Alpha-1-Antitrypsin Deficiency – Molecular Basis, Clinical Presentation, Therapeutic Options and an Integrative Approach in Diagnostics / DEFICIJENCIJA ALFA-1-ANTITRIPSINA – MOLEKULSKE OSNOVE, KLINIČKE MANIFESTACIJE, TERAPIJSKE MOGUĆNOSTI I INTEGRATIVNI PRISTUP U DIJAGNOSTICI

Open access

Summary

The primary role of alpha-1-antitrypsin (AAT), encoded by the highly polymorphic SERPINA1 gene, is to protect the lung parenchyma from proteolysis by neutrophil elastase. AAT deficiency (AATD) is an autosomal recessive disease, considered as the most important genetic cause of liver disease in children and emphysema in adults. According to frequency, deficient alleles can be classified as »common« (Z and S) and »rare« (Mmalton, Mheerlen, Mprocida etc). Type, intensity and onset of clinical disease associated with AATD occur as a result of interaction between AATD and additional genetic and acquired factors (tobacco smoking, air pollution exposure etc). The most frequent clinical manifestations include premature emphysema, chronic hepatitis, cirrhosis and hepatocellular carcinoma. Epidemiological studies highlight the need for improvement in diagnostic efficiency for AATD. It is recommended for a diagnostic approach to integrate precise, internationally recognized clinical criteria and a standardized laboratory protocol, based on a combination of biochemical and molecular methods. The predilection site of cli nical manifestations guides the therapeutic approach. Augmen tation therapy is possible in lung disease, while currently the only specific measure in patients with severe liver failure due to AATD is transplantation. In all patients, preventive measures, ammeliorating the deleterious effects of habits and environmental factors are recommended. Introduction of gene therapy is expected to additionally improve health outcomes in affected persons. Current results with an integrative AATD diagnostic strategy in the Serbian population are highly encouraging, prompting towards its further implementation in common medical practice with the ultimate goal to establish a national register of affected individuals.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • 1. Stoller JK Aboussouan LS. a-1 antitrypsin deficiency. Lancet 2005; 365: 2225-36.

  • 2. Stoller JK Brantly M. The Challenge of Detecting Alpha-1 Antitrypsin Deficiency. COPD 2013; 10(S1): 26-34.

  • 3. Mulgrew AT Taggart CC McElvaney MG. Alpha-1-antitrypsin deficiency: Current concepts. Lung 2007; 185: 191-201.

  • 4. Jepsson JO. a-1-ANTITRYPSIN. In: Ritchie RF editor. Se rum Proteins in Clinical Medicine Volume I: La boratory se c tion. 1st Edition. Atlanta: MODERNERA 1996: 8.01. 1-7.

  • 5. Tsutsuia Y Dela Cruzb R Wintrodea PL. Folding mechanism of the metastable serpin a1-antitrypsin. PNAS 2012; 109: 12: 4467-72.

  • 6. Janciauskiene SM Bals R Koczulla R Vogelmeier C Köhnlein T Welte T. The discovery of a-1-antitrypsin and its role in health and disease. Resp Med 2011; 105: 1129-39.

  • 7. Gooptu B Lomas DA. Conformational Pathology of the Serpins: Themes Variations and Therapeutic Strategies. Annu Rev Biochem 2009; 78: 147-76.

  • 8. Bergin DA Reeves EP Meleady P Henry M Me Elvany OJ et al. a-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J Clin Invest 2010; 120: 4236-50.

  • 9. Johnson AM. Amino acids peptides and proteins. In: Burtsi CA Ashwood ER Burns DE editors. Tietz textbook of clinical chemistry and molecular diagnostics. St. Louis: Elsevier Saunders 2006: 550-3.

  • 10. Crystal RG editor. Alpha1-antitrypsin deficiency. 1st edition. New York: Marcel Dekker Inc; 1996: 21-31.

  • 11. Silverman EK Sandhaus RA. Alpha1-Antitrypsin Deficiency. N Eng J Med 2009; 360: 2749-57.

  • 12. DeMeo DL Silverman EK. a-1 Antitrypsin deficiency • 2: Genetic aspects of a-1 Antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax 2004; 59: 259-64.

  • 13. Luisetti M Seersholm N. Alpha-1-antitrypsin deficiency • 1: Epidemiology of alpha 1-antitrypsin deficiency. Thorax 2004; 59: 164-9.

  • 14. Online Mendelian Inheritance in Man OMIM®. John Hopkins University Baltimore MD. MIM Number: 613490: updated: 8/17/2010. World Wide Web URL: http://omim.org/

  • 15. Blanco I de Serres FJ Fernandez-Bustillo E Lara B Miravitlles M. Estimated numbers and prevalence of PIS* and PIZ* alleles of a1-antitrypsin deficiency in European countries. Eur Respir J 2006; 27: 77-84.

  • 16. Carrell RW Lomas DA. Alpha1-Antitrypsin deficiency - a model for conformational disease. N Engl J Med 2002; 1: 45-53.

  • 17. Lomas DA Parfrey H. a-1 Antitrypsin deficiency-4: Molecular pathophysiology. Thorax 2004; 59: 529-35.

  • 18. Nelson DR Teckman J Di Bisciegli AM Brenner DA. Diagnosis and management of patients with a-1 antitrypsin (A1AT) deficiency. Clin Gastroent Hepat 2012; 10: 6: 575-80.

  • 19. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1-antitrypsin deficiency. Am J Respir Crit Care Med 2003; 168: 818-900.

  • 20. Marciniuk DD Hernandez P Balter M Bourbeau J Chapman KR Ford GT et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: A Canadian Thoracic Society clinical practice guideline. Can Respir J 2012; 19: 2: 109-16.

  • 21. Miravitlles M Herr C Ferrarotti I Jardi R Rodriguez- Frias Luisetti M et al. Laboratory testing of individuals with severe a1-antitrypsin deficiency in three European centres. Eur Respir J 2010; 35: 960-8.

  • 22. Snyder MR Katzmann JA Butz ML Yang P Dawson DB Kevin CH et al. Diagnosis of a-1-antitrypsin: an algorithm of quantification genotyping and phenotyping. Clin Chem 2006; 52: 12: 2236-42.

  • 23. Miravitlles M. Alpha-1-antitrypsin and other proteinase inhibitors. Curr Opin Pharmacol 2012; 12: 309-14.

  • 24. Flotte TR Mueller C. Gene therapy for alpha-1-antitrypsin deficiency. Hum Mol Genet 2011; 20: 1: R87-92.

  • 25. Brigham KL Lane KB Meyrick B Stecenko AA Strack S Cannon DR et al. Transfection of nasal mucosa with a normal alpha1-antitrypsin gene in alpha1-antitrypsindeficient subjects: comparison with protein therapy. Hum Gene Ther 2000; 11: 1023-32.

  • 26. Brantly ML Spencer LT Humphries M Conlon TJ Spencer CT Poirier A et al. Phase I trial of intramuscular injection of a recombinant adeno-associated virus serotype 2 alphal-antitrypsin (AAT) vector in AAT-deficient adults. Hum Gene Ther 2006; 17: 1177-86.

  • 27. Brantly ML Chulay JD Wang L Mueller C Humphries M Spencer LT et al. Sustained transgene expression despite T lymphocyte responses in a clinical trial of rAAV1-AAT gene therapy. Proc Natl Acad Sci 2009; 106: 16363-8.

  • 28. Chulay JD Ye GJ Thomas DL Knop DR Benson JM Hutt JA et al. Preclinical evaluation of a recombinant adeno-associated virus vector expressing human alpha-1 antitrypsin made using a recombinant herpes simplex virus production method. Hum Gene Ther 2011; 22: 155-65.

  • 29. Ekeowa UI Marciniak SJ Lomas DA. a-1 antitrypsin deficiency and inflammation. Expert Rev Clin Immunol 2011; 7: 2: 243-52.

  • 30. Jelić-Ivanović Z Spasojević-Kalimanovska V Topić A Spasić S Petrović V. Alpha-1 antitrypsin (Pi) polymorphism in Serbia: deviation of Pi M subtype distribution from the Hardy-Weinberg equilibrium. Gene Geogr 1994; 8: 129-35.

  • 31. Divac A Nikolić A Petrović-Stanojević N Dopuđa-Pantić V Radojković D. The frequency of Z and S mutated alleles of the alpha-1-anitrypsin gene in Serbian general population. Zvezdara Clin Proc 2004; 5: 1-2: 7-9.

  • 32. Beletić A Đorđević V Dudvarski-Ilić A Obradović I Mirković D Ilić M et al. Isoelectrofocusing and PCR amplification - Reverse Hybridization Assay in evaluation of Alpha-1-Antitrypsin Deficiency. Journal of Medical Biochemistry 2009; 28: 241-7.

  • 33. Waldenström J. Sick molecules and our concept of disease. J Intern Med 1989; 225: 221-7.

Search
Journal information
Impact Factor

IMPACT FACTOR 2018: 2.000
5-year IMPACT FACTOR: 1.075

CiteScore 2018: 1.47

SCImago Journal Rank (SJR) 2018: 0.523
Source Normalized Impact per Paper (SNIP) 2018: 0.581

Metrics
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 281 155 12
PDF Downloads 133 77 6