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a 1 -Antitrypsin deficiency:An overlooked cause of emphysema

The Journal of Respiratory DiseasesThe Journal of Respiratory Diseases Vol 28 No 3
Volume 28
Issue 3

a 1-Antitrypsin (AAT) deficiency is a genetic disorder that predisposes patients to early-onset emphysema and chronic liver disease. It is more common than is generally appreciated, occurring in about 1 in 2000 to 5000 persons.1,2 It has been estimated that 1% to 2.5% of persons with chronic obstructive pulmonary disease (COPD) in the United States have AAT deficiency.1,2

a 1-Antitrypsin (AAT) deficiency is a genetic disorder that predisposes patients to early-onset emphysema and chronic liver disease. It is more common than is generally appreciated, occurring in about 1 in 2000 to 5000 persons.1,2 It has been estimated that 1% to 2.5% of persons with chronic obstructive pulmonary disease (COPD) in the United States have AAT deficiency.1,2

The diagnosis of AAT deficiency is often overlooked. For example, a 1994 survey of 300 persons with this disorder revealed that the mean delay between symptom onset and diagnosis was 7.2 years.3 In a follow-up survey in 2003, the mean diagnostic delay was 5.6 years.4

This diagnostic delay is particularly alarming in light of the morbidity and mortality associated with the emphysema that develops in some persons with AAT deficiency.5-8 Respiratory failure is the most common cause of death in these patients. Based on an analysis of National Heart, Lung, and Blood Institute (NHLBI) registry data, Stoller and associates5 concluded that severe AAT deficiency represents a significant threat to health and that severe airflow obstruction is a major determinant of death. A recent survey by Strange and associates6 documented that AAT deficiency continues to cause devastating disease for many patients.

These and other studies have underscored the importance of improving the diagnostic recognition of AAT deficiency so that adequate treatment can be provided. The specific treatment--augmentation therapy--has been shown to slow disease progression and reduce the risk of death in patients with AAT deficiency.2,8

Making the diagnosis

Dyspnea on exertion is the most common symptom in persons with emphysema caused by AAT deficiency. Other symptoms include coughing and wheezing. Significant clues to the presence of AAT deficiency include early-onset emphysema--an onset at age 45 years or earlier--and emphysema that occurs in the absence of a smoking history or other known risk factors (Table). McElvaney and associates7 reported that persons in the NHLBI registry for AAT deficiency had a mean age of 46 years and a mean forced expiratory volume in 1 second of 43% of the predicted value.

The gold standard for the diagnosis of AAT deficiency is serum phenotyping by isoelectric focusing performed by a reliable laboratory.2 Recently, Strange and colleagues9 evaluated the feasibility of home testing for AAT deficiency in at-risk children and adolescents. A finger-stick blood spot test for AAT genotype was administered to 422 children and adolescents younger than 18 years, and a questionnaire was given to their parents or guardians. The results indicated that parents/guardians value genetic testing of their children at risk for AAT deficiency if testing can be done in a confidential setting.


The management of emphysema caused by AAT deficiency includes the standard treatments for COPD, such as smoking cessation, influenza and pneumococcal immunization, bronchodilators, supplemental oxygen (when indicated for hypoxemia), and pulmonary rehabilitation for patients with functional impairment.

In addition, augmentation therapy with intravenous purified pooled human plasma AAT is given to increase the patient's serum AAT concentration above the protective threshold. Intravenous augmentation therapy, 60 mg/kg per week, is recommended for patients with AAT deficiency who have airflow obstruction.2

Overall, the evidence suggests that augmentation therapy is clinically effective and is generally well tolerated.1,2 Specifically, it has been demonstrated to attenuate the decline in pulmonary function, slow disease progression, and reduce the risk of death in patients with emphysema associated with AAT deficiency.2,8 In one study, the absence of augmentation therapy was identified as a risk factor for death.8

Lung transplantation may be an option for certain patients who have severe functional impairment and airflow obstruction.2 Although lung volume reduction surgery is a treatment option for some patients with severe emphysema, the results of a recent study suggest that it might be less beneficial in patients with AAT deficiency than in patients with emphysema who do not have AAT deficiency.10




Stoller JK, Aboussouan LS. Alpha1-an- titrypsin deficiency.




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.



Stoller JK, Smith P, Yang P, Spray J. Physical and social impact of alpha 1-antitrypsin deficiency: results of a survey.

Cleve Clin J Med.



Stoller JK, Sandhaus RA, Turino G, et al. Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem.




Stoller JK, Tomashefski J Jr, Crystal RG, et al. Mortality in individuals with severe deficiency of alpha1-antitrypsin: findings from the National Heart, Lung, and Blood Institute Registry.




Strange C, Stoller JK, Sandhaus RA, et al. Results of a survey of patients with alpha1- antitrypsin deficiency.


2006;73: 185-190.


McElvaney NG, Stoller JK, Buist AS, et al; Alpha 1-Antitrypsin Deficiency Registry Study Group. Baseline characteristics of enrollees in the National Heart, Lung and Blood Institute Registry of alpha 1-antitrypsin deficiency.




The Alpha-1-Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin.

Am J Respir Crit Care Med.

1998;158: 49-59.


Strange C, Moseley MA, Jones Y, et al. Genetic testing of minors for alpha1-antitrypsin deficiency.

Arch Pediatr Adolesc Med.

2006; 160:531-534.


Stoller JK, Gildea TR, Ries AL, et al. Lung volume reduction surgery in patients with emphysema and alpha-1 antitrypsin deficiency.

Ann Thorac Surg.


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