Alpha1-Antitrypsin Deficiency in COPD: Clinical Implications

, College of Physicians and Surgeons, Columbia University, NY

In This Article

Asthma and Alpha1-ATD

Prevalence of asthma in alpha1-ATD. If a lack of alpha1-AT increases the tendency to airway inflammation and bronchial hyperreactivity over time, asthma should be more common in those with the deficiency.

Several studies have reported an association between alpha1-ATD and asthma.[17,18] The British Registry of patients with alpha1-ATD reported the presence of asthma in about 11% of cases.[3] Studies in populations with incomplete alpha1-ATD have documented an increase in the prevalence of asthma.[19,20] For example Colp and colleagues[20] reported an increased prevalence of the MS (18%) and MZ (7%) alpha1-ATD phenotypes in Puerto Rican children attending an asthma clinic in New York City.

Clinical relation of asthma and alpha1-ATD. Part of the difficulty in confirming the diagnosis of asthma in a patient with COPD and alpha1-ATD, is that many of the presenting symptoms and signs are common to both conditions. For example, wheezing in COPD is associated with cigarette smoking, airway hyperreactivity and altered autonomic function.[21] In addition the lack of airway structural support in emphysema results in wheezing, particularly during forced expiration.[22]

More recent data from the NHLBI Registry[23] and our own work[24] indicates that asthmatic features may be present in a majority of those patients with emphysema. Wheezing, for example, is reported in up to 90% of subjects with alpha1-ATD and airway obstruction. Wheezing with a respiratory infection is reported in over 70% and attacks of wheezing occur in over 60%. The figures for those with COPD are lower but still high enough to make wheezing a nonspecific symptom for asthma.[24] Not infrequently, the onset of wheezing predates the diagnosis of alpha1-ATD by many years.

In populations with COPD, lung function commonly shows a bronchodilator response may be associated with a lower baseline FEV1.[25,26] In addition, the Lung Health Study reported an extraordinarily high prevalence of bronchial hyperreactivity, a condition associated with a bronchodilator response, in smokers with moderate airway obstruction.[27] We have reported that over 50% of our subjects show a reversible airway obstruction after bronchodilator and there is no difference in magnitude or frequency of response in those with alpha1-ATD-related airway obstruction compared to those with COPD.[24]

Eden and associates[24] defined asthma in 38 patients with alpha1-ATD by attacks of wheezing, a bronchodilator response on lung function testing, plus the presence of two clinical criteria of allergy strongly associated with asthma.[28,29,30] These criteria were atopy, defined by skin test reactivity to intradermal antigens, and an elevated IgE of 100 IU/mL or more. In this population, the investigators found that patients with alpha1-ATD and severe emphysema showed a higher prevalence of asthma (22%) as compared to those with a similar level of airway obstruction but a normal alpha1-AT phenotype (5%).

Effect of Alpha1-AT Phenotype Abnormalities on the Severity of Airway Obstruction in Asthma and Other Airway Conditions

If a functional deficit in alpha1-AT occurs in asthma, is this simply a marker for airway inflammation or a mechanism for persistence of the asthmatic state? If the latter is true, asthma would be expected to be more severe as well as more common in those with an inherited abnormality of the alpha1-AT phenotype.

Swedish workers[19] reported that children carrying the Z allele showed a more severe clinical asthma compared with those lacking the allele. Also, Sigsgaard and coworkers[31] showed an epidemiologically significant increase in the odds ratio of developing byssinosis (an obstructive airway disease) in cotton workers homozygous for the Z allele. Therefore, current but limited evidence suggests that abnormalities in alpha1-AT phenotype may predispose to more severe airway obstruction.

Small studies suggest that abnormal alpha1-AT phenotypes are associated with an increased prevalence and severity of asthma.[18,19,20] The findings support the hypothesis that under normal circumstances, alpha1-AT modulates the effect of inflammatory mediators involved in the pathogenesis of airway hyperreactivity and asthma. With abnormalities of alpha1-antitrypsin phenotype, this control might be profoundly reduced.


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