Alpha-1-antitrypsin deficiency: diagnosis and treatment (literature review)

Alpha-1 antitrypsin deficiency is a genetic disorder characterized by low level of alfa-1-antitripsin protein (A1AT) in the blood. Usually, A1AT deficiency results in chronic obstructive pulmonary disease (COPD), emphysemas, liver disease and vessels damaging. A1AT is the main inhibitor of serine proteases in human blood. A1AT deficiency is caused by mutations in the gene SERPINA1. The most common SERPINA1 allelic variants are S (p.Glu288Val) and Z (p.Glu366Lys). However, the most of documented severe cases of A1AD are associated with PIZZ genotype. PIZZ genotype patients have loss-of-function phenotype due to accelerated lung parenchyma destruction resulting in emphysema. Z mutation genotype leads to blocking of 85% synthesized protein in hepatocytes due to wrong folding and polymerization. Accumulation of the bodied protein in hepatocytes endoplasmic reticulum results in chronic liver disease, cirrhosis and other liver pathologies. A1AT deficiency is a common disorder, however, this diagnosis is established in a small part of the patients. A1AT deficiency is often misdiagnosed as COPD, asthma or сryptogenic liver disease. Usually, due to underestimating the prevalence of the disease and its unspecific symptoms, the diagnosis delay is more than 5 years (on average about 8 years). Nowadays it is possible to treat lung form of A1AT deficiency used the augmentation therapy, that bases on intravenous infusions of pure human A1AT. Also, the active development of new drugs to improve the prognosis in the patients with liver pathology is ongoing. Modern approaches of A1AT deficiency treatment, focused on gene therapy, are becoming a promising direction in the managing of both pulmonary and hepatic pathology with A1AT deficiency.

аlpha-1 antitrypsin, аlpha-1 antitrypsin deficiency, SERPINA1, PIZZ, chronic obstructive pulmonary disease (COPD), emphysema, cirrhosis, augmentation therapy

1. Torres-Durán M., Lopez-Campos J.L., Barrecheguren M., et al. Alpha-1 antitrypsin deficiency: outstanding questions and future directions. Orphanet J Rare Dis. 2018;13(1):114.

2. Crossley D., Stockley R., Sapey E. Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease? Drugs Aging. 2019;36(9):823-840.

3. Cox D.W., Billingsley G.D., Mansfield T. DNA restriction-site polymorphisms associated with the alpha 1-antitrypsin gene. Am J Hum Genet. 1987;41(5):891-906.

4. 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(7):818-900.

5. de Serres F., Blanco I. Role of alpha-1 antitrypsin in human health and disease. J Intern Med. 2014;276(4):311-35.

6. Kalfopoulos M., Wetmore K., ElMallah M.K. Pathophysiology of Alpha-1 Antitrypsin Lung Disease. Methods Mol Biol. 2017;1639:9-19.

7. de Serres F.J., 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. Ther Adv Respir Dis. 2012;6(5):277-95.

8. Brantly M., Campos M., Davis A.M., et al. Detection of alpha-1 antitrypsin deficiency: the past, present and future. Orphanet J Rare Dis. 2020;15(1):96.

9. Stoller J.K., Aboussouan L.S. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-59.

10. Мельник С.И., Власов Н.Н., Пиневская М.В, и др. Дефицит альфа-1-антитрипсина у детей: описание серии случаев. Вопросы современной педиатрии. 2016;15(6):619-624.

11. Teckman J.H., Blomenkamp K.S. Pathophysiology of Alpha-1 Antitrypsin Deficiency Liver Disease. Methods Mol Biol. 2017;1639:1-8.

12. Al-Jameil N., Hassan A.A., Hassanato R., et al. The prevalence of PI*S and PI*Z SERPINA1 alleles in healthy individuals and COPD patients in Saudi Arabia: A case-control study. Medicine (Baltimore). 2017;96(42):e8320.

13. Craig T.J., Henao M.P. Advances in managing COPD related to α(1) -antitrypsin deficiency: An under-recognized genetic disorder. Allergy. 2018;73(11):2110-2121.

14. Silva D., Oliveira M.J., Guimarães M., et al. Alpha-1-antitrypsin (SERPINA1) mutation spectrum: Three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal. Respir Med. 2016;116:8-18.

15. Mitchell E.L., Khan Z. Liver Disease in Alpha-1 Antitrypsin Deficiency: Current Approaches and Future Directions. Curr Pathobiol Rep. 2017;5(3):243-252.

16. McGee D., Schwarz L., McClure R., et al. Is PiSS Alpha-1 Antitrypsin Deficiency Associated with Disease? Pulm Med. 2010;2010:570679.

17. Matamala N., Martínez M.T., Lara B., et al. Alternative transcripts of the SERPINA1 gene in alpha-1 antitrypsin deficiency. J Transl Med. 2015;13:211.

18. Crowther D.C., Belorgey D. Miranda E., et al. Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. Eur J Hum Genet. 2004;12(3):167-72.

19. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. 1997;75(5):397-415.

20. Lace B., Sveger T., Krams A., et al. Age of SERPINA1 gene PI Z mutation: Swedish and Latvian population analysis. Ann Hum Genet. 2008;72(Pt 3):300-4.

21. Ferrarotti I., Ottaviani S., De Silvestri A., et al. Update on α(1)-antitrypsin deficiency. Breathe (Sheff). 2018;14(2):e17-e24.

22. Miskoff J.A., Khan B., Chaudhri M., et al. Identifying Alpha-1 Antitrypsin Deficiency Based on Computed Tomography Evidence of Emphysema. Cureus. 2019;11(1):e3971.

23. DeMeo D.L., Silverman E.K. Alpha1-antitrypsin deficiency. 2: genetic aspects of alpha(1)-antitrypsin deficiency: phenotypes and genetic modifiers of emphysema risk. Thorax. 2004;59(3):259-64.

24. Chiuchiolo M.J., Crystal R.G. Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease. Ann Am Thorac Soc. 2016;13 Suppl 4(Suppl 4):S352-69.

25. Mulgrew A.T., Taggart C.C., McElvaney N.G. Alpha-1-antitrypsin deficiency: current concepts. Lung. 2007;185(4):191-201.

26. Luisetti M., Seersholm N. Alpha1-antitrypsin deficiency. 1: epidemiology of alpha1-antitrypsin deficiency. Thorax. 2004;59(2):164-9.

27. Жигальцова-Кучинская О.А., Сивицкая Л.Н., Даниленко Н.Г., и др. Дефицит альфа-1-антитрипсина: генетические основы, эпидемилогия, значение в развитии бронхо-легочной патологии. Вестник ВГМУ. 2015;14(6):39-52.

28. Blanco I., Bueno P., Diego I., et al. Alpha-1 antitrypsin Pi*SZ genotype: estimated prevalence and number of SZ subjects worldwide. Int J Chron Obstruct Pulmon Dis. 2017;12:1683-1694.

29. Greulich T., Ottaviani S., Bals R., et al. Alpha1-antitrypsin deficiency - diagnostic testing and disease awareness in Germany and Italy. Respir Med. 2013;107(9):1400-8.

30. Miravitlles M., Dirksen A., Ferrarotti I., et al. European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α(1)-antitrypsin deficiency. Eur Respir J. 2017;50(5).

31. Rigobello C., Baraldo S., Tinè M., et al. Exome Sequencing Reveals Immune Genes as Susceptibility Modifiers in Individuals with α(1)-Antitrypsin Deficiency. Sci Rep. 2019;9(1):13088.

32. Brantly M.L., Lascano J.E., Shahmohammadi A. Intravenous Alpha-1 Antitrypsin Therapy for Alpha-1 Antitrypsin Deficiency: The Current State of the Evidence. Chronic Obstr Pulm Dis. 2018;6(1): 100-114.

33. Stiles K.M., Sondhi D., Kaminsky S.M., et al. Intrapleural Gene Therapy for Alpha-1 Antitrypsin Deficiency-Related Lung Disease. Chronic Obstr Pulm Dis. 2018;5(4):244-257.

34. Kaushal S., Annamali M., Blomenkamp K., et al. Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model. Exp Biol Med (Maywood). 2010;235(6):700-9.

35. Hidvegi T., Ewing M., Hale P., et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science. 2010;329(5988):229-32.

36. Wang Y., Cobanoglu M.C., Li J., et al. An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z. PLoS One. 2019;14(1):e0209748.

37. Flotte T.R., Mueller C. Gene therapy for alpha-1 antitrypsin deficiency. Hum Mol Genet. 2011;20(R1):R87-92.