Alpha-1-antitrypsin deficiency

Asthma is an obstructive disease. So are bronchitis and emphysema, which also form part of the chronic obstructive pulmonary disease (COPD) compendium. Many patients who have had asthma for a long period of time go on to develop COPD.                                         

COPD is generally associated with smoking, and while it is true that almost 90% of people who develop COPD do so as a result of smoking, they constitute just 15% to 20% of smokers who develop this disease. Besides asthma and smoking, exposure to occupational dust and toxins can result in COPD. Finally, a small group of people have a hereditary form of COPD that results from a genetic defect known as alpha-1 antitrypsin deficiency (AATD). One in 11.3 Americans has this inherited genetic deficiency, while about 1-2% of COPD patients have AATD. Currently over 75 variants of this deficiency have been identified. About 75% of adults with severe AATD develop emphysema. Smoking increases the risk of developing COPD, and  individuals with AATD who smoke develop emphysema earlier than smokers without. They also tend to be disabled in their forties or fifties. Hence emphysema at an early age in smokers tends to be the clinical expression of AATD.

Alpha-1 antitrypsin (AAT) is a protein secreted by the liver. Its main function is to protect the lining of the lungs from the enzyme neutrophil elastase, whose job it is to absorb bacteria, foreign particles, aged and damaged lung cells. The absence of AAT means that the enzyme is not neutralized, a situation that can result in damage to healthy connective tissue, both in the lungs and in the liver.

In the liver

Lack of neutrophil elastase causes inflammation that results in irreversible scarring and fibrosis so that the liver does not function properly. In infants this deficiency is the most common cause of jaundice, cirrhosis and neonatal liver disease requiring liver transplantation. In adults it has been known to cause cirrhosis of the liver, jaundice, hepatitis, weight loss, collection of abdominal fluid (ascites), gastrointestinal bleeding, portal hypertension, spontaneous bacterial peritonitis, hepatic enceph­alopathy and hepatocellular carcinoma.

In the lungs

Lack of neutrophil elastase can cause the alveoli to lose their elasticity, hyper-inflate, and develop holes in the cell walls so that they collapse and are unable to function. This results in the development of COPD. It does not cause lung disease in children.

AATD tends to appear between the ages of 40 and 50 in nonsmokers. It can show up as much as ten years earlier in people who smoke. It can coexist with asthma and if a nonsmoker, diagnosed with asthma, shows continued deterioration in lung function, then AATD should be considered.  AATD should be suspected in emphysema in a non-smoker or if there is no identifiable cause for hepatitis or liver disease.

Symptoms and Treatment

The symptoms of AATD are similar to asthma and include cough, wheeze and shortness of breath, particularly on exertion. Diagnosis of ATTD involves physical examination, arterial blood gases, chest x-ray, pulmonary function test and serum alpha-1 antitrypsin levels. Since ATD is a single gene disorder, a more precise diagnosis of AATD can be had with a simple though expensive genetic test.

Treatment for AATD includes bronchodilators (and oxygen therapy if needed) for the emphysema, antibiotics for infections and possibly replacement therapy for the missing protein. As there is no specific treatment or cure for AATD, the goal of treatment is to slow the progression of emphysema and reduce excessive decline in lung function. Current treatment involves regular weekly injections of replacement AAT enzyme, purified from human plasma, to partially correct the biochemical defect and raise the serum levels to the necessary protective threshold. Replacement therapy may slow the progression of emphysema. While pulmonary function tests can be used to assess the response to treatment for AATD, computerized tomographic scanning may be a preferred option. If there are complications of liver disease such as bleeding, uncontrolled ascites, muscle wasting, and/or weakness, then liver transplantation becomes the only alternative.

Patients with AATD should be counselled to avoid alcohol and tobacco products, both of which accelerate the disease process. Patients with AATD are prone to infections. Hence, annual immunization against pneumococcal and influenza viruses are recommended.

Comorbid conditions of ATD include asthma, chronic bronchitis, bronchiectasis, emphysema, vasculitis, panniculitis, ulcerative colitis and hypothyroidism.

Persons with severe AATD are severely disabled due to a rapid decline in lung function. The Death Review Committee, examining 42 deaths of persons with AATD who were enrolled in the US registry, found that there was no correlation between the severity of emphysema and pulmonary function measurements. Nor was there a significant correlation between the emphysema and the degree of hepatic fibrosis. The underlying cause of death in 34 cases was emphysema.

Because AATD is often unrecognized, there is considerable delay in arriving at a diagnosis. Stoller, comparing data from 1994 and 2003 to see if there was any change in the long delay between onset of symptoms and the diagnosis of AATD, found that the delay was 7.2 +/- 8.3 years in 1994, and that the mean delay in diagnosis had changed to 5.6 +/-8.5 years by 2003.  The 2003 group experienced a shorter time to diagnosis particularly if young and/or male, and a longer time if older and female.

Patients with asthma who have chronic airflow obstruction should be tested, particularly those with early onset of disease, a family history of AATD, or unexplained liver disease. Individuals who have family members with this genetic defect should be tested and treated at the earliest possible stage of disease to prevent rapid deterioration in lung function.


Abboud RT, Nelson TN et al. Alpha1-antitrypsin deficiency: a clinical-genetic overview. Appl Clin Genet. 2011 Mar 31;4:55-65. doi: 10.2147/TACG.S10604.

Ala A, Schilsky ML. Inherited metabolic liver disease. Curr Opin Gastroenterol 2004; 20(30): 198-207

Kleerup EC, Tashkin DP. Chronic Obstructive Pulmonary Diseases in Adults. In CW Bierman, DS Pearlman, GG Shapiro, WW Busse (Eds) Allergy, asthma and immunology from infancy to adulthood. 3rd Edition. WB Saunders 1996.

Siri D1, Farah H, Hogarth DK. Distinguishing alpha1-antitrypsin deficiency from asthma. Ann Allergy Asthma Immunol. 2013 Dec;111(6):458-64. doi: 10.1016/j.anai.2013.09.019.

Stoller JK, Sandhaus RA, et al. Delay in diagnosis of alpha1-antitrypsin deficiency: a continuing problem. Chest. 2005;128(4):1989–1994. 

Stone H, Pye A, Stockley RA. Disease associations in alpha-1-antitrypsin deficiency. Respir Med. 2014 Feb;108(2):338-43. doi: 10.1016/j.rmed.2013.10.006.

Tzakis A. Early Recognition of Alpha-1 Antitrypsin Deficiency and Considerations for Liver Transplantation. Gastroenterol Hepatol (N Y). Feb 2013; 9(2): 110–112.

Tomashefski JF Jr, Crystal RG, Wiedemann HP, Mascha E, Stoller JK; Alpha 1-Antitrypsin Deficiency Registry Study Group. The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with Severe Deficiency of Alpha-1 Antitrypsin. Hum Pathol. 2004 Dec;35(12):1452-61.

Wood AM, Simmonds MJ, et al. The TNFalpha gene relates to clinical phenotype in alpha-1-antitrypsin deficiency. Respir Res. 2008;9:52