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Di Brina ALP, Palmieri O, Cannarozzi AL, Tavano F, Guerra M, Bossa F, Gentile M, Merla A, Biscaglia G, Cuttitta A, Perri F, Latiano A. Focus on Achalasia in the Omics Era. Int J Mol Sci 2024; 25:10148. [PMID: 39337632 PMCID: PMC11431880 DOI: 10.3390/ijms251810148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Achalasia is a rare and complex esophageal disease of unknown etiology characterized by difficulty in swallowing due to the lack of opening of the lower esophageal sphincter and the absence of esophageal peristalsis. Recent advancements in technology for analyzing DNA, RNA and biomolecules in high-throughput techniques are offering new opportunities to better understand the etiology and the pathogenetic mechanisms underlying achalasia. Through this narrative review of the scientific literature, we aim to provide a comprehensive assessment of the state-of-the-art knowledge on omics of achalasia, with particular attention to those considered relevant to the pathogenesis of the disease. The notion and importance of the multi-omics approach, its limitations and future directions are also introduced, and it is highlighted how the integration of single omics data will lead to new insights into the development of achalasia and offer clinical tools which will allow early diagnosis and better patient management.
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Affiliation(s)
- Anna Laura Pia Di Brina
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Orazio Palmieri
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Anna Lucia Cannarozzi
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Francesca Tavano
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Maria Guerra
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Fabrizio Bossa
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Marco Gentile
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Antonio Merla
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Giuseppe Biscaglia
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Antonello Cuttitta
- Unit of Thoracic Surgery, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Francesco Perri
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Anna Latiano
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
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Blonski W, Slone S, Richter JE. Update on the Diagnosis and Treatment of Achalasia. Dysphagia 2023; 38:596-608. [PMID: 35585208 DOI: 10.1007/s00455-022-10435-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 03/04/2022] [Indexed: 12/23/2022]
Abstract
Achalasia is a rare disease of the esophagus with impaired relaxation of the lower esophageal sphincter and aperistalsis. The etiology is unknown but speculations include a viral or autoimmune etiology. All specialists dealing with swallowing and esophageal diseases should recognize the classic symptoms of dysphagia for solids/liquids, regurgitation, and choking, especially at night. High-resolution manometry is critical for the diagnosis with endoscopy and barium esophagram having a supportive role. The disease cannot be cured but most can return to near normal swallowing and a regular diet with appropriate therapy. Treatment includes smooth muscle relaxants, botulinum toxin injections to the lower sphincter, pneumatic dilation, Heller myotomy, and peroral endoscopic myotomy. One treatment does not fit all and a tailored approach through a multidiscipline team will give the best long-term outcomes.
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Affiliation(s)
- Wojciech Blonski
- Division of Gastroenterology, James A. Haley VA Hospital, Tampa, FL, USA
- Division of Gastroenterology and Nutrition, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 72, Tampa, FL, 33612, USA
| | - Samuel Slone
- Division of Gastroenterology and Nutrition, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 72, Tampa, FL, 33612, USA
| | - Joel E Richter
- Division of Gastroenterology and Nutrition, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC 72, Tampa, FL, 33612, USA.
- Joy McCann Culverhouse Center for Esophageal Diseases, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
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Wu XY, Liu ZQ, Wang Y, Chen WF, Gao PT, Li QL, Zhou PH. The etiology of achalasia: An immune-dominant disease. J Dig Dis 2021; 22:126-135. [PMID: 33583137 DOI: 10.1111/1751-2980.12973] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 02/06/2023]
Abstract
There is accumulating evidence suggesting that an autoimmune component is involved in esophageal achalasia. An increase in immune cells, cytokines, chemokines, and autoimmune antibodies in serum and infiltration of immune cells in tissues support the view that immune-mediated inflammation is a crucial pathogenesis of inhibitory neuron degeneration in the lower esophageal sphincter. Infection of viruses such as the herpes virus family has been suspected of provoking the autoimmune reaction. Meanwhile, previous reports on immunogenetics have proposed that specific risk alleles on the human leukocyte antigen complex define the susceptible population to achalasia. In this study we reviewed current knowledge regarding the immune-related factors of achalasia, including immunology, viral infection and immunogenetic variations.
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Affiliation(s)
- Xing Yue Wu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical College, Fudan University, Shanghai, China
| | - Zu Qiang Liu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yun Wang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Feng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Ting Gao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Quan Lin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Hong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
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Prieto RG, Prieto JE, Casas F, Ballén H. Acalasia, una visión actual. REVISTA COLOMBIANA DE CIRUGÍA 2019. [DOI: 10.30944/20117582.111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
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Soffer E. Epidemiology, Diagnosis, and Medical Management of Achalasia. SHACKELFORD'S SURGERY OF THE ALIMENTARY TRACT, 2 VOLUME SET 2019:184-188. [DOI: 10.1016/b978-0-323-40232-3.00013-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Bonora E, Bianco F, Stanzani A, Giancola F, Astolfi A, Indio V, Evangelisti C, Martelli AM, Boschetti E, Lugaresi M, Ioannou A, Torresan F, Stanghellini V, Clavenzani P, Seri M, Moonen A, Van Beek K, Wouters M, Boeckxstaens GE, Zaninotto G, Mattioli S, De Giorgio R. INPP4B overexpression and c-KIT downregulation in human achalasia. Neurogastroenterol Motil 2018; 30:e13346. [PMID: 29644781 DOI: 10.1111/nmo.13346] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 03/06/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Achalasia is a rare motility disorder characterized by myenteric neuron and interstitial cells of Cajal (ICC) abnormalities leading to deranged/absent peristalsis and lack of relaxation of the lower esophageal sphincter. The mechanisms contributing to neuronal and ICC changes in achalasia are only partially understood. Our goal was to identify novel molecular features occurring in patients with primary achalasia. METHODS Esophageal full-thickness biopsies from 42 (22 females; age range: 16-82 years) clinically, radiologically, and manometrically characterized patients with primary achalasia were examined and compared to those obtained from 10 subjects (controls) undergoing surgery for uncomplicated esophageal cancer (or upper stomach disorders). Tissue RNA extracted from biopsies of cases and controls was used for library preparation and sequencing. Data analysis was performed with the "edgeR" option of R-Bioconductor. Data were validated by real-time RT-PCR, western blotting and immunohistochemistry. KEY RESULTS Quantitative transcriptome evaluation and cluster analysis revealed 111 differentially expressed genes, with a P ≤ 10-3 . Nine genes with a P ≤ 10-4 were further validated. CYR61, CTGF, c-KIT, DUSP5, EGR1 were downregulated, whereas AKAP6 and INPP4B were upregulated in patients vs controls. Compared to controls, immunohistochemical analysis revealed a clear increase in INPP4B, whereas c-KIT immunolabeling resulted downregulated. As INPP4B regulates Akt pathway, we used western blot to show that phospho-Akt was significantly reduced in achalasia patients vs controls. CONCLUSIONS & INFERENCES The identification of altered gene expression, including INPP4B, a regulator of the Akt pathway, highlights novel signaling pathways involved in the neuronal and ICC changes underlying primary achalasia.
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Affiliation(s)
- E Bonora
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| | - F Bianco
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy.,Department of Medical and Veterinary Sciences, DIMEVET, University of Bologna, Bologna, Italy
| | - A Stanzani
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy.,Department of Medical and Veterinary Sciences, DIMEVET, University of Bologna, Bologna, Italy
| | - F Giancola
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy.,Department of Medical and Veterinary Sciences, DIMEVET, University of Bologna, Bologna, Italy.,Centro di Ricerca Biomedica Applicata, St.Orsola-Malpighi Hospital, Bologna, Italy
| | - A Astolfi
- Interdepartmental Center for Cancer Research "G. Prodi" (CIRC), University of Bologna, Bologna, Italy
| | - V Indio
- Interdepartmental Center for Cancer Research "G. Prodi" (CIRC), University of Bologna, Bologna, Italy
| | - C Evangelisti
- Department of Experimental Medicine, DIMES, University of Bologna, Bologna, Italy
| | - A M Martelli
- Department of Experimental Medicine, DIMES, University of Bologna, Bologna, Italy
| | - E Boschetti
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy.,Centro di Ricerca Biomedica Applicata, St.Orsola-Malpighi Hospital, Bologna, Italy
| | - M Lugaresi
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| | - A Ioannou
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| | - F Torresan
- Department of Digestive System, St. Orsola-Malpighi Hospital, Bologna, Italy
| | - V Stanghellini
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| | - P Clavenzani
- Department of Medical and Veterinary Sciences, DIMEVET, University of Bologna, Bologna, Italy
| | - M Seri
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| | - A Moonen
- Translational Research in GastroIntestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven University, Leuven, Belgium
| | - K Van Beek
- Translational Research in GastroIntestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven University, Leuven, Belgium
| | - M Wouters
- Translational Research in GastroIntestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven University, Leuven, Belgium
| | - G E Boeckxstaens
- Translational Research in GastroIntestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, KU Leuven University, Leuven, Belgium
| | - G Zaninotto
- Division of Surgery, Imperial College London, London, UK
| | - S Mattioli
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna and St. Orsola-Malpighi Hospital, Bologna, Italy
| | - R De Giorgio
- Department of Medical Sciences, Nuovo Arcispedale S.Anna at Cona (Ferrara), University of Ferrara, Ferrara, Italy
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An original Eurasian haplotype, HLA-DRB1*14:54-DQB1*05:03, influences the susceptibility to idiopathic achalasia. PLoS One 2018; 13:e0201676. [PMID: 30092016 PMCID: PMC6084941 DOI: 10.1371/journal.pone.0201676] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 07/19/2018] [Indexed: 01/04/2023] Open
Abstract
Idiopathic achalasia is a relatively infrequent esophageal motor disorder for which major histocompatibility complex (MHC) genes are well-identified risk factors. However, no information about HLA-achalasia susceptibility in Mexicans has previously been reported. We studied a group of 91 patients diagnosed with achalasia and 234 healthy controls with Mexican admixed ancestry. HLA alleles and conserved extended haplotypes were analyzed using high-resolution HLA typing based on Sanger and next-generation sequencing technologies. Admixture estimates were determined using HLA-B and short tandem repeats. Results were analyzed by non-parametric statistical analysis and Bonferroni correction. P-values < 0.05 were considered significant. Patients with achalasia had 56.7% Native American genes, 24.7% European genes, 16.5% African genes and 2.0% Asian genes, which was comparable with the estimates in the controls. Significant increases in the frequencies of alleles DRB1*14:54 and DQB1*05:03 and the extended haplotypes DRB1*14:54-DQB1*05:03 and DRB1*11:01-DQB1*03:01, even after Bonferroni correction (pC<0.05), were found in the achalasia group compared to those in the controls. Concluding, the HLA class II alleles HLA-DRB1*14:54:01 and DQB1*05:03:01 and the extended haplotype are risk factors for achalasia in mixed-ancestry Mexican individuals. These results also suggest that the HLA-DRB1*14:54-DQB1*05:03 haplotype was introduced by admixture with European and/or Asian populations.
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Romero-Hernández F, Furuzawa-Carballeda J, Hernández-Molina G, Alejandro-Medrano E, Núñez-Álvarez CA, Hernández-Ramírez DF, Azamar-Llamas D, Olivares-Martínez E, Breña B, Palacios A, Valdovinos MA, Coss-Adame E, Ramos-Ávalos B, Torres-Landa S, Hernández-Ávila AA, Flores-Nájera A, Torres-Villalobos G. Autoimmune comorbidity in achalasia patients. J Gastroenterol Hepatol 2018; 33:203-208. [PMID: 28568312 DOI: 10.1111/jgh.13839] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/23/2017] [Accepted: 05/28/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Idiopathic achalasia is a rare esophageal motor disorder. The disease state manifests local and systemic inflammation, and it appears that an autoimmune component and specific autoantibodies participate in the pathogenesis. The study aims to determine the prevalence of autoimmune and chronic inflammatory diseases in patients with achalasia and compare the results with those from patients with gastroesophageal reflux disease (GERD). METHODS It was a cross-sectional and included 114 patients with idiopathic achalasia and 114 age-matched and sex-matched control patients with GERD. Data on the presence of autoimmune and inflammatory diseases, the time of presentation, and any family history of autoimmune disease were obtained from the hospital's medical records. RESULTS Seventy three (64%) were female patients (mean age: 42.3 ± 15.5; median disease duration: 12 months). We identified the presence of autoimmune disease in 19 patients with achalasia (16.7%), hypothyroidism was the main diagnosis, and it was present in 52.6% of patients compared with 4.2% in controls. Thirteen of the 19 achalasia patients (68.4%) with autoimmune disease had history of familial autoimmunity. We identified 11 achalasia (9.6%) and 5 GERD patients (4.16%) with an inflammatory condition. Compared with the GERD, the achalasia group was 3.8 times more likely to have an autoimmune disease (95% CI: 1.47-9.83), 3.0 times more likely to have thyroidopathies (95% CI: 1.00-9.03), and 3.02 times more likely to suffer from any chronic inflammatory disease (95% CI: 1.65-6.20). CONCLUSIONS The non-negligible number of patients with autoimmune diseases identified among the patients with idiopathic achalasia supports the hypothesis that achalasia has an autoimmune component.
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Affiliation(s)
- Fernanda Romero-Hernández
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Janette Furuzawa-Carballeda
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Gabriela Hernández-Molina
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Edgar Alejandro-Medrano
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Carlos A Núñez-Álvarez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Diego F Hernández-Ramírez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Daniel Azamar-Llamas
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Elizabeth Olivares-Martínez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Blanca Breña
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Axel Palacios
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Miguel A Valdovinos
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Enrique Coss-Adame
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Bárbara Ramos-Ávalos
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Samuel Torres-Landa
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Axel A Hernández-Ávila
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Athenea Flores-Nájera
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Gonzalo Torres-Villalobos
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Abstract
This review examines the etiology and pathogenesis of idiopathic achalasia. This disease is clinically characterized by dysphagia of solids and liquids due to the presence of simultaneous or absent esophageal contractions and impaired or absent relaxation of the lower esophageal sphincter. It includes a review of (a) etiology and pathogenesis of this inflammatory process that damage the ganglion cells of the Auerbach plexus that is limited to the esophagus; (b) genetic abnormalities and polymorphisms associated with this disease that may help explain its heterogeneity expressed by the different motility abnormalities of its phenotypes as well as differences in its clinical progression. These different genetic abnormalities may be responsible for the slow progression of types I or II phenotypes; (c) indirect evidence of viruses present in these patients that may initiate its development; (d) the abnormalities of the muscle layer that may be responsible for the dilation of the body of the esophagus that ultimately causes the sigmoid-like esophagus in the very last phase of this disease. This progression to the end-stage phase tends to occur in about 5% of patients. And, (e) the chronic inflammatory abnormalities in the squamous mucosa that may be the cause of the dysplastic and neoplastic changes that may lead to squamous cell carcinoma whose incidence in this disease is increased. These mucosal abnormalities are usually present in patients with markedly dilated body of the esophagus and severe food stasis.
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Sarnelli G, Grosso M, Palumbo I, Pesce M, D’Alessandro A, Zaninotto G, Annese V, Petruzzelli R, Izzo P, Sepulveres R, Bruzzese D, Esposito G, Cuomo R. Allele-specific transcriptional activity of the variable number of tandem repeats of the inducible nitric oxide synthase gene is associated with idiopathic achalasia. United European Gastroenterol J 2017; 5:200-207. [PMID: 28344787 PMCID: PMC5349359 DOI: 10.1177/2050640616648870] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 04/15/2016] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Polymorphisms of genes involved in the regulation of the immune response are risk factors for achalasia, but their contribution to disease pathogenesis is unknown. Nitric oxide is involved both in immune function and inhibitory neurotransmission. OBJECTIVE The objective of this article is to assess the association and the functional relevance of the CCTTT-inducible nitric oxide synthase (NOS2) gene promoter polymorphism in achalasia. METHODS Genomic DNA was isolated from 181 achalasia patients and 220 controls. Genotyping of the (CCTTT)n repeats was performed by PCR and capillary electrophoresis, and data analyzed by considering the frequency of the different alleles. HT29 cells were transfected with iNOS luciferase promoter-reporter plasmids containing different (CCTTT)n. RESULTS The alleles' distribution ranged from 7 to 18, with a peak frequency at 12 repeats. Analysis of the allele frequencies revealed that individuals carrying 10 and 13 CCTTT repeats were respectively less and more frequent in achalasia (OR 0.5, 95% CI 0.3-0.5 and OR 1.6, 95% CI 1-2.4, all p < 0.05). Long repeats were also significantly associated with an earlier onset of the disease (OR 1.69, 95% CI 1.13-2.53, p = 0.01). Transfection experiments revealed a similar allele-specific iNOS transcriptional activity. CONCLUSION The functional polymorphism (CCTTT) of NOS2 promoter is associated with achalasia, likely by an allele-specific modulation of nitric oxide production.
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Affiliation(s)
- Giovanni Sarnelli
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Michela Grosso
- Department of Biochemistry and Medical
Biotechnology, University Federico II, Naples, Italy
| | - Ilaria Palumbo
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Marcella Pesce
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Alessandra D’Alessandro
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Giovanni Zaninotto
- Imperial College-St Mary’s Hospital,
Department of Academic Surgery, London, UK
| | - Vito Annese
- Unit of Gastroenterology SOD2, Azienda
Ospedaliera Universitaria, Careggi, Firenze, Italy
| | - Raffaella Petruzzelli
- Department of Biochemistry and Medical
Biotechnology, University Federico II, Naples, Italy
| | - Paola Izzo
- Department of Biochemistry and Medical
Biotechnology, University Federico II, Naples, Italy
| | - Rossana Sepulveres
- Department of Biochemistry and Medical
Biotechnology, University Federico II, Naples, Italy
| | - Dario Bruzzese
- Department of Public Health, University
Federico II, Naples, Italy
| | - Giuseppe Esposito
- Department of Physiology and
Pharmacology, “La Sapienza” University of Rome, Italy
| | - Rosario Cuomo
- Gastroenterology Unit, Department of
Clinical Medicine and Surgery University Federico II, Naples, Italy
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11
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Gene expression of muscular and neuronal pathways is cooperatively dysregulated in patients with idiopathic achalasia. Sci Rep 2016; 6:31549. [PMID: 27511445 PMCID: PMC4980661 DOI: 10.1038/srep31549] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 07/11/2016] [Indexed: 02/07/2023] Open
Abstract
Idiopathic achalasia is characterized by the absence of peristalsis secondary to loss of neurons in the myenteric plexus that hampers proper relaxation of the lower esophageal sphincter. Achalasia can be considered a multifactorial disorder as it occurs in related individuals and is associated with HLA class II genes, thereby suggesting genetic influence. We used microarray technology and advanced in-silico functional analyses to perform the first genome-wide expression profiling of mRNA in tissue samples from 12 achalasia and 5 control patients. It revealed 1,728 differentially expressed genes, of these, 837 (48.4%) were up-regulated in cases. In particular, genes participating to the smooth muscle contraction biological function were mostly up-regulated. Functional analysis revealed a significant enrichment of neuronal/muscular and neuronal/immunity processes. Upstream regulatory analysis of 180 genes involved in these processes suggested TLR4 and IL18 as critical key-players. Two functional gene networks were significantly over-represented: one involved in organ morphology, skeletal muscle system development and function, and neurological diseases, and the other participating in cell morphology, humoral immune response and cellular movement. These results highlight on pivotal genes that may play critical roles in neuronal/muscular and neuronal/immunity processes, and that may contribute to the onset and development of achalasia.
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12
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Sodikoff JB, Lo AA, Shetuni BB, Kahrilas PJ, Yang GY, Pandolfino JE. Histopathologic patterns among achalasia subtypes. Neurogastroenterol Motil 2016; 28:139-45. [PMID: 26542087 PMCID: PMC4688144 DOI: 10.1111/nmo.12711] [Citation(s) in RCA: 88] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 09/24/2015] [Indexed: 12/14/2022]
Abstract
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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Affiliation(s)
- Jamie B Sodikoff
- Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611
| | - Amy A Lo
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611
| | - Brandon B Shetuni
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611
| | - Peter J Kahrilas
- Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611
| | - Guang-Yu Yang
- Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611
| | - John E Pandolfino
- Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL, 60611
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13
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Abstract
Idiopathic achalasia is a primary esophageal motor disorder characterized by loss of esophageal peristalsis and insufficient lower esophageal sphincter relaxation in response to deglutition. Patients with achalasia commonly complain of dysphagia to solids and liquids, bland regurgitation often unresponsive to an adequate trial of proton pump inhibitor, and chest pain. Weight loss is present in many, but not all patients. Although the precise etiology is unknown, it is often thought to be either autoimmune, viral immune, or neurodegenerative. The diagnosis is based on history of the disease, barium esophagogram, and esophageal motility testing. Endoscopic assessment of the gastroesophageal junction and gastric cardia is necessary to rule out malignancy. Newer diagnostic modalities such as high resolution manometry help in predicting treatment response in achalasia based on esophageal pressure topography patterns identifying three phenotypes of achalasia (I-III) and outcome studies suggest better treatment response with types I and II compared to type III. Although achalasia cannot be permanently cured, excellent outcomes are achieved in over 90 % of patients. Current medical and surgical therapeutic options (pneumatic dilation, endoscopic and surgical myotomy, and pharmacologic agents) aim at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Either graded pneumatic dilatation or laparoscopic surgical myotomy with a partial fundoplication are recommended as initial therapy guided by patient age, gender, preference, and local institutional expertise. The prognosis in achalasia patients is excellent. Most patients who are appropriately treated have a normal life expectancy but the disease does recur and the patient may need intermittent treatment.
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Affiliation(s)
| | - Hannah P Kim
- Department of Internal Medicine, Nashville, TN, USA
| | | | - Michael F Vaezi
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN, USA.
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14
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Ates F, Vaezi MF, Fox M, Gyawali CP, Roman S, Smout AJPM, Pandolfino JE. The Pathogenesis and Management of Achalasia: Current Status and Future Directions. Gut Liver 2015; 9:449-63. [PMID: 26087861 PMCID: PMC4477988 DOI: 10.5009/gnl14446] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Achalasia is an esophageal motility disorder that is commonly misdiagnosed initially as gastroesophageal reflux disease. Patients with achalasia often complain of dysphagia with solids and liquids but may focus on regurgitation as the primary symptom, leading to initial misdiagnosis. Diagnostic tests for achalasia include esophageal motility testing, esophagogastroduodenoscopy and barium swallow. These tests play a complimentary role in establishing the diagnosis of suspected achalasia. High-resolution manometry has now identified three subtypes of achalasia, with therapeutic implications. Pneumatic dilation and surgical myotomy are the only definitive treatment options for patients with achalasia who can undergo surgery. Botulinum toxin injection into the lower esophageal sphincter should be reserved for those who cannot undergo definitive therapy. Close follow-up is paramount because many patients will have a recurrence of symptoms and require repeat treatment.
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Affiliation(s)
| | - Michael F. Vaezi
- Correspondence to: Michael F. Vaezi, Division of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, C2104-MCN, Nashville, TN 37232, USA, Tel: +1-615-322-3739, Fax: +1-615-322-8525, E-mail:
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15
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Wouters MM, Lambrechts D, Becker J, Cleynen I, Tack J, Vigo AG, Ruiz de León A, Urcelay E, Pérez de la Serna J, Rohof W, Annese V, Latiano A, Palmieri O, Mattheisen M, Mueller M, Lang H, Fumagalli U, Laghi L, Zaninotto G, Cuomo R, Sarnelli G, Nöthen MM, Vermeire S, Knapp M, Gockel I, Schumacher J, Boeckxstaens GE. Genetic variation in the lymphotoxin-α (LTA)/tumour necrosis factor-α (TNFα) locus as a risk factor for idiopathic achalasia. Gut 2014; 63:1401-1409. [PMID: 24259423 DOI: 10.1136/gutjnl-2013-304848] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility. METHODS 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r(2)>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test. RESULTS The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication. CONCLUSIONS Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.
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Affiliation(s)
- Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium
| | - Jessica Becker
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Isabelle Cleynen
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Ana G Vigo
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Antonio Ruiz de León
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Elena Urcelay
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Julio Pérez de la Serna
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Wout Rohof
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
| | - Vito Annese
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy Unit of Gastroenterology SOD2, Azienda Ospedaliera Universitaria, Careggi, Firenze, Italy
| | - Anna Latiano
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy
| | - Orazio Palmieri
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy
| | - Manuel Mattheisen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany Institute for Genomic Mathematics, University of Bonn, Bonn, Germany Department of Biostatistics, Harvard School of Public Health, Boston, USA
| | - Michaela Mueller
- Department of Gastroenterology, German Clinic of Diagnostics, Wiesbaden, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
| | - Uberto Fumagalli
- Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy
| | - Luigi Laghi
- Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy
| | - Giovanni Zaninotto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Rosario Cuomo
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
| | - Giovanni Sarnelli
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
| | - Markus M Nöthen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Séverine Vermeire
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Michael Knapp
- Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Ines Gockel
- Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
| | - Johannes Schumacher
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
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16
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Abstract
Achalasia is a rare motility disorder of the oesophagus characterised by loss of enteric neurons leading to absence of peristalsis and impaired relaxation of the lower oesophageal sphincter. Although its cause remains largely unknown, ganglionitis resulting from an aberrant immune response triggered by a viral infection has been proposed to underlie the loss of oesophageal neurons, particularly in genetically susceptible individuals. The subsequent stasis of ingested food not only leads to symptoms of dysphagia, regurgitation, chest pain, and weight loss, but also results in an increased risk of oesophageal carcinoma. At present, pneumatic dilatation and Heller myotomy combined with an anti-reflux procedure are the treatments of choice and have comparable success rates. Per-oral endoscopic myotomy has recently been introduced as a new minimally invasive treatment for achalasia, but there have not yet been any randomised clinical trials comparing this option with pneumatic dilatation and Heller myotomy.
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Affiliation(s)
- Guy E Boeckxstaens
- Department of Gastroenterology, Translational Research Center for Gastrointestinal Disorders (TARGID), University Hospital Leuven, Catholic University of Leuven, Leuven, Belgium.
| | - Giovanni Zaninotto
- Department of Surgical and Gastroenterological Sciences, University of Padova, UOC General Surgery, Sts Giovanni e Paolo Hospital, Venice, Italy
| | - Joel E Richter
- Division of Digestive Diseases and Nutrition, Joy McCann Culverhouse Center for Esophageal and Swallowing Disorders, University of South Florida Morsani College of Medicine, Tampa, FL, USA
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17
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Sarnelli G, D’Alessandro A, Pesce M, Palumbo I, Cuomo R. Genetic contribution to motility disorders of the upper gastrointestinal tract. World J Gastrointest Pathophysiol 2013; 4:65-73. [PMID: 24244875 PMCID: PMC3829454 DOI: 10.4291/wjgp.v4.i4.65] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 08/09/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023] Open
Abstract
Motility disorders of the upper gastrointestinal tract encompass a wide range of different diseases. Esophageal achalasia and functional dyspepsia are representative disorders of impaired motility of the esophagus and stomach, respectively. In spite of their variable prevalence, what both diseases have in common is poor knowledge of their etiology and pathophysiology. There is some evidence showing that there is a genetic predisposition towards these diseases, especially for achalasia. Many authors have investigated the possible genes involved, stressing the autoimmune or the neurological hypothesis, but there is very little data available. Similarly, studies supporting a post-infective etiology, based on an altered immune response in susceptible individuals, need to be validated. Further association studies can help to explain this complex picture and find new therapeutic targets. The aim of this review is to summarize current knowledge of genetics in motility disorders of the upper gastrointestinal tract, addressing how genetics contributes to the development of achalasia and functional dyspepsia respectively.
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18
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Kallel-Sellami M, Karoui S, Romdhane H, Laadhar L, Serghini M, Boubaker J, Lahmar H, Filali A, Makni S. Circulating antimyenteric autoantibodies in Tunisian patients with idiopathic achalasia. Dis Esophagus 2012; 26:782-7. [PMID: 22947106 DOI: 10.1111/j.1442-2050.2012.01398.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
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.
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19
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Ghoshal UC, Daschakraborty SB, Singh R. Pathogenesis of achalasia cardia. World J Gastroenterol 2012; 18:3050-7. [PMID: 22791940 PMCID: PMC3386318 DOI: 10.3748/wjg.v18.i24.3050] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2011] [Revised: 10/11/2011] [Accepted: 04/28/2012] [Indexed: 02/06/2023] Open
Abstract
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.
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20
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Nuñez C, García-González MA, Santiago JL, Benito MS, Mearín F, de la Concha EG, de la Serna JP, de León AR, Urcelay E, Vigo AG. Association of IL10 promoter polymorphisms with idiopathic achalasia. Hum Immunol 2011; 72:749-52. [PMID: 21641950 DOI: 10.1016/j.humimm.2011.05.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Revised: 04/18/2011] [Accepted: 05/13/2011] [Indexed: 12/21/2022]
Abstract
Idiopathic achalasia is an esophageal motor disorder of unknown etiology. A wealth of evidence supports the concept that achalasia is an immune-mediated disease. According to this evidence, achalasia has been significantly associated with specific alleles of the human leukocyte antigen class II, PTPN22 and IL23R. Several studies have demonstrated association of the IL10 gene with different inflammatory disorders. Our aim was to evaluate the role of functional IL10 promoter polymorphisms in susceptibility to idiopathic achalasia. A case-control study was performed with the -1082, -819, and -592 IL10 promoter polymorphisms in 282 patients and 529 controls and in an independent replication set of 75 patients and 575 controls. The GCC haplotype of the IL10 promoter was reported to be associated with a lower risk of achalasia in the discovery sample (odds ratio [OR] = 0.79, 95% confidence interval [CI] = 0.64-0.98, p = 0.029). This association was validated in a replication set (OR = 0.69, 95% CI = 0.48-1.00, p = 0.04). In the combined analysis no heterogeneity was observed between the 2 sample sets and the GCC haplotype was significantly associated with the disease (OR(MH) = 0.76, 95% CI = 0.63-0.91, p = 0.003). Our results provide the first evidence for an association between IL10 promoter polymorphisms and idiopathic achalasia, suggesting that the interleukin-10 cytokine may contribute to the pathogenesis of this disease.
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Affiliation(s)
- Concepción Nuñez
- Clinical Immunology Department, Instituto de Investigación Sanitaria San Carlos, Madrid, Spain
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21
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Gockel HR, Schumacher J, Gockel I, Lang H, Haaf T, Nöthen MM. Achalasia: will genetic studies provide insights? Hum Genet 2010. [PMID: 20700745 DOI: 10.1007/s00439-010-0874-8.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
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Affiliation(s)
- Henning R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
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22
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Gockel HR, Schumacher J, Gockel I, Lang H, Haaf T, Nöthen MM. Achalasia: will genetic studies provide insights? Hum Genet 2010; 128:353-64. [PMID: 20700745 DOI: 10.1007/s00439-010-0874-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Accepted: 08/02/2010] [Indexed: 12/15/2022]
Abstract
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
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Affiliation(s)
- Henning R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
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23
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de León AR, de la Serna JP, Santiago JL, Sevilla C, Fernández-Arquero M, de la Concha EG, Nuñez C, Urcelay E, Vigo AG. Association between idiopathic achalasia and IL23R gene. Neurogastroenterol Motil 2010; 22:734-8, e218. [PMID: 20367798 DOI: 10.1111/j.1365-2982.2010.01497.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Idiopathic achalasia is a primary esophageal motor disorder of unknown etiology. Different evidences have been reported in support of achalasia as the result of an autoimmune and inflammatory process leading to neuronal cell loss. According to this, idiopathic achalasia has been significantly associated with specific alleles of the human leukocyte antigen system class II, although few reports studying association with other loci can be found in the literature. Recent studies have shown association of a non-synonymous polymorphism within the IL23R gene with different chronic inflammatory disorders, including Barrett's esophagus. The purpose of this study was to assess whether the IL23R coding variant Arg381Gln polymorphism is involved in susceptibility to idiopathic achalasia. METHODS We performed a case-control study including 262 patients with idiopathic achalasia and 802 healthy subjects, all of them white Spaniards. Achalasia patients were diagnosed on the basis of clinical, radiographic, endoscopic, and manometric criteria. All samples were genotyped for the IL23R Arg381Gln polymorphism using TaqMan technology. KEY RESULTS The minor allele of the Arg381Gln polymorphism was significantly increased in patients compared with healthy controls (OR = 1.46, 95% CI = 1.01-2.11, P = 0.036). This association seems to be specific to male patients with disease onset after 40 years (OR = 2.33, 95% CI = 1.29-4.16, P = 0.002). CONCLUSIONS & INFERENCES Our results suggest a role of IL23R in idiopathic achalasia predisposition and extend the evidence of the general influence of this gene in autoimmune and inflammatory diseases.
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Affiliation(s)
- A R de León
- Gastroenterology Department, Hospital Clínico San Carlos, Madrid, Spain
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24
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Sarnelli G. Impact of genetic polymorphisms on the pathogenesis of achalasia: an age-dependent paradigm? Neurogastroenterol Motil 2009; 21:575-8. [PMID: 19646069 DOI: 10.1111/j.1365-2982.2009.01319.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
A wealth of evidence supports the concept that achalasia represents an autoimmune disorder in which a triggering factor (probably a virus) is the starter of an uncontrolled myenteric ganglionitis leading to neurodegeneration. The reasons whereby this process occurs only in some individuals and at the oesophageal level are unknown, but it is reasonable to assume that some genetic influence may affect the achalasia phenotype, making some individuals more or less susceptible to the disease. Association studies between achalasia and polymorphisms of genes involved in the regulation of immune responses may help to explain the complexity of achalasia pathogenesis and progression.
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Affiliation(s)
- Giovanni Sarnelli
- Department of Clinical and Experimental Medicine, University of Naples Federico II, Naples, Italy.
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25
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Abstract
Achalasia, a motor disorder of the esophagus, is characterized by myenteric plexitis leading to neuronal loss. Cytotoxic T cells, isolated from the lower esophageal sphincter of achalasia patients, respond to human herpes virus-1 (HSV-1) with gamma-IFN (and to a lesser extent IL-2) production and clonal proliferation. In addition, HSV-1 DNA was demonstrated in the vast majority of patients, but also in controls. These exciting data suggest that achalasia is an immune-mediated inflammatory disease in which a (latent) infection with HSV-1 leads to persistent immune activation and self-destruction of esophageal neurons, most likely in genetic susceptible subjects only.
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Abstract
Achalasia and gastroesophageal reflux disease (GERD) represent diverse physiologic disorders both of which result from lower esophageal sphincter (LES) dysfunction. Fortunately, both diseases are benign and amenable to surgically corrective therapies. Achalasia is characterized by destruction of the smooth muscle ganglion cells of the myenteric plexus (Auerbach) resulting in motor dysfunction, incomplete LES relaxation, and progressive esophageal dilation. GERD is frequently characterized by hypotonia or shortening of the LES. Local anatomical derangements such as a hiatal hernia (eg, sliding type I hernia) can predispose to GERD. Other predisposing factors for GERD include obesity, smoking, alcohol, and pregnancy. Transient LES relaxation is the most significant factor in the development of GERD. Transient LES relaxations last from 10 to 45 seconds and are not related to swallowing. The diagnostic workup of achalasia and GERD may include barium esophagram, upper gastrointestinal endoscopy, pH monitoring, and esophageal manometry. The different medical treatment options for achalasia comprise pharmacologic treatment, botulinum toxin, and balloon dilation. Surgical interventions include Heller myotomy, which is usually combined with a partial fundoplication. GERD is managed by treating the predisposing factors, using medications (ie, anatacids or proton pump inhibitors) and surgery (ie, fundoplication). Recently, endoluminal therapy has been employed in the treatment of GERD with promising short-term results.
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27
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Abstract
Idiopathic achalasia is a primary esophageal motor disorder characterized by esophageal aperistalsis and abnormal lower esophageal sphincter (LES) relaxation in response to deglutition. It is a rare disease with an annual incidence of approximately 1/100,000 and a prevalence rate of 1/10,000. The disease can occur at any age, with a similar rate in men and women, but is usually diagnosed between 25 and 60 years. It is characterized predominantly by dysphagia to solids and liquids, bland regurgitation, and chest pain. Weight loss (usually between 5 to 10 kg) is present in most but not in all patients. Heartburn occurs in 27%-42% of achalasia patients. Etiology is unknown. Some familial cases have been reported, but the rarity of familial occurrence does not support the hypothesis that genetic inheritance is a significant etiologic factor. Association of achalasia with viral infections and auto-antibodies against myenteric plexus has been reported, but the causal relationship remains unclear. The diagnosis is based on history of the disease, radiography (barium esophagogram), and esophageal motility testing (esophageal manometry). Endoscopic examination is important to rule out malignancy as the cause of achalasia. Treatment is strictly palliative. Current medical and surgical therapeutic options (pneumatic dilation, surgical myotomy, and pharmacologic agents) aimed at reducing the LES pressure and facilitating esophageal emptying by gravity and hydrostatic pressure of retained food and liquids. Although it cannot be permanently cured, excellent palliation is available in over 90% of patients.
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Affiliation(s)
- Farnoosh Farrokhi
- Division of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Michael F Vaezi
- Division of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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28
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Poglio F, Mongini T, Cocito D. Sensory ataxic neuropathy and esophageal achalasia in a patient with Sjogren's syndrome. Muscle Nerve 2007; 35:532-5. [PMID: 17221876 DOI: 10.1002/mus.20716] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We describe a patient who developed an ataxic sensory syndrome associated with xerophthalmia and progressive dysphagia with regurgitation. Electrophysiological findings were consistent with an axonal sensory neuropathy, and superficial peroneal nerve biopsy showed a reduction in number of myelinated fibers with epineurial inflammation. Rheumatoid factor, anti-SSA/SSB and antinuclear antibodies were positive and a diagnosis of Sjogren's syndrome was made. An endoscopic investigation revealed esophageal achalasia. We suggest that there may be a common autoimmune mechanism directed to different targets on the basis of this rare association.
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Affiliation(s)
- Fabio Poglio
- Dipartimento di Neuroscienze, Università di Torino, Via Cherasco 15, 10126 Torino, Italy.
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29
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Latiano A, De Giorgio R, Volta U, Palmieri O, Zagaria C, Stanghellini V, Barbara G, Mangia A, Andriulli A, Corinaldesi R, Annese V. HLA and enteric antineuronal antibodies in patients with achalasia. Neurogastroenterol Motil 2006; 18:520-525. [PMID: 16771767 DOI: 10.1111/j.1365-2982.2006.00772.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The aetiopathogenesis of primary achalasia is largely unknown, although an immunogenetic predisposition is suspected. To establish whether a correlation exists among possible aetiological factors, including class II human leucocyte antigen (HLA) alleles and autoantibodies to enteric neurones, and clinical features of patients with achalasia, a total of 60 patients and 200 healthy subjects were typed by high-resolution HLA-DQ and HLA-DR alleles. Circulating antineuronal antibodies were investigated by using indirect immunofluorescence on enteric neurones of rat ileum and colon and immunoblotting assay in a subset of achalasic patients and in all controls. The DQB1*0502 and DQB1*0601 alleles were significantly increased in patients with achalasia compared with controls (P < 0.03, P < 0.001, respectively). Moreover a negative correlation with the DQB1*0201 allele was found (P = 0.016). As a whole, 14 of 60 (23.3%) achalasia patients were carriers of HLA risk alleles, and 10 of 41 (24.4%) presented antineuronal antibodies. No significant correlation among HLA risk alleles, antineuronal antibodies and clinical features was found. In achalasia, no correlation exists among HLA alleles, antineuronal antibodies and clinical features. However, given the association between achalasia and HLA-DQ1, further research is needed to clarify the role of HLA antigens and antineuronal antibodies in this disease.
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Affiliation(s)
- A Latiano
- U.O. Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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30
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Gockel I, Bohl JRE, Doostkam S, Eckardt VF, Junginger T. Spectrum of histopathologic findings in patients with achalasia reflects different etiologies. J Gastroenterol Hepatol 2006; 21:727-33. [PMID: 16677160 DOI: 10.1111/j.1440-1746.2006.04250.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND The etiology of achalasia is still unknown. The aim of the present study was to elucidate its underlying pathologies and their chronology by investigation of esophageal specimens in patients undergoing surgery (esophageal resection or myotomy) for achalasia. METHODS In 17 patients with achalasia, histopathologic examinations of the esophageal wall focussing on the myenteric plexus were performed. Preoperative diagnosis was based on clinical evaluation, esophagogastroscopy, barium esophagogram in all, and esophageal manometry in eight patients. The median age at the time of surgery was 54 years (range: 14-78 years). In eight cases, the complete esophageal, body and in nine cases a smooth muscle biopsy including parts of the myenteric plexus from the distal part of the esophagus (high pressure zone) was available. The tissue specimens were fixed in formalin and embedded in paraffin. The staining procedures were hematoxylin and eosin (HE), Elastica van Gieson (EvG), and periodic acid-Schiff (PAS) reaction. Immunohistochemical examinations were performed with antibodies against B and T lymphocytes, neurofilament, protein gene-related product (PGP 9.5), S-100 protein, myosin, desmin, smooth muscle actin and substance P. RESULTS In 13 of 17 patients, a significant reduction of the number of intramural ganglion cells was present. Common findings were a severe fibrosis of the smooth muscle layer (10/17) and obvious myopathic changes of the smooth muscle cells (5/17). Staining for B and T lymphocytes found signs of inflammation in mucosal and muscular areas. Three patients exhibited a marked invasion of eosinophilic granulocytes of the muscularis propria (eosinophilia). Esophageal carcinoma had developed in three patients (squamous cell carcinoma in two and carcinoma in situ in another patient with Barrett's esophagus and high-grade dysplasia). Severe inflammatory reactions (neural, eosinophilic and mucosal) dominated in patients with a longstanding history of achalasia (>10 years) as well as a marked endomysial fibrosis. CONCLUSIONS The histopathological investigations of the esophageal wall in 17 patients undergoing esophageal resection or myotomy for achalasia suggest that the reduction of intramural ganglion cells might be a secondary change, probably due to inflammation triggered by autoimmune mechanisms or a chronic degenerative process of the central and/or peripheral part of the vagal nerve. The primary lesion could also be a severe myopathy of the smooth muscle cells.
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Affiliation(s)
- Ines Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University of Mainz, Mainz, Germany.
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31
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Abstract
Achalasia, a poorly relaxing lower esophageal sphincter, produces a functional obstruction and the expected symptoms of dysphagia, regurgitation and eventually weight loss. The cause of achalasia remains largely unknown in Western countries, Chagas' disease being the most frequent etiology in Brazil. We report on two sets of monozygotic male twins with typical manifestations of achalasia. The majority of authors attribute a limited contribution unless achalasia is related to a multisystem disorder, like the triple-A or Allgrove's syndrome, an autosomal recessive disease characterized by the triad of adrenocorticotropic hormone (ACTH) resistant adrenal insufficiency, achalasia and alacrima. The four cases reported demonstrated the genetic influence of achalasia in patients without multisystem disorders. We believe that idiopathic achalasia is a syndrome with similar clinical, pathological, radiological and manometric evolution, but with a great variety of etiological agents, one of them being the congenital form.
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Affiliation(s)
- B Zilberstein
- Department of Gastroenterology, Hospital das Clínicas - University of São Paulo Medical School, Brazil.
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32
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Abstract
Idiopathic achalasia is an inflammatory disease of unknown etiology characterized by esophageal aperistalsis and failure of LES relaxation due to loss of inhibitory nitrinergic neurons in the esophageal myenteric plexus. Proposed causes of achalasia include gastroesophageal junction obstruction, neuronal degeneration, viral infection, genetic inheritance, and autoimmune disease. Current evidence suggests that the initial insult to the esophagus, perhaps a viral infection or some other environmental factor, results in myenteric plexus inflammation. The inflammation then leads to an autoimmune response in a susceptible population who may be genetically predisposed. Subsequently, chronic inflammation leads to destruction of the inhibitory myenteric ganglion cells resulting in the clinical syndrome of idiopathic achalasia. Further studies are needed to better understand the etiology and pathogenesis of achalasia-such an understanding will be important in developing safe, effective, and possibly curative therapy for achalasia.
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Affiliation(s)
- Woosuk Park
- Department of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
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Ruiz-de-León A, Mendoza J, Sevilla-Mantilla C, Fernández AM, Pérez-de-la-Serna J, Gónzalez VA, Rey E, Figueredo A, Díaz-Rubio M, De-la-Concha EG. Myenteric antiplexus antibodies and class II HLA in achalasia. Dig Dis Sci 2002. [PMID: 11837716 DOI: 10.1023/a: 1013242831900] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Achalasia, a motor disorder of the esophagus, is accompanied by autoimmune phenomena that could be playing a role in the pathogenesis of the disease. Our objective was to establish the genotypic frequency of the HLA-DR and DQ alleles in patients with achalasia and to establish their relationship with the presence of myenteric antiplexus antibodies in our geographic area. A total of 92 patients diagnosed with achalasia and two control groups with 275 healthy subjects were studied for HLA typing and 40 for autoantibodies determination. The myenteric antiplexus antibodies were positive in 50 patients (54.3%) and in 3 healthy subjects (7.5%) (P < 0.001). The patients showed a significantly higher frequency of DQA1*0103 and DQB1*0603 than was found in the controls. The heterodimer DQA1*0103-DQB1*0603 was increased in the patients [odds ratio (OR) = 2.57]. In regard to the association between the HLA DQA1 and DQB1 alleles and the antiplexus antibodies, these antibodies were found in greater prevalence in those patients with the DQA1*0103 and DQB1*0603 alleles, and the differences were statistically significant (OR = 3.17 and OR = 5.82, respectively). All of the women and 66.7% of the men with achalasia and the DQB1*0603 allele or the DQA1*0103-DQB1*0603 heterodimer were positive for antibodies.
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Affiliation(s)
- Antonio Ruiz-de-León
- Department of Gastroenterology, Hospital Universitario San Carlos, Universidad Complutense, Madrid, Spain
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García-Jiménez ME, Quiroga JA, Gutiérrez ML, Pardo M, Carreño V. Association of HLA-DR genes with mild idiopathic adulthood biliary ductopenia. Am J Gastroenterol 2001; 96:1178-82. [PMID: 11318008 DOI: 10.1111/j.1572-0241.2001.03717.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Mild idiopathic adulthood ductopenia (MIAD) is an asymptomatic chronic cholestatic liver disease characterized by the loss of interlobular bile ducts in <50% of the portal tracts. Although the underlying cause of MIAD is unknown, the host factors may contribute to the patient's susceptibility to the disease. The aim of this work was to investigate the immunogenetics in the pathogenesis of MIAD. METHODS We prospectively studied 22 Caucasian patients with MIAD. Peripheral blood was collected, and HLA-DR typing was performed by polymerase chain reaction with sequence-specific primers followed by sequencing for subtyping. Results were compared with those from 140 age- and sex-matched controls. RESULTS There was no significant association between HLA-DRB1 alleles and the disease, although a trend was found in MIAD patients with the DRB1*1502 allele (five of 44 vs four of 280 in controls; p corrected = 0.055; chi2 = 13.9). Multiple HLA-DRB1 alleles (*04, *11, *15) showed increased frequencies in MIAD patients. Further subtyping revealed a motif (positions 25-32 of the beta1 chain) present in 17 (77.3%) patients, which was significantly associated with MIAD (p = 0.049; chi2 = 3.87). Seven patients (31.8%) and 21 (15%) controls coded for this motif in their two alleles (p = 0.068; chi2 = 3.76). Among MIAD patients, those seven had abnormal ALT levels (p = 0.017) and their gamma-glutamyltransferase and ALT values tended to be more increased. CONCLUSIONS These results provide evidence of an immunogenetic basis of susceptibility to MIAD in Caucasian individuals.
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35
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Walker SJ, Byrne JP, Birbeck N. What's new in the pathology, pathophysiology and management of benign esophageal disorders? Dis Esophagus 2000; 12:219-37. [PMID: 10631918 DOI: 10.1046/j.1442-2050.1999.00056.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- S J Walker
- Department of Surgery, Blackpool Victoria Hospital, Lancs, UK
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36
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Abstract
A consolidation of ideas regarding the pathogenesis and management of esophageal motor disorders occurred over the past year. The development and application of diagnostic techniques has stimulated new thinking about the events responsible for peristalsis and has provided novel avenues for studying mechanisms of symptom production. Achalasia remains the most investigated and understood motor disorder, and the year's research focused heavily on management approaches for this important condition. Other topics addressed in this review include proximal esophageal symptoms and disorders, spastic disorders, and esophageal hypomotility.
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Affiliation(s)
- C Prakash
- Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
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