Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Treatment of alpha-1 antitrypsin deficiency

James K Stoller, MD, MS
Section Editor
Peter J Barnes, DM, DSc, FRCP, FRS
Deputy Editor
Helen Hollingsworth, MD


Severe deficiency of alpha-1 antitrypsin (AAT) is associated with early onset pulmonary emphysema and with several forms of liver disease, including cirrhosis, neonatal hepatitis, and hepatocellular carcinoma.

The discovery of the structure and function of the AAT protein, and its subsequent isolation and purification, have allowed replacement therapy (so-called "augmentation therapy") aimed at preventing progression of the associated lung disease [1,2]. Isolation of the gene and advances in gene therapy have further broadened the potential for specific therapy. The goal of most specific treatment approaches for AAT deficiency is to raise the plasma AAT level (and therefore the concentration of AAT in the lung interstitium) above the protective threshold. Other experimental approaches seek to interfere with production of abnormal AAT protein or to prevent polymerization of abnormal AAT protein and encourage secretion from the hepatocyte. Organ transplantation is another option for patients with end-stage lung or liver disease.

The treatment of AAT deficiency will be reviewed here. The clinical manifestations, genetics, and diagnosis of AAT deficiency are discussed separately. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)


Intravenous augmentation via the infusion of pooled human alpha-1 proteinase inhibitor (alpha-1 antitrypsin, AAT) is currently the most direct and efficient means of elevating AAT levels in the plasma and in the lung interstitium [3,4].

Clinical efficacy — Limited data are available regarding the clinical efficacy of intravenous AAT. Infusion therapy appears to be safe, well tolerated, and without significant side effects [5-9]. To date, no randomized trial of adequate size has definitively demonstrated the clinical efficacy of augmentation therapy, though the authors believe that the weight of available evidence favors efficacy of augmentation therapy.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jan 2017. | This topic last updated: Tue Jan 24 00:00:00 GMT 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Hubbard RC, Crystal RG. Alpha-1-antitrypsin augmentation therapy for alpha-1-antitrypsin deficiency. Am J Med 1988; 84:52.
  2. Hubbard RC, Crystal RG. Augmentation therapy of alpha 1-antitrypsin deficiency. Eur Respir J Suppl 1990; 9:44s.
  3. Stoller JK, Aboussouan LS. alpha1-Antitrypsin deficiency . 5: intravenous augmentation therapy: current understanding. Thorax 2004; 59:708.
  4. Sandhaus RA. alpha1-Antitrypsin deficiency . 6: new and emerging treatments for alpha1-antitrypsin deficiency. Thorax 2004; 59:904.
  5. Dirksen A, Piitulainen E, Parr DG, et al. Exploring the role of CT densitometry: a randomised study of augmentation therapy in alpha1-antitrypsin deficiency. Eur Respir J 2009; 33:1345.
  6. 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.
  7. Wencker M, Banik N, Buhl R, et al. Long-term treatment of alpha1-antitrypsin deficiency-related pulmonary emphysema with human alpha1-antitrypsin. Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL)-alpha1-AT-study group. Eur Respir J 1998; 11:428.
  8. Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med 2012; 185:246.
  9. Chapman KR, Burdon JG, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 386:360.
  10. Gadek JE, Klein HG, Holland PV, Crystal RG. 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.
  11. Dirksen A, Dijkman JH, Madsen F, et al. A randomized clinical trial of alpha(1)-antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999; 160:1468.
  12. McElvaney NG, Burdon J, Holmes M, et al. Long-term efficacy and safety of α1 proteinase inhibitor treatment for emphysema caused by severe α1 antitrypsin deficiency: an open-label extension trial (RAPID-OLE). Lancet Respir Med 2017; 5:51.
  13. Chapman KR, Stockley RA, Dawkins C, et al. Augmentation therapy for alpha1 antitrypsin deficiency: a meta-analysis. COPD 2009; 6:177.
  14. Gøtzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev 2010; :CD007851.
  15. A registry of patients with severe deficiency of alpha 1-antitrypsin. Design and methods. The Alpha 1-Antitrypsin Deficiency Registry Study Group. Chest 1994; 106:1223.
  16. 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.
  17. Wencker M, Fuhrmann B, Banik N, et al. Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor. Chest 2001; 119:737.
  18. 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 2003; 168:818.
  19. Marciniuk DD, Hernandez P, Balter M, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J 2012; 19:109.
  20. Sandhaus RA, Turino G, Stocks J, et al. alpha1-Antitrypsin augmentation therapy for PI*MZ heterozygotes: a cautionary note. Chest 2008; 134:831.
  21. Wewers MD, Casolaro MA, Sellers SE, et al. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema. N Engl J Med 1987; 316:1055.
  22. Moan, MJ, McElvaney, NG, Donjaili, R, Crystal, RG. Pharmacokinetics of biweekly augmentation therapy of alpha 1-antitrypsin deficiency with human plasma-derived alpha 1-antitrypsin. Am Rev Respir Dis 1993; 147:A675.
  23. Barker AF, Iwata-Morgan I, Oveson L, Roussel R. Pharmacokinetic study of alpha1-antitrypsin infusion in alpha1-antitrypsin deficiency. Chest 1997; 112:607.
  24. Hubbard RC, Sellers S, Czerski D, et al. Biochemical efficacy and safety of monthly augmentation therapy for alpha 1-antitrypsin deficiency. JAMA 1988; 260:1259.
  25. Stoller JK, Fallat R, Schluchter MD, et al. Augmentation therapy with alpha1-antitrypsin: patterns of use and adverse events. Chest 2003; 123:1425.
  26. Meyer FJ, Wencker M, Teschler H, et al. Acute allergic reaction and demonstration of specific IgE antibodies against alpha-1-protease inhibitor. Eur Respir J 1998; 12:996.
  27. "Miles, Inc Initiates Voluntary Withdrawal of Prolastin® Lots". News Release from Miles, Inc.
  28. Hay JW, Robin ED. Cost-effectiveness of alpha-1 antitrypsin replacement therapy in treatment of congenital chronic obstructive pulmonary disease. Am J Public Health 1991; 81:427.
  29. Mullins CD, Huang X, Merchant S, et al. The direct medical costs of alpha(1)-antitrypsin deficiency. Chest 2001; 119:745.
  30. Mullins CD, Wang J, Stoller JK. Major components of the direct medical costs of alpha1-antitrypsin deficiency. Chest 2003; 124:826.
  31. Gildea TR, Shermock KM, Singer ME, Stoller JK. Cost-effectiveness analysis of augmentation therapy for severe alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 2003; 167:1387.
  32. Alkins SA, O'Malley P. Should health-care systems pay for replacement therapy in patients with alpha(1)-antitrypsin deficiency? A critical review and cost-effectiveness analysis. Chest 2000; 117:875.
  33. Corda L, Bertella E, La Piana GE, et al. Inhaled corticosteroids as additional treatment in alpha-1-antitrypsin-deficiency-related COPD. Respiration 2008; 76:61.
  34. Stoller JK, Aboussouan LS, Kanner RE, et al. Characteristics of Alpha-1 Antitrypsin-Deficient Individuals in the Long-term Oxygen Treatment Trial and Comparison with Other Subjects with Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc 2015; 12:1796.
  35. Guidelines for the approach to the patient with severe hereditary alpha-1-antitrypsin deficiency. American Thoracic Society. Am Rev Respir Dis 1989; 140:1494.
  36. Rovner, MS, Stoller, JK. Therapy for alpha 1-antitrypsin deficiency. Clin Pulm Med 1994; 1:135.
  37. Hubbard RC, Crystal RG. Strategies for aerosol therapy of alpha 1-antitrypsin deficiency by the aerosol route. Lung 1990; 168 Suppl:565.
  38. Hubbard RC, Brantly ML, Sellers SE, et al. Anti-neutrophil-elastase defenses of the lower respiratory tract in alpha 1-antitrypsin deficiency directly augmented with an aerosol of alpha 1-antitrypsin. Ann Intern Med 1989; 111:206.
  39. Brand P, Schulte M, Wencker M, et al. Lung deposition of inhaled alpha1-proteinase inhibitor in cystic fibrosis and alpha1-antitrypsin deficiency. Eur Respir J 2009; 34:354.
  40. Mast AE, Salvesen G, Schnebli HP, Pizzo SV. Evaluation of the rapid plasma elimination of recombinant alpha 1-proteinase inhibitor: synthesis of polyethylene glycol conjugates with improved therapeutic potential. J Lab Clin Med 1990; 116:58.
  41. Hubbard RC, McElvaney NG, Sellers SE, et al. Recombinant DNA-produced alpha 1-antitrypsin administered by aerosol augments lower respiratory tract antineutrophil elastase defenses in individuals with alpha 1-antitrypsin deficiency. J Clin Invest 1989; 84:1349.
  42. Aronsen KF, Ekelund G, Kindmark CO, Laurell CB. Sequential changes of plasma proteins after surgical trauma. Scand J Clin Lab Invest Suppl 1972; 124:127.
  43. Novoradovskaya N, Lee J, Yu ZX, et al. Inhibition of intracellular degradation increases secretion of a mutant form of alpha1-antitrypsin associated with profound deficiency. J Clin Invest 1998; 101:2693.
  44. Wewers MD, Gadek JE, Keogh BA, et al. Evaluation of danazol therapy for patients with PiZZ alpha-1-antitrypsin deficiency. Am Rev Respir Dis 1986; 134:476.
  45. Wewers MD, Brantly ML, Casolaro MA, Crystal RG. Evaluation of tamoxifen as a therapy to augment alpha-1-antitrypsin concentrations in Z homozygous alpha-1-antitrypsin-deficient subjects. Am Rev Respir Dis 1987; 135:401.
  46. Humbert P, Faivre B, Gibey R, Agache P. Use of anti-collagenase properties of doxycycline in treatment of alpha 1-antitrypsin deficiency panniculitis. Acta Derm Venereol 1991; 71:189.
  47. Perlmutter, DH, Burrows, JA, Willis, LK. 4-phenylbutyric acid (PBA) mediates increased secretion of mutant alpha-1-antitrypsin Z in cell culture and increased blood levels of alpha-1-antitrypsin in vivo in a transgenic mouse model of alpha-1-antitrypsin deficiency (abstract). Hepatology 1999; 30:317A.
  48. Teckman JH. Lack of effect of oral 4-phenylbutyrate on serum alpha-1-antitrypsin in patients with alpha-1-antitrypsin deficiency: a preliminary study. J Pediatr Gastroenterol Nutr 2004; 39:34.
  49. Kay MA, Baley P, Rothenberg S, et al. Expression of human alpha 1-antitrypsin in dogs after autologous transplantation of retroviral transduced hepatocytes. Proc Natl Acad Sci U S A 1992; 89:89.
  50. Rosenfeld MA, Siegfried W, Yoshimura K, et al. Adenovirus-mediated transfer of a recombinant alpha 1-antitrypsin gene to the lung epithelium in vivo. Science 1991; 252:431.
  51. Lemarchand P, Jaffe HA, Danel C, et al. Adenovirus-mediated transfer of a recombinant human alpha 1-antitrypsin cDNA to human endothelial cells. Proc Natl Acad Sci U S A 1992; 89:6482.
  52. Setoguchi Y, Jaffe HA, Chu CS, Crystal RG. Intraperitoneal in vivo gene therapy to deliver alpha 1-antitrypsin to the systemic circulation. Am J Respir Cell Mol Biol 1994; 10:369.
  53. Ferkol T, Mularo F, Hilliard J, et al. Transfer of the human Alpha1-antitrypsin gene into pulmonary macrophages in vivo. Am J Respir Cell Mol Biol 1998; 18:591.
  54. Brantly ML, Chulay JD, Wang L, et al. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci U S A 2009; 106:16363.
  55. Brigham KL, Lane KB, Meyrick B, et al. Transfection of nasal mucosa with a normal alpha1-antitrypsin gene in alpha1-antitrypsin-deficient subjects: comparison with protein therapy. Hum Gene Ther 2000; 11:1023.
  56. Brantly ML, Spencer LT, Humphries M, et al. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther 2006; 17:1177.
  57. Gruntman AM, Flotte TR. Progress with Recombinant Adeno-Associated Virus Vectors for Gene Therapy of Alpha-1 Antitrypsin Deficiency. Hum Gene Ther Methods 2015; 26:77.
  58. Stoller JK, Gildea TR, Ries AL, et al. Lung volume reduction surgery in patients with emphysema and alpha-1 antitrypsin deficiency. Ann Thorac Surg 2007; 83:241.
  59. Banga A, Gildea T, Rajeswaran J, et al. The natural history of lung function after lung transplantation for α(1)-antitrypsin deficiency. Am J Respir Crit Care Med 2014; 190:274.
  60. Tanash HA, Riise GC, Hansson L, et al. Survival benefit of lung transplantation in individuals with severe α1-anti-trypsin deficiency (PiZZ) and emphysema. J Heart Lung Transplant 2011; 30:1342.
  61. Caughey GH. Should alpha 1-antitrypsin-deficient patients with emphysema continue to receive alpha 1-antitrypsin after lung transplantation? J Heart Lung Transplant 1993; 12:708.
  62. King MB, Campbell EJ, Gray BH, Hertz MI. The proteinase-antiproteinase balance in alpha-1-proteinase inhibitor-deficient lung transplant recipients. Am J Respir Crit Care Med 1994; 149:966.
  63. Strange C, Stoller JK, Sandhaus RA, et al. Results of a survey of patients with alpha-1 antitrypsin deficiency. Respiration 2006; 73:185.