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ABSTRACT Background: Alpha 1-antitrypsin deficiency (AATD) is a hereditary codominant autosomal disease. This liver disease ranges from asymptomatic cases to terminal illness, which makes early recognition and diagnosis challenging. It is the main cause of pediatric liver transplantation after biliary atresia. Objective: To describe the clinical characteristics, as well as those of histologic and laboratory tests, phenotypic and/or genetic evaluation and evolution of a cohort of pediatric patients with AATD. Methods: This is a retrospective observational study of 39 patients with confirmed or probable AATD (without phenotyping or genotyping, but with suggestive clinical features, low serum alpha 1-antitrypsin (AAT) level and liver biopsy with PAS granules, resistant diastasis). Clinical, laboratory and histological variables, presence of portal hypertension (PH) and survival with native liver have been analyzed. Results: A total of 66.7% of 39 patients were male (26/39). The initial manifestation was cholestatic jaundice in 79.5% (31/39). Liver transplantation was performed in 28.2% (11/39) of patients. Diagnosis occurred at an average of 3.1 years old and liver transplantation at 4.1 years of age. 89.2% (25/28) of the patients with confirmed AATD were PI*ZZ or ZZ. The average AAT value on admission for PI*ZZ or ZZ patients was 41.6 mg/dL. All transplanted patients with phenotyping or genotyping were PI*ZZ (or ZZ). Those who were jaundiced on admission were earlier referred to the specialized service and had higher levels of GGT and platelets on admission. There was no significant difference in the survival curve when comparing cholestatic jaundiced to non-cholestatic jaundiced patients on admission. Comparing patients who did or did not progress to PH, higher levels of AST and APRI score at diagnosis (P=0.011 and P=0.026, respectively) were observed and in the survival curves patients with PH showed impairment, with 20.2% survival with native liver in 15 years. Conclusion: Jaundice is an important clinical sign that motivates referral to a specialist, but it does not seem to compromise survival with native liver. Patients progressing to PH had higher AST, APRi score on admission and significantly impaired survival with native liver. It is important to pay attention to these signs in the follow-up of patients with AATD.
RESUMO Contexto: Deficiência de alfa 1-antitripsina (DAAT) é uma doença hereditária, de caráter autossômico codominante. A apresentação da doença hepática varia desde casos assintomáticos até doença terminal, o que dificulta reconhecimento e diagnóstico precoces. É a principal causa de transplante hepático pediátrico após atresia de vias biliares. Objetivo: Descrever as características clínicas, de exames laboratoriais, histológicos, avaliação fenotípica e/ou genética e sobrevida de uma coorte de pacientes pediátricos com DAAT. Métodos: Estudo observacional retrospectivo de 39 pacientes com diagnóstico de DAAT confirmada ou provável (sem fenotipagem ou genotipagem, mas com clínica sugestiva, baixo nível sérico de alfa 1-antitripsina (A1AT) e biópsia hepática com grânulos PAS, diástase resistentes). Variáveis clínicas, laboratoriais, histológicas, presença de hipertensão portal (HP) e sobrevida com fígado nativo foram analisadas. Resultados: Dos 39 pacientes, 66,7% eram do sexo masculino (26/39). A manifestação inicial foi icterícia colestática em 79,5% (31/39). Em 28,2% (11/39) houve necessidade de transplante hepático. O diagnóstico ocorreu com uma idade média de 3,1 anos e, o transplante hepático, 4,1 anos. Dos pacientes com DAAT confirmada, 89,2% (25/28) eram PI*ZZ ou ZZ. O valor médio de A1AT na admissão de pacientes PI*ZZ ou ZZ foi 41,6 mg/dL. Todos os transplantados com fenotipagem ou genotipagem eram PI*ZZ (ou ZZ). Os ictéricos à admissão foram referenciados mais cedo ao serviço especializado e apresentaram níveis mais elevados de GGT e plaquetas à admissão. Não houve diferença significativa na curva de sobrevida ao compararmos icterícia colestática ou não à admissão. Ao comparar os pacientes que progrediram ou não para HP, observou-se níveis mais elevados de AST e APRI escore ao diagnóstico (P=0,011 e P=0,026, respectivamente) e, nas curvas de sobrevida, pacientes com HP apresentaram comprometimento, com 20,2% de sobrevida com fígado nativo em 15 anos. Conclusão: Icterícia é um sinal clínico importante que motiva o encaminhamento ao especialista, mas parece não comprometer a sobrevida com fígado nativo. Pacientes com evolução para HP tiveram AST e escore APRi mais elevados à admissão e comprometimento significativo da sobrevida com fígado nativo. Importante atentar a esses sinais no seguimento de pacientes com DAAT.
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The underdiagnosis of alpha-1 antitrypsin (AAT) deficiency (AATD) has been recognized for many years, yet little progress has been made in treatment of the disease. In this review, we summarize the AATD disease process as well as its diagnosis and treatment by AAT augmentation therapy. AATD is a rare autosomal disease that primarily affects the lungs and liver. AATD is associated with an increased susceptibility to developing pulmonary emphysema. The specific pharmacological treatment for AATD is intravenous administration of exogenous AAT. Augmentation therapy with AAT increases serum and pulmonary epithelial AAT levels, restores anti-elastase capacity, and decreases inflammatory mediators in the lung. Augmentation therapy reduces the loss of lung density over time, thus slowing progression of the disease. The effects of augmentation therapy on outcomes, such as frequency/duration of flare-ups, quality of life, lung function decline and mortality, are assessed. Wider testing for AATD, potentially through primary care physicians, could result in earlier treatment and better outcomes for individuals with AATD-induced lung respiratory disease.
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BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is an underrecognized genetic disorder associated mainly with pulmonary emphysema and Chronic Obstructive Pulmonary Disease (COPD). All individuals with COPD regardless of age or ethnicity should be tested for AATD, but in Colombia its prevalence in unknown. MAIN OBJECTIVE: To determine the prevalence of the genetic mutations, present in AATD in adult patients with COPD in Colombia, using a genotyping test on cells from the oral mucosa. METHODS: This was a multicentre, observational, cross-sectional study which included adult patients attending seven COPD care centres in Colombia. Demographic data, medical history, including history of exposure to smoking and biomass smoke, most recent spirometry, pharmacological and non-pharmacological treatment received, serum AAT levels, and mutations detected by the genotyping test were recorded for all the recruited patients. For the comparison of variables between the groups with and without mutation, we used the X2 test for the qualitative variables and the Student's t-test or Mann-Whitney U test according to their distribution. MAIN FINDINGS: We collected a sample of 1,107 patients, the median age was 73.8 years (87.6-79.9). Mutations were documented in 144 patients (13.01%), the majority had the M/S mutation (78.50%), followed by M/Z (9.72%). One patient had a ZZ mutation and two patients had null alleles. In total, 23 patients had mutations associated with serum AAT deficiency (levels below 60 mg/dl). CONCLUSIONS: Genetic mutations were documented in 13.01% of patients with COPD in Colombia and 2.07% were AATD-related, showing that there is a significant number of underdiagnosed patients.
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Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina , Idoso , Humanos , alfa 1-Antitripsina/genética , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/epidemiologia , Deficiência de alfa 1-Antitripsina/genética , Colômbia/epidemiologia , Estudos Transversais , Mutação , Prevalência , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Idoso de 80 Anos ou maisRESUMO
Dysfunction of cellular homeostasis can lead to misfolding of proteins thus acquiring conformations prone to polymerization into pathological aggregates. This process is associated with several disorders, including neurodegenerative diseases, such as Parkinson's disease (PD), and endoplasmic reticulum storage disorders (ERSDs), like alpha-1-antitrypsin deficiency (AATD) and hereditary hypofibrinogenemia with hepatic storage (HHHS). Given the shared pathophysiological mechanisms involved in such conditions, it is necessary to deepen our understanding of the basic principles of misfolding and aggregation akin to these diseases which, although heterogeneous in symptomatology, present similarities that could lead to potential mutual treatments. Here, we review: (i) the pathological bases leading to misfolding and aggregation of proteins involved in PD, AATD, and HHHS: alpha-synuclein, alpha-1-antitrypsin, and fibrinogen, respectively, (ii) the evidence linking each protein aggregation to the stress mechanisms occurring in the endoplasmic reticulum (ER) of each pathology, (iii) a comparison of the mechanisms related to dysfunction of proteostasis and regulation of homeostasis between the diseases (such as the unfolded protein response and/or autophagy), (iv) and clinical perspectives regarding possible common treatments focused on improving the defensive responses to protein aggregation for diseases as different as PD, and ERSDs.
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Afibrinogenemia/genética , Fibrinogênio/química , Doença de Parkinson/genética , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/química , alfa-Sinucleína/química , Afibrinogenemia/tratamento farmacológico , Afibrinogenemia/metabolismo , Afibrinogenemia/patologia , Animais , Autofagia/efeitos dos fármacos , Autofagia/genética , Coagulantes/uso terapêutico , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Fibrinogênio/genética , Fibrinogênio/metabolismo , Regulação da Expressão Gênica , Humanos , Fígado/metabolismo , Fígado/patologia , Fármacos Neuroprotetores/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Inibidores de Proteases/uso terapêutico , Agregados Proteicos/efeitos dos fármacos , Dobramento de Proteína/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos dos fármacos , alfa 1-Antitripsina/genética , alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/tratamento farmacológico , Deficiência de alfa 1-Antitripsina/metabolismo , Deficiência de alfa 1-Antitripsina/patologia , alfa-Sinucleína/genética , alfa-Sinucleína/metabolismoRESUMO
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.
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Humanos , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genética , Brasil , alfa 1-Antitripsina/genética , MutaçãoRESUMO
Introduction: Small airways are not evaluated with traditional pulmonary function tests. The aim of this study was to evaluate the small airways in patients with chronic obstructive pulmonary disease (COPD) with a nitrogen washout test and to verify whether there is a difference between patients with COPD due to smoking and those with COPD due to alpha-1 antitrypsin mutation. Methods: Sixteen patients with mutation in the SERPINA1 gene and 45 patients with no mutation were included in this cross-sectional study. All pulmonary function tests, including the single breath nitrogen washout test, were performed for all patients and alpha-1 antitrypsin dosage was assessed with immunonephelometry. Results: A comparison of patients with COPD due to smoking and those with COPD due to smoking and mutation revealed a significant difference in closure volume (%), which was the poorest in the mutation group. In the group with COPD and mutation, there was an inverse correlation between smoking and closure volume (%). We also verified that similar to forced expiratory volume in the first second (FEV1), the phase III slope (%) and ΔN2 750-1250 mL (%) could be used to differentiate the severity of airflow limitation. Conclusion: Our results suggest that both variables, phase III slope and the ΔN2 750-1250 mL (%), could be related to COPD severity. Therefore, alterations at the distribution of the location of the emphysema could alter the results of closer volume and that the nitrogen washout test is more sensitive when compared to traditional pulmonary function test in evaluating COPD patients.
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Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina , Idoso , Estudos Transversais , Volume Expiratório Forçado , Humanos , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/genética , Testes de Função Respiratória , alfa 1-Antitripsina , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
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 Piâ¢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.
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 Piâ¢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.
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Pneumotórax/epidemiologia , Deficiência de alfa 1-Antitripsina/epidemiologia , Estudos Transversais , Humanos , Pneumotórax/genética , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
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.
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Humanos , Pneumotórax/epidemiologia , Deficiência de alfa 1-Antitripsina/epidemiologia , Pneumotórax/genética , Estudos Transversais , Estudos Prospectivos , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/genética , Doença Pulmonar Obstrutiva CrônicaRESUMO
INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is still underdiagnosed, despite the recommendation to determine AAT in patients with chronic obstructive pulmonary disease (COPD). OBJECTIVE: To estimate the prevalence of AATD in COPD patients adjusted according to the population of the COPD prevalence study in Argentina (EPOC.AR). MATERIAL AND METHODS: This was a multicenter prospective cross-sectional study of a population aged≥30 years of age diagnosed with COPD, involving AAT quantification in dry blood spot and subsequent genotyping in subjects with<1.5mg/dL AAT in dry blood spot (<80mg/dL in serum). AAT was defined as the detection of variants ZZ or SZ on genotyping. The EPOC.AR study population was used to calculate local adjusted prevalence. RESULTS: We included 3,254 patients (544 with AAT<80mg/dL) with a spirometric diagnosis of COPD. The prevalence of AATD in the total study population was 1.29% (95% CI 0.93-1.74), of which 0.92% (95% CI 0.62-1.31) were Pi*ZZ and 0.37% (95% CI 0.19-0.64) Pi*SZ. The adjusted prevalence of AATD in COPD patients≥40 years of age was 0.83% (95% CI 0.23-2.08). We found that AATD was negatively associated with age (OR 0.94; 95% CI 0.90-0.98; P=.006), smoking habit (OR 0.98; 95% CI 0.96-0.99; P=.009), and FEV1% (OR 0.95; 95% CI 0.91-0.99; P=.015). CONCLUSIONS: The prevalence of AATD in the adult population with COPD in Argentina is estimated to be 0.83%, which could represent 17,000 cases in our country.
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Doença Pulmonar Obstrutiva Crônica , Deficiência de alfa 1-Antitripsina , Adulto , Argentina/epidemiologia , Estudos Transversais , Humanos , Prevalência , Estudos Prospectivos , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Deficiência de alfa 1-Antitripsina/complicaçõesRESUMO
BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) frequently presents as difficult to manage asthma or asthma with fixed obstruction and is well documented as being underdiagnosed in the population. OBJECTIVE: This study aimed to better describe allergists'/immunologists' involvement in the care of patients with AATD and whether they currently contribute to the underdiagnosis by lack of screening for the condition. METHODS: Using the Research Electronic Data Capture tool, we submitted a questionnaire to 500 patients with severe AATD (ZZ, SZ, ZNull, and FZ) through the Alpha-1 Foundation Research Registry to collect information about patient diagnosis and treatment patterns. Approximately 45% completed the questionnaire, leading to a final enrollment of 226 participants. RESULTS: Seventy-eight participants (34%) had seen an allergist, but only 11 (5%) were diagnosed with AATD by their allergist. Likewise, allergists prescribed alpha-1 augmentation therapy to only 5 (8%) of the 59 patients on augmentation therapy. Nearly 46% (n = 104) of all participants were diagnosed with either asthma (28%) or allergic disease (18%) before receiving a diagnosis of AATD. Eighteen patients had been treated with immunotherapy before their diagnosis of AATD, with 94% of these participants receiving treatment for 3 years or longer. CONCLUSIONS: Our data suggest that specialists in Allergy and Immunology should consider and screen for AATD in patients with asthma in whom spirometry does not return to normal. Furthermore, we propose allergists/immunologists are well suited to screen and treat patients with AATD.
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Asma/diagnóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Deficiência de alfa 1-Antitripsina/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alergistas , Criança , Erros de Diagnóstico/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Papel do Médico , Espirometria , Inquéritos e Questionários , Adulto JovemRESUMO
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.
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Peneiramento de Líquidos , Deficiência de alfa 1-AntitripsinaRESUMO
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.
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Deficiência de alfa 1-Antitripsina/epidemiologia , Frequência do Gene/genética , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Deficiência de alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genética , alfa 1-Antitripsina/genética , Brasil/epidemiologia , Estudos Transversais , Genótipo , Prevalência , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/genética , Análise de Sequência de DNARESUMO
Este relato alerta para a deficiência de alfa1antitripsina em neonato, que se apresentou como síndrome colestática. Seu subdiagnóstico constitui-se em importante limitação para o seu reconhecimento e tratamento adequado. A boa evolução ocorre em cerca de 50% dos pacientes. Associa-se, na maioria das vezes, a acometimento extra e intra-hepático e ausência de manifestações clínicas que indiquem o seu diagnóstico. A deficiência de alfa1antitripsina está entre as doenças que precisam ser excluídas frente à colestase neonatal.
This report draws attention to the alpha 1 antitrypsin deficiency in newborns presented as a cholestatic syndrome. Its sub-diagnosis constitutes a major constraint for recognition and appropriate treatment. Good outcomes occur in approximately 50% of patients.It is associated in most cases, to extra and intra-hepatic involvement and the absence of clinical signs that indicate its diagnosis. The alpha 1 antitrypsin deficiency is among the diseases that need to be excluded when facing neonatal cholestasis.
RESUMO
INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with early onset chronic obstructive pulmonary disease (COPD) and liver disease. It is also a highly under-diagnosed condition. As early diagnosis could prompt specific interventions such as smoking cessation, testing of family members, genetic counselling and use of replacement therapy, screening programs are needed to identify affected patients. OBJECTIVE: To estimate the prevalence of severe AATD in COPD patients by routine dried blood spot testing and subsequent genotyping in patients with alpha-1 antitrypsin (AAT) levels below an established threshold. MATERIALS AND METHODS: Cross-sectional study of adult COPD patients attending the Hospital Dr. Antonio Cetrángolo (Buenos Aires, Argentina) between 2009 and 2012. The study consisted of capillary blood collection via finger stick to determine AAT levels, clinical evaluation and lung function tests. Genotype was determined in AAT-deficient patients. RESULTS: A total of 1,002 patients were evaluated, of whom 785 (78.34%) had normal AAT levels, while low AAT levels were found in 217 (21.66%). Subsequent genotyping of the latter sub-group found: 15 (1.5%, 95% CI 0.75-2.25) patients with a genotype associated with severe AATD, of whom 12 were ZZ (1.2%, 95% CI 0.52-1.87) and 3 SZ (0.3%, 95% CI 0-0.64). The remaining 202 patients were classified as: 29 Z heterozygotes (2.89%, 95% CI 1.86-3.93), 25 S heterozygotes (2.5%, 95% CI 1.53-3.46) and 4 SS (0.4%, 95% CI 0.01-0.79). A definitive diagnosis could not be reached in 144 patients (14.37%, 95% CI 12.2-16.54). CONCLUSION: The strategy using an initial serum AAT level obtained by dried blood spot testing and subsequent genotyping was a satisfactory initial approach to a screening program for severe AAT, as a definitive diagnosis was achieved in 87% of patients. However, results were not obtained for logistical reasons in the remaining 13%. This major obstacle may be overcome by the use of dried blood spot phenotyping techniques. We believe this approach for detecting AATD in COPD patients, in compliance with national and international guidelines, is supported by our results.
Assuntos
Doença Pulmonar Obstrutiva Crônica/epidemiologia , Deficiência de alfa 1-Antitripsina/epidemiologia , Adulto , Idoso , Algoritmos , Argentina/epidemiologia , Comorbidade , Estudos Transversais , Feminino , Genótipo , Humanos , Focalização Isoelétrica , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Nefelometria e Turbidimetria , Fenótipo , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Fumar/epidemiologia , Espirometria , alfa 1-Antitripsina/sangue , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/genéticaRESUMO
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.
Assuntos
Idoso , Feminino , Humanos , Antibacterianos/uso terapêutico , Divertículo/complicações , Doenças da Traqueia/complicações , Deficiência de alfa 1-Antitripsina/complicações , Divertículo/tratamento farmacológico , Imageamento por Ressonância Magnética , Enfisema Pulmonar , Tomografia Computadorizada por Raios X , Tienamicinas/uso terapêutico , Doenças da Traqueia/tratamento farmacológico , Vancomicina/uso terapêutico , Deficiência de alfa 1-Antitripsina/tratamento farmacológicoRESUMO
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.
Assuntos
Antibacterianos/uso terapêutico , Divertículo/complicações , Doenças da Traqueia/complicações , Deficiência de alfa 1-Antitripsina/complicações , Idoso , Divertículo/tratamento farmacológico , Feminino , Humanos , Imageamento por Ressonância Magnética , Meropeném , Enfisema Pulmonar , Tienamicinas/uso terapêutico , Tomografia Computadorizada por Raios X , Doenças da Traqueia/tratamento farmacológico , Vancomicina/uso terapêutico , Deficiência de alfa 1-Antitripsina/tratamento farmacológicoRESUMO
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. .
Assuntos
Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Teste em Amostras de Sangue Seco/métodos , Testes Imunológicos/métodos , Nefelometria e Turbidimetria/métodos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Deficiência de alfa 1-Antitripsina/diagnóstico , alfa 1-Antitripsina/sangue , Brasil , Estudos Transversais , Programas de Rastreamento , Pacientes Ambulatoriais , Valor Preditivo dos Testes , Padrões de ReferênciaRESUMO
The study of nasal ciliary beat frequency (CBF) and ultrastructure may contribute to the understanding of pathognomonic cases of male infertility associated with defects in sperm motility. This study was designed to report a particular case of male infertility, characterized by the association of two respiratory autosomal recessive genetic diseases (alpha-1-antitrypsin deficiency [AAT-D] and primary ciliary dyskinesia [PCD]). A 39-year-old patient with complete sperm immotility, AAT-D, and bronchiectasis was studied in the Laboratory of Male Fertility, the Department of Urology, the Respiratory Center of a Pediatric Hospital, and in the Department of Clinical Medicine of a Rehabilitation Respiratory Hospital. Family history, physical examination, hormonal analysis, microbial assays, semen analysis, nasal ciliary function, and structure study by digital high-speed video photography and transmission electron microscopy are described. A noninvasive nasal biopsy to retrieve ciliated epithelium lining the inferior surface of the inferior nasal turbinates was performed and CBF was determined. Beat pattern was slightly curved and rigid, not wide, and metacronic in all the observed fields analyzed. CBF was 8.2 Hz in average (reference value, 10-15 Hz) Ultrastructural assay revealed absence of the inner dynein arms in 97% of the cilia observed. The final infertility accurate diagnosis was achieved by the study of nasal CBF and ultrastructure contributing to the patient health management and genetic counseling while deciding fatherhood. Beyond this particular case, the present report may open a new field of studies in male infertility, mainly in cases of asthenozoospermia.
Assuntos
Deficiências na Proteostase , Deficiência de alfa 1-Antitripsina , Animais , Caenorhabditis elegans , Modelos Animais de Doenças , Humanos , Deficiências na Proteostase/complicações , Deficiências na Proteostase/terapia , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/terapiaRESUMO
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.