Suspecting and Testing for Alpha-1 Antitrypsin Deficiency—An Allergist's and/or Immunologist's Perspective

Alpha-1 antitrypsin deficiency (AATD) is a hereditary, monogenic disorder with no unique clinical features. AATD can be difficult to diagnose as patients commonly present with respiratory symptoms often mistaken for other respiratory syndromes such as asthma or smoking-related chronic obstructive pulmonary disease. In addition, symptoms related to AATD may also affect other organs, including the liver, vasculature, and skin. The severity of AATD varies between individuals, and in severe cases, the irreversible lung damage can develop into emphysema. Early diagnosis is critical to enable the implementation of lifestyle changes and therapeutic options that can slow further deterioration of pulmonary tissue. Once AATD is suspected, a range of tests are available (serum alpha-1 proteinase inhibitor [A1-PI] level measurement, phenotyping, genotyping, gene sequencing) for confirming AATD. Currently, intravenous infusion of A1-PI is the only therapy that directly addresses the underlying cause of AATD, and has demonstrated efficacy in a recent randomized, placebo-controlled trial. This review discusses the etiology, testing, and management of AATD from the allergist's and/or immunologist's perspective. It aims to raise awareness of the condition among physicians who care for people with obstructive lung disorders and are therefore likely to see patients with obstructive lung disease that may, in fact, prove to be AATD. Alpha-1 antitrypsin deficiency (AATD) is a hereditary, monogenic disorder with no unique clinical features. AATD can be difficult to diagnose as patients commonly present with respiratory symptoms often mistaken for other respiratory syndromes such as asthma or smoking-related chronic obstructive pulmonary disease. In addition, symptoms related to AATD may also affect other organs, including the liver, vasculature, and skin. The severity of AATD varies between individuals, and in severe cases, the irreversible lung damage can develop into emphysema. Early diagnosis is critical to enable the implementation of lifestyle changes and therapeutic options that can slow further deterioration of pulmonary tissue. Once AATD is suspected, a range of tests are available (serum alpha-1 proteinase inhibitor [A1-PI] level measurement, phenotyping, genotyping, gene sequencing) for confirming AATD. Currently, intravenous infusion of A1-PI is the only therapy that directly addresses the underlying cause of AATD, and has demonstrated efficacy in a recent randomized, placebo-controlled trial. This review discusses the etiology, testing, and management of AATD from the allergist's and/or immunologist's perspective. It aims to raise awareness of the condition among physicians who care for people with obstructive lung disorders and are therefore likely to see patients with obstructive lung disease that may, in fact, prove to be AATD. JT was a 29-year-old man with increasing dyspnea on exertion. His medical history was obtained from his wife. He presented with dyspnea to an allergist 2 years earlier and was diagnosed with asthma. His wife recalls his symptoms starting a few years earlier with dyspnea during exercise. He was treated with albuterol, as needed, and a combination of a long-acting beta agonist and inhaled corticosteroid. She remembered him having intermittent wheezing on his allergist's exam. He never had a chest radiograph. His wife remembers his spirometry demonstrating asthma-like changes, but he never received complete pulmonary function testing or pre- or post-bronchodilator testing. He smoked less than a pack of cigarettes per day for a total of 11-pack-year history, but was never informed to stop smoking. He had no occupational exposures. He had a dog despite positive skin tests that suggested sensitivity to dogs. His wife stated that he had no other medical illnesses and had never experienced any liver disease. After 2 years of therapy, he died suddenly during sleep. His autopsy demonstrated emphysema. Autopsy diagnosis was alpha-1 antitrypsin deficiency (AATD) with hypoxia-induced arrhythmia. Elastin is an extracellular protein contributing to the elasticity of connective tissues and is a major component of the lung. During inflammation, activated neutrophils release various proteolytic enzymes, including neutrophil elastase (NE), to defend the body against infection. If left unchecked, NE also attacks the host connective tissue by degrading elastin. AATD is caused by decreased levels or function of the proteinase inhibitor alpha-1 antitrypsin (AAT; also known as alpha-1 proteinase inhibitor, A1-PI), which arises as a consequence of mutations in a single gene (SERPINA1) located on chromosome 14.1American Thoracic SocietyEuropean 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. 2003; 168: 818-900Crossref PubMed Scopus (837) Google Scholar A1-PI is produced by the liver and plays an important role in the regulation of NE activity, irreversibly binding NE and targeting it for degradation. In A1-PI-deficient individuals, insufficient A1-PI levels lead to uncontrolled NE activity, which results in the progressive degradation of pulmonary tissue and contributes to the development of lung disease.2Stoller J.K. Aboussouan L.S. A review of alpha1-antitrypsin deficiency.Am J Respir Crit Care Med. 2012; 185: 246-259Crossref PubMed Scopus (337) Google Scholar, 3Brebner J.A. Stockley R.A. Recent advances in alpha-1-antitrypsin deficiency-related lung disease.Expert Rev Respir Med. 2013; 7 (quiz 30): 213-229Crossref PubMed Scopus (42) Google Scholar Because this tissue degradation mainly affects the small airways, especially at the level of the alveoli, the gas exchange function of the lung can be severely impaired. Individuals with AATD are often diagnosed with asthma or chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or bronchiectasis, and emphysema, which can become severe.2Stoller J.K. Aboussouan L.S. A review of alpha1-antitrypsin deficiency.Am J Respir Crit Care Med. 2012; 185: 246-259Crossref PubMed Scopus (337) Google Scholar, 4Brantly M.L. Paul L.D. Miller B.H. Falk R.T. Wu M. Crystal R.G. Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms.Am Rev Respir Dis. 1988; 138: 327-336Crossref PubMed Scopus (267) Google Scholar, 5Strange C. Airway disease in alpha-1 antitrypsin deficiency.COPD. 2013; 10: 68-73Crossref PubMed Scopus (17) Google Scholar, 6Needham M. Stockley R.A. Alpha 1-antitrypsin deficiency. 3: Clinical manifestations and natural history.Thorax. 2004; 59: 441-445Crossref PubMed Scopus (146) Google Scholar A1-PI is released into the blood and tissues, and evidence suggests that it has multiple functions (including roles in immunity and inflammation) beyond its antiprotease activity.7Hunt J.M. Tuder R. Alpha 1 anti-trypsin: one protein, many functions.Curr Mol Med. 2012; 12: 827-835Crossref PubMed Scopus (81) Google Scholar Consequently, AATD symptoms are not limited to the lung, and clinical features of the skin (eg, panniculitis), vasculature (eg, vasculitis), and liver (eg, cirrhosis) may also occur. In patients with AATD homozygous for the Z allele (ie, ZZ, see below for a description of the most common alleles), the abnormal protein accumulates in the liver, predisposing to hepatitis.1American Thoracic SocietyEuropean 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. 2003; 168: 818-900Crossref PubMed Scopus (837) Google Scholar, 2Stoller J.K. Aboussouan L.S. A review of alpha1-antitrypsin deficiency.Am J Respir Crit Care Med. 2012; 185: 246-259Crossref PubMed Scopus (337) Google Scholar, 8Köhnlein T. Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment.Am J Med. 2008; 121: 3-9Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar, 9Teckman J.H. Liver disease in alpha-1 antitrypsin deficiency: current understanding and future therapy.COPD. 2013; 10: 35-43Crossref PubMed Scopus (56) Google Scholar AATD is a hereditary, autosomal, codominant, monogenic condition for which more than 500 single nucleotide polymorphisms have been identified, although not all of these have been validated.3Brebner J.A. Stockley R.A. Recent advances in alpha-1-antitrypsin deficiency-related lung disease.Expert Rev Respir Med. 2013; 7 (quiz 30): 213-229Crossref PubMed Scopus (42) Google Scholar The most common alleles include:•M (normal allele)•Z (leading to low A1-PI levels, associated with severe AATD)•S (leading to a mild decrease in circulating A1-PI)•Null allele (no detectable A1-PI synthesis).3Brebner J.A. Stockley R.A. Recent advances in alpha-1-antitrypsin deficiency-related lung disease.Expert Rev Respir Med. 2013; 7 (quiz 30): 213-229Crossref PubMed Scopus (42) Google Scholar Different allele combinations are associated with various levels of circulating A1-PI. Individuals with only one defective allele might not present with clinical features of AATD, and not all individuals with 2 defective alleles are at the same risk of developing emphysema (Figure 1).1American Thoracic SocietyEuropean 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. 2003; 168: 818-900Crossref PubMed Scopus (837) Google Scholar, 4Brantly M.L. Paul L.D. Miller B.H. Falk R.T. Wu M. Crystal R.G. Clinical features and history of the destructive lung disease associated with alpha-1-antitrypsin deficiency of adults with pulmonary symptoms.Am Rev Respir Dis. 1988; 138: 327-336Crossref PubMed Scopus (267) Google Scholar, 10Ferrarotti I. Thun G.A. Zorzetto M. Ottaviani S. Imboden M. Schindler C. et al.Serum levels and genotype distribution of alpha1-antitrypsin in the general population.Thorax. 2012; 67: 669-674Crossref PubMed Scopus (140) Google Scholar, 11Crystal R.G. Alpha 1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis and strategies for therapy.J Clin Invest. 1990; 85: 1343-1352Crossref PubMed Scopus (404) Google Scholar, 12de Serres F.J. Blanco I. Prevalence of alpha1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review.Ther Adv Respir Dis. 2012; 6: 277-295Crossref PubMed Scopus (131) Google Scholar The progression of lung disease in individuals with AATD is slow and symptoms such as cough or wheezing often appear only within the fourth and/or fifth decade of life, although they sometimes present earlier, during the second and/or third decade of life.6Needham M. Stockley R.A. Alpha 1-antitrypsin deficiency. 3: Clinical manifestations and natural history.Thorax. 2004; 59: 441-445Crossref PubMed Scopus (146) Google Scholar Because AATD leads to irreversible lung damage, it is crucial to identify patients at risk to enable early diagnosis and implementation of management and treatment strategies aimed at reducing the progression of lung disease. In the USA, the combined prevalence for the A1-PI phenotypic classes SS, SZ, and ZZ has been estimated at 1/496.13de Serres F.J. Blanco I. Fernandez-Bustillo E. Ethnic differences in alpha-1 antitrypsin deficiency in the United States of America.Ther Adv Respir Dis. 2010; 4: 63-70Crossref PubMed Scopus (35) Google Scholar Furthermore, 1 in 17 Americans have at least one allele associated with a degree of risk for AATD (ie, S or Z), and 1 in 6211 Americans are estimated to be homozygous for the Z allele.13de Serres F.J. Blanco I. Fernandez-Bustillo E. Ethnic differences in alpha-1 antitrypsin deficiency in the United States of America.Ther Adv Respir Dis. 2010; 4: 63-70Crossref PubMed Scopus (35) Google Scholar The number of at-risk individuals tested in the USA was reported to have doubled between the years 2007 and 2010,14Campos M. Shmuels D. Walsh J. Detection of alpha-1 antitrypsin deficiency in the US.Am J Med. 2012; 125: 623-624Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar but despite this increase, AATD is still rarely diagnosed. Among the 100,000 individuals in the USA estimated to have AATD, fewer than 10% have been appropriately diagnosed.15Stoller J.K. Brantly M. The challenge of detecting alpha-1 antitrypsin deficiency.COPD. 2013; 10: 26-34Crossref PubMed Scopus (78) Google Scholar Respiratory symptoms in people with AATD include coughing, wheezing, excessive sputum production, and dyspnea, although these symptoms are also common to other respiratory diseases such as asthma and smoking-related COPD.16Bernspång E. Sveger T. Piitulainen E. Respiratory symptoms and lung function in 30-year-old individuals with alpha-1-antitrypsin deficiency.Respir Med. 2007; 101: 1971-1976Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar As a result, AATD is frequently misdiagnosed and this can result in long delays between the onset of symptoms and obtaining an accurate diagnosis of AATD. In a recent AATD support group held at Penn State University, the majority of patients first entered the health care system for their respiratory symptoms through visits with allergists and were treated for years, often with immunotherapy, before being referred and found to have AATD. Previous estimates put the average time from symptom onset to correct diagnosis of AATD at 7.2 years,17Stoller J.K. Smith P. Yang P. Spray J. Physical and social impact of alpha 1-antitrypsin deficiency: results of a survey.Cleve Clin J Med. 1994; 61: 461-467Crossref PubMed Scopus (134) Google Scholar with numerous visits to different physicians being involved. A survey of 304 patients with AATD found that 44% had seen at least 3 physicians before they received an accurate diagnosis of AATD.17Stoller J.K. Smith P. Yang P. Spray J. Physical and social impact of alpha 1-antitrypsin deficiency: results of a survey.Cleve Clin J Med. 1994; 61: 461-467Crossref PubMed Scopus (134) Google Scholar Although AATD has no unique symptoms, there are clinical presentations that should raise suspicion (Table I). In particular, any individual with asthma with incompletely reversible airflow obstruction, as well as patients with COPD, should be tested, as suggested in a joint statement from the American Thoracic Society (ATS) and the European Respiratory Society (ERS) in 2003 (summarized in Table II).1American Thoracic SocietyEuropean 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. 2003; 168: 818-900Crossref PubMed Scopus (837) Google Scholar In this statement, various recommendations are also proposed for other individuals, including the testing of asymptomatic adults with evidence of lung disease and smoking or occupational exposure, adults with necrotizing panniculitis, children or adults with unexplained liver disease, and bronchiectasis without apparent etiology. Testing should be considered for adults and adolescents with a sibling diagnosed to be homozygous for an AATD deficiency allele (eg, ZZ). As shown in Table II, the joint statement from the ATS/ERS other in which testing may be (eg, or is not (eg, and unique symptoms in AATD, and onset in most Alpha-1 antitrypsin COPD, chronic obstructive pulmonary disease. in a Table Thoracic Society/European Respiratory Society for screening and Thoracic SocietyEuropean 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. 2003; 168: 818-900Crossref PubMed Scopus (837) Google with of the American Thoracic Society. American Thoracic Society. ATS/ERS J Respir Crit Care 2003; of the American Thoracic Society. This was in of this may be of and should be the in clinical and other be with obstructive on pulmonary function tests and COPD, emphysema, or asthma incompletely reversible airflow adults with evidence of lung disease and smoking or occupational or adults with unexplained liver with necrotizing with obstructive on pulmonary function tests and with obstructive pulmonary adults with evidence of lung disease and no risk present for lung with without obstructive on pulmonary function tests and asthma reversible airflow and adolescents with a sibling homozygous for an AATD deficiency and adolescents with an a or homozygous for and AATD deficiency and adolescents with a an a or for and AATD deficiency and adolescents with a history of obstructive lung disease or liver testing in the and adolescents at risk of having of individuals with AATD or or adolescents in AATD prevalence and smoking are the of and adults without risk of with Alpha-1 antitrypsin COPD, chronic obstructive pulmonary in a AATD, Alpha-1 antitrypsin COPD, chronic obstructive pulmonary disease. AATD, Alpha-1 antitrypsin COPD, chronic obstructive pulmonary the diagnosis of AATD, physicians to be of the disease, the testing and is for their and/or in particular, may see numerous patients with symptoms and or obstruction, which in most is to but in may be to D. alpha1-antitrypsin deficiency from 2013; Full Text Full Text PDF PubMed Scopus Google Scholar that allergists and/or is respiratory symptoms in patients appear at a decade of or and such symptoms in patients should further to for J. deficiency: current in testing and Adv Respir Dis. PubMed Scopus Google Scholar of AATD include and emphysema associated with emphysema may present mainly with changes on chest or lung most patients with AATD present with and C. Airway disease in alpha-1 antitrypsin deficiency.COPD. 2013; 10: 68-73Crossref PubMed Scopus (17) Google Scholar AATD, COPD, and asthma common and symptoms, but are different diseases that can be by A1-PI levels and through phenotypic and/or testing to identify A1-PI protein and/or gene D. alpha1-antitrypsin deficiency from 2013; Full Text Full Text PDF PubMed Scopus Google Scholar As changes by may AATD. include of C. Airway disease in alpha-1 antitrypsin deficiency.COPD. 2013; 10: 68-73Crossref PubMed Scopus (17) Google Scholar of obstructive disease by screening spirometry is an for further in addition, spirometry should be to the progression of lung disease. Full pulmonary function tests are to obstructive disease, with the of and abnormal of changes are seen in the changes are A1-PI level should also be obtained in most cases, can the diagnosis of AATD and further of disease levels, it is important to that A1-PI is an protein levels can be during of challenge (eg, Thoracic SocietyEuropean 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. 2003; 168: 818-900Crossref PubMed Scopus (837) Google Scholar, in the diagnosis of alpha 1-antitrypsin Clin 2008; 121: Full Text Full Text PDF PubMed Scopus Google Scholar As a result, patients with AATD may present with or A1-PI levels, despite evidence of disease symptoms, and further testing should be considered (Table to diagnose and alpha-1 antitrypsin M. of alpha1-antitrypsin 2007; PubMed Scopus Google Scholar, M. C. I. R. M. et testing of individuals with severe alpha1-antitrypsin deficiency in European Respir J. 2010; PubMed Scopus Google blood identify is an and its level can be during in A1-PI circulating levels for each and patients can present with identify common results and and multiple to of alleles is not number of mutations can be not by to function pulmonary function disease progression lung function of lung and of and to degree of of total lung and and pulmonary a and accurate of lung lung disease Alpha-1 proteinase in a Alpha-1 proteinase and for the of the most AATD of the severity of the deficiency. such as can be to the A1-PI protein that can mutations in the gene and identify the more common A1-PI deficiency tests are allele and are with to the Z and S If of these alleles are the result is as which that and other can be In such cases, can be more as can for the of Furthermore, results may to identify alleles combined with other tests such as A1-PI level E. A diagnosis of alpha-1-antitrypsin deficiency: of a with a Clin PubMed Scopus Google Scholar this is time and difficult to with A1-PI level and In to obtaining the tests in testing with levels of are being of by of A1-PI therapy of these levels and genotyping, are more comprehensive and also include protein level measurement, phenotyping, needed, gene including Once a is diagnosed with AATD, the progression of lung disease is by spirometry in one second as an of the progression of lung airflow (Table (eg, of and of number and severity of are also to lung disease progression and to the and of the progression of emphysema and has been in clinical as an to has been shown to be more than pulmonary function and is by the as a to the progression of emphysema in J. Piitulainen E. et for a clinical Med. 2007; 101: Full Text Full Text PDF PubMed Scopus Google Scholar It should be that its in clinical is less and current raise include the of the of in and the and the received by the P. M. J. et antitrypsin deficiency testing and a Thoracic Society clinical Respir J. 2012; Google Scholar Early and correct diagnosis of AATD can enable and effective management of the disease (Table management to AATD such as smoking and can be to lung health and and further respiratory In addition, current the of and therapy to symptoms of and Early and of patients present with respiratory may the for lung such as the and should be to the risk and severity of these should be for patients with or is also Thoracic SocietyEuropean 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. 2003; 168: 818-900Crossref PubMed Scopus (837) Google Scholar and for is important in progressive ZZ individuals, liver can be effective for liver and lung disease. other AATD and for severe pulmonary disease in ZZ individuals, lung should be the is should be early and to progressive lung disease. including gene and are being the development of these is and might to in the C. therapy for alpha-1 antitrypsin deficiency.COPD. 2013; 10: PubMed Scopus (42) Google Scholar, R.A. deficiency: clinical and Mol Med. Full Text Full Text PDF PubMed Scopus Google available therapeutic to alpha-1 antitrypsin lung the of and and as per symptoms of lung tissue the of lung tissue the progression of respiratory time to respiratory Alpha-1 proteinase COPD, chronic obstructive pulmonary disease. in a Alpha-1 proteinase COPD, chronic obstructive pulmonary disease. lifestyle or management of AATD symptoms, intravenous A1-PI is the only therapy that directly addresses the underlying deficiency of AATD. A1-PI are by infusion at a of of body This is considered to raise A1-PI levels a level considered to be the as levels below this have been associated with an risk of developing Thoracic SocietyEuropean 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. 2003; 168: 818-900Crossref PubMed Scopus (837) Google Scholar, in the diagnosis of alpha 1-antitrypsin Clin 2008; 121: Full Text Full Text PDF PubMed Scopus Google Scholar, Crystal R.G. Alpha-1 antitrypsin therapy.COPD. 2013; 10: PubMed Scopus Google Scholar A1-PI include and and The of therapy is to slow the of lung tissue efficacy had only been suggested by and 2 small J.H. et clinical of J Respir Crit Care Med. PubMed Scopus Google Scholar, Piitulainen E. C. M. et the role of a of therapy in alpha1-antitrypsin Respir J. PubMed Scopus Google Scholar no in the of between treated and a was for the of lung in the treatment for further The results of the placebo-controlled in Alpha-1 which patients treated and 2 years, evidence that A1-PI therapy the progression of emphysema in individuals with severe AATD. from this with A1-PI therapy delays time to respiratory or and progression of emphysema in patients with AATD and Piitulainen et therapy lung in severe alpha-1 antitrypsin the randomized, placebo-controlled trial. Scholar As allergists and/or see numerous patients with in particular, patients with severe asthma and abnormal to be to cause of obstructive disease is AATD, and screening patients for AATD identify of the of individuals with AATD who are not J.K. Brantly M. The challenge of detecting alpha-1 antitrypsin deficiency.COPD. 2013; 10: 26-34Crossref PubMed Scopus (78) Google Scholar which the implementation of The is that in the future the diagnosis of AATD be by the allergist and/or early in the disease, and therapy to progression of the lung with with or a history of early or unexplained COPD, should be for AATD. This should enable early diagnosis and effective management of AATD to decrease and associated with this