Respiratory symptoms and lung function in 30-year-old individuals with alpha-1-antitrypsin deficiency

Bernspång, Elisabeth; Sveger, Tomas; Piitulainen, Eeva

doi:10.1016/j.rmed.2007.04.003

Cited by 47 publications

(46 citation statements)

References 23 publications

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“…[11][12][13][14] Three studies reported that providing information on AATD status to individuals identified at birth through neonatal screening programs reduced smoking rates in these individuals. In the first study adolescents with AATD identified at birth had a significantly lower current and previous smoking rate compared with matched control subjects (current smoking rate: 6% vs 17%, P < .05; previous smoking rate: 6% vs 19%, P < .05).…”

Section: Importance Of Early Diagnosismentioning

confidence: 99%

Issues in the diagnosis of α1-antitrypsin deficiency

Rachelefsky¹,

Hogarth²

2008

Journal of Allergy and Clinical Immunology

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Section: Importance Of Early Diagnosismentioning

confidence: 99%

Issues in the diagnosis of α1-antitrypsin deficiency

Rachelefsky¹,

Hogarth²

2008

Journal of Allergy and Clinical Immunology

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“…The maximum FEV 1 % predicted is not known for each individual; in order to include only positive values, the maximum observed FEV 1 % predicted in our cohort (140% predicted) was used in the numerator for all subjects. The age of initiation of FEV 1 decline is also unknown in this cohort, but Piitulainen and colleagues have demonstrated that PI Z individuals typically have normal FEV 1 values at least until age 30 [Bernspang et al, 2007]. Thus, we selected ages 20, 25, and 30 as age thresholds for the initiation of FEV 1 decline.…”

Section: Cohort and Phenotype Definitionmentioning

confidence: 99%

Heritability of Lung Function in Severe Alpha-1 Antitrypsin Deficiency

et al. 2008

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Severe alpha-1 antitrypsin (AAT) deficiency is a proven genetic risk factor for COPD, but there is marked variation in the development of COPD among AAT deficient subjects. To investigate familial aggregation of lung function in subjects with AAT deficiency, we estimated heritability for forced expiratory volume in 1 s (FEV₁) and FEV₁/forced vital capacity (FVC) in 378 AAT deficient subjects from 167 families in the AAT Genetic Modifiers Study; all subjects were verified homozygous for the Z AAT deficiency allele. Heritability was evaluated for models that included and excluded an ascertainment correction, as well as for models that excluded, included and were stratified by a cigarette smoking covariate. In models without an ascertainment correction, and in all models without a covariate for smoking, no evidence for familial aggregation of lung function was observed. In models conditioned on the index proband with covariates for smoking, post-bronchodilator FEV₁/FVC demonstrated significant heritability (0.26 ± 0.14, p = 0.03). When we limited the analysis to subjects with a smoking history, post-bronchodilator FEV₁demonstrated significant heritability (0.47 ± 0.21, p = 0.02). Severity rate phenotypes were also assessed as potential phenotypes for genetic modifier studies. Significant heritability was found with all age-of-onset threshold models that included smoking and ascertainment adjustments. Using the t-distribution, the heritability estimates ranged from 0.43 to 0.64, depending on the age-of-onset of FEV₁decline used for the severity rate calculation. Correction for ascertainment and consideration of gene-by-smoking interactions will be crucial for the identification of genes that may modify susceptibility for COPD in families with AAT deficiency.

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“…Severe AATD is characterised by low levels of A 1 -PI in blood and tissues and can lead to liver disease (cirrhosis or hepatocellular carcinoma), caused by aggregation of misfolded A 1 -PI as polymers in hepatocytes, and/or chronically progressing lung disease, including emphysema, as a result of uncontrolled degradation of lung tissue by proteases, mainly neutrophil elastase (NE) (2,3). Severe AATD presents with pulmonary symptoms, often including coughing, wheezing, shortness of breath and recurrent respiratory tract infections that are similar to those observed in typical chronic obstructive pulmonary disease (COPD) (4)(5)(6). Whilst the pathomechanism of AATD-related COPD is distinct from COPD per se, recent evidence suggests that in both emphysema is a major contributor (7,8).…”

Section: Introductionmentioning

confidence: 99%

Disease Modification in Emphysema Related to Alpha-1 Antitrypsin Deficiency

Chorostowska‐Wynimko¹

2016

COPD: Journal of Chronic Obstructive Pulmonary Disease

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Alpha-1 antitrypsin deficiency (AATD) is associated with premature onset of emphysema resulting from low serum A 1 -PI levels. The only available pharmacological treatment affecting the underlying cause of AATD is A 1 -PI therapy. AATD-related emphysema is considered a good model to study disease-modifying effects of treatment as the causative process has been identified. Disease modification is a sustained improvement in disease state following therapeutic intervention that persists when therapy is discontinued. Appropriate trial design and the use of valid study endpoints are key to illustrating disease modification, particularly in clinical trials of rare diseases where it can be difficult to recruit sufficient numbers of patients. Delayed-start trials are advantageous ethically as all patients ultimately receive active treatment and imaging techniques have proven promising as valid study endpoints. Specifically, computed tomography (CT) measured lung density has been used to monitor emphysema and is considered a more sensitive outcome than pulmonary function tests to monitor disease progression. This review will discuss the importance of clinical endpoints and trial design to determine disease modification and will review the evidence for disease modification in AATD-related emphysema. Until recently, clinical studies have not shown a significant effect of A 1 -PI therapy, possibly due to insufficient numbers of patients, short duration of clinical trials and lack of appropriate trial design. A recently completed randomised trial and open-label extension study followed a larger study population for a longer duration and incorporated a delayed-start design. The results demonstrated clinical efficacy of A 1 -PI therapy and indicate that treatment is disease-modifying.

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Respiratory symptoms and lung function in 30-year-old individuals with alpha-1-antitrypsin deficiency

Abstract: At the age of 30, the AAT-deficient individuals in this cohort report more symptoms than the control subjects. Smoking is less common in the cohort compared to controls. Their lung function is normal.

Cited by 47 publications

References 23 publications

Issues in the diagnosis of α1-antitrypsin deficiency

Issues in the diagnosis of α1-antitrypsin deficiency

Heritability of Lung Function in Severe Alpha-1 Antitrypsin Deficiency

Disease Modification in Emphysema Related to Alpha-1 Antitrypsin Deficiency

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