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(Chest. 2005;128:2076-2081.)
© 2005 American College of Chest Physicians

{alpha}1-Antitrypsin Deficiency in 26-Year-Old Subjects*

Lung, Liver, and Protease/Protease Inhibitor Studies

Eeva Piitulainen, MD, PhD; Joyce Carlson, MD, PhD; Kjell Ohlsson, MD, PhD and Tomas Sveger, MD, PhD

* From the Departments of Respiratory Medicine (Dr. Piitulainen), Clinical Chemistry (Dr. Carlson), Surgical Pathophysiology (Dr. Ohlsson), and Pediatrics (Dr. Sveger), Lund University, University Hospital, Malmö, Sweden.

Correspondence to: Tomas Sveger, MD, PhD, Department of Pediatrics, University Hospital, SE-20502 Malmö, Sweden; e-mail: tomas.sveger{at}pediatrik.mas.lu.se


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Clinical and biochemical signs of lung and liver disease have been followed prospectively in a birth cohort of individuals with {alpha}1-antitrypsin (AAT) deficiency.

Objective: At age 26 years, the focus was on clinical health, lung and liver function tests, and plasma markers of the protease/antiprotease balance. The effect of early childhood environment and symptoms was also studied.

Methods: Eligible individuals were 26-year-old subjects with AAT deficiency (PiZ, n = 122; PiZ –, n = 2; PiSZ/S–, n = 53) and control subjects (PiMM, n = 44). Of the original AAT-deficient subjects, 119 completed the clinical examination and 134 answered the questionnaire.

Results: The prevalence of respiratory symptoms did not differ between the PiZ and SZ groups. Sixteen percent of PiZ and 14% of PiSZ subjects had asthma. Four current smokers (67%) and 22% of ex-smokers/never-smokers reported recurrent wheezing (p = 0.03). No difference in FEV1 or FEV1/FVC ratio was found between the PiZ, SZ (5% being smokers), and MM individuals (all nonsmokers). A decreased FEV1/FVC ratio was found in PiZ subjects with neonatal cholestasis, compared to remaining PiZ subjects (p = 0.02). Recurrent wheezers at age 2 years with AAT deficiency had decreased FEV1/FVC ratio (p = 0.025) at age 26 years. None had clinical symptoms of liver disease. Six percent of PiZ and 9% of PiSZ subjects had a marginal increase of serum alanine aminotransferase; 7% of PiZ and 4% of PiSZ had abnormal {gamma}-glutamyl transferase test results. The PiZ and SZ individuals had decreased plasma albumin (p = 0.0002). Secretory leukocyte protease inhibitor (SLPI) was increased in PiZ and SZ subjects compared to PiMM subjects (p = 0.0001). Neutrophil lipocalin was decreased in PiZ subjects (p = 0.0004) and PiSZ subjects (p = 0.001) compared to PiMM individuals. The elastase/AAT complex concentration was lower in AAT-deficient subjects (p = 0.0001).

Conclusion: Twenty-six-year-old PiZ and SZ individuals (5% smokers) had normal lung function test results, and 4 to 9% had marginal deviations in liver test results. Analyses of SLPI and neutrophil lipocalin, a marker of neutrophil activity, indicate compensatory changes in the AAT-deficiency state.

Key Words: {alpha}1-antitrypsin deficiency • epidemiology • liver disease • lung disease • neonatal screening • neutrophil lipocalin • protease • protease inhibitor


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The development of clinical symptoms of liver and lung disease in individuals with severe {alpha}1-antitrypsin (AAT) deficiency is highly variable.1 Gene/environmental interactions, environmental influences, and modifier genes may be of importance from fetal life onwards.2

During 1972 to 1974, 200,000 Swedish newborns were screened for AAT deficiency.3 Important aims of the research project were to study the epidemiology, natural history, and pathophysiology of AAT deficiency in childhood and adolescence and to protect adolescents from smoke and environmental air pollution. Serial reports3456 from the prospective follow-up of these PiZ and SZ individuals have been published up to age 22 years.

With subjects at 26 years of age, we have focused on clinical health, lung and liver function tests, and plasma markers of the protease/protease inhibitor balance. In addition, the potential effect of environmental factors during early childhood on lung function was investigated.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
All surviving 178 AAT-deficient subjects (PiZ, n = 122; PiZ–, n = 2; and PiSZ,/PiS–, n = 53) identified by the 1972-to-1974 screening were invited to participate. Clinical examination, spirometry, and routine blood tests were performed by a chest physician at the local hospital. An age-matched control group was recruited from the University Hospital in Malmö.

Questionnaire
The physician answered a questionnaire concerning diagnosis, spirometry, and liver function tests. The patient completed a modified version of the adult respiratory disease questionnaire used in epidemiologic research.7

Lung Function Tests
Standard spirometric tests were performed at the respective department of respiratory medicine. FEV1 and FVC were expressed as a percentage of predicted values.8 The FEV1/FVC ratio was expressed as a percentage. Reversibility tests were ordered but not consistently performed.

Serum Protein Profile and Liver Tests
Serum albumin, AAT, orosomucoid, haptoglobin, ceruloplasmin, IgG, IgA, and IgM were quantified by immune nephelometry with Image Instrument (Beckman-Coulter; Fullerton, CA) calibrated with a CRM 470 calibrator (Beckman-Coulter;). The method has a lower reporting level of 0.10 g/L. The serum samples were also subjected to capillary electrophoresis, the patterns being interpreted by J. C.9 The serum alanine aminotransferase (S-ALAT) and {gamma}-glutamyl transferase (S-GT) tests were analyzed at the routine clinical chemistry laboratories of the respective hospitals with standard methods.

Protease Inhibitors and Protease/Protease Inhibitor Complex Determinations
Serum was drawn from a subgroup of the AAT-deficient subjects and the age-matched control group. All of them were clinically healthy. The samples were centrifuged within 30 min, and the samples were stored at – 20° until analyzed. {alpha}2-macroglobulin (A2M), secretory leukocyte protease inhibitor (SLPI), human elastase/{alpha}1-antitrypsin complex (HEAT), and neutrophil gelatinase-associated lipocalin (NGAL) were analyzed with methods described previously.10

Statistical Analysis
The Fisher Exact Text and the {chi}2 test were used to compare categorical variables. The Sstudent’s t test and analysis of variance (ANOVA) were used for group comparisons of continuous variables. Covariance analysis was used in the comparison of lung function between the subgroup of PiZ individuals with history of liver disease in early childhood and the remainder of PiZ individuals, with birth weight as the covariate. A p value < 0.05 was considered significant.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Clinical Examination and Lung Function
Of the 178 AAT-deficient individuals, 119 subjects (67%) underwent clinical examination at age 26 years. The patient questionnaire was answered by 134 individuals (81%). The control group of healthy volunteers included 44 PiMM individuals (21 men) with a normal AAT concentration.

Lung function test results are shown in Table 1 . No significant differences in lung function were found between the Pi subgroups. A reversibility test was performed in 71 AAT-deficient and 40 PiMM individuals. An increase of FEV1 ≥ 12% after inhaled ß2-agonist was found in 4 of 51 PiZ subjects (8%), in 2 of 20 PiSZ subjects (10%), and in none of the control subjects.


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  		Table 1.. Lung Function in 83 PiZ, 36 PiSZ, and 44 PiMM Individuals*

 
Eighteen of the PiZ subjects (22%) and 11 of the PiSZ subjects (31%) reported recurrent wheezing. Three of the PiZ subjects (4%) and one of the PiSZ subjects (3%) reported chronic phlegm. The prevalence of respiratory symptoms did not differ between the PiZ and SZ groups. The physicians reported a diagnosis of asthma in 13 PiZ subjects (16%) and 5 PiSZ subjects (14%). Other diagnoses were rheumatoid arthritis (PiSZ, n = 2), hepatitis C (PiSZ, n = 1), ulcerative colitis (PiZ, n = 1), and depression/psychological problems (PiZ, n = 2; PiSZ, n = 1).

The two PiZ– women had never smoked and had no respiratory problems. Their FEV1 percentage of predicted values were 92% and 112%, and their FEV1/FVC ratios were 79% and 78%, respectively.

Six AAT-deficient individuals participating in spirometry (5%) were current smokers, and 14 subjects (12%) were ex-smokers. Lung function did not differ significantly between the smoking subgroups and AAT-deficient nonsmokers. Four of the 6 current smokers (67%) and 25 of 118 ex-smokers/never-smokers (22%) reported recurrent wheezing (p = 0.03).

Lung function test results were compared between PiZ individuals with neonatal cholestasis and PiZ subjects with a normal neonatal period. No differences in FEV1 or FVC percentage were found. The mean FEV1 /FVC ratio was 77% (95% confidence interval [CI], 74 to 80%) in the neonatal cholestasis subgroup and 83% (95% CI, 81 to 85%) in the remainder of the PiZ subjects (p = 0.02). With birth weight as a covariable, the difference was still significant (p = 0.007).

Eleven individuals (PiZ, n = 9; PiSZ, n = 2) had recurrent wheezing at 2 years of age. No significant differences were found in FEV1 or FVC among these individuals and the remaining cohort. The mean FEV1 /FVC ratio was 78% (95% CI, 74 to 81%) in the 2-year-old wheezers and 83% (95% CI, 81 to 85%) in the remainder of the AAT-deficient individuals (p = 0.025). No differences in lung function were found between AAT-deficient individuals with mothers smoking at age 4 years (n = 39), both parents smoking (n = 21), or day-care attendance in early childhood (n = 24) and the remainder of the AAT-deficient subjects.

Thirty-four subjects (PiZ, n = 22; PiSZ, n = 12) subjects did not attend the follow-up or answer a postal survey. According to the National Bureau of Population Statistics, all of them are alive.

Liver Tests
No subjects had clinical symptoms of liver disease. Abnormal liver test results were defined as S-ALAT > 0.75 microkatals (µkat) per liter and 1.10 µkat/L, and S-GT > 0.75 µkat/L and > 1.30 µkat/L for women and men respectively.11 The numbers with abnormal liver test results are given in Table 2 .


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  		Table 2.. Abnormal Liver Test Results*

 
Three individuals had abnormal S-ALAT levels both at 26 years and 22 years of age (PiZ male, 1.58 µkat/L and 2.37 µkat/L; PiSZ male, 1.20 µkat/L and 1.90 µkat/L; and PiSZ male, 3.60 µkat/L and 2.49 µkat/L, respectively). Two subjects had abnormal S-GT levels at 26 years and 22 years of age (PiZ female, 0.86 µkat/L and 0.89µkat/L; PiSZ male, 2.10 µkat/L and 1.20 µkat/L, respectively).

Results of liver tests and plasma protein analyses for the subgroup of PiZ, PiSZ, and control subjects are given in Table 3 . Significant differences between the AAT-deficiency and control groups were observed for S-ALAT, S-GT, plasma albumin, and ceruloplasmin. None had a definite electrophoretic liver pattern.12 No difference was observed in the concentrations of IgG, IgA, and IgM between the PiMM and AAT-deficiency groups.


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  		Table 3.. Liver Test Results and Plasma Protein Concentrations in a Subsample of PiZ, PiSZ, and PiMM Individuals*

 
Markers of Protease/Protease Inhibitor Balance.
Significant differences in the concentrations of SLPI, NGAL, and HEAT were evident among PiZ, SZ, and MM individuals (Table 4) . The A2M concentration had decreased to the normal adult level, and no difference of C-reactive protein (CRP) was observed in AAT-deficient compared to control individuals.


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  		Table 4.. Protease, Protease Inhibitor, and Complex Concentrations, With Neutrophil Lipocalin (NGAL) Analyzed as an Indicator of Leukocyte Activity*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study was initiated in the 1970s to determine the natural histories of liver and lung disease in AAT deficiency and the possible effects of exogenous and endogenous factors. Other important aims were to prevent smoking and to study possible compensatory changes in the protease/protease inhibitor balance.

The 26-year-old individuals with AAT deficiency have normal lung function, as defined by a normal FEV1/FEV ratio and no difference from an age-matched control group. Seven percent of those answering the questionnaire were current smokers, compared with 17% of men and 20% of women aged 25 to 44 years in the Swedish population.13

We found a decreased mean FEV1/FEV ratio in 26-year-old subjects with AAT deficiency who had reported recurrent wheezing at 2 years of age. No difference was found now for individuals wheezing at the age of 4 years. However, transient wheezing in infants is usually not associated with a family history of asthma. The primary risk factor for this phenotype appears to be reduced lung function even in children with normal AAT.14

Day-care attendance in early childhood is another potential risk factor for transient wheezing and reduced lung function.15 Day care in this study had no significant effect on lung function in early adulthood.

Exposure to environmental tobacco smoke, both prenatal and postnatal, is linked to decreased lung growth and respiratory problems.16 The risk seems to be greatest for exposure during the intrauterine period and the first years of life. A negative effect of such exposure on lung function seen at 18 years was not evident 8 years later.17 In the present study, 29 of the AAT-deficient individuals (24%) reported occupational exposure to airway irritants, another potential risk factor for lung disease.1819 Their lung function did not differ significantly from nonexposed AAT-deficient individuals. The exposure duration is still however quite short.

Recurrent wheezing was common among both the PiSZ and PiZ 26-year-olds (31% vs 22%, respectively). A diagnosis of asthma was reported by the physician in 14% and 16% of the PiSZ and PiZ subjects, respectively. The prevalence of asthma is 5 to 12% in the Swedish adult population.20 An association between asthma and the PiZ phenotype has been suggested previously.21

PiZ individuals with clinical and laboratory signs of liver disease in infancy have a significantly lower FEV1/FVC ratio. Similar findings have been reported previously.522 Covariance analysis indicated that the difference was independent of birth weight. Thus, optimal nutrition during the months of cholestasis may be important to best attain normal lung growth.

The risk of severe liver disease is substantial during infancy and again after 50 to 60 years of age.323 None of the AAT-deficient young adults had any clinical symptoms of liver disease, and few (< 10%) had but marginally elevated liver test results. Within the normal range, a difference was found of the S-ALAT and S-GT levels between individuals having a genotype with two alleles, one allele, and no Z allele. This finding supports the accumulation theory of liver injury in AAT deficiency.1 Plasma proteins, which may be affected by liver disease, were also analyzed. A significantly lower (7%) concentration of albumin was found in AAT-deficient individuals. The difference, however, is marginal. The ceruloplasmin difference is probably due to the fact that more women in the control group used estrogen-containing oral contraceptives than PiZ women (PiZ, n = 2; PiSZ, n = 2; compared to seven PiM control women).

Since subjects were 8 years of age, A2M has been followed in AAT-deficient and control children.2425 Both A2M and AAT form complexes with elastase and collagenase in a molar combining ratio of 1:1. The molar concentration of AAT in blood of normal adults exceeds that of A2M by approximately 12 times. In the PiZ-deficiency state, the capacity of AAT to bind elastase is severely reduced by 80 to 90%. The concentration of A2M is considerably increased in childhood and adolescence and was even higher in AAT-deficient children. The level of A2M has dropped from 310 at 8 years to 215 at 18 years and now approximately 100% at 26 years of age. During childhood, the high level of A2M has theoretically protected the PiZ individuals from severe consequences of septic chock, pancreatitis, and peritonitis.262728 In animal experiments, animals die when the capacity of A2M to bind elastase is depleted.29 The practical implication of this knowledge is that AAT-substitution therapy may be indicated in AAT-deficient adult subjects during severe infections with Gram-negative bacteria in particular.

It is not yet known whether increases in plasma A2M seen during childhood are due to upregulation of A2M biosynthesis in monocytes and macrophages. A high secretion of A2M by alveolar macrophages may be of utmost importance in the AAT-deficiency state. Inflammatory cytokines are also modulated by A2M.3031

We also found that neutrophil lipocalin, analyzed as a marker of leukocyte activity, was reduced in AAT-deficient 18-year-old and 26-year-old subjects to approximately 70% of the normal concentration. The very low concentrations of HEAT in the AAT-deficiency state indicated that elastase is complexed with A2M to a great extent. A2M may act as a sensor for situations requiring coordinated cellular response. Complexed A2M may downregulate neutrophil proteases, partially compensating for the AAT deficiency, as indicated by the NGAL and HEAT test results.3233 Neutrophil lipocalin, NGAL, binds tightly to ferric siderophores and is proposed as participating in the antibacterial iron depletion strategy of the innate immune system.34

When subjects were 26 years old, but not 18 years old, SLPI was significantly higher in individuals with AAT deficiency than in control subjects. SLPI is responsible for approximately 90% of the elastase inhibitory capacity of bronchial secretions against elastase and is also thought to efficiently inhibit neutrophil elastase released into the interstitium.3536 There is a correlation between serum concentration and inflammation in the respiratory tract.3637 The level of CRP, however, was identical in AAT-deficient and control subjects. Thus, an increased SLPI secretion may serve as a protection for the respiratory tract and lung tissue.3638

In conclusion, 26-year-old individuals with AAT deficiency have essentially normal lung function, and only 7% of the 134 answering the questionnaire smoke. None have clinical symptoms of liver disease, and < 10% have marginally abnormal liver test results. Low levels of NGAL in AAT-deficient subjects indicate reduced leukocyte activity, ie, compensatory mechanisms. However, the NGAL level was considerably higher at age 26 years than at 18 years. The A2M concentration has been reduced from approximately 300% in childhood to the normal 100% adult level. The increased SLPI concentration at age 26 years indicates compensatory mechanisms. The roles of the protease inhibitors as not only inhibitors of leukocyte proteinases but also as regulators of leukocyte function, tissue repair, matrix production, and host defense against infection, normally and in the AAT-deficiency state, require further study.39


   Acknowledgements
 
The authors thank the Swedish physicians who made this study possible by reporting data to the investigators.


   Footnotes
 
Abbreviations: A2M = {alpha}2-macroglobulin; AAT = {alpha}1-antitrypsin; ANOVA = analysis of variance; CI = confidence interval; CRP = C-reactive protein; HEAT = human elastase/{alpha}1-antitrypsin complex; µkat = microkatal; NGAL = neutrophil gelatinase-associated lipocalin; S-ALAT = serum alanine aminotransferase; S-GT = {gamma}-glutamyl transferase; SLPI = secretory leukocyte protease inhibitor

This study was supported by grants from the Swedish Heart Lung Association.

Received for publication January 14, 2005. Accepted for publication April 12, 2005.


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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Screening and Familial Testing of Patients for {alpha}1-Antitrypsin Deficiency
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