Update on and future perspectives for the diagnosis of alpha-1 antitrypsin deficiency in Brazil / Atualização e perspectivas futuras para o diagnóstico da deficiência de alfa-1 antitripsina no Brasil

ABSTRACT Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disorder caused by a mutation in the SERPINA1 gene, which encodes the protease inhibitor alpha-1 antitrypsin (AAT). Severe AATD predisposes individuals to COPD and liver disease. Early diagnosis is essential for implementing preventive measures and limiting the disease burden. Although national and international guidelines for the diagnosis and management of AATD have been available for 20 years, more than 85% of cases go undiagnosed and therefore untreated. In Brazil, reasons for the underdiagnosis of AATD include a lack of awareness of the condition among physicians, a racially diverse population, serum AAT levels being assessed in a limited number of individuals, and lack of convenient diagnostic tools. The diagnosis of AATD is based on laboratory test results. The standard diagnostic approach involves the assessment of serum AAT levels, followed by phenotyping, genotyping, gene sequencing, or combinations of those, to detect the specific mutation. Over the past 10 years, new techniques have been developed, offering a rapid, minimally invasive, reliable alternative to traditional testing methods. One such test available in Brazil is the A1AT Genotyping Test, which simultaneously analyzes the 14 most prevalent AATD mutations, using DNA extracted from a buccal swab or dried blood spot. Such advances may contribute to overcoming the problem of underdiagnosis in Brazil and elsewhere, as well as being likely to increase the rate detection of AATD and therefore mitigate the harmful effects of delayed diagnosis.

RESUMO A deficiência de alfa-1 antitripsina (DAAT) é um distúrbio genético raro causado por uma mutação no gene SERPINA1, que codifica o inibidor de protease alfa-1 antitripsina (AAT). A DAAT predispõe os indivíduos a DPOC e doença hepática. O diagnóstico precoce é essencial para a implementação de medidas preventivas e para limitar a carga da doença. Embora diretrizes nacionais e internacionais para o diagnóstico e manejo da DAAT estejam disponíveis há 20 anos, mais de 85% dos casos não são diagnosticados e, portanto, não são tratados. No Brasil, os motivos para o subdiagnóstico da DAAT incluem o desconhecimento dos médicos sobre a condição, a diversidade racial da população, o fato de os níveis séricos de AAT serem avaliados em um número limitado de indivíduos e a falta de ferramentas diagnósticas convenientes. O diagnóstico da DAAT baseia-se em resultados de exames laboratoriais. A abordagem diagnóstica padrão envolve a avaliação dos níveis séricos de AAT, seguida de fenotipagem, genotipagem, sequenciamento gênico ou suas combinações para detecção da mutação específica. Nos últimos 10 anos, novas técnicas foram desenvolvidas, oferecendo uma alternativa rápida, minimamente invasiva e confiável aos métodos tradicionais de teste. Um desses testes disponíveis no Brasil é o teste de genotipagem A1AT, que analisa simultaneamente as 14 mutações mais prevalentes da DAAT usando DNA extraído de swab bucal ou de sangue em papel-filtro. Esses avanços podem contribuir para a superação do problema do subdiagnóstico no Brasil e em outros países, bem como podem aumentar a taxa de detecção da DAAT e, portanto, mitigar os malefícios do diagnóstico tardio.

Deficiencia de alfa-1 antitripsina y neumotórax espontáneo. ¿Solo una coincidencia? / Alpha-1 antitrypsin deficiency and spontaneous pneumothorax. Just a coincidence?

Resumen La deficiencia de alfa-1 antitripsina (AAT) es uno de los trastornos hereditarios más frecuentes y con mayor incidencia en pacientes con enfermedad pulmonar obstructiva crónica (EPOC). Se desconoce su prevalencia en aquellos con neumotórax espontáneo. El objetivo fue estimar la prevalencia de deficiencia de AAT en sujetos con neumotórax espontáneo. El estudio fue prospectivo y de corte transversal en pacientes con neumotórax espontáneo primario. Se excluyeron aquellos con neumotórax secundario. Se realizó cuantificación de AAT en suero por nefelometría y posterior genotipificación rápida (PCR en tiempo real) para detectar los alelos de deficiencia más prevalentes (Z y S) en aquellos con concentraciones séricas ≤ 120 mg/dl. Se incluyeron 58 pacientes con neumotórax espontáneo primario. La edad promedio fue de 34 ± 13 años con predominio de sexo masculino (72%) y alta prevalencia de tabaquismo actual y pasado (60%). Del total, el 26% (IC95%: 15-39) presentó concentraciones de AAT ≤ 120mg/dl. Encontramos 7 formas deficitarias (12%; IC 95%: 5-23%). Un paciente presentó una forma grave Pi*ZZ (1.7%), 3 fueron heterocigotos Z (5.2%) y 3 heterocigotos S (5.2%). La prevalencia de variantes deficitarias de AAT fue alta en este grupo con neumotórax espontáneo.

Abstract Alpha-1 antitrypsin (AAT) deficiency is one of the most common inherited disorders with a higher incidence in patients with chronic obstructive pulmonary disease (COPD). Its prevalence in patients with spontaneous pneumothorax is unknown. The objective was to estimate the prevalence of AAT deficiency in patients with spontaneous pneumothorax. This was a prospective cross-sectional study, in patients with spontaneous pneumothorax, where those with secondary pneumothorax were excluded. Quantification of serum AAT by nephelometry and subsequent rapid genotyping (real time PCR) was performed, in order to detect the most prevalent deficiency alleles (Z and S) in those subjects with serum AAT concentrations ≤ 120 mg/dl. Fifty-eight patients with primary spontaneous pneumothorax were included. The average age was 34 ± 13 years with male predominance (72%) and high prevalence of current and past smoking (60%). Twenty six percent of them (95% CI: 15-39) presented AAT serum concentrations ≤ 120mg/dl. We found 7 deficiency variants (12%; IC 95%: 5-23%). One patient presented a severe Pi*ZZ form (1.7%), 3 were heterozygotes Z (5.2%) and 3 heterozygotes S (5.2%). The prevalence of AAT deficient variants was high in patients with spontaneous pneumothorax.

Déficit de Alfa-1 antitripsina, una causa de hepatopatía crónica comúnmente insospechada en el adulto: presentación de 9 casos con revisión de literatura / ALFA-1 antitrypsin deficiency, a commonly missed cause of chronic liver disease in the adult: presentation of 9 cases with review of current literature

Introducción: El déficit de alfa-1 Antitripsina (a1AT) es una de las enfermedades genéticas más prevalentes en el ser humano, lastimosamente como entidad clínica tiende a ser pobremente sospechada. Con más de 100 mutaciones conocidas, las que se encuentran asociadas a enfermedad hepática son los homocigotos Z en el alelo del gen a1AT que ocurre en 1 a 2000- 3500 nacimientos. A diferencia de la enfermedad pulmonar donde las secuelas ocurren primordialmente por el déficit propio de la a1AT con destrucción enzimática de la microestructura de la vía aérea, el compromiso hepático ocurre por acúmulo intracelular de la proteína Z mutante, que se desdobla de forma aberrante, en vez de ser secretada. Esta acumulación produce lesión celular, hepatitis, fibrosis, cirrosis y carcinoma hepatocelular (CHC) por desencadenar una serie de eventos que culminan con la apoptosis hepatocitaria, regeneración e injuria crónica. Materiales y métodos: Se presentan 9 casos de pacientes que se han encontrado bajo nuestro cuidado, con edades variadas desde infantes hasta adultos mayores. Resultados: Cada uno con una presentación clínica distinta que va desde la elevación de enzimas hepáticas y otros como cirrosis que se han trasplantado con diagnóstico confirmatorio postquirúrgico. Conclusión: Se comenta acerca del manejo de la hepatopatía y su progresión a lo largo del tiempo que se han mantenido en la clínica de hígado a nuestro cargo.

Introduction: Alfa 1-antitrypsin deficiency is one of the most prevalent genetic diseases in the human being, sadly it is not a commonly suspected clinical entity. With more than 100 known mutations, those associated with hepatic disease are the Z homocygote allele mutations in the gene a1AT which occur in every 2000-3500 births. Opposing to the pulmonary disease, in which de sequelae are caused by the deficit of this protein which in turn fastens the enzymatic destruction of the airway microstructure, the hepatic compromise is secondary to the intracellular accumulation of the aberrant misfolded protein. This accumulation causes cellular damage, hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma through activation of a series of mechanisms which culminate in hepatocitary apoptosis, regeneration and chronic cellular injury. Materials and methods: 9 cases of confirmed a1AT deficiency are presented, from different ages ranging from adolescence through elderly patients. Results: Each of one of them with different clinical presentation going from asymptomatic liver enzyme elevations to transplanted cirrhosis in which the diagnosis was post procedural. Conclusion: We comment about the management of the chronic liver disease and the evolution of these patients through time in the liver clinic.

The patient profile of individuals with Alpha-1 antitrypsine gene mutations at a referral center in Brazil / Perfil dos pacientes com mutação no gene da alfa-1 antitripsina em um centro de referência no Brasil

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.

RESUMO Objetivo: Caracterização clínica, funcional, radiológica e genotípica dos pacientes portadores de mutações do gene da alfa-1 antitripsina (A1AT) em um centro de referência em doença pulmonar obstrutiva crônica (DPOC) no Brasil. Métodos: Estudo transversal de pacientes com mutação no gene da A1AT compatível com deficiência. Foram avaliadas características genotípicas, demográficas, clínicas, tomográficas, de função pulmonar, e dosagem de A1AT. Resultados: De 43 pacientes suspeitos para deficiência de alfa-1 antitripsina (DA1AT), a doença foi confirmada por genotipagem em 27. A mediana da dosagem de A1AT foi de 45 mg/dL, e 4 pacientes (15%) apresentavam dosagens normais. A idade mediana foi de 54 anos, 63% dos participantes eram do sexo masculino e a idade do início dos sintomas prevalente foi aos 40 anos. A mediana do volume expiratório forçado no primeiro segundo (VEF1) foi de 1,37 L (43% do previsto). Enfisema tomográfico foi encontrado em 77,8% dos indivíduos, sendo panlobular em 76% e de predomínio em lobos inferiores em 48%. A frequência de bronquiectasias foi de 52%, e a de espessamento brônquico, de 81,5%. O genótipo mais encontrado foi Pi*ZZ (40,7%). Os demais genótipos foram: Pi*SZ (18,5%), Pi*M1Z (14,8%), Pi*M1S (7,4%), Pi*M2Z (3,7%), Pi*M1I (3,7%), Pi*ZMnichinan (3,7%), Pi*M3Plowell (3,7%) e Pi*SF (3,7%). Não encontramos diferença significativa para idade, carga tabágica, VEF1 e presença de bronquiectasias entre os grupos com dosagem de A1AT normal versus alterada, nem entre 1 alelo versus 2 alelos com mutação para DA1AT. Conclusões: Nossos pacientes apresentaram alta frequência de enfisema, bronquiectasias e espessamento brônquico, com início precoce dos sintomas respiratórios. O genótipo mais frequente foi Pi*ZZ, embora genótipos heterozigotos e níveis normais de A1AT também tenham se manifestado com doença pulmonar significativa.

Cuando el problema es infrecuente, todos los datos son valiosos / When the problem is infrequent, all the data are valuable

Las cifras publicadas en la literatura internacional dejan en claro que el déficit de alfa 1 antitripsina (DAAT) constituye una enfermedad poco frecuente y subdiagnosticada. El subregistro de enfermedades, principalmente aquellas de baja prevalencia, constituye un problema que se debe tener en cuenta constantemente en la práctica médica, ya que día a día encontramos que nuestras líneas de pensamiento en la profesión están guiadas por posibilidades y probabilidades. Las enfermedades raras, a menos que se presenten con todas sus características en exposición, quedan relegadas a segundas o terceras consideraciones al momento de la evaluación de un paciente. De hecho, más allá de una consideración personal que parece representar esta reflexión, encuentro apoyo en el artículo de los colegas de Córdoba, quienes mencionan que "los pacientes diagnosticados precozmente se relacionan más con antecedentes familiares de DAAT que por sospecha clínica en pacientes EPOC o sintomáticos"1. Pensamos en la enfermedad infrecuente cuando se presenta con nombre y apellido

Programa de cribado para el déficit De alfa 1-antitripsina en el servicio de neumonología del Hospital Tránsito Cáceres de Allende / Alpha-1-antitrypsin deficiency screening program at the Pneumonology Department of Hospital Tránsito Cáceres de Allende

El déficit de alfa -1 Antitripsina (DAAT) es una enfermedad genética rara, asociada a un incremento a padecer enfisema pulmonar y hepatopatía crónicas en niños y adultos, frecuentemente subdiagnosticada, con largos retrasos entre el inicio de los síntomas y el diagnóstico definitivo. La alfa 1-antitripsina (AAT) es el inhibidor de proteasas más abundante en el organismo humano. Se considera déficit grave y es a lo que habitualmente se refiere la literatura científica a los siguientes fenotipos: SZ, ZZ y Null. Es necesario programas de cribado para su detección precoz, por lo que se ha descripto y validado un método sencillo y específico, mediante el cual se cuantifica el valor de AAT por nefelometría en muestras de gota de sangre en papel secante y se realiza genotipificación rápida de las variantes Z y S. Objetivos: Determinar la proporción de individuos con DAAT en una población de pacientes con enfermedades respiratorias crónicas. Identificar y caracterizar a aquellos con déficit de AAT. Materiales y Método: Estudio Observacional, Descriptivo de corte Transversal de cribado de déficit de AAT, entre el 2 de enero de 2014 a 30 de marzo de 2015. De 80 personas que cumplieron con los criterios de inclusión y que concurrieron de forma espontánea o por derivación al Servicio de Neumonología del Hospital Tránsito Cáceres de Allende, Córdoba, Argentina, se analizaron 62 pacientes que aceptaron realizarse el estudio. Se realizó dosaje de alfa1-antitripsina mediante gota de sangre en papel secante a los pacientes que cumplieron los criterios de inclusión. Se solicitó espirometría, Tomografía Computada de Tórax de Alta Resolución y genotipificación rápida solo a aquellos pacientes con valores de alfa 1-antitripsina < 1,8 mg/dL. Resultados: En el presente trabajo se estudió un total de 62 pacientes, 28 (45,2%) fueron de sexo femenino y 34 (54,8%) de sexo masculino, 37 (59,7%) tuvieron valores de alfa 1-antitripsina ≥ 1,8 mg/dL y 25 (40,3%) < 1,8 mg/dL. La obtención del genotipo por la técnica de gota seca a 25 (40,3%; 25:62) pacientes con valores < 1,8 mg/dL mostró que: 22 (88%; 22:25) fueron NoS NoZ, 2 (8%; 2:25) Heterocigoto para Z y 1 (4%; 1:25) Heterocigoto para S. El patrón espirométrico predominante según criterio de ATS/ERS fue el obstructivo (88%). El patrón en TCAR fue de enfisema en 22 pacientes (88%): 7 (31,8%) centrolobulillar, 8 (36,4%) paraseptal, 7 (31,8%) panlobulillar. Hubo 2 pacientes (8%) con bronquiectasias, y 1 (4%) fue normal. Conclusión: En una población seleccionada por síntomas y/o antecedentes se pueden identificar con el cribado con técnica de gota seca a pacientes con DAAT, que en su expresión grave es poco frecuente en la Argentina, probablemente subdiagnosticado, siendo superior el número de portadores heterocigotos PIS y PIZ. El diagnóstico precoz de DAAT es poco frecuente. Es difícil establecer conclusiones sobre el grupo de alfa 1-antitripsina <1,8 mg/dL sin ser deficiencias graves, en relación a las variables estudiadas en la muestra debido a la escases de estudios y bibliografía encontradas sobre el tema. Consideramos que los pacientes que presentan un genotipo No S No Z y los que presentan discordancia deben ser confirmados cuantitativamente y tener una caracterización del fenotipo en muestras de suero por Isoelectoenfoque y ocasionalmente el análisis molecular del gen para variantes alélicas poco frecuentes, nuevas o nulas.

Alpha-1-antitrypsin deficiency screening program at the Pneumonology Department of Hospital Tránsito Cáceres de Allende

Alpha-1-antitrypsin deficiency (AATD) is a rare genetic disease associated with an increased risk of suffering from pulmonary emphysema and chronic hepatopathy in children and adults alike. It is often underdiagnosed, with long periods elapsing between the onset of symptoms and a definite diagnosis. Alpha-1-antitrypsin (AAT) is the most abundant protease inhibitor in the human body. Scientific literature considers severe deficiency to be associated with the following phenotypes: SZ, ZZ and Null. Screening programs are required for early detection, this is why an easy and specific method has been described and validated. Through this method, AAT values are quantified using nephelometry in blood drop samples on blotting paper, then genotyping of the Z and S variants is quickly performed. Objectives: To determine the number of individuals with AATD within a population of patients with chronic respiratory diseases. To identify and define those with AAT deficiency. Materials and Method: Observational, descriptive and cross-sectional study of AAT deficiency screening, between January 2nd, 2014 and March 30th, 2015. Out of 80 individuals who fulfilled the inclusion criteria and who spontaneously attended or were referred to the Pneumonology Department of Hospital Tránsito Cáceres de Allende, Córdoba, Argentina, 62 patients who agreed to the study were analyzed. A test to determine the concentration of alpha-1-antitrypsin was performed to the patients who met all the inclusion criteria using blood drops on blotting paper. Only patients with alpha-1-antitrypsin levels < 1.8 mg/dL were requested a spirometry, a high-resolution computed tomography of the chest and quick genotyping tests. Results: A total of 62 patients was evaluated in this study, 28 (45.2%) were females and 34 (54.8%) were males, 37 (59.7%) had alpha-1-antitrypsin levels ≥ 1.8 mg/dL and 25 (40.3%) < 1.8 mg/dL. Genotype elicitation using the dried-droplet method in 25 (40.3%; 25:62) patients with values < 1.8 mg/dL showed that: 22 (88%; 22:25) were Non-S Non-Z, 2 (8%; 2:25) were heterozygote for Z and 1 (4%; 1:25) was heterozygote for S. According to ATS/ERS criteria, the predominant spirometric pattern was obstructive (88%). The HRCT pattern corresponded to emphysema in 22 patients (88%): 7 (31.8%) centrilobular, 8 (36.4%) paraseptal, 7 (31.8%) panlobular. There were 2 patients (8%) with bronchiectasis and 1 (4%) was normal. Conclusion: In a population selected by symptoms and/or history, patients with AATD can be identified using the dried-droplet method. Severe AATD is uncommon in Argentina, probably because it is underdiagnosed, and the amount of heterozygote PIS and PIZ carriers is higher. Early AATD diagnosis is uncommon. It is difficult to draw conclusions about the alpha-1-antitrypsin group below 1.8 mg/dL without severe deficiencies in connection with the variables analyzed in the sample due to the lack of studies and bibliography on this subject. We consider that patients with non-S non-Z genotypes and the ones with discrepancies must be quantitatively confirmed and their phenotype defined in serum samples using isoelectric focusing and, occasionally, they must have a molecular gene analysis to look for uncommon, new or null allelic variants.

Déficit de Alfa-1-antitripsina y su tratamiento / Alpha-1 antitrypsin deficiency and its treatment

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by a mutation in the codifying gene for the alpha-1 antitrypsin (AAT) protein, which has anti-elastase activity. While there is extensive genetic variability, the most common genotypes associated with AATD are PI*Z y PI*S. Most clinical manifestations are pulmonary (i.e. emphysema) and hepatic, though other pathologies, such as panniculitis and Wegener's granulomatosis, can also present with this disorder. To date, there is no cure for AATD, and treatment options are focused on reducing the frequency of exacerbations and relieving symptoms; among these, augmentation therapy, which raises AAT levels through serum injections of the protein to correct the deficit, has been the most effective. Novel findings of this therapy are discussed, along with research efforts that explore new treatment options based on gene therapy or the use of protein chaperones, for instance. In Chile, no epidemiological studies on AATD have been conducted, so it is unknown exactly how many individuals are affected or if they receive adequate treatment. (AU)

Deficiência de alfa-1 antitripsina: uma condição subdiagnosticada / Alpha-1 antitrypsin deficiency: an underdiagnosed condition

A deficiência de alfa-1-antitripsina (AAT) é associada ao desenvolvimento de doenças hepáticas graves e enfisema pulmonar precoce. Em todo o mundo, considera-se que apenas 2% dos casos estimados da deficiência de AAT tenham sido diagnosticados. A disciplina de Pneumologia da Universidade do Estado do Rio de Janeiro vem realizando testes de varredura para deficiência de AAT através da técnica de nefelometria em papel filtro em todos os pacientes com diagnóstico de DPOC. A prevalência de mutações graves encontradas nos genes da AAT em pacientes com DPOC foi de 2,4% e não difere dos dados existentes previamente na literatura, mas o número de outros pacientes com mutações leves é bastante elevado (4%). As autoras sugerem que a dosagem sistemática de AAT em todos os pacientes com DPOC possa ser uma estratégia eficiente para captura dos pacientes com deficiência enzimática, permitindo que medidas preventivas como a suspensão do fumo e o aconselhamento genético seja efetivadas.

Alpha-1-antitrypsin deficiency (AAT) is associated with the development of severe liver disease and early pulmonary emphysema. Around the world, only 2% of the estimated cases of AAT deficiency are believed to have been diagnosed. The discipline of Pulmonology of the University of the State of Rio de Janeiro has been conducting tests for AAT deficiency by filter nephelometry technique in all patients diagnosed with COPD. The prevalence of severe mutations found in AAT genes in patients with COPD was 2.4% and does not differ from previous data in the literature, but the number of other patients with mild mutations is quite high (4%). The authors suggest that the systematic dosing of AAT in all patients with COPD may be an effective strategy to capture patients with enzyme deficiency, allowing preventive measures such as smoking cessation and genetic counseling to be effective.

Prevalence of alpha-1 antitrypsin deficiency and allele frequency in patients with COPD in Brazil / Prevalência da deficiência de alfa-1 antitripsina e frequência alélica em pacientes com DPOC no Brasil

ABSTRACT Objective: To determine the prevalence of alpha 1-antitrypsin (AAT) deficiency (AATD), as well as allele frequency, in COPD patients in Brazil. Methods: This was a cross-sectional study involving 926 COPD patients 40 years of age or older, from five Brazilian states. All patients underwent determination of AAT levels in dried blood spot (DBS) samples by nephelometry. Those with DBS AAT levels ≤ 2.64 mg/dL underwent determination of serum AAT levels. Those with serum AAT levels of < 113 mg/dL underwent genotyping. In case of conflicting results, SERPINA1 gene sequencing was performed. Results: Of the 926 COPD patients studied, 85 had DBS AAT levels ≤ 2.64 mg/dL, and 24 (2.6% of the study sample) had serum AAT levels of < 113 mg/dL. Genotype distribution in this subset of 24 patients was as follows: PI*MS, in 3 (12.5%); PI*MZ, in 13 (54.2%); PI*SZ, in 1 (4.2%); PI*SS, in 1 (4.2%); and PI*ZZ, in 6 (25.0%). In the sample as a whole, the overall prevalence of AATD was 2.8% and the prevalence of the PI*ZZ genotype (severe AATD) was 0.8% Conclusions: The prevalence of AATD in COPD patients in Brazil is similar to that found in most countries and reinforces the recommendation that AAT levels be measured in all COPD patients.

RESUMO Objetivo: Determinar a prevalência da deficiência de alfa 1-antitripsina (AAT), bem como a frequência alélica, em pacientes com DPOC no Brasil. Métodos: Estudo transversal com 926 pacientes com DPOC, com 40 anos ou mais, oriundos de cinco estados brasileiros. Todos os pacientes foram submetidos a dosagem de AAT em amostras de sangue seco por meio de nefelometria. Aqueles em que a concentração de AAT no sangue seco foi ≤ 2,64 mg/dl foram submetidos a dosagem sérica de AAT. Aqueles em que a concentração sérica de AAT foi < 113 mg/dl foram submetidos a genotipagem. Quando os resultados foram discrepantes, foi realizado o sequenciamento do gene SERPINA1. Dos 926 pacientes com DPOC estudados, 85 apresentaram concentração de AAT em sangue seco ≤ 2,64 mg/dl, e 24 (2,6% da amostra) apresentaram concentração sérica de AAT < 113 mg/dl. A distribuição genotípica nesse subgrupo de 24 pacientes foi a seguinte: PI*MS, em 3 (12,5%); PI*MZ, em 13 (54,2%); PI*SZ, em 1 (4,2%); PI*SS, em 1 (4,2%); e PI*ZZ, em 6 (25,0%). Na amostra estudada, a prevalência global da deficiência de AAT foi de 2,8% e a prevalência do genótipo PI*ZZ (deficiência grave de AAT) foi de 0,8%. Conclusões: A prevalência da deficiência de AAT em pacientes com DPOC no Brasil é semelhante àquela encontrada na maioria dos países e reforça a recomendação de que se deve medir a concentração de AAT em todos pacientes com DPOC.

Infected tracheal diverticulum: a rare association with alpha-1 antitrypsin deficiency / Divertículo da traqueia infectado: um caso de associação rara com deficiência de alfa-1 antitripsina

Tracheal diverticulum, defined as a benign outpouching of the tracheal wall, is rarely diagnosed in clinical practice. It can be congenital or acquired in origin, and most cases are asymptomatic, typically being diagnosed postmortem. We report a case of a 69-year-old woman who was hospitalized after presenting with fever, fatigue, pleuritic chest pain, and a right neck mass complicated by dysphagia. Her medical history was significant: pulmonary emphysema (alpha-1 antitrypsin deficiency); bronchiectasis; and thyroidectomy. On physical examination, she presented diminished breath sounds and muffled heart sounds, with a systolic murmur. Laboratory tests revealed elevated inflammatory markers, a CT scan showed an air-filled, multilocular mass in the right tracheal wall, and magnetic resonance imaging confirmed the CT findings. Fiberoptic bronchoscopy failed to reveal any abnormalities. Nevertheless, the patient was diagnosed with tracheal diverticulum. The treatment approach was conservative, consisting mainly of antibiotics. After showing clinical improvement, the patient was discharged.

Divertículos da traqueia são evaginações benignas da parede traqueal e raramente diagnosticados na prática clínica. Podem ser congênitos ou adquiridos, e na maioria dos casos são assintomáticos, sendo tipicamente diagnosticados em estudos post-mortem. Relatamos o caso de uma mulher de 69 anos que foi hospitalizada após apresentar febre, fadiga, dor torácica pleurítica e uma massa cervical à direita complicada por disfagia. Tinha antecedentes pessoais de enfisema pulmonar (deficiência de alfa-1 antitripsina), bronquiectasias e tireoidectomia. Ao exame físico apresentava murmúrio vesicular diminuído, hipofonese cardíaca e um sopro sistólico. Laboratorialmente apresentava marcadores inflamatórios elevados, e uma TC mostrou uma massa aérea, multiloculada na parede direita da traqueia, achados confirmados por ressonância magnética nuclear. Realizou ainda uma fibrobroncoscopia que se revelou normal. Assumiu-se o diagnóstico de divertículo da traqueia. O tratamento proposto foi conservador, consistindo principalmente de antibioticoterapia. Após melhora clínica, a paciente recebeu alta.

Federico Chopin (1810-1849) y su enfermedad / Frederic Chopin (1810-1849), and his disease

Frédéric Chopin - a great Polish composer and pianist-suffered from a chronic disease. Both during his life and after his death, physicians disagreed on Chopin's diagnosis. His contemporaries accepted the diagnosis of tuberculosis, a common disease in the 18th century. Description of new clinical entities provoked new dilemmas in the 21th century. Although other alternative diagnoses to tuberculosis have emerged, such as cystic fibrosis or alpha-1 antitrypsin deficiency, we still sustain that the first diagnosis is the most probable. In this paper we report F. Chopin's case history and discuss cons and pros for different diseases as the cause of F. Chopin's suffering and death.

rare case of alpha 1-antitrypsin deficiency associated with hypogammaglobulinemia and recurrent pulmonary thrombosis

Alpha 1 -antitrypsin [AAT] belongs to the family of serpins [serine protease inhibitors]. Loop sheet polymerization is the pathology behind serpinopathies which encompasses AAT, anti-thrombin III and neuroserpin deficiency. To the best of our knowledge, we report the first case of alpha 1-antitrypsin deficiency associated with hypogammaglobulinemia and recurrent pulmonary thrombosis without any concomitant use of drugs

Validation and development of an immunonephelometric assay for the determination of alpha-1 antitrypsin levels in dried blood spots from patients with COPD / Desenvolvimento e validação de um método de imunonefelometria em amostras de sangue em papel-filtro para a dosagem da alfa-1 antitripsina em pacientes com DPOC

OBJECTIVE: To validate and develop an immunonephelometric assay for the determination of alpha-1 antitrypsin (AAT) levels in dried blood spots from COPD patients in Brazil. METHODS: We determined AAT levels in serum samples and dried blood spots from 192 COPD patients. For the preparation of dried blood spots, a disk (diameter, 6 mm) was placed into a tube, eluted with 200 µL of PBS, and stored overnight at 4ºC. All of the samples were analyzed by immunonephelometry in duplicate. We used the bootstrap resampling method in order to determine a cut-off point for AAT levels in dried blood spots. RESULTS: The correlation coefficient between the AAT levels in serum samples and those in dried blood spots was r = 0.45. For dried blood spots, the cut-off value was 2.02 mg/dL (97% CI: 1.45-2.64 mg/dL), with a sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 95.7%, 27.2%, and 100%, respectively. CONCLUSIONS: This method for the determination of AAT levels in dried blood spots appears to be a reliable screening tool for patients with AAT deficiency. .

OBJETIVO: Validar e desenvolver um método de dosagem de alfa-1 antitripsina (AAT) por imunonefelometria em amostras de sangue em papel-filtro em pacientes com DPOC no Brasil. MÉTODOS: Amostras de soro e de sangue em papel-filtro de 192 pacientes com DPOC foram utilizadas para a dosagem de AAT. Para a preparação das amostras de sangue em papel-filtro, um disco do papel com diâmetro de 6 mm foi colocado em um tubo e eluído com 200 µL de PBS, permanecendo por toda a noite a 4ºC. Todas as amostras foram analisadas em duplicata por imunonefelometria. O método de reamostragem bootstrap foi utilizado para a determinação de um ponto de corte para o nível de AAT nas amostras de sangue em papel-filtro. RESULTADOS: O coeficiente de correlação entre os níveis de AAT em soro e em sangue em papel-filtro foi de r = 0,45. Para as amostras em papel-filtro, o ponto de corte foi de 2,02 mg/dL (IC97%: 1,45-2,64 mg/dL), com sensibilidade, especificidade, valor preditivo positivo e valor preditivo negativo de 100%, 95,7%, 27,2% e 100%, respectivamente. CONCLUSÕES: Este método de determinação dos níveis de AAT em sangue em papel-filtro se mostrou uma ferramenta confiável para o rastreamento de pacientes com deficiência de AAT. .

Cirrose hepática secundária à deficiência de alfa-1 antitripsina em idoso / Cirrhosis secondary to deficiency of alpha-1 antitrypsin deficiency in elderly

A deficiência de alfa-1 antitripsina é um distúrbio de herança autossômica codominante que afeta principalmente pulmão e fígado. É uma das mais comuns de desordens genéticas, não sendo frequentemente reconhecida. O caso relatado é de uma mulher de 69 anos, com história de dor e aumento do volume abdominal há cinco meses. Durante investigação evidenciou-se que se tratava de cirrose hepática Child-Pugh C. Foi realizado protocolo de investigação de hepatopatia crônica e diagnosticado deficiência de alfa-1 antitripsina. Paciente recebeu alta após 60 dias de internação hospitalar e segue acompanhamento ambulatorial.

A deficiency of alpha-1 antitrypsin deficiency is a disorder of autosomal co-dominant herancia that primarily affects the lung and liver. It is one of the most common genetic disorders, is often not recognized. The case reported is from a woman of 69 years old with a history of pain and increased abdominal volume five months ago. During investigation it became clear that it is liver cirrhosis Child-Pugh C. We conducted research protocol diagnosed chronic liver disease and alpha-1 antitrypsin. The patient was discharged after 60 days of hospitalization and outpatient follow.

Transplante pulmonar no enfisema / Lung Transplantation for Emphysema

O enfisema, em conjunto com a deficiência de alfa-1 antitripsina, corresponde a 40,1% dos transplantes de pulmão. Na Universidade Federal do Rio de Janeiro, 55% dos transplantes foram realizados por enfisema pulmonar (25 pacientes), e a sobrevida em um ano foi de 72%. O transplante está indicado quando a terapia clínica está otimizada, sem mais nada a oferecer ao paciente para melhorar a sua qualidade de vida e aumentar a sua sobrevida. O transplante pode ser unilateral ou bilateral. A sobrevida em cinco anos encontra-se em 44-50%. O transplante bilateral oferece maior sobrevida principalmente para pacientes com menos de 60 anos, ainda que a capacidade de exercício seja semelhante à do transplante unilateral. A morbidade e a mortalidade operatória do transplante bilateral não são maiores do que no transplante unilateral. A hiperinsuflação do pulmão nativo mais complacente, no transplante unilateral, pode exigir algum procedimento de redução volumétrica(cirúrgico ou broncoscópico), caso haja repercussão hemodinâmica e/ou ventilatória. A hiperinsuflação classificada como leve e severa ocorre em 82% dos casos. A rejeição crônica, manifesta como bronquiolite obliterante no pulmão, é o principal obstáculo para uma maior sobrevida de longo prazo

Worldwide, pulmonary emphysema, associated with alpha-1 antitrypsin deficiency, is the indication for 40.1% of all lung transplants. Of the lung transplants performed to date at theFederal University of Rio de Janeiro, 55% were indicated because of emphysema (in 25 patients), the one-year survival rate being 72%. Lung transplantation is indicated when the clinical therapy has been optimized and there are no other treatment options to prolong survival and improve quality of life.Lung transplant can be unilateral or bilateral.The overall five-year survival rate among lung transplant recipients is 44-50%. Survival is better among recipients of bilateral lung transplants than among those of unilateral lung transplants, especially among those who are below 60 years of age.However, there is no difference between unilateral and bilateral lung transplant in terms of postoperative exercise capacity,as well as in terms of morbidity and mortality. In unilateral lung transplantation, native lung hyperinflation can require lungvolume reduction procedure (surgical or bronchoscopic) when there is hemodynamic or respiratory impairment. Hyperinflation (mild to severe) occurs in 82% of all lung transplants. Chronic rejection, manifesting as bronchiolitis obliterans, is the major obstacle to improving survival in lung transplantation

Hepatocarcinoma en hígado no cirrótico / Hepatocellular carcinoma in a non cirrhotic liver

Background: The appearance of hepatocellular carcinoma in non-cirrhotic livers is uncommon. Material and Method: We report a 62 years old woman presenting with a liver mass that was subjected to a left hepatectomy. Results: The pathology report disclosed a poorly to moderately differentiated hepatocellular carcinoma. The surrounding liver tissue was normal. Immunohistochemistry identified intracytoplasmic a-1 antitrypsin granules, confirming the suspicion of a-1 antitrypsin deficiency.

Introducción: El Carcinoma Hepatocelular (HCC), tumor hepático primario más frecuente, se presenta en general en hígados cirróticos. Un porcentaje menor se desarrolla en pacientes sin cirrosis, en los cuales deben buscarse otras etiologías. Paciente y Método: Se presenta un caso clínico y las características anato-mopatológicas de una paciente con hepatocarcinoma e hígado no cirrótico tratada en nuestro centro. Mujer de 62 años, con historia de dolor abdominal y baja de peso. Estudio por imágenes revela masa hepática de aproximadamente 8 cm de diámetro mayor, en segmentos II, III y IV, sugerente de HCC. Resultados: Se realiza hepatectomía izquierda. Evoluciona de forma satisfactoria en el postoperatorio. La biopsia muestra un HCC moderada a pobremente diferenciado. El tejido no tumoral es normal, con gránulos intracitoplasmáticos Pas y Pas diastasa (+). Inmunohistoquímica identifica gránulos intracitoplasmáticos de antitripsina, con lo que se confirma la sospecha diagnóstica de déficit de a-1 antitripsina.

Acquired alpha 1-antitrypsin deficiency in tropical pulmonary eosinophilia.

Background & objectives: Observation of an increased frequency of an intermediate deficiency of serum alpha1-antitrypsin (α1-AT) in patients with Tropical Pulmonary Eosinophilia (TPE) was earlier reported. Though the possibility of existence of an acquired deficiency was suggested, without phenotyping a hereditary α1-AT deficiency in TPE could not totally be ruled out. In this study, we have done Pi (Protease inhibitor) phenotyping to investigate the possibility of association of any heterozygous (or homozygous) α1-AT deficiency in patients with TPE. Methods: Serum a1antitrypsin (α1-AT) was measured in 103 patients (Group A) with TPE, 99 patients with pulmonary eosinophilia who had associated intestinal worm infestation (Group B) and 43 healthy volunteers who served as controls. In 19 α1-AT deficient patients (9 of Group A and 10 of Group B), α1-AT level was measured before and after treatment. In 58 patients with TPE and in 5 controls, phenotyping was done. Results: Fifteen patients of Group A and 16 from Group B showed intermediate α1-AT deficiency (150 mg % or less. None of the control subjects had α1-AT deficiency (<200 mg%). After treatment with DEC and/or deworming, in 19 patients there was a significant (P < 0.001) rise in α1-AT levels. Results of phenotyping showed that all had M1 or M2 allele and none had S or Z variant (either homozygous or heterozygous) thus ruling out any underlying genetic cause for the observed α1-AT deficiency. Interpretation & conclusions: The observed α1-AT deficiency may be due to the chronic inflammation in TPE and associated oxidative stress. However, in such α1-AT deficient patients with TPE and those with worm infested pulmonary eosinophilia, faecal α1-AT concentration and faecal α1-AT clearance should be routinely estimated to rule out the possibility of any intestinal protein loss.

[ prevalence of the alpha-1 antitrypsin deficiency in patients with chronic obstructive pulmonary disease]

Alpha 1-antitrypsin deficiency [AATD] is one of the genetic risk factors in the patients suffering from chronic obstructive pulmonary disease [COPD]. The exact number of Iranians suffering from this disease is yet not known. Therefore, the aim of this study was to determine the prevalence of the deficiency of AAT enzyme in patients suffering from COPD. The topical test of AAT serum was conducted on 125 patients affected by COPD who had referred to Ekbatan Hospital of Hamadan in 2007. The diagnoses of COPD in these patients dad been confirmed through history and spirometerty test before and after bronchodilator inhalation and the outcomes had been confirmed based on GOLD regulations. In other words, after separation of serum from blood, the specific antibody of AAT was added to the sample. The AAT serum level was read according to nephelometry measurement and the results were given in g/L. The gathered data were then analyzed using SPSS software program and statistical tests such as T-test and chi[2] [p<0.05]. Out of 125 patients, 91 were male and 34 patients were female [2.7/1]. The mean age was 63 +/- 12 years and the mean AAT serum in the patients was between 0.710g/L and 2.696g/L [mean 1.311 +/- 0.364g/L]. Almost all of the male patients had history of smoking [91%] and this smoking and its dose [Pack/Year] were significantly related to the severity of COPD. There was no significant relation between plasma levels of AAT and smoking, age or sex. The average age of patients suffering from COPD in rational AAT deficiency was significantly lower. However, the severity of symptoms had no significant difference between patients with normal levels of AAT. Based on the findings of this study, no case of exact deficiency of AAT was found in patients suffering from COPD admitted to Ekbatan Hospital of Hamadan. Regarding geographical location and number of the samples, the possibility of prevalence of this disease in Hamadan is much lower than that of European countries. However, the relative deficiency of AAT [20% in this study] was higher than the amounts obtained from similar studies in European countries