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Kaizuka M, Tatsuta T, Kawaguchi S, Yoshizawa T, Yoshida S, Tateda T, Sawada Y, Ota S, Hayamizu S, Hasui K, Kikuchi H, Hiraga H, Chinda D, Muroya T, Hakamada K, Kijima H, Mikami T, Fukuda S, Sakuraba H. Toll-Like Receptor 7-Expressed Macrophages Are Involved in the Pathogenesis of Esophageal Achalasia and Esophagogastric Junction Outflow Obstruction. Digestion 2024; 105:436-447. [PMID: 39102805 PMCID: PMC11633874 DOI: 10.1159/000540693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
INTRODUCTION Esophageal achalasia is a typical esophageal motility disorder (EMD). Although viral infections have been hypothesized to play a role in the pathogenesis of esophageal achalasia, its etiology remains unclear. This study used esophageal muscle layer specimens collected during per-oral endoscopic myotomy (POEM) procedures to investigate the association between esophageal achalasia and esophagogastric junction outflow obstruction (EGJOO) and pattern recognition receptors. METHODS Patients with esophageal achalasia and EGJOO who underwent POEM were allocated to the EMD group. Biopsies of the inner circular muscle were conducted during the POEM procedure. The control group comprised individuals diagnosed with esophageal squamous cell carcinoma who underwent surgical resection. Expression of pattern recognition receptors, including Toll-like receptor (TLR) 7, was examined by polymerase chain reaction. Immunohistochemical staining was performed to determine TLR7 expression sites in the esophageal muscle layer, and the relationship between TLR7 mRNA expression and clinical score was investigated. RESULTS Our analysis revealed a notable upregulation of TLR7 mRNA levels within the muscle layer of esophageal achalasia and EGJOO, in contrast to those of control specimens. In contrast, the correlation between TLR7 and clinical score was not significant. Immunohistochemical staining revealed increased numbers of TLR7-expressing macrophages between the muscle layers. CONCLUSIONS TLR7-expressing macrophages are involved in the innate immune response underlying esophageal achalasia and EGJOO. This result will lead to the elucidation of new pathogenetic mechanisms and the development of novel therapeutic targets.
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Affiliation(s)
- Masatoshi Kaizuka
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan,
| | - Tetsuya Tatsuta
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shogo Kawaguchi
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Department of Vascular and Inflammatory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tadashi Yoshizawa
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shukuko Yoshida
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Shibata Irika Co., Hirosaki, Japan
| | - Tetsuyuki Tateda
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yohei Sawada
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shinji Ota
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shiro Hayamizu
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Keisuke Hasui
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hidezumi Kikuchi
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Department of Community Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hiroto Hiraga
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Daisuke Chinda
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Division of Endoscopy, Hirosaki University Hospital, Hirosaki, Japan
| | - Takahiro Muroya
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hiroshi Kijima
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Hirosaki University, Hirosaki, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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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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Mari A, Abu Baker F, Pellicano R, Khoury T. Diagnosis and Management of Achalasia: Updates of the Last Two Years. J Clin Med 2021; 10:3607. [PMID: 34441901 PMCID: PMC8397142 DOI: 10.3390/jcm10163607] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/10/2021] [Accepted: 08/12/2021] [Indexed: 02/06/2023] Open
Abstract
Achalasia is a rare neurodegenerative disorder causing dysphagia and is characterized by abnormal esophageal motor function as well as the loss of lower esophageal sphincter (LES) relaxation. The assessment and management of achalasia has significantly progressed in recent years due to the advances in high-resolution manometry (HRM) technology along with the improvements and innovations of therapeutic endoscopy procedures. The recent evolution of HRM technology with the inclusion of an adjunctive test, fluoroscopy, and EndoFLIP has enabled more precise diagnoses of achalasia to be made and the subgrouping into therapeutically meaningful subtypes. Current management possibilities include endoscopic treatments such as Botulinum toxin injected to the LES and pneumatic balloon dilation. Surgical treatment includes laparoscopic Heller myotomy and esophagectomy. Furthermore, in recent years, per oral endoscopic myotomy (POEM) has established itself as a principal endoscopic therapeutic alternative to the traditional laparoscopic Heller myotomy. The latest randomized trials report that POEM, pneumatic balloon dilatation, and laparoscopic Heller's myotomy have comparable effectiveness and complications rates. The aim of the current review is to provide a practical clinical approach to dysphagia and to shed light on the most recent improvements in diagnostics and treatment of achalasia over the last two years.
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Affiliation(s)
- Amir Mari
- Department of Gastroenterology, Nazareth Hospital, Faculty of Medicine, Bar-Ilan University, Safed 16100, Israel
| | - Fadi Abu Baker
- Hillel Yaffe Medical Center, Department of Gastroenterology and Hepatology, Hadera 38100, Israel;
| | | | - Tawfik Khoury
- Galilee Medical Center, Department of Gastroenterology, Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13100, Israel;
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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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Rieder E, Fernandez-Becker NQ, Sarosiek J, Guillaume A, Azagury DE, Clarke JO. Achalasia: physiology and diagnosis. Ann N Y Acad Sci 2020; 1482:85-94. [PMID: 33140485 DOI: 10.1111/nyas.14510] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 09/17/2020] [Accepted: 09/22/2020] [Indexed: 12/18/2022]
Abstract
Achalasia is a rare motility disorder with incomplete relaxation of the lower esophageal sphincter and ineffective contractions of the esophageal body. It has been hypothesized that achalasia does not result from only one pathway but rather involves a combination of infectious, autoimmune, and familial etiological components. On the basis of other observations, a novel hypothesis suggests that a muscular form of eosinophilic esophagitis is involved in the pathophysiology of achalasia in some patients. This appears to progressively diminish the myenteric plexus at stage III, gradually destroy it at stage II, and finally eliminate it at stage I, the most advanced and final stage of achalasia. Although high-resolution manometry has identified these three different types of achalasia, another subset of patients with a normal-appearing sphincter relaxation has been proposed. Provocative maneuvers, such as the rapid drinking challenge, have recently been demonstrated to improve diagnosis in certain borderline patients, but have to be studied in more detail. However, whether the different types of achalasia will have a long-term impact on tailored therapies is still a matter of debate. Additionally, novel aspects of the standard timed barium swallow appear to be an important adjunct of diagnosis, as it has been shown to have a diagnostic as well as a predictive value.
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Affiliation(s)
- Erwin Rieder
- Department of Surgery, Medical University of Vienna, Vienna, Austria
| | | | - Jerzy Sarosiek
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas
| | - Alexandra Guillaume
- Gastrointestinal Motility Center, Renaissance School of Medicine, Stony Brook University Hospital, Stony Brook, New York
| | - Dan E Azagury
- Minimally Invasive & Bariatric Surgery, Stanford University School of Medicine, Palo Alto, California
| | - John O Clarke
- Department of Medicine, Stanford University, Redwood City, California
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6
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Moradi A, Fazlollahi N, Eshraghi A, Gholipour M, Khoshnia M, Javid N, Montazeri SA, Mikaeli J. Is There Any Evidence for a Viral Cause in Achalasia? Middle East J Dig Dis 2018; 10:169-173. [PMID: 30186580 PMCID: PMC6119833 DOI: 10.15171/mejdd.2018.106] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 06/18/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND
Achalasia, as an incurable disease is defined by the lack of normal esophageal peristalsis and
loss of lower esophageal sphincter relaxation due to impaired myenteric neural plexus. The exact
cause of myenteric neural cells degeneration in achalasia is still unknown. One hypothesis is that
certain neurotropic viruses and autoimmune factors cause the inflammatory response in myenteric
network, which consequently destroy neural cells. This study was designed to find the evidence of
viral causes of achalasia.
METHODS
In this case-control study, 52 patients with achalasia and 50 controls referred to Shariati Hospital,
were evaluated for the genome of neurotropic viruses, HPV, and adenovirus by polymerase chain
reaction (PCR) and reverse transcription (RT) PCR techniques.
RESULTS
Genome assessment of neurotropic DNA viruses turned out negative in the patients, however,
the genome of HSV-1 (Herpes simplex virus) was found in tissues of six controls. No neurotropic
RNA viruses were observed in the tissue samples and whole blood of both the patients and controls.
Among non-neurotropic viruses, adenovirus genome was positive in tissues of two out of 52
patients and three out of 50 controls. In addition, one out of 52 patients and two out of 50 controls
were positive for HPV infection in tissues.
CONCLUSION
We could not detect any significant relationship between achalasia and HPV, adenovirus, and
neurotropic viruses in the cases. Nevertheless, it does not exclude the hypothesis of either an alternate
viral species or resolved viral infection as the etiology of achalasia.
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Affiliation(s)
- Abdolvahab Moradi
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Narges Fazlollahi
- Autoimmune and Motility Disorders Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Amid Eshraghi
- Autoimmune and Motility Disorders Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahin Gholipour
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Masoud Khoshnia
- Golestan Research Center of Gastroenterology and Hepatology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Naeme Javid
- Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seyed Ali Montazeri
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Mikaeli
- Autoimmune and Motility Disorders Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
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Patel DA, Lappas BM, Vaezi MF. An Overview of Achalasia and Its Subtypes. Gastroenterol Hepatol (N Y) 2017; 13:411-421. [PMID: 28867969 PMCID: PMC5572971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Achalasia is one of the most studied esophageal motility disorders. However, the pathophysiology and reasons that patients develop achalasia are still unclear. Patients often present with dysphagia to solids and liquids, regurgitation, and varying degrees of weight loss. There is significant latency prior to diagnosis, which can have nutritional implications. The diagnosis is suspected based on clinical history and confirmed by esophageal high-resolution manometry testing. Esophagogastroduodenoscopy is necessary to rule out potential malignancy that can mimic achalasia. Recent data presented in abstract form suggest that patients with type II achalasia may be most likely, and patients with type III achalasia may be least likely, to report weight loss compared to patients with type I achalasia. Although achalasia cannot be permanently cured, palliation of symptoms is possible in over 90% of patients with the treatment modalities currently available (pneumatic dilation, Heller myotomy, or peroral endoscopic myotomy). This article reviews the clinical presentation, diagnosis, and management options in patients with achalasia, as well as potential insights into histopathologic differences and nutritional implications of the subtypes of achalasia.
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Affiliation(s)
- Dhyanesh A Patel
- Dr Patel is a gastroenterology fellow in the Division of Gastroenterology, Hepatology and Nutrition; Dr Lappas is an internal medicine resident in the Department of Internal Medicine; and Dr Vaezi is a professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition at Vanderbilt University Medical Center in Nashville, Tennessee
| | - Brian M Lappas
- Dr Patel is a gastroenterology fellow in the Division of Gastroenterology, Hepatology and Nutrition; Dr Lappas is an internal medicine resident in the Department of Internal Medicine; and Dr Vaezi is a professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition at Vanderbilt University Medical Center in Nashville, Tennessee
| | - Michael F Vaezi
- Dr Patel is a gastroenterology fellow in the Division of Gastroenterology, Hepatology and Nutrition; Dr Lappas is an internal medicine resident in the Department of Internal Medicine; and Dr Vaezi is a professor of medicine in the Division of Gastroenterology, Hepatology and Nutrition at Vanderbilt University Medical Center in Nashville, Tennessee
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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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9
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Comprehensive epidemiological and genotype-phenotype analyses in a large European sample with idiopathic achalasia. Eur J Gastroenterol Hepatol 2016; 28:689-95. [PMID: 26882171 DOI: 10.1097/meg.0000000000000602] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Although an eight-residue insertion in HLA-DQβ1 has been recently identified as a genetic risk factor for idiopathic achalasia, other risk factors are still unknown. In the present study, we carried out an epidemiological survey and a genotype-phenotype (G×P) analysis to gain further insights into the etiology of achalasia. METHODS We obtained medical data from 696 achalasia patients and 410 controls, as well as their first-degree relatives (2543 of patients and 1497 of controls). For the G×P analysis, we stratified the patients into HLA-DQβ1 insertion carriers and noncarriers. RESULTS Our data show that patients are more often affected by viral infections before achalasia onset (P<0.0001, most significantly for varicella zoster virus infections). In addition, allergic (P=0.0005) and autoimmune disorders (P=0.0007, most significantly for psoriasis and Sjögren's syndrome) represent comorbid disease conditions. First-degree relatives of patients also show higher prevalence rates of allergic disorders (P=0.0007) and psoriasis (P=0.016) compared with control relatives. Moreover, the G×P analysis reveals that achalasia is triggered by pregnancies in female HLA-DQβ1 insertion carriers (P=0.031). CONCLUSION Our data point to a role of viral infections in the development of achalasia. In addition, they provide evidence for a relationship between achalasia and allergic, as well as autoimmune, disorders. Furthermore, pregnancy seems to be a disease-triggering factor in female HLA-DQβ1 insertion carriers, which points to hormonal and/or immunosuppressive factors influencing disease development.
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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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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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12
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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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Betalli P, Carretto E, Cananzi M, Zanatta L, Salvador R, Galeazzi F, Guariso G, Gamba P, Costantini M. Autism and esophageal achalasia in childhood: a possible correlation? Report on three cases. Dis Esophagus 2013; 26:237-40. [PMID: 22607127 DOI: 10.1111/j.1442-2050.2012.01358.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chronic gastrointestinal symptoms are commonly reported in autistic patients. Dysphagia is often present, and it is generally related to behavioral eating disorders. The association between autism and esophageal achalasia has not been described in literature yet. We report our experience with three cases of autistic children we recently treated for esophageal achalasia. In the first case (a 14-year-old male), achalasia was diagnosed with barium swallow and esophageal manometry and was successfully treated with three pneumatic endoscopic dilatations (follow-up: 3 years). In the second case (a 12-year-old female), achalasia was diagnosed with barium swallow and esophageal manometry and was treated with Heller myotomy after two unsuccessful pneumatic endoscopic attempts (follow-up: 3 months). In the last case, a 15-year-old male underwent barium swallow and endoscopy that confirmed achalasia. He was treated with Heller myotomy, and he is asymptomatic at a 6-month follow-up. To our knowledge, this is the first report of a possible association between autism and esophageal achalasia. Because of the rarity of both diseases, their association in the same patient is unlikely to be casual even if speculation on their common etiology is impossible at present. This finding needs further confirmation, but it is sufficient, in our opinion, to indicate proper evaluation with barium swallow and/or manometry in any autistic children with eating difficulty.
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Affiliation(s)
- P Betalli
- Department of Pediatrics, Pediatric Surgery Department of Surgical and Gastroenterological Sciences, Clinica Chirurgica 1 Department of Surgical and Gastroenterological Sciences, Gastroenterology Department of Pediatrics, Pediatric Gastroenterology, University of Padua, Padua, Italy
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14
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Hoshino M, Omura N, Yano F, Tsuboi K, Kashiwagi H, Yanaga K. Immunohistochemical study of the muscularis externa of the esophagus in achalasia patients. Dis Esophagus 2013; 26:14-21. [PMID: 22309323 DOI: 10.1111/j.1442-2050.2011.01318.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The etiology of achalasia is believed to be the neuropathy associated with chronic inflammation of the nerve plexus, but the cause of plexus inflammation is unknown. The purpose of this study was to evaluate the pathophysiology of achalasia by examining the muscularis externa of the esophagus. We used the muscularis externa of the esophagus of 62 patients with achalasia (median 44 years, male : female 32:30) who underwent surgical treatment (achalasia group) and of 10 patients (median 65.5 years, male : female 9:1) who underwent esophagectomy for thoracic esophageal cancer (control group) to perform immunohistochemical staining with S-100, CD43, c-kit (CD117), n-NOS, vasoactive intestinal polypeptide (VIP), and ubiquitin. The cell counts that were positive for S-100, n-NOS, VIP, and ubiquitin were significantly lower in the achalasia group compared with the control group (P < 0.001, P= 0.001, P < 0.001, and P= 0.001, respectively). There were no statistically significant differences with respect to CD43 and c-kit staining (P= 0.586 and P= 0.209, respectively). In conclusion, the pathophysiology of achalasia is therefore considered to be an impaired production of NO and VIP, which both affect interstitial cell of Cajal and smooth muscles, and this impairment is therefore considered to play a role in the pathophysiology of achalasia.
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Affiliation(s)
- M Hoshino
- Department of Surgery, Jikei University School of Medicine, 3-19-18 Nishishinbashi, Minato-ku, Tokyo, Japan.
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15
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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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16
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Petersen RP, Martin AV, Pellegrini CA, Oelschlager BK. Synopsis of investigations into proposed theories on the etiology of achalasia. Dis Esophagus 2012; 25:305-10. [PMID: 20002702 DOI: 10.1111/j.1442-2050.2009.01030.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
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.
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Affiliation(s)
- R P Petersen
- University of Washington School of Medicine, Department of Surgery, Seattle, WA, USA
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17
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Ganem D, Kistler A, DeRisi J. Achalasia and viral infection: new insights from veterinary medicine. Sci Transl Med 2010; 2:33ps24. [PMID: 20505212 DOI: 10.1126/scitranslmed.3000986] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Achalasia is a serious disorder in which the movement of food and liquids through the esophagus is impaired. It is currently thought to be caused by an inflammatory process that destroys neurons in myenteric ganglia, which affect peristalsis in the esophagus. The factor(s) that precipitate this inflammatory process are unknown; possibilities include environmental agents (such as microbes or toxins) and/or cell-mediated autoimmune reactivity. Recently, infection with a newly described bornavirus has been strongly linked to a disease of exotic birds that displays many striking similarities to achalasia. These findings demonstrate that viruses can induce achalasia-like pathophysiology and have renewed interest in the search for infectious agents in this enigmatic human disease.
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Affiliation(s)
- Don Ganem
- Department of Medicine, University of California, San Francisco, CA 94143, USA.
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18
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Villanacci V, Annese V, Cuttitta A, Fisogni S, Scaramuzzi G, De Santo E, Corazzi N, Bassotti G. An immunohistochemical study of the myenteric plexus in idiopathic achalasia. J Clin Gastroenterol 2010; 44:407-410. [PMID: 19834336 DOI: 10.1097/mcg.0b013e3181bc9ebf] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Achalasia is a primary esophageal motor disorder characterized by degenerative changes of the myenteric plexus. The pathophysiologic abnormalities may be the final result of several intermeshing mechanisms, and more than one single factor may cause the motor abnormalities. AIMS To report our experience in investigating the myenteric plexus of achalasia patients undergoing esophagomyotomy. PATIENTS AND METHODS Tissue samples from 12 patients undergoing Heller myotomy for achalasia were evaluated and compared with esophageal tissue specimens from 7 controls. Enteric neurons and interstitial cells of Cajal (ICC) were assessed by immunohistochemical methods, and the presence of vasoactive intestinal polypeptide ergic fibers and of CD3 lymphocytes. The possible presence of herpesvirus was also assessed by immunohistochemistry, whereas that of papillomavirus was assessed by in-situ hybridization. RESULTS Compared with controls, achalasia patients displayed a significant decrease of both enteric neurons and ICC. Immunoreactivity for vasoactive intestinal polypeptide was completely absent in each patient. CD3 staining disclosed myenteric plexitis in 5 (42%) patients; no control patient had plexitis. All patients were completely negative for the presence of both herpes simplex virus and human papillomavirus. CONCLUSIONS The enteric nervous system of the lower esophageal sphincter area is impaired in patients with "idiopathic achalasia," and the abnormalities involve ICC and neurons in many patients. The triggering factors for these abnormalities are, however, still unknown.
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Brun P, Giron MC, Zoppellaro C, Bin A, Porzionato A, De Caro R, Barbara G, Stanghellini V, Corinaldesi R, Zaninotto G, Palù G, Gaion RM, Tonini M, De Giorgio R, Castagliuolo I. Herpes simplex virus type 1 infection of the rat enteric nervous system evokes small-bowel neuromuscular abnormalities. Gastroenterology 2010; 138:1790-801. [PMID: 20102717 DOI: 10.1053/j.gastro.2010.01.036] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2009] [Revised: 01/13/2010] [Accepted: 01/20/2010] [Indexed: 01/15/2023]
Abstract
BACKGROUND & AIMS Infectious agents, such as neurotropic viruses, are proposed to disrupt the enteric neuromuscular system, leading to dysmotility, although the mechanisms are unknown. Our purpose was to assess whether herpes simplex virus type-1 (HSV-1) establishes an enteric-neuronal infection and induces gut dysmotility. METHODS Rats were inoculated with HSV-1 intranasally and after 4 weeks intragastrically. After 1-10 weeks, infection was determined by molecular analysis whereas neuromuscular function was evaluated by pharmacologic/electrical stimulation of longitudinal ileal segments and by gastrointestinal transit and by [(3)H]acetylcholine release measurements. Inflammation in the neuromuscular layer was assessed by myeloperoxidase and cytokine levels and by anti-CD3(+) immunohistochemistry. RESULTS After 1-10 weeks of intragastric inoculation, HSV-1 latency-associated messenger RNA transcripts were detected in the brain and in ileal neurons with no signs of illness or histologic gut abnormalities. By using a recombinant HSV-1 carrying the lacZ gene, HSV-1 virions were localized in myenteric ganglia by in situ X-gal staining. Interleukin-2 and IFN-gamma levels were increased significantly 1 and 6 weeks after inoculation. CD3(+) cells were found around the myenteric ganglia 6 weeks after inoculation. Smooth muscle responses to carbachol, CaCl(2), and gut transit were increased significantly after 1 and 6 weeks, whereas KCl- and electrical field stimulation-mediated contractions were modified significantly only 1-2 weeks after HSV-1 administration. The release of [(3)H]acetylcholine was reduced significantly in ileum segments after 1 and 6 weeks. CONCLUSIONS After intragastric inoculation, HSV-1 establishes a latent infection in the rat myenteric ganglia, which leads to gut dysmotility.
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Affiliation(s)
- Paola Brun
- Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, Padua, Italy
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20
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Kilic A, Schuchert MJ, Pennathur A, Gilbert S, Landreneau RJ, Luketich JD. Long-term outcomes of laparoscopic Heller myotomy for achalasia. Surgery 2009; 146:826-833. [PMID: 19789044 DOI: 10.1016/j.surg.2009.06.049] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2009] [Accepted: 06/12/2009] [Indexed: 12/16/2022]
Abstract
BACKGROUND Short-term outcomes of laparoscopic Heller myotomy (LHM) for achalasia have been excellent, although the long-term durability of this operation remains to be established. The aim of this study was to evaluate the long-term outcomes of LHM. METHODS A single-institution review of patients undergoing LHM between 1992 and 2003 with > or =5 years follow-up. Failure was defined as symptom recurrence requiring reoperation. Univariate and multiple regression analysis were performed to identify preoperative variables predictive of long-term success. RESULTS A total of 46 patients underwent LHM with Toupet (n = 42) or Dor (n = 4) fundoplication. At a mean follow-up of 6.4 years, 37 (80%) patients remained free from failure. Mean time to symptom recurrence in those failing LHM was 21.3 months (range, 0.5-77). Causes of failure included nonfunctioning end-stage esophagus (n = 4), fibrotic narrowing at the gastroesophageal junction (n = 4), and tight wrap (n = 1). Univariate analysis identified high preoperative lower esophageal sphincter pressure (LESP), no prior therapy, short duration of symptoms, and absence of sigmoidal esophagus as predictors of long-term success (P < or = .044 each). High LESP remained the only predictor of long-term durability in multiple regression analysis (P = .043). Reoperations included redo myotomy (n = 2), esophagectomy (n = 6), or both (n = 1). At final follow-up, 44 (96%) patients reported significant symptom improvement compared with pre-LHM severity. CONCLUSION LHM is associated with an 80% long-term success rate. Successful LHM may be predicted by high LESP, no prior therapy, short symptom duration, or absence of sigmoidal esophagus. In this series, failures of LHM underwent reoperation (redo myotomy or esophagectomy) with good results.
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Affiliation(s)
- Arman Kilic
- Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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21
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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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22
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Abstract
Esophageal dysphagia can arise from a variety of causes such as motility disorders, mechanical and inflammatory diseases. Adequate management includes a detailed history, evaluation with upper endoscopy, barium radiography and manometry. Treatment is usually tailored to the underlying disease process and in some cases, as in inoperable cancer, palliative management may be necessary.
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Affiliation(s)
- Adeyemi Lawal
- Medical College of Wisconsin, Department of Medicine, Division of Gastroenterology and Hepatology, Froedtert East, FEC-4510, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
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23
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Abstract
The enteric nervous system is an integrative brain with collection of neurons in the gastrointestinal tract which is capable of functioning independently of the central nervous system (CNS). The enteric nervous system modulates motility, secretions, microcirculation, immune and inflammatory responses of the gastrointestinal tract. Dysphagia, feeding intolerance, gastroesophageal reflux, abdominal pain, and constipation are few of the medical problems frequently encountered in children with developmental disabilities. Alteration in bowel motility have been described in most of these disorders and can results from a primary defect in the enteric neurons or central modulation. The development and physiology of the enteric nervous system is discussed along with the basic mechanisms involved in controlling various functions of the gastrointestinal tract. The intestinal motility, neurogastric reflexes, and brain perception of visceral hyperalgesia are also discussed. This will help better understand the pathophysiology of these disorders in children with developmental disabilities.
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Affiliation(s)
- Muhammad A Altaf
- Division of Pediatric Gastroenterology, The Medical College of Wisconsin, Milwaukee, WI 53226, USA
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24
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Kilic A, Krasinskas AM, Owens SR, Luketich JD, Landreneau RJ, Schuchert MJ. Variations in inflammation and nerve fiber loss reflect different subsets of achalasia patients. J Surg Res 2007; 143:177-182. [PMID: 17950090 DOI: 10.1016/j.jss.2007.03.050] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2007] [Revised: 03/01/2007] [Accepted: 03/12/2007] [Indexed: 12/13/2022]
Abstract
BACKGROUND Achalasia is a debilitating motility disorder with an unknown etiology. Past research has demonstrated a spectrum of histological findings. The objective of this study was to further characterize the histopathology of achalasia, with attention to subsets of findings that may exist, possibly reflecting different pathogeneses. MATERIALS AND METHODS Lower esophageal muscle was obtained during surgery for achalasia (n = 12) or cancer (n = 9). Immunohistochemistry was performed to identify various inflammatory cells and nerve fibers, and grading was done by an expert pathologist. Clinical data were taken from medical records. RESULTS There were two subsets of achalasia specimens with different histological findings. Group A (7/12; 58%) had an inflammatory infiltrate in the myenteric plexus consisting primarily of T-lymphocytes. Group B (5/12; 42%) had no such infiltrate and had less myenteric plexus macrophages versus Group A (P = 0.03). The loss of nerve fibers was most evident in the muscularis propria in achalasia as compared to controls (P = 0.01), and this loss was more striking in Group B versus A (P = 0.04). The mean duration of symptoms was 16.6 (A) versus 6.4 years (B) (P = NS). CONCLUSIONS Two subsets of achalasia patients exist with different histological findings. Group A had T-cell-rich inflammation present with associated macrophages. Group B, with no inflammation, had greater loss of nerve fibers in the muscularis propria versus Group A, and therefore, may represent more aggressive disease with shorter duration of symptoms. These results suggest that various pathogeneses of achalasia may exist that share a common pathway of aganglionosis.
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Affiliation(s)
- Arman Kilic
- Department of Surgery, Heart, Lung, and Esophageal Surgery Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
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25
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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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26
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Mearin F, García-González MA, Strunk M, Zárate N, Malagelada JR, Lanas A. Association between achalasia and nitric oxide synthase gene polymorphisms. Am J Gastroenterol 2006; 101:1979-84. [PMID: 16848803 DOI: 10.1111/j.1572-0241.2006.00762.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Our group previously reported the absence of nitric oxide synthase (NOS) in the gastroesophageal junction of patients with achalasia. NOS exists in three distinct isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible isoform (iNOS). Some studies have shown that NO production is regulated by NOS polymorphisms. AIM To assess whether some functional polymorphisms in the nNOS, iNOS, or eNOS genes are involved in susceptibility to suffer from achalasia. METHODS Genomic DNA from 80 unrelated Spanish Caucasian patients with sporadic achalasia and 144 healthy subjects matched for age (+/-5 yr) and gender was typed by PCR and RFLP methods for the 27-bp variable number of tandem repeat (VNTR) polymorphism in intron 4 of the eNOS gene, a CA microsatellite repeat and a Nla III (C-->T) restriction fragment length polymorphism (RFLP) in exon 29 of the nNOS gene, and two nucleotide substitutions located in exon 16 (C-->T) and exon 22 (G-->A) of the iNOS gene. RESULTS No significant differences in carriage, genotype, and allele frequencies of the nNOS, iNOS, or eNOS gene polymorphisms were found between patients with achalasia and controls. Individuals homozygous for genotype iNOS22*A/A tended to be more frequent in achalasia (20%vs 11%, odds ratio [OR] 1.79, 95% confidence interval [CI] 0.89-3.59, p= 0.09) as were those homozygous for the rare eNOS*4a allele (6.2%vs 1.4%, OR 4.5, 95% CI 0.89-22.67, p= 0.1) although the difference did not reach statistical significance. No differences in genotype and allele distribution were found with respect to epidemiological and clinical characteristics of patients with achalasia. CONCLUSION Our data suggest that NOS gene polymorphisms are not involved in the susceptibility to and nature of the clinical course of sporadic achalasia. However, studies in a greater number of patients are required to analyze the tendency toward a higher prevalence of genotypes iNOS22*A/A and eNOS*4a4a.
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Affiliation(s)
- Fermín Mearin
- Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain
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27
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Okawada M, Okazaki T, Yamataka A, Lane GJ, Miyano T. Down's syndrome and esophageal achalasia: a rare but important clinical entity. Pediatr Surg Int 2005; 21:997-1000. [PMID: 16261371 DOI: 10.1007/s00383-005-1528-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
We report a case of esophageal achalasia (EA) in Downa9s syndrome. A six-year-old girl with DS was referred from another hospital for further management of dysphagia and growth retardation (weight 16.3 kg, height 105.4 cm: both below -1.5 SD). Dysphagia commenced when she was one year old and gastroesophageal reflux (GER) was diagnosed when she was four. Routine investigations suggested EA or esophageal stenosis secondary to GER. While dissecting the esophago-gastric junction in preparation for a Heller-Dor esophagocardiomyotomy (HD-ECM), the crus of the diaphragm was noted to be narrowed, severely fibrosed and attached to the lower esophagus which was covered by dense scar tissue suggestive of an old esophageal perforation secondary to GER esophagitis. A Nissen fundoplication was performed, but dysphagia persisted postoperatively, and a narrowing 2 cm above the fundoplication wrap with proximal dilatation was found on repeated barium studies. At re-laparotomy, the fundoplication was unwrapped and HD-ECM performed. Eight months postoperatively, she is well with no recurrence. EA must be considered in any DS patient presenting with dysphagia.
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Affiliation(s)
- Manabu Okawada
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan
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28
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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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29
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Liu JF, Zhang J, Tian ZQ, Wang QZ, Li BQ, Wang FS, Cao FM, Zhang YF, Li Y, Fan Z, Han JJ, Liu H. Long-term outcome of esophageal myotomy for achalasia. World J Gastroenterol 2004; 10:287-91. [PMID: 14716841 PMCID: PMC4717022 DOI: 10.3748/wjg.v10.i2.287] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Modified Heller’s myotomy is still the first choice for achalasia and the assessment of surgical outcomes is usually made based on the subjective sensation of patients. This study was to objectively assess the long-term outcomes of esophageal myotomy for achalasia using esophageal manometry, 24-hourour pH monitoring, esophageal scintigraphy and fiberoptic esophagoscopy.
METHODS: From February 1979 to October 2000, 176 patients with achalasia underwent modified Heller’s myotomy, including esophageal myotomy alone in 146 patients, myotomy in combination with Gallone or Dor antireflux procedure in 22 and 8 patients, respectively. Clinical score, pressure of the lower esophageal sphincter (LES), esophageal clearance rate and gastroesophageal reflux were determined before and 1 to 22 years after surgery.
RESULTS: After a median follow-up of 14 years, 84.5% of patients had a good or excellent relief of symptoms, and clinical scores as well as resting pressures of the esophageal body and LES were reduced compared with preoperative values (P < 0.001). However, there was no significant difference in DeMeester score between pre- and postoperative patients (P = 0.51). Esophageal transit was improved in postoperative patients, but still slower than that in normal controls. The incidence of gastroesophageal reflux in patients who underwent esophageal myotomy alone was 63.6% compared to 27.3% in those who underwent myotomy and antireflux procedure (P = 0.087). Three (1.7%) patients were complicated with esophageal cancer after surgery.
CONCLUSION: Esophageal myotomy for achalasia can reduce the resting pressures of the esophageal body and LES and improve esophageal transit and dysphagia. Myotomy in combination with antireflux procedure can prevent gastroesophageal reflux to a certain extent, but further randomized studies should be carried out to demonstrate its efficacy.
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Affiliation(s)
- Jun-Feng Liu
- Department of Thoracic Surgery, Fourth Hospital, Hebei Medical University, Shijiazhuang 050011, Hebei Province, China.
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30
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Castagliuolo I, Brun P, Costantini M, Rizzetto C, Palù G, Costantino M, Baldan N, Zaninotto G. Esophageal achalasia: is the herpes simplex virus really innocent? J Gastrointest Surg 2004; 8:24-30; discussion 30. [PMID: 14746832 DOI: 10.1016/j.gassur.2003.10.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
This study was designed to test the hypothesis that mononuclear cells in the myenteric plexus of patients with achalasia may be activated by herpes simplex virus type 1 (HSV-1). Strips of esophageal muscle were obtained from patients with achalasia and multiorgan transplant donors who served as control subjects. After muscle digestion, mononuclear cells were purified through a Percoll gradient and cultured in medium, either alone or containing ultraviolet-inactivated HSV-1 or poliovirus (multiplicity of infection 1:1.5). As an indicator of HSV-1-induced lymphocyte activation, we determined T-cell proliferation by means of 3H-thymidine incorporation and interferon gamma release. DNA was extracted from esophageal muscle of achalasia patients and control subjects, and used as a template for PCR analysis using primer pairs specific for HSV-1. Circulating anti-HSV-1 and HSV-2 antibodies were detected by enzyme-linked immunosorbent assay on serum samples. Fifteen patients with naive achalasia and eight control subjects were studied. The prevalence of circulating anti-HSV-1 and HSV-2 antibodies proved similar in the two groups, and no HSV-1 DNA was detected by polyermase chain reaction in the esophageal muscle samples. The proliferative index in mononuclear cells from achalasia patients stimulated with HSV-1 showed a 3.4-fold increase in comparison with control subjects (P<0.01). In addition, a 1.4-fold increase in interferon gamma release after incubation with HSV-1 was observed in cells from achalasia patients but not control subjects. The results of this study indicate that HSV-1-reactive immune cells are present in lower esophageal sphincter muscles of patients with achalasia. We hypothesize that the HSV-1-reactive lymphocytes in lower esophageal sphincter muscles of achalasia patients may contribute to damage of the neurons in the myenteric plexus and lead to the motor dysfunction.
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Affiliation(s)
- Ignazio Castagliuolo
- Department of Histology, Medical and Surgical Sciences-Clinica Chirurgica 4, University of Padova School of Medicine, Padova, Italy
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31
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Zárate N, Mearin F, Hidalgo A, Malagelada JR. Prospective evaluation of esophageal motor dysfunction in Down's syndrome. Am J Gastroenterol 2001; 96:1718-24. [PMID: 11419820 DOI: 10.1111/j.1572-0241.2001.03864.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to determine the prevalence and way of presentation of esophageal motor dysfunction in a nonselected population of subjects with Down's syndrome. METHODS The study was conducted in 58 Down's syndrome patients and 38 healthy controls. A global symptom score and individual scores for dysphagia for liquids and solids, heartburn, vomiting/regurgitation, and chest pain were obtained. Esophageal function was evaluated initially by scintigraphy using liquid and semisolid bolus. Time-activity curves based on the mean condensed images were used to calculate residual activity at 100 s after swallowing. According to both scintigraphy and clinical evaluation results, participants underwent a radiological and manometric study. RESULTS The most frequent symptoms in Down's syndrome patients were: dysphagia for liquids (n = 9), dysphagia for solids (n = 10), vomiting/regurgitation (n = 8), and chest pain (n = 2). Liquid and semisolid retention of the tracer was significantly higher in Down's syndrome patients than in controls (p < 0.05). In 15 participants with Down's syndrome, tracer retention was higher than the 95 percentile of controls' retention. No correlation was found between the global or individual symptom score and esophageal retention quantified by scintigraphy. Hypothyroidism was unrelated to esophageal symptoms or retention. Five of the 15 esophagograms performed were abnormal, showing barium retention and/or esophageal dilation. Manometry showed achalasia in two subjects, total body aperistalsis in one, and nonspecific esophageal motor disorder in two. CONCLUSION Esophageal motor disorders, particularly achalasia, are frequent in individuals with Down's syndrome. Awareness of esophageal dysmotility in this population is important, even though symptoms are not evident, to avoid potential complications.
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Affiliation(s)
- N Zárate
- Radiology Department, Hospital General Vall d'Hebron, Barcelona, Spain
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32
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Affiliation(s)
- D G Field
- Department of Pediatrics, Milton S. Hershey Children's Hospital, Hershey, Pennsylvania 17033-0850, USA
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33
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Katilius M, Velanovich V. Heller myotomy for achalasia: quality of life comparison of laparoscopic and open approaches. JSLS 2001; 5:227-31. [PMID: 11548827 PMCID: PMC3015449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND Achalasia is a relatively rare disorder with a variety of treatment options. Although laparoscopic Heller myotomy has become the surgical treatment of choice, little data exist on the overall quality of life of patients undergoing this technique versus standard open approaches. METHODS We prospectively evaluated all patients surgically treated for achalasia by a single surgeon. Laparoscopic Heller myotomy consisted of a long (> or = 6 cm) esophageal cardiomyotomy extending at least 2 cm onto the gastric cardia, with a concomitant Dor fundoplication. Patients were evaluated preoperatively and postoperatively for symptoms and quality of life using the SF-36, a standardized, generic quality of life instrument. RESULTS A total of 23 patients were surgically treated: 15 patients had a planned laparoscopic procedure, with 3 conversions; 8 had planned open procedures. Dysphagia resolved in 20 of 21 patients, with 1 patient in the laparoscopic group requiring reoperation due to an inadequate gastric myotomy. Compared with preoperative scores, a statistically significant improvement occurred in the general health domain of the SF-36 (70 to 82, P = 0.04). Compared with that in patients undergoing open surgery, the laparoscopic group had better scores in the domains of physical functioning and bodily pain. CONCLUSIONS Laparoscopic Heller myotomy has comparable success to open Heller myotomy, and causes less early detriment to quality of life. This should be the primary treatment in all fit surgical patients with achalasia.
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Affiliation(s)
- M Katilius
- Division of General Surgery, Henry Ford Hospital, Detroit, Michigan 48202-2689, USA
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34
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Rinaldi R, Cortelli P, Di Simone MP, Pierangeli G, D'Alessandro R, Mattioli S. Cardiovascular autonomic function in patients with primary achalasia. Dig Dis Sci 2000; 45:825-9. [PMID: 10759256 DOI: 10.1023/a:1005472400263] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Impaired gastrointestinal function outside the esophagus has been found in achalasic patients. Moreover, achalasia may occur in diseases in which a systemic dysautonomia is evident. These findings raise the question of whether a generalized subclinical alteration of autonomic control is also present in primary achalasia. Cardiovascular reflex tests and power spectral analysis of heart rate variability were studied in patients with primary achalasia to establish whether autonomic nervous system changes are present in districts other than the gastrointestinal tract. Nineteen normotensive patients with untreated primary achalasia and with no history of cardiac, renal, or endocrinological diseases were examined. Cardiovascular reflex tests included: the tilt test (10 min at 65 degrees), Valsalva maneuver (40 mm Hg for 15 sec), deep breathing (6 breaths/min), and sustained handgrip (30% of maximal effort for 5 min). The parameters evaluated were systolic and diastolic blood pressure (continuously recorded), ECG, oronasal and thoracic respiration, tachogram, and plethysmogram. To evaluate the balance between parasympathetic and sympathetic functions, power spectral analysis of the heart rate variability was carried out. Each patient was paired with two sex- and age-matched healthy controls. In achalasic patients the head-up tilt test, Valsalva maneuver, deep breathing test, and sustained handgrip did not show significant differences from the control group. Low-frequency (LF) and high-frequency (HF) spectral powers and the ratio of LF to HF did not differ in both groups. This study failed to disclose impaired cardiovascular autonomic control in achalasic patients. We suggest that in primary achalasia the defect is limited to the gastrointestinal tract.
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Affiliation(s)
- R Rinaldi
- Center for the Study and Therapy of Diseases of the Esophagus of the University of Bologna, Italy
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35
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Greaves RR, Mulcahy HE, Patchett SE, Gorard DA, Fairclough PD, Alstead EM, Farthing MJ. Early experience with intrasphincteric botulinum toxin in the treatment of achalasia. Aliment Pharmacol Ther 1999; 13:1221-5. [PMID: 10468705 DOI: 10.1046/j.1365-2036.1999.00609.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND Recent reports have suggested that intrasphincteric injection of botulinum toxin is effective and long-lasting in the treatment of achalasia. AIM To report our experience of botulinum toxin injection in a prospective series of consecutive patients with achalasia. METHODS Eleven consecutive patients with achalasia (eight male, mean age 55 years, range 20-87) were treated with 60 units of botulinum toxin (Dysport; Speywood Pharmaceuticals Ltd, UK) into each of four quadrants at the lower oesophageal sphincter. Patients were assessed pre-treatment and 1 month after treatment using a symptom score and oesophageal manometry. Median follow-up was 12 months (range 6-28). RESULTS The injection procedure was simple to perform and free of adverse effects. Although treatment had a beneficial effect on dysphagia (median pre-treatment score 3 [interquartile range 3-3]; post-treatment score 2 [0-3]: P=0.03) 1 month following therapy, there was no significant improvement in chest pain or regurgitation scores. Similarly, no significant reduction in median lower oesophageal sphincter pressure was observed (29.5 mmHg [21-42] pre-treatment, 28.5 [17.5-55.5] post-treatment P=0.67). Four patients (36%) required further therapy within 3 months and the overall relapse rate was 73% (eight of 11) within 2 years. CONCLUSION Although botulinum toxin injection was well tolerated, these results using Dysport at a dose of 240 mouse units question its efficacy as a treatment for achalasia.
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Affiliation(s)
- R R Greaves
- Digestive Diseases Research Centre, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Turner Street, London, UK
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36
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Abstract
Achalasia is a rare but important condition affecting the myenteric neurons of the esophagus. A number of studies have provided evidence for the preservation of cholinergic innervation to the esophagus in achalasia. This forms the rationale for the treatment of achalasia with botulinum toxin. Identification of nitric oxide as the primary inhibitory neurotransmitter of the gastrointestinal tract has improved our understanding of the pathophysiology of primary achalasia. Neurons containing nitric oxide are absent within the myenteric plexuses of patients with achalasia, and the experimental inhibition of nitric oxide produces a picture that manometrically mimics achalasia. Recent advances have provided insights into the genetic basis and pathogenesis of a growing number of secondary forms of achalasia. Examples of such secondary disorders include Allgrove's syndrome, autoimmune polyglandular syndrome, and multiple endocrine neoplasia type 2B.
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Affiliation(s)
- I Hirano
- Northwestern University Medical School, Division of Gastroenterology and Hepatology, Searle 10-563, 303 East Chicago Avenue, Chicago, IL 60611, USA
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37
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Zárate N, Mearin F, Gil-Vernet JM, Camarasa F, Malagelada JR. Achalasia and Down's syndrome: coincidental association or something else? Am J Gastroenterol 1999; 94:1674-7. [PMID: 10364043 DOI: 10.1111/j.1572-0241.1999.01161.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Achalasia is an uncommon esophageal motor disorder. It has been associated with other diseases such as Parkinson's disease and depressive disorders, but coincidence of achalasia and Down's syndrome is rare. We report five cases of achalasia in Down's syndrome patients seen in our institution. Two of the five cases were diagnosed at pediatric age. Respiratory symptoms and growth retardation were the main clinical manifestations in pediatric patients, whereas adult patients mainly complained of dysphagia. Taking into account the prevalence rate of both disorders, the association seems higher than that expected by chance. The possible etiopathogenic implications of this association, as well as its clinical relevance, are discussed.
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Affiliation(s)
- N Zárate
- Digestive System Research Unit, Hospital General Universitari Vall d'Hebron, Barcelona, Spain
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38
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Koshy SS, Nostrant TT. Pathophysiology and endoscopic/balloon treatment of esophageal motility disorders. Surg Clin North Am 1997; 77:971-92. [PMID: 9347827 DOI: 10.1016/s0039-6109(05)70601-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Diagnostic and therapeutic dilemmas associated with esophageal dysmotility syndromes continue to confront physicians managing these patient populations. Although modern manometric systems have allowed us to better define normal parameters of esophageal motility, with the exception of primary achalasia, the clinical relevance of many aberrant motor patterns remains unclear. The novel use of botulinum toxin in idiopathic achalasia stems from increased understanding of the pathogenesis of the disease. Similarly, as our knowledge of the pathophysiology of other esophageal motor disorders grows, in conjunction with improved diagnostic capabilities, more effective management strategies may be used in the future.
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Affiliation(s)
- S S Koshy
- Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, USA
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39
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Birgisson S, Galinski MS, Goldblum JR, Rice TW, Richter JE. Achalasia is not associated with measles or known herpes and human papilloma viruses. Dig Dis Sci 1997; 42:300-6. [PMID: 9052510 DOI: 10.1023/a:1018805600276] [Citation(s) in RCA: 54] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Achalasia is an esophageal motility disorder of unknown etiology. Several studies suggest possible herpes or measles virus etiology, but results are inconclusive. The aim of this study was to test whether herpesvirus (HV), measles (MV), or human papilloma virus (HPV) sequences could be detected in myotomy specimens from a wide spectrum of achalasia patients, using the polymerase chain reaction (PCR) technique. Myotomy specimens from 13 achalasia patients, esophagectomy specimens from nine esophageal cancer patients, and autopsy specimens from six fetuses were studied with the PCR technique. Paired oligonucleotide primers of HV (HSV-1 and 2, CMV, EBV, VZV, and HHV-6), MV and HPV sequences and exon 3 of the HPRT gene were used for the PCR DNA amplification. Amplified products were resolved on agarose gels and stained with ethidium bromide. All specimens yielded the appropriate-sized products for exon 3 of the HPRT and viral controls. No amplified products were seen in the achalasia specimens or controls corresponding to any of the virus sequences tested. The absence of HV, MV, and HPV sequences suggests that these viruses are not associated with achalasia but does not exclude the possibility of a previously unidentified virus as a causal agent. Further studies aimed at identifying an unknown viral agent as a cause for achalasia are warranted.
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Affiliation(s)
- S Birgisson
- Department of Gastroenterology, Cleveland Clinic Foundation, Ohio 44195, USA
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40
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Verne GN, Sallustio JE, Eaker EY. Anti-myenteric neuronal antibodies in patients with achalasia. A prospective study. Dig Dis Sci 1997. [PMID: 9052511 DOI: 10.1023/a: 1018857617115] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Achalasia is a motility disorder of the esophagus characterized by the loss of inhibitory neurons in the distal esophagus. Although idiopathic in nature, autoimmune mechanisms have been proposed, and we set out to determine the presence of myenteric neuronal antibodies. We prospectively studied 18 patients with well-characterized achalasia (by clinical, x-ray, and manometric evidence), nine with gastroesophageal reflux disease, and analyzed the sera from 22 disease-free controls. Using double-label, indirect immunofluorescence techniques, rat esophageal and intestinal sections were double-labeled with sera (dilutions of 1:50 to 1:400) from the three groups and with neurofilament antibody to localize neurons. Seven of 18 achalasia patients had sera that stained the majority of neurons within plexi in the esophageal and intestinal sections, including both NADPH diaphorase (nitric oxide synthase) -positive and -negative neurons. None of the gastroesophageal reflux patients or the controls showed staining. Neuronal antibodies in achalasia provide an attractive hypothesis to explain this diffuse, possibly immune-based disorder.
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Affiliation(s)
- G N Verne
- Division of Gastroenterology, University of Florida, Gainesville, USA
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41
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Verne GN, Sallustio JE, Eaker EY. Anti-myenteric neuronal antibodies in patients with achalasia. A prospective study. Dig Dis Sci 1997; 42:307-13. [PMID: 9052511 DOI: 10.1023/a:1018857617115] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Achalasia is a motility disorder of the esophagus characterized by the loss of inhibitory neurons in the distal esophagus. Although idiopathic in nature, autoimmune mechanisms have been proposed, and we set out to determine the presence of myenteric neuronal antibodies. We prospectively studied 18 patients with well-characterized achalasia (by clinical, x-ray, and manometric evidence), nine with gastroesophageal reflux disease, and analyzed the sera from 22 disease-free controls. Using double-label, indirect immunofluorescence techniques, rat esophageal and intestinal sections were double-labeled with sera (dilutions of 1:50 to 1:400) from the three groups and with neurofilament antibody to localize neurons. Seven of 18 achalasia patients had sera that stained the majority of neurons within plexi in the esophageal and intestinal sections, including both NADPH diaphorase (nitric oxide synthase) -positive and -negative neurons. None of the gastroesophageal reflux patients or the controls showed staining. Neuronal antibodies in achalasia provide an attractive hypothesis to explain this diffuse, possibly immune-based disorder.
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Affiliation(s)
- G N Verne
- Division of Gastroenterology, University of Florida, Gainesville, USA
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42
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Birgisson S, Galinski MS, Goldblum JR, Rice TW, Richter JE. Achalasia is not associated with measles or known herpes and human papilloma viruses. Dig Dis Sci 1997. [PMID: 9052510 DOI: 10.1023/a: 1018805600276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Achalasia is an esophageal motility disorder of unknown etiology. Several studies suggest possible herpes or measles virus etiology, but results are inconclusive. The aim of this study was to test whether herpesvirus (HV), measles (MV), or human papilloma virus (HPV) sequences could be detected in myotomy specimens from a wide spectrum of achalasia patients, using the polymerase chain reaction (PCR) technique. Myotomy specimens from 13 achalasia patients, esophagectomy specimens from nine esophageal cancer patients, and autopsy specimens from six fetuses were studied with the PCR technique. Paired oligonucleotide primers of HV (HSV-1 and 2, CMV, EBV, VZV, and HHV-6), MV and HPV sequences and exon 3 of the HPRT gene were used for the PCR DNA amplification. Amplified products were resolved on agarose gels and stained with ethidium bromide. All specimens yielded the appropriate-sized products for exon 3 of the HPRT and viral controls. No amplified products were seen in the achalasia specimens or controls corresponding to any of the virus sequences tested. The absence of HV, MV, and HPV sequences suggests that these viruses are not associated with achalasia but does not exclude the possibility of a previously unidentified virus as a causal agent. Further studies aimed at identifying an unknown viral agent as a cause for achalasia are warranted.
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Affiliation(s)
- S Birgisson
- Department of Gastroenterology, Cleveland Clinic Foundation, Ohio 44195, USA
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43
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Benini L, Sembenini C, Bulighin GM, Polo A, Ederle A, Zambito A, Vantini I. Achalasia. A possible late cause of postpolio dysphagia. Dig Dis Sci 1996; 41:516-8. [PMID: 8617125 DOI: 10.1007/bf02282328] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The aim of this paper is to describe a patient with severe postpolio problems who developed achalasia. A 66-year-old patient came to our observation for severe dysphagia. He had suffered from paralytic poliomyelitis at the age of 7 months and had severe residual deficits. At the age of 62 he presented with sudden pain localized in the distribution of the C4 and C5 dermatomes and an inability to abduct the left arm. At the time, he experienced only occasional and mild dysphagia; his esophagus was not dilated and emptied normally. Over the following months his muscular function improved, but dysphagia worsened. We found a megaesophagus with a sigmoid appearance and the manometric features of achalasia. Pneumatic dilatation produced good resolution of dysphagia. A year later manometry showed the reappearance of peristalsis after all wet swallows. In patients with postpolio dysphagia, the possible presence of achalasia must be considered.
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Affiliation(s)
- L Benini
- Department of Gastroenterology, Rehabilitation Hospital of Valeggio Sul Mincio, University of Verona, Italy
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44
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Niwamoto H, Okamoto E, Fujimoto J, Takeuchi M, Furuyama J, Yamamoto Y. Are human herpes viruses or measles virus associated with esophageal achalasia? Dig Dis Sci 1995; 40:859-64. [PMID: 7720482 DOI: 10.1007/bf02064992] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
In order to test the hypothesis that esophageal achalasia may be due to neurotropic viral damage to the esophageal myenteric plexus, esophageal tissue with or without achalasia was analyzed by polymerase chain reaction for the presence of human herpes virus DNA or measles virus RNA. The DNA and RNA were extracted from the esophageal muscle of 12 patients with achalasia and six patients with upper esophageal carcinoma. Peripheral blood mononuclear cells from eight adult volunteers and two samples of umbilical blood mononuclear cells were also used as controls. PCR amplification with a pair of primers specific for herpes simplex type 1 and 2 viruses identified 92-bp fragments in nearly all specimens, including those without achalasia. Each 92-bp fragment was confirmed to be identical to a single herpes simplex virus sequence by automated DNA sequence analysis. No amplification for five other herpes viruses or measles virus was detected. Therefore, a specific viral etiology for achalasia was not identified in this study.
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Affiliation(s)
- H Niwamoto
- First Department of Surgery, Hyogo College of Medicine, Japan
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45
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Abstract
It has been previously shown that patients with achalasia may have motor abnormalities of the stomach, small bowel and biliary system. This study investigates whether a disturbance of extraintestinal autonomic function occurs. Autonomic function studies were performed in 15 patients with achalasia and 15 age- and sex-matched healthy controls. Pupillograms were obtained during darkness, light exposure and after pilocarpine administration. Cardiovascular function studies included determinations of heart rate variation during deep breathing and orthostasis. In addition, we determined blood pressure changes in response to sustained handgrip, cold exposure and orthostasis. Neurohormonal function was investigated by measuring serum pancreatic polypeptide (PP) levels prior to and following sham feeding. Pupillary function did not differ in patients as compared with controls. However, 9 of 15 patients (95% CI: 32-84%) and none of the controls showed at least one abnormal autonomic cardiovascular response. A significant difference between the two groups was observed in sympathetic function (P = 0.023). More patients than controls did not respond to sham feeding with a PP increase. It is concluded that some patients with achalasia exhibit an abnormality of the autonomic nervous system that extends beyond the gastrointestinal tract. These abnormalities mainly concern cardiovascular function but may also involve neurohormonal responses.
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Affiliation(s)
- V F Eckardt
- Gastroenterologisches Institut Wiesbaden, Universität Mainz, Germany
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46
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Abstract
In a search for past or present infection with herpes viruses, serum antibody titres to herpes simplex type 1 virus, cytomegalovirus, and varicella-zoster virus were measured by complement fixation test in 58 patients with achalasia. Serum was also taken from 40 age and sex matched patients without oesophageal symptoms who formed a control group. All titres were low, and those for herpes simplex type 1 virus and cytomegalovirus did not differ in the achalasia patients and the controls. However, the incidence of varicella-zoster virus antibodies was significantly greater in the achalasia than in the control group (p < 0.05). Using oesophageal tissue containing myenteric plexus removed at the time of cardiomyotomy in nine patients with achalasia, in situ DNA hybridisation showed evidence of varicella-zoster virus in three, but all were negative for the other two viruses. No positive results were obtained for herpes simplex type 1 virus, cytomegalovirus, or varicella-zoster virus in oesophageal tissue from 20 patients undergoing oesophageal resection for diseases other than achalasia. The incidence of positivity for varicella-zoster virus was significantly increased in the achalasia group compared with the controls (p < 0.02). The findings indicate that varicella-zoster virus DNA may persist in the oesophageal myenteric plexus in some patients with achalasia and raise the possibility that this virus is of aetiological importance in achalasia.
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47
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Frieling T, Berges W, Borchard F, Lübke HJ, Enck P, Wienbeck M. Family occurrence of achalasia and diffuse spasm of the oesophagus. Gut 1988; 29:1595-602. [PMID: 3061886 PMCID: PMC1433819 DOI: 10.1136/gut.29.11.1595] [Citation(s) in RCA: 31] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
In view of the unknown aetiology of achalasia and diffuse oesophageal spasm we report four families (father/son, mother/son, brother/brother, cousin/cousin) with achalasia and oesophageal spasm examined by radiology, endoscopy and manometry. Family occurrence of oesophageal motor disorders supports the hypothesis that a genetic trait may play a role in the pathogenesis. The family coincidence of achalasia and oesophageal spasm supports a close relationship between the two diseases.
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Affiliation(s)
- T Frieling
- Department of Gastroenterology, University of Düsseldorf, FR Germany
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48
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Abstract
Esophageal achalasia, characterized by failure of the lower esophageal sphincter to relax normally with swallowing and esophageal aperistalsis, may be primary or secondary to another disorder (in the United States most often cancer). Primary achalasia is of unclear etiology but almost certainly is a disorder of the innervation of the smooth muscle portion of the esophagus. This article reviews the classification and clinical features of achalasia syndromes, as well as current concepts of pathogenesis, diagnosis, complications, and therapy of this group of disorders.
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Affiliation(s)
- M Feldman
- University of Texas Health Science Center, Dallas
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