Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency.
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.
Petrache
Irina
I
Department of Medicine, Indiana, University School of Medicine, Indianapolis, Indiana, USA. ipetrach@iupui.edu
Hajjar
Joud
J
Campos
Michael
M
Semin Respir Crit Care Med. 2005 Apr;26(2):154-66
16088434
N Engl J Med. 1987 Apr 23;316(17):1055-62
3494198
Eur J Clin Pharmacol. 2003 Jun;59(2):151-6
12728289
Clin Sci (Lond). 2006 Jan;110(1):21-35
16336202
Am J Respir Crit Care Med. 1999 Nov;160(5 Pt 1):1468-72
10556107
Respir Res. 2005 Jan 31;6:12
15683545
Chest. 2001 Mar;119(3):737-44
11243951
Lung. 1990;168 Suppl:565-78
2117165
Thorax. 2008 Jul;63(7):621-6
18250185
Infect Immun. 2005 Mar;73(3):1271-4
15731023
Chest. 1997 Sep;112(3):607-13
9315791
Eur Respir J. 2008 Feb;31(2):416-69
18238951
Am Rev Respir Dis. 1986 Sep;134(3):476-80
3530071
Am J Respir Crit Care Med. 2003 Oct 1;168(7):818-900
14522813
COPD. 2006 Mar;3(1):17-23
17175661
Am J Respir Cell Mol Biol. 2007 Aug;37(2):130-4
17541009
Thorax. 2004 Oct;59(10):843-9
15454649
J Biol Chem. 1990 Oct 5;265(28):16713-6
2211587
Thorax. 2006 Dec;61(12):1059-64
16928711
Chest. 2000 Nov;118(5):1480-5
11083705
Am Rev Respir Dis. 1987 Feb;135(2):401-2
3492949
Int J Biochem Cell Biol. 2008;40(2):258-71
17869162
Curr Opin Rheumatol. 1998 Jan;10(1):3-11
9448984
J Clin Invest. 1981 Nov;68(5):1158-65
7028785
Respir Med. 1997 May;91(5):275-9
9176645
Am J Respir Crit Care Med. 1994 Apr;149(4 Pt 1):966-71
8143063
Am Rev Respir Dis. 1989 Oct;140(4):961-6
2679271
Eur Respir J. 1998 Oct;12(4):996-7
9817182
JAMA. 1988 Sep 2;260(9):1259-64
3261353
Eur Respir J. 1997 Oct;10(10):2260-3
9387950
Am J Respir Crit Care Med. 1998 Jul;158(1):49-59
9655706
Curr Med Res Opin. 2005 Jun;21(6):877-83
15969888
Nat Rev Drug Discov. 2007 Jan;6(1):67-74
17195033
J Pharmacol Exp Ther. 2000 Dec;295(3):904-11
11082423
Pediatrics. 1978 Jul;62(1):22-5
308215
FEBS J. 2008 May;275(9):2008-20
18341586
J Clin Invest. 1999 Apr;103(7):999-1006
10194472
Ann Intern Med. 2002 Feb 19;136(4):270-9
11848724
Am J Hum Genet. 1991 Jun;48(6):1154-8
2035534
Chest. 2009 Mar;135(3):600-608
19017884
Chest. 2000 Mar;117(3):875-80
10713018
N Engl J Med. 2005 May 12;352(19):2030-1
15888711
Chest. 1996 Dec;110(6 Suppl):284S-294S
8989166
Am J Public Health. 1991 Apr;81(4):427-33
1900677
Am J Pathol. 2005 Feb;166(2):377-86
15681822
COPD. 2009 Feb;6(1):31-40
19229706
Am J Pathol. 2006 Oct;169(4):1155-66
17003475
J Biol Chem. 2000 Sep 1;275(35):27258-65
10867014
Am J Respir Crit Care Med. 2003 May 15;167(10):1387-92
12574076
Chest. 2008 Oct;134(4):831-834
18842915
Dermatol Clin. 2008 Oct;26(4):447-51, vi
18793976
Gene Ther. 1998 Feb;5(2):181-8
9578837
Am J Respir Crit Care Med. 2000 Dec;162(6):2069-72
11112116
Am J Respir Crit Care Med. 2002 Jun 1;165(11):1494-8
12045122
Am J Respir Crit Care Med. 1997 Feb;155(2):536-41
9032191
J Biol Chem. 2001 Sep 7;276(36):33345-52
11435427
Eur Respir J. 2005 Jun;25(6):992-1000
15929953
Am J Respir Crit Care Med. 2006 Jun 1;173(11):1222-8
16514110
Eur Respir J. 2009 Jun;33(6):1345-53
19196813
Biologics. 2009;3:63-75
19707397
Chest. 2002 Jul;122(1):66-74
12114340
Respir Med. 1998 Mar;92(3):367-77
9692092
COPD. 2008 Jun;5(3):153-62
18568839
Am J Respir Cell Mol Biol. 2009 Sep;41(3):261-70
19131639
Chest. 2001 Mar;119(3):745-52
11243952
Respir Med. 2007 Sep;101(9):1924-30
17644366
Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):796-801
10712324
Cell Death Differ. 2009 Jan;16(1):39-45
18617899
Eur Respir J. 1998 Feb;11(2):428-33
9551749
Chest. 2003 May;123(5):1425-34
12740257
Am J Physiol Lung Cell Mol Physiol. 2005 May;288(5):L820-30
15626748
Chest. 2004 May;125(5):1952-7
15136414
Ann Pharmacother. 2008 May;42(5):640-6
18413692
J Pediatr. 1978 Jun;92(6):1006-10
307054
Chest. 2003 Sep;124(3):826-31
12970004
Am J Respir Cell Mol Biol. 2007 Aug;37(2):144-51
17395890