Article information
Studies undertaken in Spain indicate that 9% of the general population aged between 40 and 70 years is affected by chronic obstructive pulmonary disease (COPD). Although tobacco smoke is the causative factor in more than 90% of cases, it is estimated that only 10% to 20% of smokers develop COPD. This may be explained by the existence of genetic or environmental factors that modulate the toxic effects of tobacco. The best known genetic factor is α1-antitrypsin deficiency, which is associated with an increased risk of developing pulmonary emphysema in smokers. The most recent guidelines from both the World Health Organization and the American Thoracic Society/European Respiratory Society recommend the establishment of screening programs for the detection of α1-antitrypsin deficiency in patients with COPD. This strategy is crucial in Spain, where the disease is under diagnosed, mainly due to a low index of suspicion among doctors.
Key words:
α1-Antitrypsin deficiency
Diagnosis
Prevalence
COPD
Estudios realizados en España señalan que un 9% de la población general de entre 40 y 70 años està afectada de enfermedad pulmonar obstructiva crónica (EPOC). El humo del tabaco es el factor causal en màs del 90% de los casos; sin embargo, se ha estimado que sólo un 10–20% de los fumadores desarrollan EPOC. La causa se puede encontrar en la existencia de factores genéticos o ambientales que modu-lan el efecto tóxico del tabaco. El factor genético màs conocido es el déficit de alfa-1-antitripsina, que comporta un riesgo aumentado de desarrollar enfisema pulmonar en fumadores. Tanto la Organización Mundial de la Salud como la American Thoracic Society/European Respiratory Society en sus recientes normativas recomiendan establecer programas de detección del déficit de alfa-1-antitripsina en pacientes con EPOC. Esta estrategia es crucial en España, donde la enfermedad està infradiagnosticada, sobre todo de-bido a un bajo índice de sospecha entre los médicos.
Palabras clave:
Déficit de alfa-1-antitripsina
Diagnóstico
Prevalencia
EPOC
Full text is only aviable in PDF
REFERENCES
[1]
V Sobradillo, M Miravitlles, R Gabriel, C Jiménez-Ruiz, C Villasante, JF Masa, JL Viejo, et al.
Geographic variations in prevalence and underdiagnosis of COPD: results of the IBERPOC multicentre epidemiological study.
Chest, 118 (2000), pp. 981-989
[2]
EK Silverman, FE Speizer.
Risk factors for the development of chronic obstructive pulmonary disease.
Med Clin North Am, 80 (1996), pp. 501-522
[3]
C Fletcher, R Peto, C Tinker, FE Speizer.
The natural history of chronic bronchitis. An eight year follow up study of working men in London, Oxford University Press, (1976),
[4]
R Bascom.
Differential susceptibility to tobacco smoke: possible mechanism.
Pharmacogenetics, 1 (1991), pp. 102-106
[5]
IB Tager, B Rosner, PV Tishler, FE Speizer.
Household aggregation of pulmonary function and chronic bronchitis.
Am Rev Respir Dis, 114 (1976), pp. 485-492
[6]
IB Tager, PV Tishler, B Rosner, FE Speizer.
Studies of the familial aggregation of chronic bronchitis and obstructive airways disease.
Int J Epidemiol, 15 (1986), pp. 65-72
[7]
BH Cohen, EL Diamond, CG Graves.
A common familial component in lung cancer and chronic obstructive pulmonary disease.
Lancet, 10 (1977), pp. 523-526
[8]
M Higgins, J Keller.
Familial occurrence of chronic respiratory disease and familial resemblance in ventilatory capacity.
J Chron Dis, 28 (1975), pp. 239-251
[9]
F Kauffmann, IB Tager, A Muñoz, FE Speizer.
Familial factors related to lung function in children aged 6–10 years.
Am J Epidemiol, 129 (1989), pp. 1289-1299
[10]
EJ Devor, MH Crawford.
Family resemblance for normal pulmonary function.
Ann Hum Biol, 11 (1984), pp. 439-448
[11]
BA Rybicki, TH Beaty, BH Cohen.
Major genetic mechanisms in pulmonary function.
J Clin Epidemiol, 43 (1990), pp. 670-675
[12]
JA Astemborski, TH Beaty, BH Cohen.
Variance components analysis of forced expiration in families.
Am J Med Genet, 21 (1985), pp. 741-753
[13]
S Redline, PV Tishler, B Rosner, FI Lewitter, M Vandenburg, ST Weis, et al.
Genotypic and phenotypic similarities in pulmonary function among family members of adult monozygotic and dizygotic twins.
Am J Epidemiol, 129 (1989), pp. 827-836
[14]
N Zamel, P Webster, E Lorimer, S Man.
Environment versus genetics in determining bronchial susceptibility to cigarette smoking.
Chest, 80 (1981), pp. 57S
[15]
SFP Man, N Zamel.
Genetic influences on normal variability of maximum expiratory flow-volume curves.
J Appl Physiol, 41 (1976), pp. 874-877
[16]
E Silverman, H Chapman, J Drazen.
Early-onset chronic obstructive pulmonary disease (COPD): preliminary evidence for genetic factors other than Pi type.
Am J Respir Crit Care Med, 153 (1996), pp. A48
[17]
M Miravitlles, R Vidal, J de Gracia.
Enfisema por déficit de alfa1 antitripsina. Situación actual y nuevas perspectivas para el tratamiento.
Arch Bronconeumol, 28 (1992), pp. 296-302
[18]
CB Laurell, S Erikson.
The electrophoretic alpha1 globulin pattern of serum in alpha1 antitrypsin deficiency.
Scan J Clin Invest, 15 (1963), pp. 132-140
[19]
JF Mornex, A Chytil-Weir, Y Martinet, M Courtney.
Expression of the alpha1 antitrypsin gene in mononuclear phagocytes of normal and alpha1 antitrypsin deficient individuals.
J Clin Invest, 77 (1986), pp. 1952-1961
[21]
MK Fagerhol, CB Laurell.
The Pi system: inherited variants of serum alpha1 antitrypsin.
Prog Med Genet, 7 (1970), pp. 96-111
[22]
RC Allen, RA Harley, RC Talamo.
A new method for determination of alpha1 antitrypsin phenotypes using isoelectric focusing on polyacrylamide gel slabs.
Am J Clin Pathol, 62 (1974), pp. 732-739
[23]
P Birrer, NG McElvaney, RG Crystal.
Alpha-1 antitrypsin deficiency and liver disease.
J Inher Metab Dis, 14 (1991), pp. 512-525
[24]
I Blanco, E Fernández.
Alpha-1 antitrypsin Pi phenotypes S and Z in Spain: an analysis of the published surveys.
Respir Med, 95 (2001), pp. 109-114
[25]
R Vidal, M Miravitlles, R Jardí, M Torrella, F Rodríguez-Frías, P Moral, et al.
Estudio de la frecuencia de los diferentes fenotipos de la alfa-1-antitripsina en una población de Barcelona.
Med Clin (Bare), 107 (1996), pp. 211-214
[26]
J Lieberman, B Winter, A Sastre.
Alpha antitrypsin Pi-types in 965 COPD patients.
Chest, 89 (1986), pp. 370-373
[27]
L Álvarez-Granda, MJ Cabero-Pérez, A Bustamante-Ruiz, D Gonzalez Lamuño, M Delgado Rodríguez, M García Fuentes.
Pi SZ phenotype in chronic obstructive pulmonary disease.
Thorax, 52 (1997), pp. 659-661
[28]
DCS Hutchinson, MJ Tobin, PJL Cook.
Alpha-1 antitrypsin deficiency: clinical and physiological features in heterozygotes of Pi type SZ. A survey by the British Thoracic Association.
Br J Dis Chest, 77 (1983), pp. 28-34
[29]
GM Turino, AF Barker, ML Brantly.
Clinical features of individuals with Pi SZ phenotype of alpha1 antitrypsin deficiency.
Am J Respir Crit Care Med, 154 (1996), pp. 1718-1725
[30]
C Larsson, H Dirksen, G Sunstrom, S Eriksson.
Lung function studies in asymptomatic individuals with moderately (Pi SZ) and severely (PiZ) reduced levels of alpha one antitrypsin.
Scand J Respir Dis, 57 (1976), pp. 267-280
[31]
M Dahl, CP Hersh, NP Ly, C Berkey, E Silverman, B Nordestgaard.
The protease inhibitor PI*S allele and COPD: a meta-analysis.
Eur Respir J, 26 (2005), pp. 67-76
[32]
MD Holmes, ML Brantly, RG Crystal.
Molecular analysis of the heterogeneity among the P-family of alpha-1-antitrypsin alleles.
Am Rev Respir Dis, 142 (1990), pp. 1185-1192
[33]
JP Faber, S Weidinger, HW Goedde, K Ole.
The deficient alpha-I-antitrypsin phenotype PI P is associated with an A-to-T transversion in exon III of the gene.
Am J Hum Genet, 45 (1989), pp. 161-163
[34]
J Hildesheim, G Kinsley, M Bissell, J Pierce, M Brantly.
Genetic diversity from a limited repertoire of mutations on different common allelic backgrounds: alpha 1-antitrypsin deficiency variant Pduarte.
Hum Mutat, 2 (1993), pp. 221-228
[35]
R Jardí, F Rodríguez-Frías, F Casas, M Cotrina, R Vidal, M Miravitlles, et al.
Caracterización molecular de 2 variantes del déficit de alfa-1-antitripsina: PI Mpalermo y PIPlovel.
Med Clin (Bare), 109 (1997), pp. 463-466
[36]
JP Faber, W Poller, S Weidinger, M Kirchgesser, R Schwaab, F Bidlingmaier, et al.
Identification and DNA sequence analysis of 15 new alpha 1-antitrypsin variants, including two PI*Q0 alleles and one deficient PI*M allele.
Am J Hum Genet, 55 (1994), pp. 1113-1121
[37]
R Jardí, F Rodríguez Frías, JC López Talavera, M Miravitlles, M Cortina, X Costa, et al.
Characterization of the new alpha-1-antitrypsin deficient Pi M type allele, Pi Mvall d'hebron (Pro369Ser).
Hum Hered, 50 (2000), pp. 320-321
[38]
R Jardí, F Rodríguez, M Miravitlles, R Vidal, M Cotrina, J Quer, et al.
Identification and molecular characterization of the new alpha-1-antitrypsin deficient allele PI Y barcelona (Asp256˜Val and Pro391˜His).
Hum Mutat, 12 (1998), pp. 213
[40]
LF Black, F Kueppers.
Alpha1 antitrypsin deficiency in nonsmokers.
Am Rev Respir Dis, 117 (1978), pp. 421-428
[41]
ED Janus, NT Philips, RW Carrell.
Smoking, lung function and alpha1 antitrypsin deficiency.
Lancet, 19 (1985), pp. 152-154
[42]
ML Brantly, LD Paul, BH Miller, RT Falk, M Wu.
Clinical features and history of the destructive lung disease associated with alpha1 antitrypsin deficiency of adults with pulmonary symptoms.
Am Rev Respir Dis, 138 (1988), pp. 327-336
[43]
MJ Tobin, PJL Cook, DCS Hutchinson.
Alpha1 antitrypsin deficiency: the clinical and physiological features of pulmonary emphysema in subjects homozygous for Pi type Z; a survey by the British Thoracic Association.
Br J Dis Chest, 77 (1983), pp. 14-27
[44]
N Seersholm, A Kok-Jensen, A Dirksen.
Survival of patients with severe alpha 1–antitrypsin deficiency with special reference to non-index cases.
Thorax, 49 (1994), pp. 695-698
[45]
EK Silverman, JA Pierce, MA Province, DC Rao, EJ Campbell.
Variability of pulmonary function in alpha-1–antitrypsin deficiency: clinical correlates.
Ann Intern Med, 111 (1989), pp. 982-991
[46]
A Novoradovsky, ML Brantly, MA Waclawiw.
Endothelial nitric oxide synthase as a potential susceptibility gene in the pathogenesis of emphysema in alpha1 antitrypsin deficiency.
Am J Respir Cell Mol Biol, 20 (1999), pp. 441-447
[47]
P Terrier, AJ Townsend, JM Coindre, TJ Triche, KH Cowan.
An immunohistological study of Pi class glutathione S-transferase expression in normal human tissue.
Am J Patol, 137 (1990), pp. 845-853
[48]
AGM Sunberg, R Nilsson, EL Appelkvist, G Dallner.
Immunohistochemical location of alpha and mu class glutathione transferases in normal tissues.
Pharmacol Toxicology, 72 (1993), pp. 321-331
[49]
R Whalen, T Boyer.
Human glutathione S-transferases.
Semin Liver Dis, 18 (1998), pp. 345-358
[50]
F Rodríguez, C de la Roza, R Jardí, M Schaper, R Vidal, M Miravitlles.
Glutathione S-transferase P1 and lung function in patients with alpha-1 antitrypsin deficiency.
Chest, 127 (2005), pp. 1537-1543
[51]
FJ de Serres.
Worldwide racial and ethnic distribution of alpha-1 antitrypsin deficiency.
Chest, 122 (2002), pp. 1818-1829
[52]
I Blanco, E Fernández-Bustillo, FJ de Serres, D Alkassam, C Rodríguez Menéndez.
Déficit de alfa-1–antitripsina en España (variantes deficientes PI*S y PI*Z): prevalencia estimada y número de sujetos calculados para cada fenotipo.
Med Clin (Bare), 123 (2004), pp. 761-765
[53]
R Vidal, Miravitlles M y Grupo de Estudio del Déficit de Alfa-1 antitripsina.
Informe del Registro Español de Pacientes con Déficit de Alfa-1-antitripsina.
Arch Bronconeumol, 31 (1995), pp. 299-302
[54]
M Miravitlles, R Vidal, JC Barros-Tizón, A Bustamante, PP España, F Casas, et al.
Usefulness of a national Registry of alpha-1-antitrypsin deficiency. The Spanish experience.
Respir Med, 92 (1998), pp. 1181-1187
[55]
M Miravitlles, R Vidal, JC Barros-Tizón, A Bustamante, PP España, F Casas, et al.
Estado actual del tratamiento sustitutivo en el enfisema congénito por déficit de alfa-1-antitripsina. Informe del Registro Nacional.
Arch Bronconeumol, 35 (1999), pp. 446-454
[56]
D Hutchinson.
Alpha-1 antitrypsin deficiency in Europe: geographical distribution of Pi types S and Z.
Respir Med, 92 (1998), pp. 367-377
[57]
M Luisetti, M Miravitlles, RA Stockley.
Alpha-1 antitrypsin deficiency: a report from the 2nd meeting of the Alpha One International Registry, Rapallo (Genoa, Italy), 2001.
Eur Respir J, 20 (2002), pp. 1050-1056
[58]
AJ Sandford, TD Weir, PD Paré.
Genetic risk factors for chronic obstructive pulmonary disease.
Eur Respir J, 10 (1997), pp. 1380-1391
[59]
RM Bruce, BH Cohen, EL Diamond, et al.
Collaborative study to assess risk of lung disease in Pi MZ phenotype subjects.
Am Rev Respir Dis, 130 (1984), pp. 386-390
[60]
NB Pride, SF Tattersall, RP Pereira, D Hunter, G Blundell.
Lung distensibility and airway function in intermediate alpha 1-antitrypsin deficiency (PiMZ).
Chest, 77 (1980), pp. 253-255
[61]
FO Horton III, AV Mackenthun, PS Anderson Jr, CD Patterson, JF Hammarsten.
Alpha 1 antitrypsin heterozygotes (Pi type MZ). A longitudinal study of the risk of development of chronic air flow limitation.
Chest, 77 (1980), pp. 261-264
[62]
DM Cooper, V Hoeppner, D Cox, N Zamel, AC Bryan, H Levison.
Lung function in alpha1–antitrypsin heterozygotes (Pi type MZ).
Am Rev Respir Dis, 110 (1974), pp. 708-715
[63]
M Dahl, A Tybjaerg-Hansen, P Lange, J Vestbo, BG Nordestgaard.
Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin mz heterozygotes: a longitudinal study of the general population.
Ann Intern Med, 136 (2002), pp. 270-279
[64]
C Mittman, J Lieberman, J Rumsfeld.
Prevalence of abnormal protease inhibitor phenotypes in patients with chronic obstructive lung disease.
Am Rev Respir Dis, 109 (1974), pp. 295-296
[65]
TB Barnett, D Gottovi, AM Johnson.
Protease inhibitors in chronic obstructive pulmonary disease.
Am Rev Respir Dis, 111 (1975), pp. 587-593
[66]
DW Cox, VH Hoeppner, H Levison.
Protease inhibitors in patients with chronic obstructive pulmonary disease: the alpha-antitrypsin heterozygote controversy.
Am Rev Respir Dis, 113 (1976), pp. 601-606
[67]
JW Shigeoka, WJ Hall, RW Hyde, RH Schwartz, GS Mudholkar, DM Speers, et al.
The prevalence of alpha-antitrypsin heterozygotes (Pi MZ) in patients with obstructive pulmonary disease.
Am Rev Respir Dis, 114 (1976), pp. 1077-1084
[68]
K Bartmann, M Fooke, G Koch, I Schutz, E Weis, M Zierski.
Heterozygosity in the Pi-system as a pathogenetic cofactor in chronic obstructive pulmonary disease (COPD).
Eur J Respir Dis, 66 (1985), pp. 284-296
[70]
FJ de Serres.
Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosed.
Environ Health Perspect, 111 (2003), pp. 1851-1854
[71]
RM Katz, J Lieberman, SC Siegel.
Alpha-1 antitrypsin levels and prevalence of Pi variant phenotypes in asthmatic children.
J Allergy Clin Immunol, 57 (1976), pp. 41-45
[72]
C Colp, W Talavera, D Goldman, J Green, A Multz, J Lieberman.
Profile of bronchospastic disease in Puerto Rican patients in New York City. A possible relationship to alpha 1-antitrypsin variants.
Arch Intern Med, 150 (1990), pp. 2349-2354
[73]
M Miravitlles, S Vila, M Torrella, E Balcells, F Rodríguez-Frías, C de la Roza, et al.
Influence of deficient alpha1-anti-trypsin phenotypes on clinical characteristics and severity of asthma in adults.
Respir Med, 96 (2002), pp. 186-192
[74]
NG McElvaney, JK Stoller, AS Buist, UBS Prakash, ML Brantly, MD Schluchter.
Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of alpha-1-antitrypsin deficiency.
Chest, 111 (1997), pp. 394-403
[75]
JA Barberà, G Peces-Barba, A Agustí, JL Izquierdo, E Monsó, T Montemayor, JL Viejo.
Guía clínica para el diagnóstico y el tratamiento de la enfermedad pulmonar obstructiva crónica.
Arch Bronconeumol, 37 (2001), pp. 297-316
[76]
M Miravitlles, R Vidal, M Torrella, JM Bofill, M Cotrina, J de Gracia.
Evaluación del tratamiento sustitutivo del enfisema por déficit de alfa-1 antitripsina.
Arch Bronconeumol, 30 (1994), pp. 479-484
[77]
CA Blank, M Brantly.
Clinical features and molecular characteristics of α1-antitrypsin deficiency.
Ann Allergy, 72 (1994), pp. 105-111
[78]
M Miravitlles, R Jardí, F Rodríguez-Frías, M Torrella, D Pelegrí, R Vidal.
Utilidad de la cuantificación de la banda alfa-1 del proteinograma sérico en el cribado del déficit de alfa-1 antitripsina.
Arch Bronconeumol, 34 (1998), pp. 536-540
[79]
Alpha-1 antitrypsin deficiency: memorandum from a WHO meeting.
Bull World Health Organ, 75 (1997), pp. 397-415
[80]
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
[81]
M Luisetti, G Massi, M Massobrio, P Guarraci, M Menchicchi.
A national program for detection of alpha1-antitrypsin deficiency in Italy.
Respir Med, 93 (1999), pp. 169-172
[82]
M Wencker, A Marx, N Konietzko, B Schaefer, EJ Campbell.
Screening for alpha1-Pi deficiency in patients with lung diseases.
Eur Respir J, 20 (2002), pp. 319-324
[83]
M Brantly, V Mishra, L Zienko.
Statewide targeted screening and detection of AAT deficiency.
Am J Respir Crit Care Med, 167 (2003), pp. A222
[84]
C de la Roza, F Rodríguez-Frías, B Lara, R Vidal, R Jardí, M Miravitlles.
Results of a case-detection program for alpha-1 antitrypsin deficiency in COPD patients.
Eur Respir J, 26 (2005), pp. 21622
[85]
X Costa, R Jardí, F Rodríguez, M Miravitlles, M Cotrina, C Pascual, et al.
Easy method for screening dried blood spot specimens on filter paper for alpha-1 antitrypsin deficiency.
Eur Respir J, 15 (2000), pp. 1111-1115
[86]
F Rodríguez, R Jardí, X Costa, M Cotrina, R Galimany, R Vidal, et al.
Rapid screening for alpha1-antitrypsin deficiency in patients with chronic obstructive pulmonary disease using dried blood specimens.
Am J Respir Crit Care Med, 166 (2002), pp. 814-817
[87]
C de la Roza, X Costa, R Vidal, S Vila, F Rodríguez-Frías, R Jardí, et al.
Programa de cribado para el déficit de α;1-antitripsina en pacientes con EPOC mediante el uso de gota de sangre en papel secante.
Arch Bronconeumol, 39 (2003), pp. 8-12
[88]
M Miravitlles.
Enfisema por déficit de alfa-1 antitripsina: ¿ies realmente una enfermedad infrecuente?.
Med Clin (Bare), 123 (2004), pp. 778-779
This work was funded by Red Respira grant RTIC 03/111SCII.
Copyright © 2006. Sociedad Española de Neumología y Cirugía Torácica (SEPAR)
