Pulmonology Pulmonology
Case series
Diagnosis of alpha1-antitrypsin deficiency not just in severe COPD
A. Nuñez, M. Barrecheguren, E. Rodríguez, M. Miravitlles, C. Esquinas,
Pneumology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain
Received 17 November 2017, Accepted 10 May 2018
Abstract

Alpha1-antitrypsin deficiency (AATD) is a well known genetic risk factor for pulmonary disease and is the most frequent hereditary disease diagnosed in adults. Despite being one of the most common hereditary diseases, AATD remains under-diagnosed because of its variable clinical presentation and the poor knowledge of this disease by physicians. With the aim of identifying clinical differences that could influence early diagnosis, we compared two groups of six AATD Pi*ZZ patients with different lung function severity and clinical expression at diagnosis. On comparing the two groups, we observed a younger mean age at diagnosis and more exacerbations in the severe group, but the percentage of smokers did not statistically differ between the two groups. Our results suggest that AATD continues being a disease suspected on younger patients with a worse lung function. In addition these findings confirm the clinical variability of the disease and that there are still unknown factors that contribute to its development. Therefore, early diagnosis may modify the prognosis of this disease.

Keywords
COPD, Alpha1-antitrypsin deficiency, Diagnosis
This article is only available in PDF
Introduction

Alpha1-antitrypsin deficiency (AATD) is a well known genetic risk factor for pulmonary disease and is the most frequent hereditary disease diagnosed in adults. AATD has a prevalence of less than 5 cases per 10,000 habitants, accounting for 1–2% of patients with emphysema.1,2 Despite being one of the most common hereditary diseases, AATD remains under-diagnosed because of its variable clinical presentation and the poor knowledge that physicians have of this disease. Tobacco exposure is the most important risk factor for the development of emphysema in AATD.3,4

Although forced expiratory volume in the first second (FEV1) and diffusing lung capacity for carbon monoxide (DLCO) are the usual parameters used in clinical practice to follow disease progression,5 their great variability makes them less suitable to be used as outcomes in clinical trials.6 Loss of lung density measured by quantitative computed tomography has demonstrated to be a more accurate outcome measure7–9 and has a good long-term correlation with FEV1, DLCO, and survival.10,11

Despite the data reported from patient registries, the evolution of lung disease associated with AATD is not fully understood.12,13

Since this is a progressive disease, early diagnosis and treatment may change the natural course of the disease.

With the aim of identifying clinical differences that could influence early diagnosis, we consecutively selected patients from our database of AATD patients, and we compared two groups according to the severity of the disease. Severe disease defined as FEV1<45% at diagnosis and then we found patients with FEV1>65% paired by age and gender.

Clinical observationsModerate group

Six AATD Pi*ZZ patients with relatively preserved lung function at diagnosis (FEV165%) were included. The mean age at diagnosis was 51 years (SD=4) and four of patients were men. Two patients were never smokers and 4 were former smokers. The mean FEV1 at diagnosis was 93% (SD=29). Regarding comorbidities, one patient had bronchiectasis, another cardiovascular disease and one had severe liver disease requiring liver transplantation. None of the six patients had had more than one exacerbation during the previous year. Two patients had radiologically confirmed emphysema with a FEV1 of 65 and 67% respectively and intravenous augmentation treatment was initiated after diagnosis (Table 1).

Table 1.

Demographic and clinical characteristics.

Variables  Moderate n=Severe n=p 
Current age  61.7 (7.7)  61.0 (10.5)  0.937 
Age at diagnosis  51.2 (4)  42.7 (6.4)  0.041 
Gender0.999 
-Men  4 (66.7%)  4 (66.7%)   
-Women  2 (33.3%)  2 (33.3%)   
Number of smokers0.135 
-Never smoker  2 (33.3%)   
-Current smoker  2 (33.3%)   
-Former smoker  4 (66.7%)  4 (66.7%)   
FEV1% at diagnosis  93 (29)  44 (6.7)  0.002 
Other comorbidities
-Bronchiectasis  1 (16.7%)  1 (16.7%)  0.098 
-Cardiovascular disease  1 (16.7%)  2 (33.3%)  0.125 
-Liver disease  1 (16.7%)   
Bronchodilator treatment  4 (66.7%)  6 (100%)  0.225 
-β2 agonists  4 (66.7%)  6 (100%)  0.065 
-Inhaled corticosteroids  6 (100%)  0.025 
Exacerbations per year (≥2)  4 (66.7%)  0.049 
Intravenous augmentation treatment with AAT  2 (33.3%)  4 (66.7%)  0.248 

Data are expressed as mean and percentages.

Severe group

Six AATD Pi*ZZ patients with impaired lung function at diagnosis (FEV1≤45%) were analyzed. The mean age was 43 years (SD=6.4) and four were men. Two patients were current smokers and 4 were former smokers. The mean FEV1 at diagnosis was 44% (SD=6.7). We observed bronchiectasis in one patient and cardiovascular disease in two patients and none presented significant liver disease. All had had two or more exacerbations during the last year. Four patients initiated intravenous augmentation treatment after diagnosis, the two remaining patients were active smokers and therefore augmentation treatment was not indicated.

Discussion

Diagnosis of lung disease in AATD is usually delayed for some years after the first clinical manifestations.14 We compared two groups of patients diagnosed with lung disease of different severity to try to understand factors associated with early diagnosis.

On comparing the two groups, we observed a younger mean age at diagnosis and more exacerbations in the severe group, but the percentage of smokers did not statistically differ between the two groups.

Our results suggest that AATD continues to be a disease which is suspected in younger patients with a worse lung function. In addition these findings confirm the clinical variability of the disease and that there are still unknown factors that contribute to its development. Therefore, early diagnosis may modify the prognosis of this disease. It is estimated that a total of 253,404 ZZ individuals are distributed mainly in Europe and North America.2 Nevertheless AATD is under-diagnosed because of the poor knowledge of this disease by physicians. Indeed, in the study by Greulich et al. only 18 and 25% of physicians in Italy and Germany, respectively, stated that they tested all their patients with chronic obstructive pulmonary disease (COPD) and asthma.15 Likewise, in another survey conducted by Esquinas et al. in Spain and Portugal only 15.8% of physicians tested all of their COPD patients for AATD, and only 45.2% knew the AAT serum concentrations needed to consider severe deficiency.16

These data are in contrast with the worldwide recommendation of testing all COPD patients at least once in their lives.1,17,18 A population-based study performed in primary care in our region demonstrated that requests for AAT determinations were low compared to the number of COPD patients diagnosed per year.19 In addition, an important number of determinations were not prescribed because of pulmonary disease.20

Conclusion

In conclusion, lung disease associated with AATD may evolve in different ways and predisposing factors are not completely understood, which makes its early diagnosis even more important. Early diagnosis would help to improve strategies such as tobacco cessation, vaccination, initiation of optimum COPD treatment and augmentation therapy with AAT when indicated, to prevent disease progression. In addition, physicians should have a broader knowledge of the disease which would facilitate early diagnosis and thereby implement more efficient health care interventions.

Conflicts of interest

Marc Miravitlles has received speaker or consulting fees from (in alphabetical order) Bial, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, Laboratorios Esteve, Gebro Pharma, GlaxoSmithKline, Grifols, Menarini, Mereo Biopharma, Novartis, pH Pharma, Rovi, TEVA, Verona Pharma and Zambon, and research grants from GlaxoSmithKline and Grifols.

References
1
F. Casas,I. Blanco,M.T. Martínez,A. Bustamante,M. Miravitlles,S. Cadenas
Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update
Arch Bronconeumol, 51 (2015), pp. 185-192 http://dx.doi.org/10.1016/j.arbres.2014.05.008
2
I. Blanco,P. Bueno,I. Diego,S. Pérez-Holanda,F. Casas-Maldonado,C. Esquinas
Alpha 1 antitrypsin Pi*Z gene frequency and Pi*ZZ genotype numbers worldwide: an update
Int J Chron Obstruct Pulmon Dis, 12 (2017), pp. 561-569 http://dx.doi.org/10.2147/COPD.S125389
3
M.C. Wu,S. Eriksson
Lung function, smoking and survival in severe alpha-1-antitrypsin deficiency, PiZZ
J Clin Epidemiol, 41 (1988), pp. 1157-1165
4
E.D. Janus,N.T. Phillips,R.W. Carrell
Smoking, lung function, and alpha-1-antitrypsin deficiency
5
R. Stockley,M. Miravitlles,C. Vogelmeier,Behalf of Alpha One International Registry (A.I.R.)
Augmentation therapy for alpha-1 antitrypsin deficiency: towards a personalised approach
Orphanet J Rare Dis, 8 (2013), pp. 149 http://dx.doi.org/10.1186/1750-1172-8-149
6
M. Schluchter,J. Stoller,A. Barker,S. Buist,R. Crystal,J. Donohue
for the Alpha1-Antitrypsin Deficiency Registry Group. Feasibility of a clinical trial of augmentation therapy for alpha1-antitrypsin deficiency
Am J Respir Crit Care Med, 161 (2000), pp. 796-801 http://dx.doi.org/10.1164/ajrccm.161.3.9906011
7
D.G. Parr,B.C. Stoel,J. Stolk,R.A. Stockley
Validation of computed tomographic lung densitometry for monitoring emphysema in a1-antitrypsin deficiency
8
D.G. Parr,M. Sevenoaks,C. Deng,B.C. Stoel,R.A. Stockley
Detection of emphysema progression in alpha 1-antitrypsin deficiency using CT densitometry; methodological advances
9
K.R. Chapman,J.G. Burdon,E. Piitulainen,R.A. Sandhaus,N. Seersholm,J.M. Stocks,RAPID Trial Study Group
Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial
10
J. Stolk,W.H. Ng,M.E. Bakker,J.H.C. Reiber,K.F. Rabe,H. Ptter
Correlation between annual change in health status and computer tomography derived lung density in subjects with alpha1-antitrypsin deficiency
Thorax, 58 (2003), pp. 1027-1030
11
L.J. Dowson,P.J. Guest,R.A. Stockley
Longitudinal changes in physiological, radiological, and health status measurements in alpha(1)-antitrypsin deficiency and factors associated with decline
Am J Respir Crit Care Med, 164 (2001), pp. 1805-1809 http://dx.doi.org/10.1164/ajrccm.164.10.2106036
12
Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group
Am J Respir Crit Care Med, 158 (1998), pp. 49-59 http://dx.doi.org/10.1164/ajrccm.158.1.9712017
13
G. Tirado-Conde,B. Lara,F. Casas,I. Blanco,A. Bustamante,S. Cadenas
Factors associated with the evolution of lung function in patients with alpha-1 antitrypsin deficiency in the Spanish registry
Arch Bronconeumol, 47 (2011), pp. 495-503 http://dx.doi.org/10.1016/j.arbres.2011.06.002
14
T. Köhnlein,S. Janciauskiene,T. Welte
Diagnostic delay and clinical modifiers in alpha-1 antitrypsin deficiency
Ther Adv Respir Dis, 4 (2010), pp. 279-287 http://dx.doi.org/10.1177/1753465810376407
15
T. Greulich,S. Ottaviani,R. Bals,P.M. Lepper,C. Vogelmeier,M. Luisetti
Alpha1-antitrypsin deficiency – diagnostic testing and disease awareness in Germany and Italy
Respir Med, 107 (2013), pp. 1400-1408 http://dx.doi.org/10.1016/j.rmed.2013.04.023
16
C. Esquinas,M. Barrecheguren,M. Sucena,E. Rodriguez,S. Fernandez,M. Miravitlles
Practice and knowledge about diagnosis and treatment of alpha-1 antitrypsin deficiency in Spain and Portugal
BMC Pulm Med, 16 (2016), pp. 64
17
American Thoracic Society; European Respiratory Society
American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency
Am J Respir Crit Care Med, 168 (2003), pp. 818-900 http://dx.doi.org/10.1164/rccm.168.7.818
18
Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting
Bull World Health Organ, 75 (1997), pp. 397-415
19
M. Barrecheguren,M. Monteagudo,P. Simonet,C. Llor,E. Rodriguez,J. Ferrer
Diagnosis of alpha-1 antitrypsin deficiency: a population-based study
Int J Chron Obstruct Pulmon Dis, 11 (2016), pp. 999-1004 http://dx.doi.org/10.2147/COPD.S108505
20
M. Barrecheguren,M. Monteagudo,J. Ferrer,E. Borrell,C. Llor,C. Esquinas
Treatment patterns in COPD patients newly diagnosed in primary care. A population-based study
Respir Med, 111 (2016), pp. 47-53 http://dx.doi.org/10.1016/j.rmed.2015.12.004
Corresponding author. (C. Esquinas crise4@hotmail.com)
Copyright © 2018. Sociedade Portuguesa de Pneumologia
Cookies Policy
x
To improve our services and products, we use cookies (own or third parties authorized) to show advertising related to client preferences through the analyses of navigation customer behavior. Continuing navigation will be considered as acceptance of this use. You can change the settings or obtain more information by clicking here.