title: Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency.
abstract: Alpha-1-antitrypsin deficiency (AATD), also known as alpha1-proteinase inhibitor deficiency, is an autosomal co-dominant condition. The genotypes associated with AATD include null, deficient, and dysfunctional alpha-1-antitrypsin (A1AT) variants, which result in low levels of circulating functional A1AT, unbalanced protease activity, and an increased risk of developing lung emphysema, the leading cause of morbidity in these patients. Furthermore, the most common abnormal genotype, Pi*ZZ may also cause trapping of abnormally folded protein polymers in hepatocytes causing liver dysfunction. A major focus of therapy for patients with lung disease due to AATD is to correct the A1AT deficiency state by augmenting serum levels with intravenous infusions of human plasma-derived A1AT. This strategy has been associated with effective elevations of A1AT levels and function in serum and lung epithelial fluid and observational studies suggest that it may lead to attenuation in lung function decline, particularly in patients with moderate impairment of lung function. In addition, an observational study suggests that augmentation therapy is associated with a reduction of mortality in subjects with AATD and moderate to severe lung impairment. More recent randomized placebo-controlled studies utilizing computer scan densitometry suggest that this therapy attenuates lung tissue loss. Augmentation therapy has a relative paucity of side effects, but it is highly expensive. Therefore, this therapy is recommended for patients with AATD who have a high-risk A1AT genotype with plasma A1AT below protective levels (11 microM) and evidence of obstructive lung disease. In this article, we review the published evidence of A1AT augmentation therapy efficacy, side effects, and safety profile.
authors.affiliation: Department of Medicine, Indiana, University School of Medicine, Indianapolis, Indiana, USA. ipetrach@iupui.edu
authors.forename: Irina
authors.initials: I
authors.lastname: Petrache
authors.forename: Joud
authors.initials: J
authors.lastname: Hajjar
authors.forename: Michael
authors.initials: M
authors.lastname: Campos
references.citation: Semin Respir Crit Care Med. 2005 Apr;26(2):154-66
references.pmid: 16088434
references.citation: N Engl J Med. 1987 Apr 23;316(17):1055-62
references.pmid: 3494198
references.citation: Eur J Clin Pharmacol. 2003 Jun;59(2):151-6
references.pmid: 12728289
references.citation: Clin Sci (Lond). 2006 Jan;110(1):21-35
references.pmid: 16336202
references.citation: Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 1):1468-72
references.pmid: 10556107
references.citation: Respir Res. 2005 Jan 31;6:12
references.pmid: 15683545
references.citation: Chest. 2001 Mar;119(3):737-44
references.pmid: 11243951
references.citation: Lung. 1990;168 Suppl:565-78
references.pmid: 2117165
references.citation: Thorax. 2008 Jul;63(7):621-6
references.pmid: 18250185
references.citation: Infect Immun. 2005 Mar;73(3):1271-4
references.pmid: 15731023
references.citation: Chest. 1997 Sep;112(3):607-13
references.pmid: 9315791
references.citation: Eur Respir J. 2008 Feb;31(2):416-69
references.pmid: 18238951
references.citation: Am Rev Respir Dis. 1986 Sep;134(3):476-80
references.pmid: 3530071
references.citation: Am J Respir Crit Care Med. 2003 Oct 1;168(7):818-900
references.pmid: 14522813
references.citation: COPD. 2006 Mar;3(1):17-23
references.pmid: 17175661
references.citation: Am J Respir Cell Mol Biol. 2007 Aug;37(2):130-4
references.pmid: 17541009
references.citation: Thorax. 2004 Oct;59(10):843-9
references.pmid: 15454649
references.citation: J Biol Chem. 1990 Oct 5;265(28):16713-6
references.pmid: 2211587
references.citation: Thorax. 2006 Dec;61(12):1059-64
references.pmid: 16928711
references.citation: Chest. 2000 Nov;118(5):1480-5
references.pmid: 11083705
references.citation: Am Rev Respir Dis. 1987 Feb;135(2):401-2
references.pmid: 3492949
references.citation: Int J Biochem Cell Biol. 2008;40(2):258-71
references.pmid: 17869162
references.citation: Curr Opin Rheumatol. 1998 Jan;10(1):3-11
references.pmid: 9448984
references.citation: J Clin Invest. 1981 Nov;68(5):1158-65
references.pmid: 7028785
references.citation: Respir Med. 1997 May;91(5):275-9
references.pmid: 9176645
references.citation: Am J Respir Crit Care Med. 1994 Apr;149(4 Pt 1):966-71
references.pmid: 8143063
references.citation: Am Rev Respir Dis. 1989 Oct;140(4):961-6
references.pmid: 2679271
references.citation: Eur Respir J. 1998 Oct;12(4):996-7
references.pmid: 9817182
references.citation: JAMA. 1988 Sep 2;260(9):1259-64
references.pmid: 3261353
references.citation: Eur Respir J. 1997 Oct;10(10):2260-3
references.pmid: 9387950
references.citation: Am J Respir Crit Care Med. 1998 Jul;158(1):49-59
references.pmid: 9655706
references.citation: Curr Med Res Opin. 2005 Jun;21(6):877-83
references.pmid: 15969888
references.citation: Nat Rev Drug Discov. 2007 Jan;6(1):67-74
references.pmid: 17195033
references.citation: J Pharmacol Exp Ther. 2000 Dec;295(3):904-11
references.pmid: 11082423
references.citation: Pediatrics. 1978 Jul;62(1):22-5
references.pmid: 308215
references.citation: FEBS J. 2008 May;275(9):2008-20
references.pmid: 18341586
references.citation: J Clin Invest. 1999 Apr;103(7):999-1006
references.pmid: 10194472
references.citation: Ann Intern Med. 2002 Feb 19;136(4):270-9
references.pmid: 11848724
references.citation: Am J Hum Genet. 1991 Jun;48(6):1154-8
references.pmid: 2035534
references.citation: Chest. 2009 Mar;135(3):600-608
references.pmid: 19017884
references.citation: Chest. 2000 Mar;117(3):875-80
references.pmid: 10713018
references.citation: N Engl J Med. 2005 May 12;352(19):2030-1
references.pmid: 15888711
references.citation: Chest. 1996 Dec;110(6 Suppl):284S-294S
references.pmid: 8989166
references.citation: Am J Public Health. 1991 Apr;81(4):427-33
references.pmid: 1900677
references.citation: Am J Pathol. 2005 Feb;166(2):377-86
references.pmid: 15681822
references.citation: COPD. 2009 Feb;6(1):31-40
references.pmid: 19229706
references.citation: Am J Pathol. 2006 Oct;169(4):1155-66
references.pmid: 17003475
references.citation: J Biol Chem. 2000 Sep 1;275(35):27258-65
references.pmid: 10867014
references.citation: Am J Respir Crit Care Med. 2003 May 15;167(10):1387-92
references.pmid: 12574076
references.citation: Chest. 2008 Oct;134(4):831-834
references.pmid: 18842915
references.citation: Dermatol Clin. 2008 Oct;26(4):447-51, vi
references.pmid: 18793976
references.citation: Gene Ther. 1998 Feb;5(2):181-8
references.pmid: 9578837
references.citation: Am J Respir Crit Care Med. 2000 Dec;162(6):2069-72
references.pmid: 11112116
references.citation: Am J Respir Crit Care Med. 2002 Jun 1;165(11):1494-8
references.pmid: 12045122
references.citation: Am J Respir Crit Care Med. 1997 Feb;155(2):536-41
references.pmid: 9032191
references.citation: J Biol Chem. 2001 Sep 7;276(36):33345-52
references.pmid: 11435427
references.citation: Eur Respir J. 2005 Jun;25(6):992-1000
references.pmid: 15929953
references.citation: Am J Respir Crit Care Med. 2006 Jun 1;173(11):1222-8
references.pmid: 16514110
references.citation: Eur Respir J. 2009 Jun;33(6):1345-53
references.pmid: 19196813
references.citation: Biologics. 2009;3:63-75
references.pmid: 19707397
references.citation: Chest. 2002 Jul;122(1):66-74
references.pmid: 12114340
references.citation: Respir Med. 1998 Mar;92(3):367-77
references.pmid: 9692092
references.citation: COPD. 2008 Jun;5(3):153-62
references.pmid: 18568839
references.citation: Am J Respir Cell Mol Biol. 2009 Sep;41(3):261-70
references.pmid: 19131639
references.citation: Chest. 2001 Mar;119(3):745-52
references.pmid: 11243952
references.citation: Respir Med. 2007 Sep;101(9):1924-30
references.pmid: 17644366
references.citation: Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):796-801
references.pmid: 10712324
references.citation: Cell Death Differ. 2009 Jan;16(1):39-45
references.pmid: 18617899
references.citation: Eur Respir J. 1998 Feb;11(2):428-33
references.pmid: 9551749
references.citation: Chest. 2003 May;123(5):1425-34
references.pmid: 12740257
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L820-30
references.pmid: 15626748
references.citation: Chest. 2004 May;125(5):1952-7
references.pmid: 15136414
references.citation: Ann Pharmacother. 2008 May;42(5):640-6
references.pmid: 18413692
references.citation: J Pediatr. 1978 Jun;92(6):1006-10
references.pmid: 307054
references.citation: Chest. 2003 Sep;124(3):826-31
references.pmid: 12970004
references.citation: Am J Respir Cell Mol Biol. 2007 Aug;37(2):144-51
references.pmid: 17395890