Diagnostic flow chart for targeted detection of Alpha1-antitrypsin deficiency

Università degli Studi di Brescia, Brescia, Lombardy, Italy
Respiratory Medicine (Impact Factor: 3.09). 04/2006; 100(3):463-70. DOI: 10.1016/j.rmed.2005.06.009
Source: PubMed


Alpha1-antitrypsin (AAT) deficiency is under-recognized, probably because many individuals affected show no clinical impairment. The targeted detection is a tool to increase its recognition.
We prospectively submitted to AAT serum levels determination, phenotyping and, if doubtful, genotyping: (i) patients with the early onset of emphysema, emphysema in absence of recognized risk or pneumothorax (path P), antineutrophil cytoplasm antibodies (ANCA) positive vasculitis (path V), cervical artery dissection (path A), Periodic acid-Schiff (PAS) positive bodies in the liver cell or unexplained abnormal transaminase level (Path L) [index cases: IC] and (ii) subjects with low-serum alpha1-globulin (path e) and close relatives of patients with AAT deficiency (path r) [non index cases: NIC]. We determined and compared gender, age, AAT serum levels values, the ratio between AAT deficiency subjects identified and all subjects examined (identified/examined). Receiver operating characteristic (ROC) curve was plotted to find the best threshold for AAT serum levels.
Two hundred and eighty-five individuals were examined and 211 with AAT deficiency identified: 66 were IC and 145 NIC. The ratio identified/examined resulted 0.74. A serum level of 120 mg/dL was able to identify AAT deficiency with a specificity of 73% and a sensitivity of 97%. IC showed male prevalence (P=0.005), more advanced age (P=0.02), lower AAT serum levels (P=0.008).
Our protocol is effective to detect AAT deficiency in a selected population. About 120 mg/dL (nephelometric method) is a reliable AAT serum level cut-off for selecting subjects/patients to submit to phenotype or genotype; as compared to NIC, IC are older, mostly male and with lower AAT serum levels.

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Available from: Laura Pini
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    • "Previously reported AATD percentage in unselected COPD patients, ranging from 0.5 to 10.4 (10), was much lower than the prevalence obtained in this study. Additionally, in a group of randomly collected Serbian COPD patients AATD prevalence was found to be 2.9% (11) There is only one report on AATD prevalence among targeted COPD patients (premature emphysema, emphysema with no recognized risk factor, pneumothorax) which exceeded 40% (12). Taken together with the last example, our results might suggest that targeting on patients with premature COPD might be a useful mode to increase AATD detection rate. "
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    ABSTRACT: Introduction: Alpha-1-antitrypsin deficiency (AATD), genetic risk factor for premature chronic obstructive pulmonary disease (COPD), often remains undetected. The aim of our study was to analyse the effectiveness of an integrative laboratory algorithm for AATD detection in patients diagnosed with COPD by the age of 45 years, in comparison with the screening approach based on AAT concentration measurement alone. Subjects and methods: 50 unrelated patients (28 males/22 females, age 52 (24–75 years) diagnosed with COPD before the age of 45 years were enrolled. Immunonephelometric assay for alpha-1-antitrypsin (AAT) and PCR-reverse hybridization for Z and S allele were first-line, and isoelectric focusing and DNA sequencing (ABI Prism BigDye) were reflex tests. Results: AATD associated genotypes were detected in 7 patients (5 ZZ, 1 ZMmalton, 1 ZQ0amersfoort), 10 were heterozygous carriers (8 MZ and 2 MS genotypes) and 33 were without AATD (MM genotype). Carriers and patients without AATD had comparable AAT concentrations (P = 0.125). In majority of participants (48) first line tests were sufficient to analyze AATD presence. In two remaining cases reflex tests identified rare alleles, Mmalton and Q0amersfoort, the later one being reported for the first time in Serbian population. Detection rate did not differ between algorithm and screening both for AATD (P = 0.500) and carriers (P = 0.063). Conclusion: There is a high prevalence of AATD affected subjects and carriers in a group of patients with premature COPD. The use of integrative laboratory algorithm does not improve the effectiveness of AATD detection in comparison with the screening based on AAT concentration alone.
    Full-text · Article · Jun 2014 · Biochemia Medica
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    • "Nowadays, the efforts are directed towards determination of the cut-off values with high specificity and sensitivity, in order to separate normal from deficient phenotypes. The value of A1AT serum level of 22 M (1, 2 g/L) has been determined as a reliable cut-off able to identify A1ATD with a specificity of 73% and a sensitivity of 97% (Corda et al., 2006). The lower value of 18.5 M (1.00 g/L) was able to detect heterozygous A1ATD (Simsek et al., 2011), while cut-off value of 14.7 M (0.8 g/L) was proposed for detection of all patients who are at risk of A1ATD (Prins et al., 2008). "

    Full-text · Chapter · Mar 2012
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    • "In view of these results, the new SEPAR guidelines on treatment of AAT deficiency insist on the need for performing the determination of serum AAT in all patients with COPD [Vidal et al. 2006b]. Similar case-detection programs have been carried out in other countries with different protocols and results [Bals et al. 2007; Corda et al. 2006; Wencker et al. 2002; Luisetti et al. 1999]. Despite the differences between them, these initiatives have been useful in increasing the awareness of the disease among healthcare professionals and detecting new cases at an earlier stage when medical intervention can offer better opportunities and improve the quality of life of these patients. "
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    ABSTRACT: Alpha-1 antitrypsin deficiency (AAT) is a hereditary recessive autosomal disease caused by mutations in the AAT gene. This disease is characterized by abnormally low AAT concentrations in plasma, which, in its homozygote form, carries a high risk for the development of early pulmonary emphysema and liver damage. Since the end of the 1980s augmentation therapy with AAT from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has been demonstrated to be safe and weekly infusions of AAT have resulted in plasma AAT concentrations above those considered protective for the lungs. However, life-long weekly infusions are not well accepted by patients, therefore pharmacokinetic studies have been performed to try to individualize the therapeutic regimen in order to obtain adequate trough serum AAT levels with prolonged intervals of administration. Therapeutic regimens administered every two weeks appear to be safe and result in adequate trough serum concentrations, but less-frequent administrations result in trough levels below the target. Alpha-1-antitrypsin deficiency is largely unrecognized and underdiagnosed. The foundation of national and international registries is a valid strategy to increase awareness about the disease and collect information about the natural history of this deficiency. Furthermore, the identification of a large number of patients will allow the development of new clinical trials aimed at finding better treatments for this infrequent condition.
    Full-text · Article · Mar 2008 · Therapeutic Advances in Respiratory Disease
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