RESUMEN
OBJECTIVES: Although histologic features in biopsies suggesting a possibility of achalasia would be helpful diagnostically, such features remain unknown. The goal of this study was to explore the prevalence, histologic features, and immunophenotype of lymphocytic esophagitis (LyE) in achalasia biopsies. METHODS: The study group consisted of 57 patients with achalasia. Controls comprised 52 patients with severe gastroesophageal reflux disease (GERD) and normal esophageal motility. CD4/CD8 immunophenotype of lymphocytes was analyzed by immunohistochemistry. RESULTS: LyE was identified in 30% (17/57) of patients with achalasia and 6% (3/52) of patients with GERD, indicating a strong association with achalasia (odds ratio, 6.94; 95% confidence interval, 1.90-25.38). LyE was focal in 59% (10/17) of the cases and diffuse in 41% (7/17). CD4 T-cell predominance over CD8 T cells was observed in 88% of patients with achalasia and LyE. T helper 1 (Th1) cells, but not T helper 2 cells, were expanded in CD4 T cells; in the absence of evident infection, this was compatible with the role of Th1 cells in organ-specific autoimmunity. CONCLUSIONS: Achalasia should be considered in the differential diagnosis of clinical entities associated with CD4-predominant LyE. Additional studies to explore the significance of Th1 cells in achalasia-associated LyE are warranted.
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Acalasia del Esófago/inmunología , Acalasia del Esófago/patología , Esofagitis/patología , Células TH1/inmunología , Adulto , Anciano , Linfocitos T CD4-Positivos/inmunología , Acalasia del Esófago/diagnóstico , Esofagitis/epidemiología , Esofagitis/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , PrevalenciaRESUMEN
BACKGROUND: Eosinophils and mast cells are key effectors of allergy. When they accumulate in the esophagus, their myoactive, pro-inflammatory, and cytotoxic products potentially could cause achalasia-like motility abnormalities and neuronal degeneration. We hypothesized that there is an allergy-mediated form of achalasia. METHODS: LES muscle samples obtained during Heller myotomy from patients with achalasia or EGJ outflow obstruction (EGJOO) and from organ donor controls were immunostained for tryptase. Eosinophil and mast cell density, and mast cell degranulation were assessed. LES muscle was evaluated by qPCR for genes mediating smooth muscle Ca2+ handling and contraction. KEY RESULTS: There were 13 patients (7 men, median age 59; 10 achalasia, 3 EGJOO) and 7 controls (4 men, median age 42). Eosinophils were infrequent in LES muscle, but mast cells were plentiful. Patients and controls did not differ significantly in LES mast cell density. However, 12 of 13 patients exhibited profound LES mast cell degranulation involving perimysium and myenteric plexus nerves, while only mild degranulation was seen in 2 of 7 controls. Hierarchical clustering analysis of qPCR data revealed two "mototype" LES gene expression patterns, with all type II patients in one mototype, and type I and III patients in the other. CONCLUSIONS & INFERENCES: LES muscle of patients with achalasia or EGJOO exhibits striking mast cell degranulation, and patients with different achalasia manometric phenotypes exhibit different LES patterns of expression for genes mediating Ca2+ handling and muscle contraction. Although these findings are not definitive, they support our hypothesis that achalasia can be allergy-driven.
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Degranulación de la Célula/inmunología , Acalasia del Esófago/patología , Esfínter Esofágico Inferior/patología , Mastocitos/patología , Adulto , Anciano , Estudios de Casos y Controles , Análisis por Conglomerados , Eosinófilos/inmunología , Eosinófilos/patología , Acalasia del Esófago/inmunología , Esfínter Esofágico Inferior/inmunología , Esfínter Esofágico Inferior/metabolismo , Unión Esofagogástrica/inmunología , Unión Esofagogástrica/metabolismo , Unión Esofagogástrica/patología , Femenino , Expresión Génica , Humanos , Masculino , Mastocitos/inmunología , Mastocitos/metabolismo , Persona de Mediana Edad , Plexo Mientérico/inmunología , Plexo Mientérico/patología , Adulto JovenRESUMEN
BACKGROUND: Idiopathic achalasia is an uncommon esophageal motor disorder. The disease involves interaction between inflammatory and autoimmune responses. However, the antigens related to the disease are still unknown. AIM: To identify the possible antigen targets in muscle biopsies from lower esophageal sphincter (LES) of achalasia patients. METHODS: Esophageal biopsies of patients with type I and type II achalasia and esophagogastric junction outflow obstruction (EGJOO) were analyzed. Lower esophageal sphincter muscle biopsy from a Healthy organ Donor (HD) was included as control for two-dimensional gel electrophoresis. Immunoblotting of muscle from LES lysate with sera of type I, type II achalasia, or type III achalasia, sera of EGJOO and sera of healthy subjects (HS) was performed. The target proteins of the serum were identified by mass spectrometry Matrix-assited laser desorption/ionization time-of-flight (MALDI-TOF). KEY RESULTS: The proteomic map of muscle from LES tissue lysates of type I, and type II achalasia, EGJOO, and HD were analyzed and divided into three important regions. We found a difference in the concentration of certain spots. Further, we observed the serum reactivity of type I achalasia and type II achalasia against 45 and 25 kDa bands of type I achalasia tissue. Serum of type III achalasia and EGJOO mainly recognized 25 kDa band. Bands correspond to triosephosphate isomerase (TPI) (25 kDa), carbonic anhydrase (CA) (25 kDa) and creatinine kinase-brain (CKB) isoform (45 kDa). CONCLUSIONS AND INFERENCES: We identify three antigen targets, TPI, CA, and CKB isoform, which are recognized by sera from patients with achalasia.
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Antígenos/inmunología , Anhidrasas Carbónicas/inmunología , Forma BB de la Creatina-Quinasa/inmunología , Acalasia del Esófago/inmunología , Triosa-Fosfato Isomerasa/inmunología , Adulto , Anciano , Acalasia del Esófago/sangre , Esfínter Esofágico Inferior/inmunología , Esfínter Esofágico Inferior/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteómica , Adulto JovenRESUMEN
Idiopathic achalasia and Barrett's esophagus (BE) are preneoplastic conditions of the esophagus. BE increases the risk of esophageal adenocarcinoma (EAC), while achalasia is associated with both EAC and esophageal squamous cell carcinoma (ESCC). However, while the molecular mechanisms underlying the transformation of esophageal epithelial cells in BE are relatively well characterized, less is known regarding these processes in achalasia. Nevertheless, both conditions are associated with chronic inflammation and BE can occur in achalasia patients, and it is likely that similar processes underlie cancer risk in both diseases. The present review will discuss possible lessons that we can learn from the molecular analysis of BE for the study of achalasia-associated cancer and contrast findings in BE with those in achalasia. First, we will describe cellular fate during development of BE, EAC, and ESCC, and consider the inflammatory status of the epithelial barrier in BE and achalasia in terms of its contribution to carcinogenesis. Next, we will summarize current data on genetic alterations and molecular pathways involved in these processes. Lastly, the plausible role of the microbiota in achalasia-associated carcinogenesis and its contribution to abnormal lower esophageal sphincter (LES) functioning, the maintenance of chronic inflammatory status and influence on the esophageal mucosa through carcinogenic by-products, will be discussed.
Asunto(s)
Esófago de Barrett/inmunología , Acalasia del Esófago/inmunología , Neoplasias Esofágicas/etiología , Adenocarcinoma/etiología , Adenocarcinoma/genética , Esófago de Barrett/complicaciones , Esófago de Barrett/genética , Progresión de la Enfermedad , Acalasia del Esófago/complicaciones , Acalasia del Esófago/genética , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/etiología , Carcinoma de Células Escamosas de Esófago/genética , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , HumanosRESUMEN
An elevation of serum inflammatory biomarkers in achalasia patients compared with controls recently was demonstrated. It has not been determined whether the elevation of inflammatory cytokines is unique to achalasia or occurs with other diseases involving the esophagus. The primary aim of our study was to compare the differences in plasma immunological profiles (TNF- α receptor, IL-6, IFN-γ, IL-12, IL-17, IL-22, and IL-23) of patients with achalasia, eosinophilic esophagitis (EoE), and gastroesophageal reflux disease (GERD). A secondary aim of this study was to classify these same plasma cytokine profiles in the three achalasia subtypes. METHODS: Plasma from 53 patients with achalasia, 22 with EoE, and 20 with GERD (symptoms plus esophagitis or + reflux study) were analyzed. EXCLUSION CRITERIA: malignancy, autoimmune condition, immunodeficiency disorder, and treatment with steroids/immune modulating drugs. Cytokine levels were assayed via multiplex enzyme-linked immunosorbent assay (ELISA). RESULTS: Our key finding revealed significant elevations in IL- 6 (p = 0.0158) in achalasia patients compared with EoE patients. Overall, plasma inflammatory biomarker patterns were not different in the three subtypes of achalasia. CONCLUSION: There were no differences between the cytokine levels of any of the measured biomarkers between the achalasia and GERD groups suggesting that luminal stasis does increase biomarker levels for any of the cytokines examined in our study. While these results are an early first step towards clarifying some aspects of the pathogenesis of achalasia, they bring about many more questions that require further investigation and expansion. Further investigation with a larger cohort and a broader panel of biomarkers is needed.
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Citocinas/sangre , Esofagitis Eosinofílica/inmunología , Acalasia del Esófago/inmunología , Reflujo Gastroesofágico/inmunología , Biomarcadores/sangre , Acalasia del Esófago/clasificación , Femenino , Humanos , Interferón gamma/sangre , Interleucina-12/sangre , Interleucina-17/sangre , Interleucina-23/sangre , Interleucina-6/sangre , Interleucinas/sangre , Masculino , Persona de Mediana Edad , Factor de Necrosis Tumoral alfa/sangre , Interleucina-22RESUMEN
OBJECTIVES: Achalasia is a primary esophageal motility disorder resulting from selective loss of inhibitory neurons in the esophageal myenteric plexus, likely due to an autoimmune response with involvement of the adaptive immune system. Innate immune processes of the host constitute the bridge between environmental etiological factors and the adaptive immune system. Although these remain poorly investigated, they might be of diagnostic and therapeutic relevance. In view of the role of extracellular proteolysis in organ-specific autoimmunity, we studied gelatinases of the matrix metalloproteinase (MMP) family in achalasia patients. METHODS: The presence of MMP-2 and MMP-9 proteoforms was analyzed in sera of two cohorts of achalasia patients. Additionally, with the use of immunohistopathological analysis, in situ MMP-2 and MMP-9 expression was investigated. Finally, we tested the paradigm of remnant epitopes generating autoimmunity (REGA) for achalasia-associated autoantigens by evaluating whether autoantigenic proteins are cleaved by MMP-9 into remnant epitopes. RESULTS: We showed significantly increased ratios of MMP-9/MMP-2 and activated MMP-9/proMMP-9 in sera of achalasia patients (n = 88) versus controls (n = 60). MMP-9-positive and MMP-2-positive cells were more abundant in achalasia (n = 49) versus control biopsies from transplant donors (n = 10). Furthermore, extensive damage within the plexus was found in the tissues with more MMP-9-positive cells. Additionally, we documented achalasia-associated autoantigens PNMA2, Ri, GAD65, and VIP as novel MMP-9 substrates. CONCLUSIONS: We provide new biomarkers and insights into innate immune mechanisms in the autoimmune pathology of achalasia. Our results imply that extracellular protease inhibition is worthwhile to test as therapeutic intervention in achalasia.
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Autoinmunidad , Acalasia del Esófago/inmunología , Inmunidad Innata , Metaloproteinasa 9 de la Matriz/sangre , Adolescente , Adulto , Anciano , Autoantígenos/sangre , Biomarcadores/sangre , Biopsia , Acalasia del Esófago/clasificación , Femenino , Humanos , Inmunohistoquímica , Masculino , Metaloproteinasa 2 de la Matriz/sangre , Persona de Mediana Edad , Adulto JovenRESUMEN
Eosinophilic esophagitis (EoE), a disorder identified by its esophageal mucosal features, often is associated with esophageal motility abnormalities, which are manifestations of esophageal muscle dysfunction. Those motility abnormalities sometimes normalize with treatments that reduce esophageal eosinophilia, suggesting that eosinophils can cause reversible esophageal motility disturbances, perhaps by releasing myoactive and neuroactive eosinophil products. Although achalasia uncommonly is associated with EoE as currently defined, most achalasia patients have evidence of an abnormal accumulation of eosinophils and/or their degranulation products in the esophageal muscularis propria, a location inaccessible to routine endoscopic evaluation. Achalasia is an idiopathic condition resulting from destruction of neurons in the myenteric plexus of the esophagus, and degranulating eosinophils release toxic proteins capable of destroying those neurons, thereby causing the irreversible motility abnormalities of achalasia. This report reviews data on the association of esophageal eosinophilia with achalasia and other esophageal motility abnormalities. Based on this review, we propose that EoE, like eosinophilic gastroenteritis, might have mucosal-predominant and muscle-predominant forms with different clinical manifestations. A muscle-predominant form of EoE could underlie a variety of reversible and irreversible esophageal motility disorders, including achalasia. The concept that esophageal motility abnormalities might develop from a muscle-predominant form of EoE warrants serious consideration and further investigation.
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Esofagitis Eosinofílica/complicaciones , Eosinófilos/inmunología , Acalasia del Esófago/inmunología , Mucosa Esofágica/fisiopatología , Esfínter Esofágico Inferior/fisiopatología , Esofagitis Eosinofílica/inmunología , Esofagitis Eosinofílica/fisiopatología , Acalasia del Esófago/fisiopatología , Mucosa Esofágica/citología , Mucosa Esofágica/inmunología , Esfínter Esofágico Inferior/citología , Esfínter Esofágico Inferior/inmunología , Humanos , Recuento de LeucocitosRESUMEN
BACKGROUND: The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti-ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO). METHODS: First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups. RESULTS: In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia. CONCLUSIONS: These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders.
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Enfermedades Autoinmunes/inmunología , Enfermedades del Sistema Nervioso Autónomo/inmunología , Enfermedades Gastrointestinales/inmunología , Motilidad Gastrointestinal/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/fisiopatología , Enfermedades del Sistema Nervioso Autónomo/fisiopatología , Niño , Enfermedad Crónica , Estudios de Cohortes , Acalasia del Esófago/inmunología , Acalasia del Esófago/fisiopatología , Femenino , Ganglios Autónomos/inmunología , Enfermedades Gastrointestinales/fisiopatología , Humanos , Seudoobstrucción Intestinal/inmunología , Seudoobstrucción Intestinal/fisiopatología , Japón , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Receptores Colinérgicos/inmunología , Estudios RetrospectivosRESUMEN
BACKGROUND The aim of this study was to undertake a histological evaluation of the presence of eosinophils in esophageal muscle in patients with achalasia before treatment with peroral endoscopic myotomy (POEM), with clinical follow-up at one year. MATERIAL AND METHODS Before treatment, esophageal biopsies including mucosa and esophageal muscle were obtained from 28 patients with achalasia. Nine patients who had undergone esophagectomy for esophageal carcinoma were included in the control group. The Eckardt Score was used to evaluate the clinical symptoms of achalasia. Histology of routinely processed tissue sections was used to perform eosinophil cell counts (0 to +++), and immunohistochemistry was used to detect expression of eosinophil major basic protein (MBP), eosinophil-derived neurotoxin (EDN), and S100 protein in cases of achalasia (n=28) and controls (n=9). The findings in patients with achalasia were compared before and one year following POEM. RESULTS Esophageal tissue from patients with achalasia showed eosinophils infiltrating into the muscularis externa in 85.7% (24/28), into the muscularis propria in 28.6% (8/28), and in 89% (25/28) there were few remaining myenteric ganglion cells, before POEM. The extent of inflammation was similar in all regions of the esophagus and between subtypes of achalasia. At one year following POEM, the Eckardt Scores between the former eosinophil (0) group and the eosinophil (+++) group were significantly different (Z=3.50, P=0.030). CONCLUSIONS Achalasia of the esophagus was associated with infiltration of the esophageal muscle by activated eosinophils and a decrease in the density of ganglion cells in the myenteric esophageal plexus.
Asunto(s)
Eosinófilos/citología , Acalasia del Esófago/inmunología , Acalasia del Esófago/fisiopatología , Adulto , Anciano , Biopsia , China/epidemiología , Eosinófilos/metabolismo , Eosinófilos/fisiología , Acalasia del Esófago/cirugía , Esfínter Esofágico Inferior/cirugía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Liso/patología , Cirugía Endoscópica por Orificios Naturales/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Achalasia has three distinct manometric phenotypes. This study aimed to determine if there were corresponding histopathologic patterns. METHODS: We retrospectively examined surgical muscularis propria biopsies obtained from 46 patients during laparoscopic esophagomyotomy. Pre-operative (conventional) manometry tracings were reviewed by two expert gastroenterologists who categorized patients into Chicago Classification subtypes. Pathology specimens were graded on degree of neuronal loss, inflammation, fibrosis, and muscle changes. KEY RESULTS: Manometry studies were categorized as follows: type I (n = 20), type II (n = 20), type III (n = 3), and esophagogastric junction outflow obstruction (EGJOO) (n = 3). On histopathology, complete ganglion cell loss occurred in 74% of specimens, inflammation in 17%, fibrosis in 11%, and muscle atrophy in 2%. Comparing type I and type II specimens, there was a statistically significant greater proportion of type I specimens with aganglionosis (19/20 vs 13/20, p = 0.044) and a statistically significant greater degree of ganglion cell loss in type I specimens (Wilcoxon Rank-Sum, p = 0.016). CD3(+) /CD8(+) cytotoxic T cells represented the predominant inflammatory infiltrate on immunohistochemistry. Three patients had completely normal appearing tissue (1 each in type II, type III, EGJOO). CONCLUSIONS & INFERENCES: The greater degree, but similar pattern, of ganglion cell loss observed in type I compared to type II achalasia specimens suggests that type I achalasia represents a progression from type II achalasia. The spectrum of histopathologic findings - from complete neuronal loss to lymphocytic inflammation to apparently normal histopathology - emphasizes that 'achalasia' represents a pathogenically heterogeneous patient group with the commonality being EGJ outflow obstruction.
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Acalasia del Esófago/patología , Esfínter Esofágico Inferior/patología , Unión Esofagogástrica/patología , Atrofia Muscular/patología , Neuronas/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Acalasia del Esófago/clasificación , Acalasia del Esófago/inmunología , Acalasia del Esófago/fisiopatología , Esfínter Esofágico Inferior/inmunología , Esfínter Esofágico Inferior/fisiopatología , Unión Esofagogástrica/inmunología , Unión Esofagogástrica/fisiopatología , Esófago/inmunología , Esófago/patología , Esófago/fisiopatología , Femenino , Fibrosis , Ganglios/citología , Ganglios/patología , Humanos , Inmunohistoquímica , Inflamación/inmunología , Inflamación/patología , Masculino , Manometría , Persona de Mediana Edad , Estudios Retrospectivos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Adulto JovenRESUMEN
Idiopathic achalasia is a disease of unknown etiology. The loss of myenteric plexus associated with inflammatory infiltrates and autoantibodies support the hypothesis of an autoimmune mechanism. Thirty-two patients diagnosed by high-resolution manometry with achalasia were included. Twenty-six specimens from lower esophageal sphincter muscle were compared with 5 esophagectomy biopsies (control). Immunohistochemical (biopsies) and flow cytometry (peripheral blood) analyses were performed. Circulating anti-myenteric autoantibodies were evaluated by indirect immunofluorescence. Herpes simplex virus-1 (HSV-1) infection was determined by in situ hybridization, RT-PCR, and immunohistochemistry. Histopathological analysis showed capillaritis (51%), plexitis (23%), nerve hypertrophy (16%), venulitis (7%), and fibrosis (3%). Achalasia tissue exhibited an increase in the expression of proteins involved in extracellular matrix turnover, apoptosis, proinflammatory and profibrogenic cytokines, and Tregs and Bregs versus controls (P < 0.001). Circulating Th22/Th17/Th2/Th1 percentage showed a significant increase versus healthy donors (P < 0.01). Type III achalasia patients exhibited the highest inflammatory response versus types I and II. Prevalence of both anti-myenteric antibodies and HSV-1 infection in achalasia patients was 100% versus 0% in controls. Our results suggest that achalasia is a disease with an important local and systemic inflammatory autoimmune component, associated with the presence of specific anti-myenteric autoantibodies, as well as HSV-1 infection.
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Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Acalasia del Esófago/inmunología , Acalasia del Esófago/patología , Inflamación/inmunología , Inflamación/patología , Adulto , Anciano , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/virología , Estudios de Casos y Controles , Estudios Transversales , Acalasia del Esófago/virología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta/métodos , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Humanos , Inmunohistoquímica/métodos , Inflamación/virología , Masculino , Persona de Mediana Edad , Plexo Mientérico/inmunología , Plexo Mientérico/patología , Plexo Mientérico/virologíaRESUMEN
Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQß1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQß1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.
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Acalasia del Esófago/genética , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Alelos , Sustitución de Aminoácidos , Estudios de Casos y Controles , Acalasia del Esófago/inmunología , Femenino , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad , Antígenos HLA-DQ/química , Haplotipos , Humanos , Modelos Logísticos , Masculino , Modelos Moleculares , Polimorfismo de Nucleótido SimpleRESUMEN
The physiopathology of idiopathic achalasia is still unknown. The description of circulating antimyenteric autoantibodies (CAA), directed against enteric neurons in sera of patients, suggests an autoimmune process. Recent data showed controversies according to the existence and the significance of CAA. The aims of this study were to investigate whether CAA are detected in Tunisian patients with idiopathic achalasia and to look for associated clinical or manometrical factors with CAA positivity. Twenty-seven patients with idiopathic achalasia and 57 healthy controls were prospectively studied. CAA were assessed by indirect immunofluorescence on intestinal monkey tissue sections. Western blot on primate cerebellum protein extract and dot technique with highly purified recombinant neuronal antigens (Hu, Ri, and Yo) were further used to analyze target antigens of CAA. CAA were significantly increased in achalasia patients compared with controls when considering nuclear or cytoplasmic fluorescence patterns. (33% vs. 12%, P = 0.03 and 48% vs. 23%, P = 0.001 respectively). By immunoblot analysis, CAA did not target neuronal antigens, however 52/53 and 49 kDa bands were consistently detected. CAA positivity was not correlated to specific clinical features. The results are along with previous studies demonstrating high CAA prevalence in achalasia patients. When reviewing technical protocols and interpretation criteria, several discrepancies which could explain controversies between studies were noted.
Asunto(s)
Autoanticuerpos/inmunología , Acalasia del Esófago/inmunología , Esfínter Esofágico Inferior/inervación , Ganglios Autónomos/inmunología , Plexo Mientérico/inmunología , Adulto , Estudios de Casos y Controles , Acalasia del Esófago/fisiopatología , Esfínter Esofágico Inferior/fisiopatología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Masculino , Manometría , Persona de Mediana Edad , Adulto JovenRESUMEN
Many cases have been published showing a co-existence of autoimmune thyroid diseases (AITDs) and other autoimmune diseases. About a quarter of patients with achalasia have a concurrent thyroid disease, most commonly associated with hypothyroidism. Although relatively rare, the association of achalasia and hyperthyroidism requires attention. The physiopathology of Grave's Disease (GD) involves B- and T-mediator lymphocytes, which have an affinity for known thyroid antigens: thyroglobulin, thyroid-peroxidase, and thyrotrophin receptor. Currently, however, the real physiopathogenesis of achalasia continues to be unknown. Some important findings are suggestive of an autoimmune mechanism: significant infiltration of the myoenteric plexus by monocytes, presence of the class II-Human Histocompatibility Complex DQwl antigen and antibodies to myoenteric neurons. The present case reports a patient who, despite testing negative for Chagas' disease, had achalasia, progressed to developing significant wasting and worsening of his quality of life, was later diagnosed with hyperthyroidism. After endoscopic esophageal dilatation and radioiodine ablation of the thyroid gland, there was great improvement in the patient clinical condition. Arq Bras Endocrinol Metab. 2012;56(9):677-82.
Muitos casos têm sido publicados mostrando uma coexistência entre as doenças autoimunes da tireoide (DAIT) e outras doenças autoimunes. Cerca de um quarto dos pacientes com acalasia têm doenças da tireoide concomitantemente, sendo a mais comum a associação com hipotireoidismo. Apesar de ser relativamente rara, a associação da acalasia e hipertireoidismo requer atenção. A fisiopatologia da doença de Graves (DG) envolve os linfócitos B e T-mediados, os quais têm afinidade pelos antígenos da tireoide: tireoglobulina, tireoperoxidase e receptor de tireotrofina. Atualmente, a real fisiopatogenia da acalasia continua desconhecida. No entanto, alguns importantes achados em análise são sugestivos de mecanismo autoimune: infiltração significativa do plexo mioentérico pelos monócitos, presença do antígeno-DQwl do Complexo Humano de Histocompatibilidade classe II e presença de anticorpos contra neurônios mioentéricos. Este presente caso aborda um paciente que, apesar de testes negativos para doença de Chagas, tem acalasia que progrediu para o desenvolvimento de significativa perda ponderal e piora da sua qualidade de vida, posteriormente, diagnosticado com hipertireoidismo. Após dilatação endoscópica esofágica e ablação da glândula tireoide com radioiodo, houve grande melhora na condição clínica do paciente. Arq Bras Endocrinol Metab. 2012;56(9):677-82.
Asunto(s)
Humanos , Masculino , Persona de Mediana Edad , Acalasia del Esófago/complicaciones , Enfermedad de Graves/complicaciones , Tiroiditis Autoinmune/etiología , Acalasia del Esófago/inmunología , Glándula Tiroides/inmunologíaRESUMEN
Achalasia cardia is one of the common causes of motor dysphagia. Though the disease was first described more than 300 years ago, exact pathogenesis of this condition still remains enigmatic. Pathophysiologically, achalasia cardia is caused by loss of inhibitory ganglion in the myenteric plexus of the esophagus. In the initial stage, degeneration of inhibitory nerves in the esophagus results in unopposed action of excitatory neurotransmitters such as acetylcholine, resulting in high amplitude non-peristaltic contractions (vigorous achalasia); progressive loss of cholinergic neurons over time results in dilation and low amplitude simultaneous contractions in the esophageal body (classic achalasia). Since the initial description, several studies have attempted to explore initiating agents that may cause the disease, such as viral infection, other environmental factors, autoimmunity, and genetic factors. Though Chagas disease, which mimics achalasia, is caused by an infective agent, available evidence suggests that infection may not be an independent cause of primary achalasia. A genetic basis for achalasia is supported by reports showing occurrence of disease in monozygotic twins, siblings and other first-degree relatives and occurrence in association with other genetic diseases such as Down's syndrome and Parkinson's disease. Polymorphisms in genes encoding for nitric oxide synthase, receptors for vasoactive intestinal peptide, interleukin 23 and the ALADIN gene have been reported. However, studies on larger numbers of patients and controls from different ethnic groups are needed before definite conclusions can be obtained. Currently, the disease is believed to be multi-factorial, with autoimmune mechanisms triggered by infection in a genetically predisposed individual leading to degeneration of inhibitory ganglia in the wall of the esophagus.
Asunto(s)
Trastornos de Deglución/etiología , Acalasia del Esófago/etiología , Esófago/inervación , Ganglios/fisiopatología , Deglución , Trastornos de Deglución/genética , Trastornos de Deglución/inmunología , Trastornos de Deglución/fisiopatología , Progresión de la Enfermedad , Acalasia del Esófago/genética , Acalasia del Esófago/inmunología , Acalasia del Esófago/fisiopatología , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Pronóstico , Medición de Riesgo , Factores de RiesgoRESUMEN
Many cases have been published showing a co-existence of autoimmune thyroid diseases (AITDs) and other autoimmune diseases. About a quarter of patients with achalasia have a concurrent thyroid disease, most commonly associated with hypothyroidism. Although relatively rare, the association of achalasia and hyperthyroidism requires attention. The physiopathology of Grave's Disease (GD) involves B- and T-mediator lymphocytes, which have an affinity for known thyroid antigens: thyroglobulin, thyroid-peroxidase, and thyrotrophin receptor. Currently, however, the real physiopathogenesis of achalasia continues to be unknown. Some important findings are suggestive of an autoimmune mechanism: significant infiltration of the myoenteric plexus by monocytes, presence of the class II-Human Histocompatibility Complex DQwl antigen and antibodies to myoenteric neurons. The present case reports a patient who, despite testing negative for Chagas' disease, had achalasia, progressed to developing significant wasting and worsening of his quality of life, was later diagnosed with hyperthyroidism. After endoscopic esophageal dilatation and radioiodine ablation of the thyroid gland, there was great improvement in the patient clinical condition.
Asunto(s)
Acalasia del Esófago/complicaciones , Enfermedad de Graves/complicaciones , Tiroiditis Autoinmune/etiología , Acalasia del Esófago/inmunología , Humanos , Masculino , Persona de Mediana Edad , Glándula Tiroides/inmunologíaRESUMEN
Achalasia is a rare disease of the esophagus that has an unknown etiology. Genetic, infectious, and autoimmune mechanisms have each been proposed. Autoimmune diseases often occur in association with one another, either within a single individual or in a family. There have been separate case reports of patients with both achalasia and one or more autoimmune diseases, but no study has yet determined the prevalence of autoimmune diseases in the achalasia population. This paper aims to compare the prevalence of autoimmune disease in patients with esophageal achalasia to the general population. We retrospectively reviewed the charts of 193 achalasia patients who received treatment at Toronto's University Health Network between January 2000 and May 2010 to identify other autoimmune diseases and a number of control conditions. We determined the general population prevalence of autoimmune diseases from published epidemiological studies. The achalasia sample was, on average, 10-15 years older and had slightly more men than the control populations. Compared to the general population, patients with achalasia were 5.4 times more likely to have type I diabetes mellitus (95% confidence interval [CI] 1.5-19), 8.5 times as likely to have hypothyroidism (95% CI 5.0-14), 37 times as likely to have Sjögren's syndrome (95% CI 1.9-205), 43 times as likely to have systemic lupus erythematosus (95% CI 12-154), and 259 times as likely to have uveitis (95% CI 13-1438). Overall, patients with achalasia were 3.6 times more likely to suffer from any autoimmune condition (95% CI 2.5-5.3). Our findings are consistent with the impression that achalasia's etiology has an autoimmune component. Further research is needed to more conclusively define achalasia as an autoimmune disease.
Asunto(s)
Enfermedades Autoinmunes/epidemiología , Acalasia del Esófago/epidemiología , Acalasia del Esófago/inmunología , Adulto , Factores de Edad , Canadá/epidemiología , Intervalos de Confianza , Estudios Transversales , Diabetes Mellitus/epidemiología , Femenino , Humanos , Hipotiroidismo/epidemiología , Lupus Eritematoso Sistémico/epidemiología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Estudios Retrospectivos , Síndrome de Sjögren/epidemiología , Uveítis/epidemiologíaRESUMEN
The current state of research into the etiology of achalasia only allows for speculation. To date, several studies have been performed investigating genetic, immune, and infectious disease mechanisms; however, none of these have been conclusive. Further research into this topic is warranted given the severity of the disease, and it may be possible that all of these mechanisms are involved in the pathophysiology of the disease.
Asunto(s)
Acalasia del Esófago/etiología , Virosis/complicaciones , Insuficiencia Suprarrenal/genética , Acalasia del Esófago/genética , Acalasia del Esófago/inmunología , Humanos , Polimorfismo de Nucleótido SimpleRESUMEN
We report a patient who developed subacute facial-predominant numbness and anhidrosis, oral incoordination, and esophageal achalasia with resultant cachexia. Great auricular nerve biopsy showed extensive epineurial perivascular inflammatory infiltrates. Sensation, sweating, and swallowing improved with pulse intravenous methylprednisolone given over 5 years. We suggest that the patient's deficits, including achalasia, were due to an immune-mediated sensory and autonomic neuropathy and that, in such cases, pathologic studies of the great auricular nerve may be diagnostically informative.