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.

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.

Journal of Medical Biochemistry

The Journal of Society of Medical Biochemists of Serbia

Journal Information


IMPACT FACTOR 2017: 1.378
5-year IMPACT FACTOR: 0.704



CiteScore 2017: 1.05

SCImago Journal Rank (SJR) 2017: 0.307
Source Normalized Impact per Paper (SNIP) 2017: 0.532

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 162 161 17
PDF Downloads 84 84 9