Development of Predictive Models for Airflow Obstruction in Alpha-1 Antitrypsin Deficiency.

Castaldi, PJ; Dl, DeMeo; Dm, Kent; Campbell, E. J. M.; Barker, A. J.; Brantly, ML; Eden, EE; McElvaney, N.G.; Rennard, SI; Stocks, JM; Stoller, J. K.; Strange, Charlie; Turino, Gerard M.; Sandhaus, RA; Griffith, JL; Silverman, EK

doi:10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a3499

Cited by 5 publications

(4 citation statements)

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“…The data presented here show a clear difference in anti-elastin antibody levels between smokers and those who have never smoked in AATD, and a relationship between pack-yrs smoked and antibody levels. There was also a threshold level of smoke exposure apparent, a feature identified in another large cohort of AATD subjects recently, which contributed to their predictive model for FEV1 [21].…”

Section: Discussionmentioning

confidence: 92%

Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

Wood¹,

Pablo²,

Buckley³

et al. 2010

European Respiratory Journal

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Liberation of elastin peptides from damaged lung may be a mechanism of autoimmune lung disease. Citrullination, and anti-citrullinated protein antibody formation occurs in smokers, but the role of smoking in autoantibody generation relevant to pulmonary disease is unclear.Anti-elastin, anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) antibodies were measured in 257 subjects with a 1 -antitrypsin deficiency (AATD), 113 subjects with usual chronic obstructive pulmonary disease (COPD) and 22 healthy nonsmokers. Levels were compared between groups, against phenotypic features and against smoke exposure.Anti-elastin antibodies were higher in controls relative to AATD (p50.008) and usual COPD (p,0.00001), and in AATD relative to usual COPD (p,0.00001). Anti-elastin levels showed a threshold at 10 pack-yrs, being higher in those who had smoked less (p50.004). No relationships between antibody levels and clinical phenotype were seen after adjustment for smoke exposure. Anti-CCP antibodies were higher in usual COPD than AATD (p50.002) but the relationship to smoke exposure was less clear.Smoke exposure is the main determinant of anti-elastin antibody levels, which fall after 10 packyrs. Local antibody complexes may be a better measure of elastin directed autoimmunity than circulating levels.KEYWORDS: a 1 -Antitrypsin deficiency, autoimmune disease, chronic obstructive pulmonary disease, smoking and health T he protease-antiprotease hypothesis of the pathogenesis of chronic obstructive pulmonary disease (COPD) concerns imbalances between proteases that digest elastin and other components of the extracellular matrix in the lung parenchyma, and antiproteases that protect [1][2]. The origin of this theory comes from the observation that patients with a 1 -antitrypsin deficiency (AATD) develop early onset emphysema [3]. a 1 -Antitrypsin (AAT) is an antiprotease, which acts predominantly to block the action of neutrophil elastase, a protease released by neutrophils. Neutrophil elastase is a serine protease, the first of three classes of protease important in COPD. The remaining two classes are the cysteine proteases, such as cathepsin-B, and the matrix metalloproteases (MMPs) [4]. In general, the serine and cysteine proteases are capable of degrading elastin and some forms of collagen [4], whilst MMPs have more of an effect on collagen, gelatin and laminin [2], all of which are components of the extracellular matrix of the lung.Breakdown of the extracellular matrix, particularly elastin, in the lung is a key feature of both COPD and AATD, as shown by the presence of high levels of elastin breakdown products. A desmosine cross-link is unique to elastin and may be used as a marker of its degradation [5]. Desmosine and elastin peptides are elevated in the plasma, urine and sputum of COPD patients [6], whilst urinary levels positively correlate with the annual rate of decline in forced expiratory volume in 1 s (FEV1) in smokers [7]. In general, elastin breakdown is greater i...

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Section: Discussionmentioning

confidence: 92%

Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

Wood¹,

Pablo²,

Buckley³

et al. 2010

European Respiratory Journal

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“…Important predictors of an increased rate of FEV 1 decline include smoking status (i.e., current vs. ever vs. never), male sex, age 30 to 44 years, FEV 1 between 35 and 79% of predicted value, decreased serum AAT level, and bronchodilator responsiveness (134,136,147). In one model, age, sex, pack-years of smoking, bronchodilator responsiveness, chronic bronchitis symptoms, and index case status accounted for 50% of the variance in FEV 1 (148). Single-nucleotide polymorphisms of IL-10 have also been associated with COPD in patients with severe AAT deficiency (149).…”

Section: Natural History Of Emphysema In Aatdmentioning

confidence: 99%

A Review of α₁-Antitrypsin Deficiency

Stoller

Aboussouan

2012

Am J Respir Crit Care Med

387

330

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α(1)-Antitrypsin (AAT) deficiency is an underrecognized genetic condition that affects approximately 1 in 2,000 to 1 in 5,000 individuals and predisposes to liver disease and early-onset emphysema. AAT is mainly produced in the liver and functions to protect the lung against proteolytic damage (e.g., from neutrophil elastase). Among the approximately 120 variant alleles described to date, the Z allele is most commonly responsible for severe deficiency and disease. Z-type AAT molecules polymerize within the hepatocyte, precluding secretion into the blood and causing low serum AAT levels (∼ 3-7 μM with normal serum levels of 20-53 μM). A serum AAT level of 11 μM represents the protective threshold value below which the risk of emphysema is believed to increase. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma-so-called "augmentation therapy"-represents a specific therapy for AAT deficiency and raises serum levels above the protective threshold. Although definitive evidence from randomized controlled trials of augmentation therapy is lacking and therapy is expensive, the available evidence suggests that this approach is safe and can slow the decline of lung function and emphysema progression. Promising novel therapies are under active investigation.

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“…There is a compensatory development in airway AAT, but an excess of elastase indicates protease/anti-protease imbalance [ 8 ]. Studies have revealed that the presence of asthma with frequent exacerbations is a risk factor for an accelerated decline in FEV 1 [ 9 , 10 ].…”

Section: Discussionmentioning

confidence: 99%

Alpha-1 antitrypsin deficiency in the elderly: a case report

et al. 2021

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Background Generally, alpha-1 antitrypsin deficiency (AATD) is suspected in young patients with pulmonary emphysema or chronic obstructive pulmonary disease (COPD). Patients often suffer from diagnostic gaps and are misdiagnosed with chronic obstructive pulmonary disease (COPD), asthma, and airway hyperresponsiveness (AHR), as AATD may present with nonspecific respiratory symptoms. It is never too late to suspect AATD, especially in a patient with an unusual medical history. In recent years, evidence is beginning to emerge that there may be value in identifying and treating patients who do not already have deterioration of functional parameters. Case presentation We describe a case of a 69-year-old Caucasian female patient, late diagnosis of AATD, with both severe bronchial hyperreactivity and numerous exacerbations due to the peculiar clinical history and the presence of a rare mutation; although not presenting forced expiratory volume in 1 second (FEV1) between 30 and 65%, the patient was treated with alpha-1 antitrypsin (AAT) augmentation therapy and achieved clinical and functional improvement. Conclusion AATD should always be suspected. The Alpha-1 Foundation recommendations for the diagnosis and management of AATD in adult patients indicate that treatment should be provided for patients with FEV1 between 30 and 65%. It may be useful to evaluate and treat patients based on clinical symptoms, even outside the established parameters, in particular cases.

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Development of Predictive Models for Airflow Obstruction in Alpha-1 Antitrypsin Deficiency.

Cited by 5 publications

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Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

A Review of α₁-Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency in the elderly: a case report

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Development of Predictive Models for Airflow Obstruction in Alpha-1 Antitrypsin Deficiency.

Cited by 5 publications

References 0 publications

Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

Smoke exposure as a determinant of autoantibody titre in 1-antitrypsin deficiency and COPD

A Review of α1-Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency in the elderly: a case report

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Product

Resources

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A Review of α₁-Antitrypsin Deficiency