The patient profile of individuals with Alpha-1 antitrypsine gene mutations at a referral center in Brazil

J Bras Pneumol. 2018;44(5):383-389 http://dx.doi.org/10.1590/S1806-37562017000000420 ORIGINAL ARTICLE The patient profile of individuals with Alpha-1 antitrypsine gene mutations at a referral center in Brazil Manuela Brisot Felisbino1,a, Frederico Leon Arrabal Fernandes2,b, Maria Cecília Nieves Maiorano de Nucci2,c, Regina Maria de Carvalho Pinto2,d, Emilio Pizzichini1,e, Alberto Cukier2,f 1. Post-graduate Program in Medical Sciences, Universidade Federal de Santa Catarina, Florianópolis (SC) Brazil. 2. Pulmonology Division, Instituto do Coração, Hospital das Clínicas, School of Medicine, Universidade de São Paulo, São Paulo (SP) Brazil. a. http://orcid.org/0000-0001-7431-9290 http://orcid.org/0000-0002-3057-5716 b. http://orcid.org/0000-0003-1892-4618 c. http://orcid.org/0000-0002-6344-2127 d. http://orcid.org/0000-0001-7046-9996 e. http://orcid.org/0000-0002-7217-9498 f. Received: November 17, 2017. Approved: March 26, 2018. Study carried out at the Pulmonology Division, Instituto do Coração – InCor – Hospital das Clínicas, School of Medicine, Universidade de São Paulo, São Paulo (SP) Brazil. ABSTRACT Objective: The clinical, functional, radiological and genotypic descriptions of patients with an alpha-1 antitrypsin (A1AT) gene mutation in a referral center for COPD in Brazil. Methods: A cross-sectional study of patients with an A1AT gene mutation compatible with deficiency. We evaluated the A1AT dosage and genotypic, demographic, clinical, tomographic, and functional characteristics of these patients. Results: Among the 43 patients suspected of A1AT deficiency (A1ATD), the disease was confirmed by genotyping in 27 of them. The A1AT median dosage was 45 mg/dL, and 4 patients (15%) had a normal dosage. Median age was 54, 63% of the patients were male, and the respiratory symptoms started at the age of 40. The median FEV1 was 1.37L (43% predicted). Tomographic emphysema was found in 77.8% of the individuals. The emphysema was panlobular in 76% of them and 48% had lower lobe predominance. The frequency of bronchiectasis was 52% and the frequency of bronchial thickening was 81.5%. The most common genotype was Pi*ZZ in 40.7% of participants. The other genotypes found were: Pi*SZ (18.5%), PiM1Z (14.8%), Pi*M1S (7.4%), Pi*M2Z (3.7%), Pi*M1I (3.7%), Pi*ZMnichinan (3.7%), Pi*M3Plowell (3.7%), and Pi*SF (3.7%). We did not find any significant difference in age, smoking load, FEV1, or the presence of bronchiectasis between the groups with a normal and a reduced A1AT dosage, neither for 1 nor 2-allele mutation for A1ATD. Conclusions: Our patients presented a high frequency of emphysema, bronchiectasis and bronchial thickening, and early-beginning respiratory symptoms. The most frequent genotype was Pi*ZZ. Heterozygous genotypes and normal levels of A1AT also manifested significant lung disease. Keywords: Alpha-1 antitrypsin; Emphysema; Alleles. INTRODUCTION Alpha-1 antitrypsin deficiency (A1ATD) is a rare genetic disease that is related to the development of early emphysema and liver disease. Epidemiological studies estimate that A1ATD affects 1 in every 2,000 to 5,000 individuals born alive.(1) The only Brazilian study reporting on the prevalence of A1ATD estimates that 2.8% of patients with chronic obstructive pulmonary disease (COPD) have this deficiency.(2) The Platino study showed that, in the city of São Paulo, 15.8% of individuals aged 40 years or older had COPD,(3) which indicates that there is probably a large number of patients with undiagnosed A1ATD. Alpha-1 antitrypsin (A1AT), a highly pleomorphic glycoprotein, has more than 100 identified alleles, and its main function is to inhibit several proteases.(4,5) Its variants are inherited by codominance, and they are classified according to the protease inhibitor (PI) system.(6,7) The phenotypes that have the highest risk of developing pulmonary emphysema are those associated with low A1AT production, the most common being the Z mutation. However, other mutations, such as S, I, Mmalton, Mnichinan, Plowell and Null, can lead to low dosages of A1AT.(6) The production of a dysfunctional protein can also occur, as in Pittsburgh and F mutations. The most common mutated alleles that occur with normal A1AT serum levels are the M variants, which still do not have a defined clinical significance.(4,6,7) A1AT is produced primarily in the liver and, through the bloodstream, it reaches the lungs, where it performs its antielastolytic function.(4) When it is deficient, pulmonary emphysema occurs due to an imbalance in the protease-antiprotease ratio, which makes it incapable of protecting the lungs from the elastolytic action of neutrophil elastase,(8) among other aggressions, such as smoking and environmental exposures, leading to accelerated lung damage. Its diagnosis is made through examining the clinical patterns of the disease and the corresponding laboratory changes. When there is evidence of reduced A1AT serum levels, genotyping should be performed in order to identify their variants.(4,5,9) However, A1AT is an acute phase protein, and its levels may be increased in situations of inflammation, thus a diagnosis of A1ATD cannot be not excluded even with a single normal dosage.(4) Correspondence to: Manuela Brisot Felisbino. Centro de Ciências da Saúde, Programa de Pós-Graduação em Ciências Médicas, Hospital Universitário. Campus Universitário, Trindade, CEP 88040-970, Florianópolis, SC, Brasil. E-mail: Financial Support: None. © 2018 Sociedade Brasileira de Pneumologia e Tisiologia ISSN 1806-3713 383 The patient profile of individuals with Alpha-1 antitrypsine gene mutations at a referral center in Brazil To date, we do not have a clinical, radiological and functional description of patients with A1ATD in Brazil. Although the A1AT dosage is recommended to be checked routinely in patients with COPD, as suggested by the World Health Organization (WHO), the examination is rarely done due to unawareness, the unavailability of the test, and its high cost to the health system. Knowledge about these characteristics in a Brazilian population of patients can allow for a systematic screening criteria to be designed for individuals with high pretest probability for positive screening,(10) saving costs associated with the generalized screening for all patients with COPD. The primary objective of this study was the clinical, functional, radiological and genotypic characterization of A1ATD in a referral center specialized in respiratory diseases in Brazil, and to enable the design of a protocol for systematically tracking patients with COPD. We also compared the normal and altered A1AT dosage groups, and the groups with genotypes associated with one and two allele mutations for A1ATD. METHODS Study design A cross-sectional study with patients that have a mutation in the A1AT gene, who were treated at the COPD Outpatient Clinic of the Pulmonary Division of the Hospital das Clínicas at the Faculdade de Medicina of the Universidade de São Paulo ( (...truncated)