Available screening procedures for the detection of α1-antitrypsin-deficient (AATD) mutations have suboptimal cost-effectiveness ratios. The aim in this study was to evaluate and compare the viability of a composite approach, primarily based on the α1-globulin fraction, in identifying AAT genetic analysis eligible patients against standard screening procedures, based on clinically compatible profiling and circulating AAT < 1 g/L.
A total of 21,094 subjects were screened for AATD and deemed eligible when meeting one of these criteria: α1-globulin ≤2.6%; α1-globulin 2.6%–2.9% and AST: >37 U/L and ALT: > 78 U/L; α1-globulin %: 2.9–4.6% and AST: >37 U/L and ALT: >78 U/L and erythrocyte sedimentation rate (ESR) >34 mm/h and C-reactive protein (CRP) >3 mg/L. Subjects were genotyped for the AAT gene mutation. Detection rates, including those of the rarest variants, were compared with results from standard clinical screenings. Siblings of mutated subjects were included in the study, and their results compared.
Eighty-two subjects were identified. Among these, 51.2% were found to carry some Pi*M variant versus 15.9% who were clinically screened. The detection rates of the screening, including relatives, were: 50.5% for the proposed algorithm and 18.9% for the clinically-based screening. Pi*M variant prevalence in the screened population was in line with previous studies. Interestingly, 46% of subjects with Pi*M variants had an AAT plasma level above the 1 g/L threshold.
A composite algorithm primarily based on the α1-globulin fraction could effectively identify carriers of Pi*M gene mutation. This approach, not requiring clinical evaluation or AAT serum determination, seems suitable for clinical and epidemiological purposes.
Authors wish to acknowledge the technical and data management support received by Katia Monnati, Eng., and Alessandra Bollettieri, Eng., at Help Desk Medarchiver board; Marco Venditti, Eng., head of the IT Operations Unit at Campus Bio Medico University and Teaching Hospital.
Author contributions: SSc, SSan and RAI participated in the study concept and design; SSc, SSan, PF and DF collected the data; IF, SO and AGC were in charge of the blood sample genotyping; SSc and PF performed data analyses; SSc, SSan, PF, IF, AGC, MM and RAI reviewed the manuscript for important intellectual content. The authors fulfill authorship criteria, they revised the final version of the manuscript and consented to publication.
Research funding: None declared.
Competing interests: Authors state no conflict of interest.
Informed consent: Informed consent was obtained from all individuals included in this study.
Ethical approval: Local ethical board approval released on September 21st 2016, protocol number: 43/16 OSS ComEt CBM.
1. Esquinas C, Serreri S, Barrecheguren M, Rodriguez E, Nuñez A, Casas-Maldonado F, et al. Long-term evolution of lung function in individuals with α1-antitrypsin deficiency from the Spanish registry (REDAAT). Int J Chron Obstruct Pulmon Dis 2018;13:1001–7.10.2147/COPD.S155226Search in Google Scholar
2. Soriano JB, Lucas SJ, Jones R, Miravitlles M, Carter V, Small I, et al. Respiratory Effectiveness Group Trends of testing for and diagnosis of α1-antitrypsin deficiency in the UK: more testing is needed. Eur Respir J 2018;75:397–415. Search in Google Scholar
3. (α1-antitrypsin) deficiency: Memorandum from a WHO meeting – ProQuest. https://search.proquest.com/openview/cbc69103dbd276091b9d33887c12ff6d/1?pq-origsite=gscholar&cbl=38034. Accessed: 28 Sep 2018.Search in Google Scholar
4. Miravitlles M, Dirksen A, Ferrarotti I, Koblizek V, Lange P, Mahadeva R, et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency. Eur Respir J 2017;50:1700610.10.1183/13993003.00610-2017Search in Google Scholar
5. Miravitlles M, Herr C, Ferrarotti I, Jardi R, Rodriguez-Frias F, Luisetti M, et al. Laboratory testing of individuals with severe α1-antitrypsin deficiency in three European centres. Eur Respir J 2010;35:960–8.10.1183/09031936.00069709Search in Google Scholar
6. Greulich T, Rodríguez-Frias F, Belmonte I, Klemmer A, Vogelmeier CF, Miravitlles M. Real world evaluation of a novel lateral flow assay (AlphaKit® QuickScreen) for the detection of α1-antitrypsin deficiency. Respir Res 2018;19:151.10.1186/s12931-018-0826-8Search in Google Scholar
7. Greulich T, Ottaviani S, Bals R, Lepper PM, Vogelmeier C, Luisetti M, et al. α1-antitrypsin deficiency – diagnostic testing and disease awareness in Germany and Italy. Respir Med 2013;107:1400–8.10.1016/j.rmed.2013.04.023Search in Google Scholar
8. Barrecheguren M, Monteagudo M, Simonet P, Llor C, Rodriguez E, Ferrer J, et al. Diagnosis of α1-1 antitrypsin deficiency: a population-based study. Int J Chron Obstruct Pulm Dis 2016;11:999–1004.10.2147/COPD.S108505Search in Google Scholar
9. Ritchie RF, Palomaki GE, Neveux LM, Navolotskaia O. Reference distributions for the positive acute phase proteins, α1-acid glycoprotein (orosomucoid), α1-antitrypsin, and haptoglobin: a comparison of a large cohort to the world’s literature. J Clin Lab Anal 2000;14:265–70.10.1002/1098-2825(20001212)14:6<265::AID-JCLA3>3.0.CO;2-ASearch in Google Scholar
11. Bornhorst JA, Greene DN, Ashwood ER, Grenache DG. α1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population. Chest 2013;143:1000–8.10.1378/chest.12-0564Search in Google Scholar
12. Donato LJ, Jenkins SM, Smith C, Katzmann JA, Snyder MR. Reference and interpretive ranges for α1-antitrypsin quantitation by phenotype in adult and pediatric populations. Am J Clin Pathol 2012;138:398–405.10.1309/AJCPMEEJK32ACYFPSearch in Google Scholar
13. Ferrarotti I, Thun GA, Zorzetto M, Ottaviani S, Imboden M, Schindler C, et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax 2012;67:669–74.10.1136/thoraxjnl-2011-201321Search in Google Scholar
14. Bals R, Koczulla R, Kotke V, Andress J, Blackert K, Vogelmeier C. Identification of individuals with α1-antitrypsin deficiency by a targeted screening program. Respir Med 2007;101:1708–14.10.1016/j.rmed.2007.02.024Search in Google Scholar
15. High-density lipoproteins contribute to the α-1-globulin zone in capillary electrophoresis of human serum proteins – Luraschi – 2004 – ELECTROPHORESIS – Wiley Online Library. https://onlinelibrary.wiley.com/doi/abs/10.1002/elps.200305828. Accessed: 28 Sep 2018.Search in Google Scholar
16. Slev PR, Williams BG, Harville TO, Ashwood ER, Bornhorst JA. Efficacy of the detection of the α1-antitrypsin “Z” deficiency variant by routine serum protein electrophoresis. Am J Clin Pathol 2008;130:568–72.10.1309/JWEWE4QRQKJ5EJEUSearch in Google Scholar
17. Ferrarotti I, Poplawska-Wisniewska B, Trevisan MT, Koepke J, Dresel M, Koczulla R, et al. How can we improve the detection of α1-antitrypsin deficiency? PLoS One 2005;10:e0135316.10.1371/journal.pone.0135316Search in Google Scholar
18. Miravitlles M, Jardí R, Rodríguez-Frías F, Torrella M, Pelegrí D, Vidal R. Usefulness of the quantification of the alpha 1 serous protein band in the screening of alpha -1-antitrypsin deficiency. Arch Bronconeumol 1998;34:536–40.10.1016/S0300-2896(15)30335-5Search in Google Scholar
19. Ferrarotti I, Scabini R, Campo I, Ottavini S, Zorzetto M, Gorrini M, et al. Laboratory diagnosis of α1-antitrypsin deficiency. Transl Res 2007;150:267–74.10.1016/j.trsl.2007.08.001Search in Google Scholar PubMed
21. American Thoracic Society, European Respiratory Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with α1-antitrypsin deficiency. Am J Respir Crit Care Med 2003;168:818–900.10.1164/rccm.168.7.818Search in Google Scholar PubMed
22. Santangelo S, Scarlata S, Poeta ML, Bialas AJ, Paone G, Incalzi RA. α1-antitrypsin deficiency: current perspective from genetics to diagnosis and therapeutic approaches. Curr Med Chem 2017;24:65–90.10.2174/0929867324666161118125827Search in Google Scholar PubMed
24. Corda L, Bertella E, Pini L, Pezzini A, Medicina D, Boni E, et al. Diagnostic flow chart for targeted detection of α1-antitrypsin deficiency. Respir Med 2006;100:463–70.10.1016/j.rmed.2005.06.009Search in Google Scholar PubMed
25. Ferrarotti I, Gorrini M, Scabini R, Ottaviani S, Mazzola P, Campo I, et al. Secondary outputs of α1-antitrypsin deficiency targeted detection programme. Respir Med 2008;102: 354–58.10.1016/j.rmed.2007.10.015Search in Google Scholar PubMed
26. De la Roza C, Rodríguez-Frías F, Lara B, Vidal R, Jardí R, Miravitlles M. Results of a case-detection programme for α1-antitrypsin deficiency in COPD patients. Eur Respir J 2005;26:616–22.10.1183/09031936.05.00007305Search in Google Scholar PubMed
27. de Serres FJ, Blanco I. Prevalence of α1-antitrypsin deficiency alleles PI*S and PI*Z worldwide and effective screening for each of the five phenotypic classes PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: a comprehensive review, 2012 [Internet]. http://journals.sagepub.com/doi/abs/10.1177/1753465812457113. Accessed: 28 Sep 2018.10.1177/1753465812457113Search in Google Scholar PubMed
29. Hersh CP, Dahl M, Ly NP, Berkey CS, Nordestgaard BG, Silverman EK. Chronic obstructive pulmonary disease in α1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax 2004;59:843–9.10.1136/thx.2004.022541Search in Google Scholar PubMed PubMed Central
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