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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
The prevalence of age-related macular degeneration (AMD) has increased in the last years. Although anti-VEGF agents have improved the prognosis of exudative AMD, dry AMD has still devastating effects on elderly people vision. Oxidative stress and inflammation are mechanisms involved in AMD pathogenesis and its progression. Molecular pathways involving epidermal growth factor receptor (EGFR), bone morphogenetic protein (BMP4) and the nuclear erythroid related factor 2 (Nrf2) are behind oxidative stress in AMD due to their participation in antioxidant cellular pathways. As a consequence of the disbalance produced in the antioxidant mechanisms, there is an activation of innate and adaptative immune response with cell recruitment, changes in complement factors expression, and modification of cellular milieu. Different therapies are being studied to treat dry AMD based on the possible effects on antioxidant molecular pathways or their action on the immune response. There is a wide range of treatments presented in this review, from natural antioxidant compounds to cell and gene therapy, based on their mechanisms. Finally, we hypothesize that alpha-1-antitrypsin (AAT), an anti-inflammatory and immunomodulatory molecule that can also modulate antioxidant cellular defenses, could be a good candidate for testing in AMD. This article is part of the special ssue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
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Degeneração Macular/fisiopatologia , Degeneração Macular/terapia , Estresse Oxidativo , Envelhecimento , Animais , Antioxidantes , Humanos , Degeneração Macular/imunologia , Degeneração Macular/metabolismoRESUMO
INTRODUCTION: Alpha-1 antitrypsin deficiency (AATD) is a risk factor for liver disease. PASD-positive inclusions have been found unexpectedly in approximately 10% of liver explants in patients with no previous diagnosis of AATD, particularly, in patients with non-alcoholic steatohepatitis (NASH), supporting a synergistic mechanism of liver injury between AATD and environmental factors. We aimed to determine the clinical characteristics of mestizo patients in which AATD was diagnosed before or after liver transplantation. METHODS: Liver explants of patients with cryptogenic, alcoholic, and NAFLD/NASH cirrhosis undergoing orthotopic liver transplantation (OLT) were included. Liver histopathology was assessed by two expert pathologists. Hematoxylin and eosin staining, PASD staining, and confirmatory AAT immunohistochemistry were performed. In explants with positive histopathology, genotyping for SERPINA1 was performed. RESULTS: A total of 180 liver transplants were performed during the study period. Of these, 44 patients with cryptogenic cirrhosis, NASH, and alcoholic cirrhosis were included. Of these patients, two liver explants (4.5%) had PASD-positive inclusions stain and confirmatory immunochemistry. During the period evaluated, another two patients with a diagnosis of AATD before the OLT were also included. The four patients had overweight or obesity, three had type 2 diabetes mellitus, and two developed liver steatosis after the OLT. CONCLUSION: AATD was found to be an infrequent finding in patients with cryptogenic, NASH/NAFLD, and alcoholic cirrhosis in our population. However, it is important to consider this entity as it may represent an additional factor in the appearance and progression of liver fibrosis in patients with metabolic syndrome.
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Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Deficiência de alfa 1-Antitripsina , Humanos , Cirrose Hepática , Cirrose Hepática Alcoólica , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Prevalência , Deficiência de alfa 1-Antitripsina/complicações , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/epidemiologiaRESUMO
AIMS: Evaluate the abundance of the selected targets, alpha-1-antitrypsin (A1AT) and macrophage migration inhibitory factor (MIF), and correlate these findings with the risk of developing severe oral mucositis (OM). MATERIALS AND METHODS: Head and neck squamous cell carcinoma (HNSCC) patients submitted to radiotherapy (RT) or chemoradiotherapy (CRT) were assessed. OM grade and pain were evaluated daily during treatment. Two protein targets, A1AT and MIF, were evaluated, using selected reaction monitoring-mass spectrometry (SRM-MS), in whole saliva, collected prior to oncologic treatment. The results obtained from the targeted proteomic analysis were correlated with OM clinical outcomes. RESULTS: A total of 27 patients were included, of whom 21 (77.8%) had locally advanced disease (clinical stage III or IV). Most patients (70.4%) received CRT. OM grades 2 (40.8%) and 3 (33.3%) were the most prevalent during RT with a mean highest reported OM-related pain of 3.22 through the visual analogue scale (VAS). The abundance of A1AT and MIF correlated significantly with severe (grades 3 or 4, p < 0.02) compared with moderate-low (grades 1 or 2, p < 0.04) OM grade. CONCLUSIONS: There is a correlation between the abundance of salivary A1AT and MIF and oncologic treatment-induced OM. The correlation of MIF expression with severe OM appears to be compatible with its physiological pro-inflammatory role. These results open up great possibilities for the use of salivary MIF and A1AT levels as prognostic markers for effective therapeutic interventions, such as photobiomodulation therapy, patient-controlled analgesia, or personalized medicaments.
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Biomarcadores/metabolismo , Neoplasias de Cabeça e Pescoço/complicações , Fatores Inibidores da Migração de Macrófagos/metabolismo , Qualidade de Vida/psicologia , Saliva/metabolismo , Estomatite/induzido quimicamente , alfa 1-Antitripsina/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto JovemRESUMO
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
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
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.