Serum levels and genotype distribution of α<sub>1</sub>-antitrypsin in the general population

Ferrarotti, Ilaria; Thun, Gian Andri; Zorzetto, Michele; Ottaviani, Stefania; Imboden, Medea; Schindler, Christian; Eckardstein, Arnold von; Rohrer, Lucia; Rochat, Thierry; Russi, Erich W.; Probst‐Hensch, Nicole; Luisetti, Maurizio

doi:10.1136/thoraxjnl-2011-201321

Cited by 173 publications

(165 citation statements)

References 35 publications

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“…However, the curve of PI*SZ individuals was displaced by 20-30%, meaning that for any given quantity of smoking consumption a PI*SZ subject had an FEV1 % pred that was between 20% and 30% better than a Pi*ZZ subject. If we bear in mind the marked difference in confidence intervals of a 1 -AT serum level values in PI*ZZ and PI*SZ individuals [38], this would further support the concept that the risk for lung impairment is inversely related to serum a 1 -AT levels. Another interesting observation from the curve was that the impact of smoking is greater at the beginning of the habit.…”

Section: Discussionmentioning

confidence: 70%

Clinical phenotypes of Italian and Spanish patients with α₁-antitrypsin deficiency

et al. 2012

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With the aim of providing better clinical characterisation of patients with a 1 -antitrypsin deficiency (AATD), we analysed the data of adult patients with severe AATD enrolled in the Spanish and Italian national registries.We assessed 745 subjects, 416 of whom were enrolled in the Spanish registry and 329 in the Italian registry. 57.2% were male and 64.9% were smokers or former smokers with a mean¡SD age of 49.9¡13.8 years. Most (81.2%) were index cases, mainly having the PI*ZZ genotype (73.4%), and the mean¡SD diagnostic delay was 9.0¡12.1 years.Patients with chronic bronchitis were younger, had better preserved lung function and lower tobacco consumption. Overlap patients (chronic obstructive pulmonary disease with asthma) were mainly females, more frequently never-smokers and received respiratory medications more often. 48% of emphysema, 27.5% of chronic bronchitis and 44.8% of overlap subjects were receiving augmentation therapy. Compared with PI*ZZ patients (n5547), the PI*SZ (n5124) subjects were older at diagnosis and had more preserved lung function, despite a higher mean smoking consumption.Early diagnosis of AATD is still an unmet need. Augmentation therapy is administered to similar proportions of patients with different clinical phenotypes. PI*ZZ patients in both registries had more severe respiratory disease than those with PI*SZ, despite lower smoking levels. @ERSpublications New characterisation of clinical phenotypes in patients with alpha-1 antitrypsin deficiency

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Section: Discussionmentioning

confidence: 70%

Clinical phenotypes of Italian and Spanish patients with α₁-antitrypsin deficiency

et al. 2012

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“…The decision to include targeted polymerase chain reaction (PCR) for the detection of Pi*S and Pi*Z as a concomitant first step or only in low-level samples is dependent on the funding that is available and on the primary goal of the algorithm: two recent publications showed that the negative predictive value of the AAT serum level (cutoff 104 mg/dl, 113 mg/dl) is 99.8% and 100%, respectively [Ferrarotti et al 2012;Greulich et al 2015]. In other words: if the serum level exceeds these thresholds, the probability to carry a homozygous mutation for AAT is extremely low.…”

Section: Initial Tests For Aatdmentioning

confidence: 99%

Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis

Greulich¹,

Vogelmeier

2015

Ther Adv Respir Dis

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Alpha-1-antitrypsin deficiency (AATD) is a hereditary disorder that is characterized by a low serum level of alpha-1-antitrypsin (AAT). The loss of anti-inflammatory and antiproteolytic functions, together with pro-inflammatory effects of polymerized AAT contribute to protein degradation and increased inflammation resulting in an increased risk of developing chronic obstructive pulmonary disease (COPD) and emphysema, especially in smokers. AATD is a rare disease that is significantly underdiagnosed. According to recent data that are based on extrapolations, in many countries only 5-15% of homozygous individuals have been identified. Furthermore, the diagnostic delay typically exceeds 5 years, resulting in an average age at diagnosis of about 45 years. Although the American Thoracic Society/ European Respiratory Society recommendations state that all symptomatic adults with persistent airway obstruction should be screened, these recommendations are not being followed. Potential reasons for that include missing knowledge about the disease and the appropriate tests, and the low awareness of physicians with regard to the disorder. Once the decision to initiate testing has been made, a screening test (AAT serum level or other) should be performed. Further diagnostic evaluation is based on the following techniques: polymerase chain reaction (PCR) for frequent and clinically important mutations, isoelectric focusing (IEF) with or without immunoblotting, and sequencing of the gene locus coding for AAT. Various diagnostic algorithms have been published for AATD detection (severe deficiency or carrier status). Modern laboratory approaches like the use of serum separator cards, a lateral flow assay to detect the Z-protein, and a broader availability of next-generation sequencing are recent advances, likely to alter existing algorithms.

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“…Based upon the findings of FERRAROTTI et al [17], the following cut-off points have been suggested. 1) If the aim is to identify genotypes with increased risk for emphysema, a cut-off point of 1 g·L −1 (95.8% sensitivity, 94.8% specificity) has proven satisfactory.…”

Section: What Is the Optimal Aat Level Cut-off Point?mentioning

confidence: 99%

Diagnosing α₁-antitrypsin deficiency: how to improve the current algorithm

McElvaney

2015

Eur Respir Rev

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Over the past 10–15 years, the diagnosis of α1-antitrypsin deficiency (AATD) has markedly improved as a result of increasing awareness and the publication of diagnostic recommendations by the American Thoracic Society (ATS)/European Respiratory Society (ERS). Nevertheless, the condition remains substantially underdiagnosed. Furthermore, when AATD is diagnosed there is a delay before treatment is introduced. This may help explain why AATD is the fourth most common cause of lung transplantation. Clearly we need to do better. The ATS/ERS recommend testing high-risk groups, such as: all chronic obstructive pulmonary disease patients; all nonresponsive asthmatic adults/adolescents; all cases of cryptogenic cirrhosis/liver disease; subjects with granulomatosis with polyangitis; bronchiectasis of unknown aetiology; panniculitis and first-degree relatives of patients with AATD. In terms of laboratory diagnosis, measurement of α1-antitrypsin levels will identify patients with protein deficiency, but cannot differentiate between the various genetic subtypes of AATD. Phenotyping is the current gold standard for detecting rare variants of AATD (except null variants), while advances in molecular diagnostics are making genotyping more effective. An accurate diagnosis facilitates the physician's ability to actively intervene with measures such as smoking cessation and perhaps augmentation therapy, and it will also help provide a better understanding of the natural history of the disease.

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Serum levels and genotype distribution of α₁-antitrypsin in the general population

Cited by 173 publications

References 35 publications

Clinical phenotypes of Italian and Spanish patients with α₁-antitrypsin deficiency

Clinical phenotypes of Italian and Spanish patients with α₁-antitrypsin deficiency

Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis

Diagnosing α₁-antitrypsin deficiency: how to improve the current algorithm

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Serum levels and genotype distribution of α1-antitrypsin in the general population

Cited by 173 publications

References 35 publications

Clinical phenotypes of Italian and Spanish patients with α1-antitrypsin deficiency

Clinical phenotypes of Italian and Spanish patients with α1-antitrypsin deficiency

Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis

Diagnosing α1-antitrypsin deficiency: how to improve the current algorithm

Contact Info

Product

Resources

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Serum levels and genotype distribution of α₁-antitrypsin in the general population

Clinical phenotypes of Italian and Spanish patients with α₁-antitrypsin deficiency

Clinical phenotypes of Italian and Spanish patients with α₁-antitrypsin deficiency

Diagnosing α₁-antitrypsin deficiency: how to improve the current algorithm