249 51 192 243
Total 140 245 385 51 470 521 133 380 513

Co, control; To, total
Odds ratio (OR) for CB = 1.06 (1.02 < OR < 2.87), P = 0.77 (NS).
Odds ratio (OR) for BA = 0.10 (0.04 <  OR < 0.26), P = 0.04, X2 = 4.14 (*).
Odds ratio (OR) for EM = 1.64 (1.07 < OR < 2.52), P < 0.01, X2  =5.8G (*).
Retrospective Cohort
This design is conducted to determine the association of exposure and disease. The impact of pollution on disease. The impact of pollution on disease outcome by case control study is not really valid because the statement of exposure was obtained from the respondent and not by laboratory measurement. The environmental quality of the polluted workplace located in the production unit of a cement industry was measured every 2 months. Exposed respondents were defined as workers who worked in the production unit. The prevalence of chronic bronchitis was 184 (20.44%), bronchial asthma was 53 (5.8%) and pulmonary emphysema was 6 (0.6%) out of 900 exposed respondents, while pulmonary emphysema could not be analysed due to the very few cases. Total sample (exposed and non-exposed) was 3077 respondents (Table 5). Exposure to dust contributes to the development of chronic bronchitis 44.86-fold relative to non-exposed respondents. Bronchial asthma was 2.41 times higher than in non-exposed respondents, while pulmonary emphysema was undefined due to small cases. Workers exposed to smoking faced a risk 31.90 times higher for chronic bronchitis than non exposed and non-smokers. Bronchial asthma was 2.71 times higher and pulmonary emphysema was undefined.
Table 5   The association between chronic bronchitis (CB), bronchial asthma (BA), pulmonary emphysema (EM), and exposure to dust

Exposure CB Normal Total BA Normal Total EM Normal Total
Yes 184 927 1111 53 927 980 6 927 933
No 7 1582 1589 25 1582 1607 0 1582 1582
Total 191 2509 2700 78 2509 2587 6 2509 2515

Co, control; To, total
Relative risk (RR) for CB = 44.86 (20.18 < RR < 105.22), P < 0.01 (*).
Relative risk (RR) for BA = 2.41 (1.45 < RR < 4.02), P < 0.01 (*).
Relative risk (RR) for EM (SM) = 'Undefined' EM P  =0.0000.
Cohort
To increase the validity of the case control study and to prove the dose-response and temporal sequence of the different variables, a cohort study was used. Exposed subjects were monitored every 4 years, and every year an interview, physical examination and lung function test were carried out. Moreover, a1AT concentration was measured at the end of the research (after 8 years). The incidence of chronic bronchitis increased from seven to 103 cases and that of asthma from 16 to 41 cases, for production unit workers during 8 years follow up versus the control group in whom there was no significant increase. Lung function tends to decline after 4 years of exposure: 311 respondents having normal lung function at the beginning of study, 274 having mild obstruction, 12 having moderate obstruction and four having severe obstruction after working for 8 years.
Prospective Analysis  
Fourteen pneumonia cases were monitored and a1AT serum was measured during the acute phase and 2 weeks after recovery. The differences in a1AT level between acute and recovery was 280.5 mg/dL (P = 0.000). This result shows that increasing production of a1AT is needed to protect the impact of protease released by the inflammatory against process. 
DISCUSSION
Hereditary deficiency of  a1AT is only one genetic risk factor known to cause COPD. In the protease antiprotease theory of pulmonary emphysema, it is the imbalance of these two factors that causes injury to lung tissue, which is characteristic of emphysema.8 In the pathogenesis of chronic bronchitis, proteases may cause hyperplasia of secretary cells and proliferation of mucous glands, the manifestation of which is excessive production of sputum.
This study revealed that the incidence of diminished a1AT concentration in serum was 18.16%, which consisted of 14.35% mildly diminished, 3.15% moderately diminished and 0.7% severely diminished individuals, respectively. Sixty percent of PI homozygous cases developed pulmonary emphysema, while individuals with heterozygous phenotype (e.g. PIMZ), had a risk of developing emphysema that was three times higher than the normal phenotype.9 This research revealed that the related risk for individuals with a diminished a1AT concentration in serum to develop chronic bronchitis was 3.09 and pulmonary emphysema was 4.37, while with asthma there was no consequence (Table 1). Diminished serum a1AT concentration combined with smoking increases the risk of developing pulmonary emphysema 10.67 times, while the risk of chronic bronchitis is 9.59 times higher than in smoking in non-smoking individuals (Table 3). Chi-squared trend analysis of the correlation between diminished serum a1AT concentration and chronic bronchitis or pulmonary emphysema indicated a cause-effect relationship.
Indonesia is a developing country, where infection is still a major problem. Repeated respiratory infection during childhood may play an important role in the pathogenesis of COPD. This study has proven that during acute infection, serum a1AT level increased significantly. A high level of serum a1AT could be suggested as a protective mechanism against overwhelming protease production. If that protective mechanism is not sufficient, degradation of the extra cellular matrix will occur. Although this study did not evaluate the role of infection in the pathogenesis of COPD, a longitudinal study of children with diminished a1AT concentration in serum should be done to prove that hypothesis.
Cigarette Smoking
Tobacco contributes to the risk of COPD. However, not all smokers develop clinically significant COPD. This study showed that 67.5% of the 398 male subjects were smokers, while among the female smokers were only 0.86% of 115. Of the total 513 respondents, 133 had pulmonary emphysema and 380 were healthy control subjects. The smoking-related risk of pulmonary emphysema was 1.06 times the risk of a non smoker  (Table 4). This result may be questionable because it is unclear why the risk is not as great as estimated before. Diminished a1AT concentration in Role of a1AT in COPD
Table 6   The association between chronic bronchitis (CB), bronchial asthma (BA), pulmonary emphysema (EM), and exposure to dust based no smoking habit.

Smoker Non-smoker
Exposure   

CB

N To BA N To EM N To

CB

N To BA N To EM N To

Yes 128 477 506 23 730 753 3 477 480 56 450 506 30 650 680 3 450 453
No 2 348 350 3 347 350 0 348 348 5 1234 1239 22 1219 1241 0 1234 1234
Total 130 825 955 26 1077 1103 3 825 828 61 1684 1745 52 1869 1921 3 1684 1687

N, normal; To, total.
CB (SM) adjusted relative risk (RR) = 31.09 (13.90 < RR < 73.22), P < 0.01, X2 = 182 (*).
BA adjusted relative risk (R) = 2.71 (1.64 < RR < 4.47), P < 0.05, X2 = 15.64 (*).
EM, undefined.
serum combined with smoking increase the risk of developing emphysema 10.67 times (Table 3). There for an endogenous factor (diminished serum a1AT) in creases the risk.
Occupational dust
Occupational dust can cause COPD if the exposures are sufficiently intense or prolonged. This study found that the incidence of chronic bronchitis increases from 1.18% to 26.09%, after 8 years of exposure. This result suggested that interaction of two risk factors increased the risk of disease and a decline in lung function, and that there was a cause effect relationship. The risk of chronic bronchitis dust exposure was 44.86 (Table 5). A combination of dust exposure and smoking had an additive effect on the risk of developing chronic bronchitis by 31.90 times (Table 6). Prolonged exposure to dust led to a decline of lung function (FEV1, FEV1/FVC, PEFR and MMEF). The decline in FEV1 after 4 years was 205 ml, and after 8 years was  517 mL. The increase in incidence of mild obstruction after 4 years was from 11 to 20 cases and by 143 by the eight year.
In conclusion, endogenous factors could modify to disease manifestation. Diminished serum a1AT concentration was a causal factors for emphysema and chronic bronchitis. Smoking cigarettes and exposure to dust will contributes toward diminished serum a1AT.
REFERENCES
1. Widjaja A. Penelitian Epidemiologi Pengaruh lingkungan pada Penyakit Paru Obstruktif Menahun di 37 Puskesmas, Mewakili semua Kabupaten di Jawa Timur. Kumpulan Naskah Ilmiah Konas VI Perhimpunan Dokter Paru Indonesia (PDPI), Surakarta, 1993 (in Indinesian).
2. Sluiter HJ, Koeter GH, de Monchy JGR. The Dutch Hypothesis (chronic non-specific lung disease) Revised. Eur J. 1991; 4: 479-89.
3. Buist SA. Alpha 1 antitrypsin deficiency-diagnosis, treatment, and control: Identification of patients. Lung 1990: (Suppl.): 543-51.
4. Schlesselman JJ, Stolley PD, Case Control Studies. Design, Conduct, Analysis. Oxford University Press, New York, 1982.
5. American Thoracic Society. Lung function testing selection of reference interpretative strategies. Am. Rev. Respir. Dis. 1991; 144: 1202 - 18.
6. Alsagaff H. dan Mangunnegoro H. Nilai Normal Faal Paru Orang Indonesia pada Usia Sekolah dan Pekerja Dewasa Berdasarkan Rekomendasi  American Thoracic Society (ATS) 1987. Airlangga University Press, Surabaya 1993 (in Indonesian).
7. Enright PL, Hyatt RE. A Practical Guide to the Selection and Use of Spirometer. Lea Febiger, Philadelphia 1987.
8. Erikson S. Alpha 1 antitrypsin deficiency: lesson learned from the bedside to the gene ang back again. Chest 1989; 95: 181 - 9.
9. Kamboh MI. Biochemical and genetic aspects of human serum alphat-proteinase inhibator protein. Disease Markers 1985; 3: 135 - 54.

Correspondence: 
Muhammad Amin 
Program Pascasarjana, Universitas Airlangga 
Jl. Darmawangsa Dalam Selatan
Surabaya 60286, East Java - Indonesia 
E-mail: amin@pasca.unair.ac.id



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