Alpha-1 Antitrypsin Deficiency: Whom to Test, Whom to Treat?

ABSTRACT

Alpha-1 antitrypsin deficiency (AATD) is the major identified genetic risk factor for chronic obstructive pulmonary disease (COPD). The biochemical events leading to lung destruction in AATD are well understood, and most of our understanding of the pathogenesis of COPD in general has been acquired through the study of AATD. There is a growing appreciation that early diagnosis of AATD can affect the course of disease and allow for appropriate treatment decisions to be made. Although there is published guidance regarding testing and treatment of AATD, the impact of this guidance has been minimal. AATD is underdiagnosed, and the evidence for current treatment recommendations is not without controversy. This article reviews the current recommendations for testing and treatment of AATD. Some of these recommendations are expected to change as legislation to prevent genetic discrimination is refined and new therapies for this relatively common genetic predisposition are developed. Additional genetic modifiers of COPD will be found, and the path set by AATD will facilitate their incorporation into our future management of COPD.

Alpha-1 antitrypsin deficiency - chronic obstructive pulmonary disease - emphysema - genetic testing - augmentation therapy

REFERENCES

• 1 Silverman E K, Sandhaus R A. Clinical practice. Alpha1-antitrypsin deficiency.  N Engl J Med. 2009;  360 2749-2757
• 2 Brantly M. Efficient and accurate approaches to the laboratory diagnosis of alpha1-antitrypsin deficiency: the promise of early diagnosis and intervention.  Clin Chem. 2006;  52 2180-2181
• 3 de Serres F J, Blanco I, Fernández-Bustillo E. Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America.  Clin Genet. 2003;  64 382-397
• 4 Silverman E K, Miletich J P, Pierce J A et al.. Alpha-1-antitrypsin deficiency: high prevalence in the St. Louis area determined by direct population screening.  Am Rev Respir Dis. 1989;  140 961-966
• 5 Lieberman J, Winter B, Sastre A. Alpha 1-antitrypsin Pi-types in 965 COPD patients.  Chest. 1986;  89 370-373
• 6 Janoff A. Inhibition of human granulocyte elastase by serum alpha-1-antitrypsin.  Am Rev Respir Dis. 1972;  105 121-122
• 7 Janoff A, Sandhaus R A, Hospelhorn V D, Rosenberg R. Digestion of lung proteins by human leukocyte granules in vitro.  Proc Soc Exp Biol Med. 1972;  140 516-519
• 8 Janoff A. Elastases and emphysema: current assessment of the protease-antiprotease hypothesis.  Am Rev Respir Dis. 1985;  132 417-433
• 9 Campos M A, Alazemi S, Zhang G, Wanner A, Sandhaus R A. Effects of a disease management program in individuals with alpha-1 antitrypsin deficiency.  COPD. 2009;  6 31-40
• 10 Mayer A S, Stoller J K, Vedal S et al.. Risk factors for symptom onset in PI*Z alpha-1 antitrypsin deficiency.  Int J Chron Obstruct Pulmon Dis. 2006;  1 485-492
• 11 Fagerhol M K, Laurell C B. The Pi system-inherited variants of serum alpha 1-antitrypsin.  Prog Med Genet. 1970;  7 96-111
• 12 Jeppsson J O, Laurell C B, Nosslin B, Cox D W. Catabolic rate of alpha1-antitrypsin of Pi types S, and MMalton and of asialylated M-protein in man.  Clin Sci Mol Med. 1978;  55 103-107
• 13 Blundell G, Cole R B, Nevin N C, Bradley B. Letter: Alpha 1-antitrypsin null gene (pi-).  Lancet. 1974;  2 404
• 14 Laurell C B, Eriksson S. The electrophoretic alpha-1-globulin pattern of serum in alpha-1 antitrypsin deficiency.  Scand J Clin Lab Invest. 1963;  15 132-140
• 15 Sharp H L, Bridges R A, Krivit W, Freier E F. Cirrhosis associated with alpha-1-antitrypsin deficiency: a previously unrecognized inherited disorder.  J Lab Clin Med. 1969;  73 934-939
• 16 American Thoracic Society . Guidelines for the approach to the patient with severe hereditary alpha-1-antitrypsin deficiency.  Am Rev Respir Dis. 1989;  140 1494-1497
• 17 Fabbri L, Pauwels R A, Hurd S S. GOLD Scientific Committee . Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary updated 2003.  COPD. 2004;  1 105-141 discussion 103-104
• 18 Celli B R, MacNee W. ATS/ERS Task Force . Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper.  Eur Respir J. 2004;  23 932-946
• 19 American Thoracic 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;  168 818-900
• 20 Gadek J E, Klein H G, Holland P V, Crystal R G. Replacement therapy of alpha 1-antitrypsin deficiency: reversal of protease-antiprotease imbalance within the alveolar structures of PiZ subjects.  J Clin Invest. 1981;  68 1158-1165
• 21 Wewers M D, Casolaro M A, Sellers S E et al.. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema.  N Engl J Med. 1987;  316 1055-1062
• 22 Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group.  Am J Respir Crit Care Med. 1998;  158 49-59
• 23 Seersholm N, Wencker M, Banik N et al.. Does alpha1-antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha1-antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) alpha1-AT study group.  Eur Respir J. 1997;  10 2260-2263
• 24 Chapman K R, Stockley R A, Dawkins C, Wilkes M M, Navickis R J. Augmentation therapy for alpha1 antitrypsin deficiency: a meta-analysis.  COPD. 2009;  6 177-184
• 25 Dirksen A, Piitulainen E, Parr D G et al.. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency.  Eur Respir J. 2009;  33 1345-1353
• 26 Shermock K M, Gildea T R, Singer M, Stoller J K. Cost-effectiveness of population screening for alpha-1 antitrypsin deficiency: a decision analysis.  COPD. 2005;  2 411-418