1
|
Plum PS, Niebisch S, Gockel I. State-of-the-Art Surgery in Achalasia. Visc Med 2024; 40:293-298. [PMID: 39664092 PMCID: PMC11631102 DOI: 10.1159/000541928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 10/08/2024] [Indexed: 12/13/2024] Open
Abstract
Background Achalasia is a motility disorder of the esophagus and depending on its type, esophageal tubular hypo- or hypermotility can cause typical symptoms, such as dysphagia, chest pain, weight loss, or regurgitation. Clinical symptoms during initial diagnosis as well as over the course of therapy can be measured by the Eckardt score. Diagnostics include high-resolution manometry (HR manometry), (timed barium) esophagogram, upper gastrointestinal endoscopy, multiple rapid swallow response, and Endo-FLIP measurement. In this work, we provide a review of the recent literature on surgical treatment of achalasia. Summary Besides pharmacological and endoscopic interventions, surgical procedures of laparoscopic/robotic Heller myotomy (LHM/RHM) and 180° anterior Dor's semifundoplication versus 270° dorsal Toupet's fundoplication are primary therapeutic options, especially for type I and II achalasia. Both surgical procedures display little morbidity and mortality. Postsurgical results are comparable between LHM and RHM. RHM allows better angulation during myotomy, lower rates of intraoperative mucosal laceration, and better visualization of the muscles in the lower esophageal sphincter area. Surgery can also be performed safely after failed endoscopic treatments. Key Messages Surgery in achalasia is especially indicated in patients ≤40 years and also recommended after repeated unsuccessful or complicated endoscopic interventions. In selected patients with end-stage achalasia and sigmoid-shaped megaesophagus, esophagectomy is a reasonable option in order to improve quality of life.
Collapse
Affiliation(s)
- Patrick S. Plum
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Stefan Niebisch
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital Leipzig, Leipzig, Germany
| | | |
Collapse
|
2
|
Di Brina ALP, Palmieri O, Cannarozzi AL, Tavano F, Guerra M, Bossa F, Gentile M, Merla A, Biscaglia G, Cuttitta A, Perri F, Latiano A. Focus on Achalasia in the Omics Era. Int J Mol Sci 2024; 25:10148. [PMID: 39337632 PMCID: PMC11431880 DOI: 10.3390/ijms251810148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 09/17/2024] [Accepted: 09/18/2024] [Indexed: 09/30/2024] Open
Abstract
Achalasia is a rare and complex esophageal disease of unknown etiology characterized by difficulty in swallowing due to the lack of opening of the lower esophageal sphincter and the absence of esophageal peristalsis. Recent advancements in technology for analyzing DNA, RNA and biomolecules in high-throughput techniques are offering new opportunities to better understand the etiology and the pathogenetic mechanisms underlying achalasia. Through this narrative review of the scientific literature, we aim to provide a comprehensive assessment of the state-of-the-art knowledge on omics of achalasia, with particular attention to those considered relevant to the pathogenesis of the disease. The notion and importance of the multi-omics approach, its limitations and future directions are also introduced, and it is highlighted how the integration of single omics data will lead to new insights into the development of achalasia and offer clinical tools which will allow early diagnosis and better patient management.
Collapse
Affiliation(s)
- Anna Laura Pia Di Brina
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Orazio Palmieri
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Anna Lucia Cannarozzi
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Francesca Tavano
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Maria Guerra
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Fabrizio Bossa
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Marco Gentile
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Antonio Merla
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Giuseppe Biscaglia
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Antonello Cuttitta
- Unit of Thoracic Surgery, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy;
| | - Francesco Perri
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| | - Anna Latiano
- Division of Gastroenterology and Endoscopy, Fondazione IRCCS Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo, Italy; (A.L.P.D.B.); (O.P.); (A.L.C.); (F.T.); (M.G.); (F.B.); (M.G.); (A.M.); (G.B.); (F.P.)
| |
Collapse
|
3
|
Savarino EV, Salvador R, Ghisa M, Mari A, Forattini F, Costantini A, De Giorgio R, Zaninotto G. Research gap in esophageal achalasia: a narrative review. Dis Esophagus 2024; 37:doae024. [PMID: 38525929 DOI: 10.1093/dote/doae024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 03/08/2024] [Indexed: 03/26/2024]
Abstract
In recent years, new translational evidence, diagnostic techniques, and innovative therapies have shed new light on esophageal achalasia and revamped the attention on this relatively rare motility disorder. This narrative review aims to highlight the most recent progress and the areas where further research is needed. The four senior authors identified five topics commonly discussed in achalasia management: i.e. pathogenesis, role of functional lumen imaging probe in the diagnostic flow chart of achalasia, how to define the outcome of achalasia treatments, how to manage persistent chest pain after the treatment, and if achalasia patients' may benefit from a regular follow-up. We searched the bibliographic databases to identify systematic reviews, meta-analyses, randomized control trials, and original research articles in English up to December 2023. We provide a summary with the most recent findings in each of the five topics and the critical points where to address future research, such as the immune-genetic patterns of achalasia that might explain the transition among the different phenotypes, the need for a validated clinical definition of treatment success, the use of neuromodulators to manage chest pain, and the need for identifying achalasia patients at risk for cancer and who may benefit of long-term follow-up. Although undoubtedly, progress has been made on the definition and management of achalasia, unmet needs remain. Debated aspects range from mechanistic insights, symptoms, objective measure relationships, and accurate clinical responses to therapeutic interventions. Translational research is eagerly awaited to answer these unresolved questions.
Collapse
Affiliation(s)
- Edoardo Vincenzo Savarino
- Gastroenterology Unit, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Renato Salvador
- Chirurgia Generale 1, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Matteo Ghisa
- Gastroenterology Unit, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Amir Mari
- Gastroenterology Unit, Nazareth Hospital EMMS, The Azrieli Faculty of Medicine, Bar-Ilan University, Tel Aviv, Israel
| | - Francesca Forattini
- Chirurgia Generale 1, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Andrea Costantini
- Chirurgia Generale 1, Azienda Ospedale Università of Padua, Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | - Roberto De Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | | |
Collapse
|
4
|
Chanpong A, Alves MM, Bonora E, De Giorgio R, Thapar N. Evaluating the molecular and genetic mechanisms underlying gut motility disorders. Expert Rev Gastroenterol Hepatol 2023; 17:1301-1312. [PMID: 38117595 DOI: 10.1080/17474124.2023.2296558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 12/14/2023] [Indexed: 12/22/2023]
Abstract
INTRODUCTION Gastrointestinal (GI) motility disorders comprise a wide range of different diseases affecting the structural or functional integrity of the GI neuromusculature. Their clinical presentation and burden of disease depends on the predominant location and extent of gut involvement as well as the component of the gut neuromusculature affected. AREAS COVERED A comprehensive literature review was conducted using the PubMed and Medline databases to identify articles related to GI motility and functional disorders, published between 2016 and 2023. In this article, we highlight the current knowledge of molecular and genetic mechanisms underlying GI dysmotility, including disorders of gut-brain interaction, which involve both GI motor and sensory disturbance. EXPERT OPINION Although the pathophysiology and molecular mechanisms underlying many such disorders remain unclear, recent advances in the assessment of intestinal tissue samples, genetic testing with the application of 'omics' technologies and the use of animal models will provide better insights into disease pathogenesis as well as opportunities to improve therapy.
Collapse
Affiliation(s)
- Atchariya Chanpong
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
- Neurogastroenterology & Motility Unit, Gastroenterology Department, Great Ormond Street Hospital for Children, London, UK
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Elena Bonora
- Department of Medical and Surgical Sciences, DIMEC, University of Bologna, Bologna, Italy
- U.O. Genetica Medica, IRCCS Azienda Ospedaliero-Universitaria di Bologna, AOUB, Bologna, Italy
| | - Roberto De Giorgio
- Department of Translational Sciences, University of Ferrara, Ferrara, Italy
| | - Nikhil Thapar
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
- Gastroenterology, Hepatology and Liver Transplant, Queensland Children's Hospital, Brisbane, Australia
- School of Medicine, University of Queensland, Brisbane, Australia
- Woolworths Centre for Child Nutrition Research, Queensland University of Technology, Brisbane, Australia
| |
Collapse
|
5
|
Travers PM, Francis DL. Burn Pits: A Possible Trigger for Achalasia. Cureus 2023; 15:e36071. [PMID: 37065318 PMCID: PMC10096746 DOI: 10.7759/cureus.36071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/12/2023] [Indexed: 03/18/2023] Open
Abstract
A 45-year-old female veteran of the United States Air Force (USAF), who was exposed to burn pits on multiple occasions while deployed in the Middle East, presented for a second opinion regarding ongoing chest pain and regurgitation after a Heller myotomy for achalasia. An esophageal X-ray showed no meaningful peristalsis, a slight diverticulum in the distal esophagus, and easy passage of liquids through the lower esophageal sphincter (LES). Esophageal manometry findings were consistent with type 3 achalasia. Based on these and endoscopic evaluation, the prior surgical intervention appeared to be successful for lower esophageal sphincter disruption, so symptoms were managed medically with a proton pump inhibitor, trazodone, and a long-acting nitrate resulting in 70% improvement. We present this case because the patient developed achalasia with a notable history of exposure to open-air burn pits during her military service. While we acknowledge that causality cannot be proven, our case is the first we are aware of that shows a temporal association between burn pit exposure and achalasia. In August of 2022, the United States Congress passed the Promise to Address Comprehensive Toxics (PACT) Act, which expanded the healthcare benefits of veterans exposed to burn pits, making identification of associated conditions a relevant and important endeavor.
Collapse
|
6
|
Jerie M, Vackova Z, Vojtech Z, Mares J, Meluzinova E, Krajciova J, Vymazal J, Cerna H, Martinek J. Prevalence of neurodegenerative/demyelinating disorders in patients with achalasia. Transl Neurosci 2022; 13:361-368. [PMID: 36304096 PMCID: PMC9552774 DOI: 10.1515/tnsci-2022-0249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/28/2022] [Accepted: 09/05/2022] [Indexed: 11/06/2022] Open
Abstract
Introduction Esophageal achalasia is a primary motility disorder. Although the exact pathogenesis is unknown, autoimmune, and neurodegenerative processes seem to be involved similarly to neurodegenerative and/or demyelinating disorders (NDDs). We hypothesized that the prevalence of NDD may be higher among patients with achalasia and vice versa as the background pathogenetic mechanisms are similar. Methods This was a prospective, comparative questionnaire-based study. Patients with achalasia and patients with NDD were enrolled. Selected patients with achalasia were thoroughly examined by a neurologist and selected patients with NDD were examined by a gastroenterologist to confirm or rule out NDD or achalasia. We assessed the prevalence of both achalasia and NDD and compared them with their prevalence in general population. Results A total of 150 patients with achalasia and 112 patients with NDD were enrolled. We observed an increased prevalence of NDD among patients with achalasia (6.0% (9/150); 95% CI (confidence interval): 3.1–11.2%) as compared to the estimated 2.0% prevalence in general population (p = 0.003). Although 32 out of 112 patients (28.6%) with NDD reported dysphagia, we did not observe significantly increased prevalence of achalasia in these patients (1.8% (2/112) vs 0.8% in general population, p = 0.226). Conclusion The prevalence of NDD was significantly higher among patients with achalasia (6.0%) compared to general population (2.0%), suggesting an association of these disorders. Large-volume studies are necessary to confirm this finding.
Collapse
Affiliation(s)
- Martin Jerie
- First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic
- Department of Neurology, Na Homolce Hospital, 15000 Prague, Czech Republic
| | - Zuzana Vackova
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
- Institute of Physiology, First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic
| | - Zdenek Vojtech
- Department of Neurology, Na Homolce Hospital, 15000 Prague, Czech Republic
- Charles University, Third Faculty of Medicine, 10000 Prague, Czech Republic
| | - Jan Mares
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
| | - Eva Meluzinova
- Department of Neurology, Second Faculty of Medicine, Charles University, Motol University Hospital, 15000 Prague, Czech Republic
| | - Jana Krajciova
- Institute of Physiology, First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic
- ResTrial s.r.o., 16000 Prague, Czech Republic
| | - Josef Vymazal
- Department of Radiology, Na Homolce Hospital, 15000 Prague, Czech Republic
| | - Hana Cerna
- Sarkamed s.r.o., 27401 Slany, Czech Republic
| | - Jan Martinek
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic
- Institute of Physiology, First Faculty of Medicine, Charles University, 12108 Prague, Czech Republic
| |
Collapse
|
7
|
Abstract
Idiopathic achalasia is a motility disorder affecting the lower esophageal sphincter. Dysphagia is a hallmark symptom, but patients may exhibit other symptoms. The aim of this review is to compare achalasia symptoms globally. PubMed and Google Scholar were filtered from 1952–2021 with the search terms achalasia, epidemiology, diet, countries, and genetics. A total of 14 articles addressed demographics, symptom profiles, genetics, and diagnosis criteria amongst 2463 patients. Data on countries’ climate and diet were obtained through Arc Geographic Information System (GIS) and Our World in Data. Countries were grouped by similar climate zones and diets. Achalasia symptoms varied by region. In West Africa, patients exhibit parotid swelling, anemia, and dehydration; diminished appetite in East Asia; dysphagia and weight loss in West Asia and Europe; respiratory symptoms, reflux, and retrosternal pain in North America; and vomiting in Southern Asia. Weighted percentages of dietary oils/fats were (24.3%) in North America, Western Asia (17.8%); Europe (17.7%); East Asia (17.6%); West Africa (14.7%); Southern Asia (13.8%); North Africa (12.4%); Northeast Africa (10.1%). Conditions such as Down Syndrome and Triple A syndrome are associated with achalasia. There was no correlation for achalasia presentation and climate zones. Achalasia symptoms are likely multifactorial. Diet, genetics, and environmental factors may play significant roles.
Collapse
|
8
|
Bell SM, Evans JM, Evans KM, Tsai KL, Noorai RE, Famula TR, Holle DM, Clark LA. Congenital idiopathic megaesophagus in the German shepherd dog is a sex-differentiated trait and is associated with an intronic variable number tandem repeat in Melanin-Concentrating Hormone Receptor 2. PLoS Genet 2022; 18:e1010044. [PMID: 35271580 PMCID: PMC8912139 DOI: 10.1371/journal.pgen.1010044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 01/20/2022] [Indexed: 11/19/2022] Open
Abstract
Congenital idiopathic megaesophagus (CIM) is a gastrointestinal (GI) motility disorder of dogs in which reduced peristaltic activity and dilation of the esophagus prevent the normal transport of food into the stomach. Affected puppies regurgitate meals and water, fail to thrive, and experience complications such as aspiration pneumonia that may necessitate euthanasia. The German shepherd dog (GSD) has the highest disease incidence, indicative of a genetic predisposition. Here, we discover that male GSDs are twice as likely to be affected as females and show that the sex bias is independent of body size. We propose that female endogenous factors (e.g., estrogen) are protective via their role in promoting relaxation of the sphincter between the esophagus and stomach, facilitating food passage. A genome-wide association study for CIM revealed an association on canine chromosome 12 (P-val = 3.12x10-13), with the lead SNPs located upstream or within Melanin-Concentrating Hormone Receptor 2 (MCHR2), a compelling positional candidate gene having a role in appetite, weight, and GI motility. Within the first intron of MCHR2, we identified a 33 bp variable number tandem repeat (VNTR) containing a consensus binding sequence for the T-box family of transcription factors. Across dogs and wolves, the major allele includes two copies of the repeat, whereas the predominant alleles in GSDs have one or three copies. The single-copy allele is strongly associated with CIM (P-val = 1.32x10-17), with homozygosity for this allele posing the most significant risk. Our findings suggest that the number of T-box protein binding motifs may correlate with MCHR2 expression and that an imbalance of melanin-concentrating hormone plays a role in CIM. We describe herein the first genetic factors identified in CIM: sex and a major locus on chromosome 12, which together predict disease state in the GSD with greater than 75% accuracy. German shepherd dogs (GSDs) are predisposed to an inherited motility disorder of the esophagus, termed congenital idiopathic megaesophagus (CIM), in which swallowing is ineffective and the esophagus is enlarged. Affected puppies are unable to properly pass food into their stomachs and consequently regurgitate their meals and show a failure to thrive, often leading to euthanasia. Here, we discovered that male GSDs are affected at a ratio of almost 2-to-1 over females, suggesting a protective biological advantage in females. In humans, estrogen is thought to play a role in the male predominance of esophageal disorders like reflux esophagitis and esophageal cancer. In a genome-wide scan, we identified an association with CIM on chromosome 12 and, within this region, a repetitive sequence in MCHR2. This gene encodes a receptor for melanin-concentrating hormone, a signaling molecule that is linked to appetite, weight, and gut motility. Together, sex and the MCHR2 repeat sequence accurately predict affection status in over 75% of dogs, and a genetic test is now available to facilitate breeding decisions aimed at reducing disease incidence.
Collapse
Affiliation(s)
- Sarah M. Bell
- Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America
| | - Jacquelyn M. Evans
- Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America
- Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Katy M. Evans
- The Seeing Eye Inc., Morristown, New Jersey, United States of America
- School of Veterinary Medicine and Science, University of Nottingham, Sutton Bonington, United Kingdom
| | - Kate L. Tsai
- Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America
| | - Rooksana E. Noorai
- Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America
- Clemson University Genomics and Bioinformatics Facility, Clemson University, Clemson, South Carolina, United States of America
| | - Thomas R. Famula
- Department of Animal Science, University of California, Davis, California, United States of America
| | - Dolores M. Holle
- The Seeing Eye Inc., Morristown, New Jersey, United States of America
| | - Leigh Anne Clark
- Department of Genetics and Biochemistry, Clemson University, Clemson, South Carolina, United States of America
- * E-mail:
| |
Collapse
|
9
|
Tanaka S, Abe H, Sato H, Shiwaku H, Minami H, Sato C, Ogawa R, Shimamura Y, Yokomichi H, Inoue H. Frequency and clinical characteristics of special types of achalasia in Japan: A large-scale, multicenter database study. J Gastroenterol Hepatol 2021; 36:2828-2833. [PMID: 34032322 DOI: 10.1111/jgh.15557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 03/18/2021] [Accepted: 05/23/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Achalasia is a rare disease, with an incidence of one in 100 000. Genetic factors and autoimmune involvement have been reported in its etiology, and their involvement is strongly suspected, especially in patients with familial achalasia and those with comorbid hereditary or autoimmune diseases. However, these special types of achalasia are rare, and their frequency and clinical characteristics remain unclear. METHODS This retrospective, multicenter cohort study included Japanese patients with a diagnosis of achalasia, treated between 2010 and 2019 across six tertiary centers in Japan. The frequency and clinical characteristics of special types of achalasia, namely, familial achalasia, achalasia with a comorbid hereditary disease, and achalasia with a comorbid autoimmune disease, were retrospectively investigated using a large-scale multicenter database. RESULTS During the study period, 1115 patients were treated for achalasia at six tertiary centers. Familial achalasia, achalasia with a comorbid hereditary disease, and achalasia with a comorbid autoimmune disease occurred in 7 (0.63%), 11 (0.99%), and 27 (2.4%) patients, respectively. Familial achalasia had a slightly younger age of onset (37.6 ± 12.1 years old) and a higher incidence in male patients (six patients; 85.7%). Down's syndrome was the most common hereditary comorbidity, and thyroid disease was the most common autoimmune comorbidity. CONCLUSIONS We clarified the frequency and clinical characteristics of special types of achalasia. Although special types of achalasia are rare, these comorbidities should be considered when treating patients with achalasia.
Collapse
Affiliation(s)
- Shinwa Tanaka
- Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Hirofumi Abe
- Division of Gastroenterology, Department of Internal Medicine, Graduate School of Medicine, Kobe University, Kobe, Japan
| | - Hiroki Sato
- Division of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata, Japan
| | - Hironari Shiwaku
- Department of Gastroenterological Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Hitomi Minami
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | - Chiaki Sato
- Division of Advanced Surgical Science and Technology, School of Medicine, Tohoku University, Sendai, Japan
| | - Ryo Ogawa
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Yuto Shimamura
- Digestive Diseases Center, Showa University Koto Toyosu Hospital, Tokyo, Japan
| | | | - Haruhiro Inoue
- Digestive Diseases Center, Showa University Koto Toyosu Hospital, Tokyo, Japan
| |
Collapse
|
10
|
Li Q, Chen W, Wang C, Liu Z, Gu Y, Xu X, Xu J, Jiang T, Xu M, Wang Y, Chen C, Zhong Y, Zhang Y, Yao L, Jin G, Hu Z, Zhou P. Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia. Am J Hum Genet 2021; 108:1478-1487. [PMID: 34197731 DOI: 10.1016/j.ajhg.2021.06.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 06/02/2021] [Indexed: 11/15/2022] Open
Abstract
Idiopathic achalasia (IA) is a severe motility disorder characterized by neuronal degeneration in the myenteric plexus, but the etiology remains largely unknown. We performed whole-exome sequencing (WES) in 100 IA-affected individuals and 313 non-IA control subjects and validated the results in 230 IA-affected individuals and 1,760 non-IA control subjects. Common missense variants rs1705003 (CUTA, GenBank: NC_000006.11:g.33385953A>G) and rs1126511 (HLA-DPB1, GenBank: NC_000006.11:g.33048466G>T) at 6p21.32 were reproducibly associated with increased risk of IA (rs1126511: OR = 1.83, p = 2.34 × 10-9; rs1705003: OR = 2.37, p = 3.21 × 10-7), meeting exome-wide significance. Both variants can affect the expression of their target genes at the transcript level. An array-based association analysis in 280 affected individuals and 1,121 control subjects determined the same signal at 6p21.32. Further conditional analyses supported that the two missense variants identified in WES-based association study were potential causal variants of IA. For rare variants, the top genes identified by gene-based analysis were significantly enriched in nerve and muscle phenotypic genes in the mouse. Moreover, the functional rare variants in these genes tended to cooccur in IA-affected individuals. In an independent cohort, we successfully validated three rare variants (CREB5, GenBank: NC_000007.13:g.28848865G>T; ESYT3, GenBank: NC_000003.11:g.138183253C>T; and LPIN1, GenBank: NC_000002.11:g.11925128A>G) which heightens the risk of developing IA. Our study identified and validated two common variants and three rare variants associated with IA in immunologic and neurological genes, providing new insight into the etiology of IA.
Collapse
Affiliation(s)
- Quanlin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Weifeng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Cheng Wang
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China; Department of Bioinformatics, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing 211116, China
| | - Zuqiang Liu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yayun Gu
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Xiaoyue Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Jiaxing Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Tao Jiang
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Meidong Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yifeng Wang
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Congcong Chen
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Yunshi Zhong
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yiqun Zhang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liqing Yao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Guangfu Jin
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Center of Global Health, School of Public Health, Nanjing Medical University, Nanjing 211166, China; State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 211166, China.
| | - Pinghong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| |
Collapse
|
11
|
Huang S, Ren Y, Peng W, Gao Q, Peng Y, Gong W, Tang X. Peroral endoscopic shorter versus longer myotomy for the treatment of achalasia: a comparative retrospective study. Esophagus 2020; 17:477-483. [PMID: 32361976 DOI: 10.1007/s10388-020-00739-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Peroral esophageal myotomy (POEM) is a novel endoscopic treatment for achalasia. It has gained popularity worldwide among surgeons and endoscopists, but no studies have compared peroral endoscopic short with long myotomy for achalasia. We aimed to compare the clinical efficacy and safety between peroral endoscopic shorter and longer myotomy. METHODS The retrospective study enrolled 129 achalasia patients who underwent POEM from July 2011 to September 2017. Based on the myotomy length (ML), patients were divided into shorter myotomy (SM) group (ML ≤ 7 cm, n = 36) and longer myotomy (LM) group (ML > 7 cm, n = 74). Procedure-related parameters, symptom scores, adverse events and manometric data were compared between two groups. RESULTS The mean ML was 6.0 ± 0.6 cm in SM group, and 11.5 ± 3.1 cm in LM group (p < 0.001). The mean operation time was significantly less in SM group than LM group (46.6 ± 18.5 min vs 62.1 ± 25.2 min, p = 0.001). During a mean follow-up period of 28.7 months, treatment success (Eckardt score ≤ 3) was achieved in 94.4% (34/36) of patients in SM group and 91.9% (68/74) in LM group (p = 0.926). There was no statistical difference in the incidence of intraoperative complications (8.4% vs 8.2%, p = 0.823) and reflux rate (8.3% vs. 14.9%, p = 0.510) between two groups. CONCLUSIONS Peroral endoscopic shorter myotomy is comparable with longer myotomy for treating achalasia with regard to clinical efficacy and has the advantage of shorter procedure time.
Collapse
Affiliation(s)
- Silin Huang
- Departmemt of Gastroenterology, Shenzhen Hospital, Southern Medical University, No.1333 Xinhu Road, Baoan District, Shenzhen, 518000, China
| | - Yutang Ren
- Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Wei Peng
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Street Taiping No.25, Region Jiangyang, Luzhou, 646099, Sichuan Province, China
| | - Qiaoping Gao
- Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yan Peng
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Street Taiping No.25, Region Jiangyang, Luzhou, 646099, Sichuan Province, China
| | - Wei Gong
- Departmemt of Gastroenterology, Shenzhen Hospital, Southern Medical University, No.1333 Xinhu Road, Baoan District, Shenzhen, 518000, China.
| | - Xiaowei Tang
- Department of Gastroenterology, Affiliated Hospital of Southwest Medical University, Street Taiping No.25, Region Jiangyang, Luzhou, 646099, Sichuan Province, China.
| |
Collapse
|
12
|
Hanisch M, Wiemann S, Bohner L, Jung S, Kleinheinz J, Igelbrink S. Oral Health-Related Quality of Life in People with Achalasia. ACTA ACUST UNITED AC 2020; 56:medicina56060286. [PMID: 32545217 PMCID: PMC7353885 DOI: 10.3390/medicina56060286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/08/2020] [Accepted: 06/09/2020] [Indexed: 12/02/2022]
Abstract
Background and Objective: The oral health-related quality of life (OHRQoL) of patients with achalasia has not been evaluated to date. Therefore, the aim of this study was to assess the OHRQoL of patients with achalasia and to get information about the time taken for diagnosis and oral symptoms. Materials and Methods: The study was conceived of as an anonymous epidemiological survey study in people with achalasia in order to assess their OHRQoL in each case. For this, a questionnaire was developed consisting of free-text questions and of the standardized German version of the OHIP-14 questionnaire. Results: In total, forty-four questionnaires were analyzed including 31 female and 13 male participants. Regardless of gender, the mean age was 50.57 years (range: 17–78). Of the surveyed individuals, seventy-nine-point-five-five percent had been diagnosed between 25 and 60 years of age. The period from the first signs of the disease to diagnosis was 6.15 years, irrespective of gender. The overall OHIP-14 score without gender differentiation was 8.72 points (range 0–48); the mean score of female participants was 11.13 (range: 0–48), and the OHIP score of male participants was 3.15 on average. Two participants reported oral symptoms. Conclusions: The already known problem of the delayed diagnosis of rare diseases was also confirmed in the case of achalasia. Females with achalasia seemed to be significantly affected by lower OHRQoL than males with achalasia and women of the general population. Demineralization of the tooth structure was described in two participants.
Collapse
|
13
|
Lin S, Gao P, Li Q, Zhang Y, Hu J, Cai M, Qin W, Ma L, Ren Z, Zhang Z, Cai X, Yao L, Chen W, Zhou P. Aflatoxin influences achalasia symptomatology. Mol Med Rep 2020; 21:1276-1284. [PMID: 31922241 PMCID: PMC7002977 DOI: 10.3892/mmr.2020.10914] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Accepted: 12/06/2019] [Indexed: 12/21/2022] Open
Abstract
Achalasia is characterized by impaired swallowing due to lower esophageal sphincter (LES) dysfunction and an increased risk of esophageal carcinoma. Aflatoxin is a known carcinogen. Esophageal retention is relieved by per oral endoscopic myotomy (POEM), which lowers the esophageal cancer risk. The present study determined whether aflatoxin is involved in the pathogenesis of achalasia or esophageal cancer. A total of 75 patients with achalasia were prospectively enrolled from a tertiary center. Aflatoxin levels in their esophageal contents were measured using ELISA, and esophageal mucosal specimens were immunohistochemically evaluated for Ki67 and p53 expression prior to and 3 months after POEM. The effect of aflatoxin on esophageal contractility was assessed using murine specimens. Aflatoxin was detected in 67 patients before POEM and only 2 patients after POEM. The number of Ki67- and p53-immunopositive cells in the esophageal mucosa significantly decreased after POEM: [Ki67: 27.8% (95% confidence interval (CI), 25.98–29.70) vs. 20.7% (95% CI, 19.78–24.03), P=0.04 and p53: 2.14% (95% CI, 1.85–2.41) vs. 1.45% (95% CI, 1.22–1.68), P=0.03]. In vitro experiments revealed that 500 ng/ml aflatoxin significantly increased the amplitude (P<0.05) and frequency (P<0.05) of spontaneous LES contractions compared with the control group. These increases were blocked by co-treatment with atropine sulfate (P<0.05), but not with a nitric oxide synthase inhibitor (P>0.05). Aflatoxin was found in most patients with achalasia and was eliminated following POEM. Reduced Ki67 and p53 expression after POEM indicated a decreased risk of carcinogenesis. Aflatoxin accumulation increased LES contractility via cholinergic signaling. Therefore, aflatoxin may maintain achalasia symptoms and increase esophageal cancer risk.
Collapse
Affiliation(s)
- Shengli Lin
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Pingting Gao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Quanlin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Yiqun Zhang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Jianwei Hu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Mingyan Cai
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Wenzheng Qin
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Lili Ma
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhong Ren
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Zhen Zhang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Xianli Cai
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Liqing Yao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Weifeng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Pinghong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| |
Collapse
|
14
|
Tustumi F, Szor DJ, Sallum RAA, Cecconello I. Stem cell factor receptor gene mutation: Achalasia, mastocytosis and gastrointestinal stromal tumors. Cancer Genet 2019; 241:66. [PMID: 31780427 DOI: 10.1016/j.cancergen.2019.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 08/22/2019] [Accepted: 11/18/2019] [Indexed: 10/25/2022]
Affiliation(s)
- Francisco Tustumi
- Department of Gastroenterology. Digestive Surgery Division,University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 255, São Paulo, SP, CEP 05403-000, Brazil.
| | - Daniel José Szor
- Department of Gastroenterology. Digestive Surgery Division,University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 255, São Paulo, SP, CEP 05403-000, Brazil
| | - Rubens Antonio Aissar Sallum
- Department of Gastroenterology. Digestive Surgery Division,University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 255, São Paulo, SP, CEP 05403-000, Brazil
| | - Ivan Cecconello
- Department of Gastroenterology. Digestive Surgery Division,University of São Paulo, Av. Dr. Eneas de Carvalho Aguiar 255, São Paulo, SP, CEP 05403-000, Brazil
| |
Collapse
|
15
|
Sato H, Yokomichi H, Takahashi K, Tominaga K, Mizusawa T, Kimura N, Kawata Y, Terai S. Epidemiological analysis of achalasia in Japan using a large-scale claims database. J Gastroenterol 2019; 54:621-627. [PMID: 30607612 DOI: 10.1007/s00535-018-01544-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 12/26/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND Achalasia is a well-known esophageal motility disorder, but epidemiological studies in Japan are lacking. We investigated the incidence and period prevalence of achalasia in Japan, including the rate of coexistence of esophageal carcinoma, and evaluated treatment trends. METHODS To estimate the nationwide number of patients with achalasia, a large-scale insurance claims database from 2005 to 2017 were used for our analyses. Patients with achalasia and coexistence of esophageal carcinoma were identified based on the diagnosis code registered. Interventional treatment was also evaluated. RESULTS Of the total 5,493,650 populations, 385 were diagnosed with primary achalasia. The incidence was calculated as 0.81-1.37 per 100,000 person-years (male-to-female ratio was almost 1; mean age at diagnosis was 43.3 ± 14.4 years). The period prevalence was 7.0 per 100,000 persons. There were statistically significant trends of increase in the incidence and period prevalence over age groups (all p values < 0.0001). Four men with achalasia developed esophageal carcinoma, and the incidence of esophageal carcinoma with achalasia was estimated as 0.25 per 100 person-years. With regard to intervention, esophageal dilation was performed as a first treatment in 64.7% of patients, with repeat intervention required in 56.9% of these. The proportion of patients treated using peroral endoscopic myotomy (POEM) increased annually to 41.1% in 2017. CONCLUSIONS In Japan, the incidence and period prevalence of achalasia is comparable to that in other countries. The absolute risk of esophageal carcinoma is rather low. Esophageal dilation has been the mainstay of achalasia treatment, and the role of POEM has increased annually.
Collapse
Affiliation(s)
- Hiroki Sato
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
| | - Hiroshi Yokomichi
- Department of Health Sciences, University of Yamanashi, Chuo City, Yamanashi, Japan
| | - Kazuya Takahashi
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Kentaro Tominaga
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Takeshi Mizusawa
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Naruhiro Kimura
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Yuzo Kawata
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| |
Collapse
|
16
|
Vackova Z, Niebisch S, Triantafyllou T, Becker J, Hess T, Kreuser N, Kanoni S, Deloukas P, Schüller V, Heinrichs SKM, Thieme R, Nöthen MM, Knapp M, Spicak J, Gockel I, Schumacher J, Theodorou D, Martinek J. First genotype-phenotype study reveals HLA-DQβ1 insertion heterogeneity in high-resolution manometry achalasia subtypes. United European Gastroenterol J 2019; 7:45-51. [PMID: 30788115 PMCID: PMC6374847 DOI: 10.1177/2050640618804717] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 09/03/2018] [Indexed: 12/11/2022] Open
Abstract
Background Achalasia is a primary oesophageal motility disorder. Although aetiology remains mainly unknown, a genetic risk variant, rs28688207 in HLA-DQB1, showed strong achalasia association suggesting involvement of immune-mediated processes in the pathogenesis. High-resolution manometry recognises three types of achalasia. The aim of our study was to perform the first genotype-phenotype analysis investigating the frequency of rs28688207 across the high-resolution manometry subtypes. Methods This was a cross-sectional retrospective study. Achalasia patients from tertiary centres in the Czech Republic (n = 163), Germany (n = 114), Greece (n = 70) and controls were enrolled. All subjects were genotyped for the rs28688207 insertion. The Kruskal-Wallis test was used for the genotype-phenotype analysis. Results A total of 347 achalasia patients (type I - 89, II - 210, III - 48) were included. The overall frequency of the rs28688207 was 10.3%. The distribution of the insertion was significantly different across the high-resolution manometry subtypes (p = 0.038), being most prevalent in type I (14.6%), followed by type II (9.5%) and III (6.3%). Conclusion The frequency of the HLA-DQB1 insertion differs among high-resolution manometry achalasia subtypes. The insertion is most prevalent in type I, suggesting that immune-mediated mechanisms triggered by the insertion may play a more prominent role in the pathogenesis of this subtype.
Collapse
Affiliation(s)
- Zuzana Vackova
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Stefan Niebisch
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Tania Triantafyllou
- Foregut Surgery Department, Hippokration General Hospital of Athens, Athens, Greece
| | - Jessica Becker
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, University of Bonn, Bonn, Germany
| | - Timo Hess
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, University of Bonn, Bonn, Germany
| | - Nicole Kreuser
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Stavroula Kanoni
- William Harvey Research Institute, University of London, London, UK
| | - Panos Deloukas
- William Harvey Research Institute, University of London, London, UK
| | - Vitalia Schüller
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, University of Bonn, Bonn, Germany
| | - Sophie KM Heinrichs
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, University of Bonn, Bonn, Germany
| | - René Thieme
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Markus M Nöthen
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, University of Bonn, Bonn, Germany
| | - Michael Knapp
- Institute for Medical Biometry, Informatics and Epidemiology (IMBIE), University of Bonn, Bonn, Germany
| | - Julius Spicak
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | - Johannes Schumacher
- Institute of Human Genetics, University of Bonn, Bonn, Germany
- Department of Genomics, University of Bonn, Bonn, Germany
| | - Dimitris Theodorou
- Foregut Surgery Department, Hippokration General Hospital of Athens, Athens, Greece
| | - Jan Martinek
- Department of Hepatogastroenterology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Institute of Physiology, Charles University in Prague, Prague, Czech Republic
- Faculty of Medicine, Ostrava University, Ostrava, Czech Republic
| |
Collapse
|
17
|
Vona B, Maroofian R, Bellacchio E, Najafi M, Thompson K, Alahmad A, He L, Ahangari N, Rad A, Shahrokhzadeh S, Bahena P, Mittag F, Traub F, Movaffagh J, Amiri N, Doosti M, Boostani R, Shirzadeh E, Haaf T, Diodato D, Schmidts M, Taylor RW, Karimiani EG. Expanding the clinical phenotype of IARS2-related mitochondrial disease. BMC MEDICAL GENETICS 2018; 19:196. [PMID: 30419932 PMCID: PMC6233262 DOI: 10.1186/s12881-018-0709-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 10/25/2018] [Indexed: 11/20/2022]
Abstract
BACKGROUND IARS2 encodes a mitochondrial isoleucyl-tRNA synthetase, a highly conserved nuclear-encoded enzyme required for the charging of tRNAs with their cognate amino acid for translation. Recently, pathogenic IARS2 variants have been identified in a number of patients presenting broad clinical phenotypes with autosomal recessive inheritance. These phenotypes range from Leigh and West syndrome to a new syndrome abbreviated CAGSSS that is characterised by cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, as well as cataract with no additional anomalies. METHODS Genomic DNA from Iranian probands from two families with consanguineous parental background and overlapping CAGSSS features were subjected to exome sequencing and bioinformatics analysis. RESULTS Exome sequencing and data analysis revealed a novel homozygous missense variant (c.2625C > T, p.Pro909Ser, NM_018060.3) within a 14.3 Mb run of homozygosity in proband 1 and a novel homozygous missense variant (c.2282A > G, p.His761Arg) residing in an ~ 8 Mb region of homozygosity in a proband of the second family. Patient-derived fibroblasts from proband 1 showed normal respiratory chain enzyme activity, as well as unchanged oxidative phosphorylation protein subunits and IARS2 levels. Homology modelling of the known and novel amino acid residue substitutions in IARS2 provided insight into the possible consequence of these variants on function and structure of the protein. CONCLUSIONS This study further expands the phenotypic spectrum of IARS2 pathogenic variants to include two patients (patients 2 and 3) with cataract and skeletal dysplasia and no other features of CAGSSS to the possible presentation of the defects in IARS2. Additionally, this study suggests that adult patients with CAGSSS may manifest central adrenal insufficiency and type II esophageal achalasia and proposes that a variable sensorineural hearing loss onset, proportionate short stature, polyneuropathy, and mild dysmorphic features are possible, as seen in patient 1. Our findings support that even though biallelic IARS2 pathogenic variants can result in a distinctive, clinically recognisable phenotype in humans, it can also show a wide range of clinical presentation from severe pediatric neurological disorders of Leigh and West syndrome to both non-syndromic cataract and cataract accompanied by skeletal dysplasia.
Collapse
Affiliation(s)
- Barbara Vona
- Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany
- Department of Otorhinolaryngology, Head and Neck Surgery, Tübingen Hearing Research Centre (THRC), Eberhard Karls University Tübingen, 72076 Tübingen, Germany
| | - Reza Maroofian
- Genetics and Molecular Cell Sciences Research Centre, St George’s, University of London, Cranmer Terrace, London, SW17 0RE UK
| | - Emanuele Bellacchio
- Genetics and Rare Diseases, Research Division, ‘Bambino Gesù’ Children Hospital, Rome, Italy
| | - Maryam Najafi
- Genome Research Division, Human Genetics Department, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525KL, Nijmegen, The Netherlands
| | - Kyle Thompson
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Ahmad Alahmad
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Langping He
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Najmeh Ahangari
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Next Generation Genetic Clinic, Mashhad, Iran
| | - Abolfazl Rad
- Genome Research Division, Human Genetics Department, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525KL, Nijmegen, The Netherlands
- Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
| | | | - Paulina Bahena
- Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany
| | - Falk Mittag
- Department of Orthopaedic Surgery, University Hospital of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany
| | - Frank Traub
- Department of Orthopaedic Surgery, University Hospital of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany
| | - Jebrail Movaffagh
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, University of Medical Sciences, Mashhad, Iran
| | - Nafise Amiri
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, University of Medical Sciences, Mashhad, Iran
| | | | - Reza Boostani
- Department of Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Thomas Haaf
- Institute of Human Genetics, Julius Maximilians University Würzburg, Würzburg, Germany
| | - Daria Diodato
- Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, ‘Bambino Gesu’ Children’s Research Hospital, Rome, Italy
| | - Miriam Schmidts
- Genome Research Division, Human Genetics Department, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Geert Grooteplein Zuid 10, 6525KL, Nijmegen, The Netherlands
- Center for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Faculty of Medicine, Mathildenstrasse 1, 79112 Freiburg, Germany
| | - Robert W. Taylor
- Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Ehsan Ghayoor Karimiani
- Genetics and Molecular Cell Sciences Research Centre, St George’s, University of London, Cranmer Terrace, London, SW17 0RE UK
- Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
18
|
Wang Z, Zhang J, Mi J, Ma H, Zhao D. Expression and significance of interleukin-17 and interleukin-22 in the serum and the lower esophageal sphincter of patients with achalasia. Saudi J Gastroenterol 2018; 24:242-248. [PMID: 29806597 PMCID: PMC6080156 DOI: 10.4103/sjg.sjg_562_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background/Aim : We studied the expression of interleukin-17 and interleukin-22 in the serum and the lower esophageal sphincter (LES) in healthy individuals and in patients diagnosed with achalasia (AC) to gain a better understanding of the etiopathogenesis of AC. Patients and Methods Our study comprised 14 randomly selected patients with AC who underwent peroral endoscopic myotomy and 14 randomly selected healthy individuals who served as controls. Venous blood samples were evaluated in all study subjects to detect the expression of interleukin-17 and interleukin-22 in the serum using an enzyme-linked immunosorbent assay. Immunohistochemistry studies were performed to evaluate LES myofilaments obtained from both groups, as well as from 12 patients diagnosed with a subendothelial non-invasive tumor and who had undergone submucosal tunneling endoscopic resection, to assess the expression of interleukin-17 and interleukin-22 in LES myofilaments. Results Compared with that in the control group, the expression of interleukin-17 and interleukin-22 in the serum and LES, in patients with AC, was significantly increased and was positively correlated. Conclusion Interleukin-17 and interleukin-22 are upregulated in the serum and LES in patients with AC, suggesting that both interleukin-17 and interleukin-22 are involved in the pathogenesis of AC, and that AC may be an immune-mediated inflammatory disease.
Collapse
Affiliation(s)
- Zeyu Wang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jun Zhang
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Jianwei Mi
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Huihui Ma
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Dongqiang Zhao
- Department of Gastroenterology, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
19
|
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.
Collapse
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
| |
Collapse
|
20
|
Sato H, Takahashi K, Mizuno KI, Hashimoto S, Yokoyama J, Hasegawa G, Terai S. Esophageal motility disorders: new perspectives from high-resolution manometry and histopathology. J Gastroenterol 2018; 53:484-493. [PMID: 29134329 DOI: 10.1007/s00535-017-1413-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Accepted: 11/09/2017] [Indexed: 02/04/2023]
Abstract
High-resolution manometry (HRM) and peroral endoscopic myotomy (POEM) have contributed significantly to the field of esophageal motility disorders in recent years. The development of HRM has categorized various esophageal motility disorders with a focus on a diverse range of manometric anomalies. Additionally, the Chicago classification criteria is widely used for manometric diagnosis. Moreover, POEM was introduced as a minimally invasive radical therapy for achalasia and shows promise for other spastic esophageal motility disorders as well. POEM has also enabled a transluminal endoscopic approach for determining the histology of the esophageal muscle layer, which is expected to assist in elucidating the etiology of disorders associated with esophageal motility. The purpose of this review is to update the diagnosis, pathology, and treatment of esophageal motility disorders, with a focus on the recent advances in this field.
Collapse
Affiliation(s)
- Hiroki Sato
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan.
| | - Kazuya Takahashi
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Ken-Ichi Mizuno
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Satoru Hashimoto
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Junji Yokoyama
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| | - Go Hasegawa
- Division of Cellular and Molecular Pathology, Department of Cellular Function, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Medical and Dental Hospital, 757-1, Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8510, Japan
| |
Collapse
|
21
|
Schlottmann F, Neto RML, Herbella FAM, Patti MG. Esophageal Achalasia: Pathophysiology, Clinical Presentation, and Diagnostic Evaluation. Am Surg 2018. [DOI: 10.1177/000313481808400415] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Esophageal achalasia is a primary esophageal motility disorder characterized by the absence of esophageal peristalsis and failure of the lower esophageal sphincter to relax in response to swallowing. These abnormalities lead to impaired emptying of food from the esophagus into the stomach with resulting food stasis. Most patients experience severe dysphagia, and regurgitation can lead to aspiration and respiratory problems. Consequently, the quality of life of patients affected by achalasia is severely impacted. A thorough evaluation with upper endoscopy, barium swallow, and esophageal manometry is mandatory to establish the diagnosis and plan the optimal treatment. In selected patients, an ambulatory pH monitoring is recommended to distinguish between gastroesophageal reflux disease and achalasia.
Collapse
Affiliation(s)
- Francisco Schlottmann
- Department of Medicine and Surgery, University of North Carolina, Chapel Hill, North Carolina and
| | - Rafael M. L. Neto
- Department of Surgery, Escola Paulista de Medicina, Federal University of Sao Paulo, Sao Paulo, Brazil
| | - Fernando A. M. Herbella
- Department of Surgery, Escola Paulista de Medicina, Federal University of Sao Paulo, Sao Paulo, Brazil
| | - Marco G. Patti
- Department of Medicine and Surgery, University of North Carolina, Chapel Hill, North Carolina and
| |
Collapse
|
22
|
Gockel I, Rabe SM, Niebisch S. Before and after Esophageal Surgery: Which Information Is Needed from the Functional Laboratory? Visc Med 2018; 34:116-121. [PMID: 29888240 PMCID: PMC5981625 DOI: 10.1159/000486556] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Indications for benign esophageal surgery and postoperative follow-up need to be highly elaborated with differentiated and structured algorithms, based on objective functional workup in the esophageal laboratory. Functional outcome is of utmost interest and has to be driven by the need for comprehensive but purposeful diagnostic methods. METHODS Preoperative diagnostic workup procedures by the functional laboratory include 24-h pH-monitoring, impedance testing, and high-resolution manometry (HRM) - in addition to upper gastrointestinal endoscopy and barium swallow/timed barium esophagogram. RESULTS The most frequent indications for benign esophageal surgery are gastroesophageal reflux disease and achalasia; quite rare indications are esophageal diverticula and benign tumors. Esophageal motility testing in addition to 24-h pH-monitoring is crucial before antireflux surgery (ARS) in order to rule out ineffective esophageal motility and to tailor the wrap. With respect to achalasia surgery, the exact type of achalasia (I-III) has to be labeled according to the Chicago classification, and other motility disorders have to be excluded. The postoperative functional evaluation in the early phase (6 months) after either ARS or Heller's myotomy serves as the new baseline motility testing in case of later occurring disturbances in the follow-up. CONCLUSION A complete and proper preoperative esophageal function assessment is crucial in order to rule out a primary motility disorder and to avoid postoperative functional complications.
Collapse
Affiliation(s)
- Ines Gockel
- Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| | | | | |
Collapse
|
23
|
Schlottmann F, Herbella F, Allaix ME, Patti MG. Modern management of esophageal achalasia: From pathophysiology to treatment. Curr Probl Surg 2018; 55:10-37. [DOI: 10.1067/j.cpsurg.2018.01.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
24
|
Tang X, Gong W, Deng Z, Zhou J, Ren Y, Zhang Q, Chen Z, Jiang B. Feasibility and safety of peroral endoscopic myotomy for achalasia after failed endoscopic interventions. Dis Esophagus 2017; 30:1-6. [PMID: 27878898 DOI: 10.1111/dote.12457] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
With advances in natural orifice transluminal endoscopic surgery, peroral endoscopic myotomy (POEM) has become a novel treatment for esophageal achalasia. In this study, we investigated the feasibility and safety of POEM in patients with achalasia after failed endoscopic interventions. Data on all patients undergoing POEM treatment of achalasia were collected prospectively. We enrolled 61 patients who underwent POEM for achalasia between July 2011 and January 2014. The preoperative intervention group included patients who had undergone botulinum toxin injection or pneumatic balloon dilation before POEM. The preoperative, operative, and short-term outcome data between the groups were compared. Among preoperative intervention group, 22 patients received endoscopic therapy before being referred for operation (18 dilation only, 2 botulinum toxin only, and 2 both treatments). Procedure time in the preoperative intervention group was similar to the nonpreoperative intervention group (60.8 ± 30.9 vs. 62.0 ± 21.0 minutes, P = 0.863). Both groups demonstrated significant improvement in Eckardt scores and manometric outcomes at 1-year follow-up. There were no significant differences in pretreatment and posttreatment D-values of symptom scores and lower esophageal sphincter pressures between groups (6.2 ± 2.2 vs. 6.1 ± 1.8, P = 0.840; 27.9 ± 17.6 vs. 24.9 ± 15.2; P = 0.569). There was also no significant difference in the incidence of intraoperative complications (P = 0.958) and gastroesophageal reflux rate (23.5% vs. 20.0%, P = 0.771) between the two groups. Our study demonstrated that POEM is safe and effective, even for treating achalasia in the setting of failed endoscopic interventions.
Collapse
Affiliation(s)
- X Tang
- Department of Gastroenterology, Guangdong Provincial key laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, Beijing, China
| | - W Gong
- Department of Gastroenterology, Guangdong Provincial key laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Z Deng
- Department of Gastroenterology, Guangdong Provincial key laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - J Zhou
- Department of Gastroenterology, Guangdong Provincial key laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, Beijing, China
| | - Y Ren
- Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, Beijing, China
| | - Q Zhang
- Department of Gastroenterology, Guangdong Provincial key laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Z Chen
- Department of Gastroenterology, Guangdong Provincial key laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - B Jiang
- Department of Gastroenterology, Guangdong Provincial key laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.,Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University, Beijing, China
| |
Collapse
|
25
|
Gockel HR, Lesse M, Schumacher J, Müller M, Gockel I. Esophagus-Related Symptoms in First-Degree Relatives of Patients with Achalasia: Is Screening Necessary? Visc Med 2016; 32:369-374. [PMID: 27921050 DOI: 10.1159/000445790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Despite an increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia, its association with well-defined genetic syndromes, the candidate gene approach, and recent presentation of the first systematic genome-wide association study on achalasia suggest the involvement of genetic factors. METHODS In this study we analyzed the frequency with which symptoms associated with esophageal function (swallowing difficulties, regurgitations, retrosternal cramps/pain, heartburn) occur in first-degree relatives of patients with achalasia to determine if screening is useful and justified against the background of early diagnosis in a genetically predisposed population. The survey of data was carried out in 759 relatives of the 359 achalasia patients included in this study by means of structured interviews. RESULTS Swallowing difficulties as the principal symptom of achalasia were found to occur at least occasionally in 11.2% of first-degree relatives. In comparison with the prevalence of dysphagia in the general population of 7-10% up to 22%, as described in the literature, the frequency of swallowing difficulties does not seem to be increased in our population of relatives. CONCLUSION Screening measures do not appear to be justified in spite of the potential genetic background of achalasia.
Collapse
Affiliation(s)
- Henning R Gockel
- Institute of Human Genetics, Life and Brain, University of Bonn, Bonn, Germany
| | - Moritz Lesse
- Clinic of Internal Medicine, Dr. Horst Schmidt-Klinik (HSK Helios-Klinik), Wiesbaden, Germany
| | - Johannes Schumacher
- Institute of Human Genetics, Life and Brain, University of Bonn, Bonn, Germany
| | - Michaela Müller
- Department of Gastroenterology, German Clinic for Diagnostics (DKD Helios-Klink), Wiesbaden, Germany
| | - Ines Gockel
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany
| |
Collapse
|
26
|
Ren Y, Tang X, Chen Y, Chen F, Zou Y, Deng Z, Wu J, Li Y, Huang S, Jiang B, Gong W. Pre-treatment Eckardt score is a simple factor for predicting one-year peroral endoscopic myotomy failure in patients with achalasia. Surg Endosc 2016; 31:3234-3241. [PMID: 27864723 DOI: 10.1007/s00464-016-5352-5] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Accepted: 11/09/2016] [Indexed: 02/05/2023]
Affiliation(s)
- Yutang Ren
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, Medical Center, Tsinghua University, Beijing, China
| | - Xiaowei Tang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Gastroenterology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China
| | - Yanmin Chen
- Department of Gastroenterology, First People's Hospital of Yunnan Province, Kunming, China
| | - Fengping Chen
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yingying Zou
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiliang Deng
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jianuan Wu
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yan Li
- Department of Gastroenterology, First People's Hospital of Yunnan Province, Kunming, China
| | - Silin Huang
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bo Jiang
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, Medical Center, Tsinghua University, Beijing, China
| | - Wei Gong
- Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| |
Collapse
|
27
|
Tang X, Gong W, Deng Z, Zhou J, Ren Y, Zhang Q, Chen Z, Jiang B. Comparison of conventional versus Hybrid knife peroral endoscopic myotomy methods for esophageal achalasia: a case-control study. Scand J Gastroenterol 2016. [PMID: 26212517 DOI: 10.3109/00365521.2015.1059878] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Peroral endoscopic myotomy (POEM) has been developed to treat achalasia as a novel less invasive modality. We aimed to compare the efficacy and safety of conventional knife versus Hybrid knife (HK) during POEM procedure. MATERIALS AND METHODS Between June 2012 and July 2014, 31 patients underwent POEM using HK in our department (HK group), and 36 patients underwent POEM using conventional method (injection needle and triangular tip [TT] knife, TT group). Procedure-related parameters, symptom relief, adverse events were compared between two groups. RESULTS There were no significant differences in the age, sex and other baseline characteristics between the two groups. The mean procedural time was significantly shorter in HK group than TT group (53.0 ± 17.2 vs. 67.6 ± 28.4 min, p = 0.015). The mean frequency of devices exchange was 4.7 ± 1.7 in HK group and 10.9 ± 1.8 in TT group (p = 0.000). No serious adverse events occurred postoperatively in both groups. At one-year follow-up, a total of 94% treatment success was achieved in all patients (93.5% in HK group and 94.4% in TT group, p = 0.877). CONCLUSION HK in POEM can shorten the procedural time, and achieve similar treatment success compared to conventional TT knife.
Collapse
Affiliation(s)
- Xiaowei Tang
- a 1 Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China.,b 2 Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University , Beijing, China
| | - Wei Gong
- a 1 Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Zhiliang Deng
- a 1 Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Jieqiong Zhou
- a 1 Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China.,b 2 Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University , Beijing, China
| | - Yutang Ren
- b 2 Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University , Beijing, China
| | - Qiang Zhang
- a 1 Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Zhenyu Chen
- a 1 Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China
| | - Bo Jiang
- a 1 Department of Gastroenterology, Nanfang Hospital, Southern Medical University , Guangzhou, China.,b 2 Departmemt of Gastroenterology, Beijing Tsinghua Changgung Hospital Medical Center, Tsinghua University , Beijing, China
| |
Collapse
|
28
|
Tebaibia A, Boudjella MA, Boutarene D, Benmediouni F, Brahimi H, Oumnia N. Incidence, clinical features and para-clinical findings of achalasia in Algeria: Experience of 25 years. World J Gastroenterol 2016; 22:8615-8623. [PMID: 27784974 PMCID: PMC5064043 DOI: 10.3748/wjg.v22.i38.8615] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Revised: 07/06/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the incidence of achalasia in Algeria and to determine its clinical and para-clinical profile. To evaluate the impact of continuing medical education (CME) on the incidence of this disease.
METHODS From 1990 to 2014, 1256 patients with achalasia were enrolled in this prospective study. A campaign of CME on diagnosis involving different regions of the country was conducted between 1999 and 2003. Annual incidence and prevalence were calculated by relating the number of diagnosed cases to 105 inhabitants. Each patient completed a standardized questionnaire, and underwent upper endoscopy, barium swallow and esophageal manometry. We systematically looked for Allgrove syndrome and familial achalasia.
RESULTS The mean annual incidence raised from 0.04 (95%CI: 0.028-0.052) during the 1990s to 0.27/105 inhabitants/year (95%CI: 0.215-0.321) during the 2000s. The incidence of the disease was two and half times higher in the north and the center compared to the south of the country. One-hundred-and-twenty-nine (10%) were children and 97 (7.7%) had Allgrove syndrome. Familial achalasia was noted in 18 different families. Patients had dysphagia (99%), regurgitation (83%), chest pain (51%), heartburn 24.5% and weight loss (70%). The lower esophageal sphincter was hypertensive in 53% and hypotensive in 0.6%.
CONCLUSION The mean incidence of achalasia in Algeria is at least 0.27/105 inhabitants. A good impact on the incidence of CME was noted. A gradient of incidence between different regions of the country was found. This variability is probably related to genetic and environmental factors. The discovery of an infantile achalasia must lead to looking for Allgrove syndrome and similar cases in the family.
Collapse
|
29
|
Vaezi MF, Felix VN, Penagini R, Mauro A, de Moura EGH, Pu LZCT, Martínek J, Rieder E. Achalasia: from diagnosis to management. Ann N Y Acad Sci 2016; 1381:34-44. [DOI: 10.1111/nyas.13176] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/09/2016] [Accepted: 06/14/2016] [Indexed: 12/16/2022]
Affiliation(s)
- Michael F. Vaezi
- Division of Gastroenterology, Hepatology, and Nutrition, Center for Swallowing and Esophageal Disorders; Vanderbilt University Medical Center; Nashville Tennessee
| | - Valter N. Felix
- FMUSP and Nucleus of General and Specialized Surgery; Sao Paulo Brazil
| | - Roberto Penagini
- Gastroenterology and Endoscopy Unit; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation, Università degli Studi; Milan Italy
| | - Aurelio Mauro
- Gastroenterology and Endoscopy Unit; Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, and Department of Pathophysiology and Transplantation, Università degli Studi; Milan Italy
| | - Eduardo Guimarães Hourneaux de Moura
- Gastrointestinal Endoscopy Unit, Department of Gastrointestinal Surgery; Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo; São Paulo Brazil
| | - Leonardo Zorrón Cheng Tao Pu
- Gastrointestinal Endoscopy Unit, Department of Gastrointestinal Surgery; Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo; São Paulo Brazil
| | - Jan Martínek
- Department of Hepatogastroenterology; IKEM; Prague Czech Republic
| | - Erwin Rieder
- Department of Surgery; Medical University of Vienna; Vienna Austria
| |
Collapse
|
30
|
Sarnelli G, Grosso M, Palumbo I, Pesce M, D'Alessandro A, Zaninotto G, Annese V, Petruzzelli R, Izzo P, Sepulveres R, Bruzzese D, Esposito G, Cuomo R. Allele-specific transcriptional activity of the variable number of tandem repeats of the inducible nitric oxide synthase gene is associated with idiopathic achalasia. United European Gastroenterol J 2016; 5:200-207. [PMID: 28344787 DOI: 10.1177/2050640616648870] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2016] [Accepted: 04/15/2016] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Polymorphisms of genes involved in the regulation of the immune response are risk factors for achalasia, but their contribution to disease pathogenesis is unknown. Nitric oxide is involved both in immune function and inhibitory neurotransmission. OBJECTIVE The objective of this article is to assess the association and the functional relevance of the CCTTT-inducible nitric oxide synthase (NOS2) gene promoter polymorphism in achalasia. METHODS Genomic DNA was isolated from 181 achalasia patients and 220 controls. Genotyping of the (CCTTT)n repeats was performed by PCR and capillary electrophoresis, and data analyzed by considering the frequency of the different alleles. HT29 cells were transfected with iNOS luciferase promoter-reporter plasmids containing different (CCTTT)n. RESULTS The alleles' distribution ranged from 7 to 18, with a peak frequency at 12 repeats. Analysis of the allele frequencies revealed that individuals carrying 10 and 13 CCTTT repeats were respectively less and more frequent in achalasia (OR 0.5, 95% CI 0.3-0.5 and OR 1.6, 95% CI 1-2.4, all p < 0.05). Long repeats were also significantly associated with an earlier onset of the disease (OR 1.69, 95% CI 1.13-2.53, p = 0.01). Transfection experiments revealed a similar allele-specific iNOS transcriptional activity. CONCLUSION The functional polymorphism (CCTTT) of NOS2 promoter is associated with achalasia, likely by an allele-specific modulation of nitric oxide production.
Collapse
Affiliation(s)
- Giovanni Sarnelli
- Gastroenterology Unit, Department of Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Michela Grosso
- Department of Biochemistry and Medical Biotechnology, University Federico II, Naples, Italy
| | - Ilaria Palumbo
- Gastroenterology Unit, Department of Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Marcella Pesce
- Gastroenterology Unit, Department of Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Alessandra D'Alessandro
- Gastroenterology Unit, Department of Clinical Medicine and Surgery University Federico II, Naples, Italy
| | - Giovanni Zaninotto
- Imperial College-St Mary's Hospital, Department of Academic Surgery, London, UK
| | - Vito Annese
- Unit of Gastroenterology SOD2, Azienda Ospedaliera Universitaria, Careggi, Firenze, Italy
| | - Raffaella Petruzzelli
- Department of Biochemistry and Medical Biotechnology, University Federico II, Naples, Italy
| | - Paola Izzo
- Department of Biochemistry and Medical Biotechnology, University Federico II, Naples, Italy
| | - Rossana Sepulveres
- Department of Biochemistry and Medical Biotechnology, University Federico II, Naples, Italy
| | - Dario Bruzzese
- Department of Public Health, University Federico II, Naples, Italy
| | - Giuseppe Esposito
- Department of Physiology and Pharmacology, "La Sapienza" University of Rome, Italy
| | - Rosario Cuomo
- Gastroenterology Unit, Department of Clinical Medicine and Surgery University Federico II, Naples, Italy
| |
Collapse
|
31
|
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.
Collapse
|
32
|
Esposito D, Maione F, D’Alessandro A, Sarnelli G, De Palma GD. Endoscopic treatment of esophageal achalasia. World J Gastrointest Endosc 2016; 8:30-39. [PMID: 26839644 PMCID: PMC4724029 DOI: 10.4253/wjge.v8.i2.30] [Citation(s) in RCA: 5] [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: 06/27/2015] [Revised: 09/19/2015] [Accepted: 12/15/2015] [Indexed: 02/05/2023] Open
Abstract
Achalasia is a motility disorder of the esophagus characterized by dysphagia, regurgitation of undigested food, chest pain, weight loss and respiratory symptoms. The most common form of achalasia is the idiopathic one. Diagnosis largely relies upon endoscopy, barium swallow study, and high resolution esophageal manometry (HRM). Barium swallow and manometry after treatment are also good predictors of success of treatment as it is the residue symptomatology. Short term improvement in the symptomatology of achalasia can be achieved with medical therapy with calcium channel blockers or endoscopic botulin toxin injection. Even though few patients can be cured with only one treatment and repeat procedure might be needed, long term relief from dysphagia can be obtained in about 90% of cases with either surgical interventions such as laparoscopic Heller myotomy or with endoscopic techniques such pneumatic dilatation or, more recently, with per-oral endoscopic myotomy. Age, sex, and manometric type by HRM are also predictors of responsiveness to treatment. Older patients, females and type II achalasia are better after treatment compared to younger patients, males and type III achalasia. Self-expandable metallic stents are an alternative in patients non responding to conventional therapies.
Collapse
|
33
|
The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north-south gradient among Europeans. Eur J Hum Genet 2016; 24:1228-31. [PMID: 26733285 DOI: 10.1038/ejhg.2015.262] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 10/26/2015] [Accepted: 11/15/2015] [Indexed: 12/14/2022] Open
Abstract
Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10(-04), Sweden P=7.44 × 10(-05)). Combining all five European data sets - Central Europe, Italy, Spain, Poland and Sweden - the insertion is achalasia associated with Pcombined=1.67 × 10(-35). In addition, we observe that the frequency of the insertion shows a geospatial north-south gradient. The insertion is less common in northern (around 6-7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.
Collapse
|
34
|
Tebaibia A, Boudjella MA, Boutarene D, Benmediouni F, Brahimi H, Oumnia N. Incidence, clinical features and para-clinical findings of achalasia in Algeria: Experience of 25 years. World J Gastroenterol 2016; 22:8615. [DOI: https:/doi.org/10.3748/wjg.v22.i38.8615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2023] Open
|
35
|
Hernández Mondragón OV, Rascón Martínez DM, Muñoz Bautista A, Altamirano Castañeda ML, Blanco-Velasco G, Blancas Valencia JM. The Per Oral Endoscopic Myotomy (POEM) technique: how many preclinical procedures are needed to master it? Endosc Int Open 2015; 3:E559-65. [PMID: 26716112 PMCID: PMC4683141 DOI: 10.1055/s-0034-1392807] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 07/13/2015] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND AND STUDY AIM Per oral endoscopic myotomy (POEM) is a complex technique used in achalasia. Preclinical training is essential but little is known about the number of procedures needed. The aim of this study was to determine the number of procedures required to master POEM in an animal model. PATIENTS AND METHODS This prospective comparative study was conducted in two swine models at a single institution in Mexico City between November 2012 and October 2014: Group 1 (G1) = 30 ex vivo and Group 2 (G2) = 20 live swine models. POEM was mastered after finishing the five steps without complications. Time, characteristics, and complications were recorded. Velocity of tunnelization and myotomy (VTM) was determined. Ex vivo analysis was done in G1 immediately after finishing POEM and at day 30 in G2. RESULTS A total of 50 POEM were done in both groups (G1 = 30, G2 = 20). The mean times were 90.17 min (G1) and 89.50 min (G2) (P = 0.92). Myotomy was faster in G2 (21.10 vs 27.97 min; P = 0.009) with a slightly slower tunnelization (40.35 vs 41.13 min; P = 0.86). Myotomy was longer in G2 (9.25 vs 8.83 cm; P = 0.26). VTM between the groups was similar (G1 = 0.159 vs G2 = 0.157 cm/min; P = 0.925). Complications were: mucosotomy (G1 = 18 %, G2 = 8 %; P = 0.430), mediastinal perforation (G1 = 12 %, G2 = 8 %; P = 1.0), and perforation at the gastroesophageal junction (GEJ) level (G1 = 16 %, G2 = 4 %; P = 0.149). Seven models in G2 presented minor bleeding and there was one death not attributed to the procedure. Mastery was obtained after 26 cases. CONCLUSIONS We suggest that centers interested in learning POEM consider 26 procedures in animal models to master it before performing it in patients with achalasia.
Collapse
Affiliation(s)
- Oscar Víctor Hernández Mondragón
- Department of Endoscopy, Specialties Hospital, National Medical Center Century XXI, Mexico City, Mexico,Corresponding author Oscar Víctor Hernández Mondragón Department of EndoscopySpecialties HospitalNational Medical Center Century XXICuauhtémoc Avenue 33006700 Mexico CityMexico+52-555-5752379
| | - Dulce Maria Rascón Martínez
- Department of Anesthesiology and Biostatistics, Specialties Hospital, National Medical Center Century XXI, Mexico City, Mexico
| | - Aracely Muñoz Bautista
- Department of Veterinarian Surgery, Specialties Hospital, National Medical Center Century XXI, Mexico City, Mexico
| | | | - Gerardo Blanco-Velasco
- Department of Endoscopy, Specialties Hospital, National Medical Center Century XXI, Mexico City, Mexico
| | | |
Collapse
|
36
|
Singh R, Ghoshal UC, Misra A, Mittal B. Achalasia Is Associated With eNOS4a4a, iNOS22GA, and nNOS29TT Genotypes: A Case-control Study. J Neurogastroenterol Motil 2015; 21:380-9. [PMID: 26088023 PMCID: PMC4496906 DOI: 10.5056/jnm14123] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2014] [Revised: 01/25/2015] [Accepted: 01/25/2015] [Indexed: 12/16/2022] Open
Abstract
Background/Aims Achalasia is known to result from degeneration of inhibitory neurons, which are mostly nitrinergic. Characteristic features of achalasia include incomplete lower esophageal sphincter (LES) relaxation and esophageal aperistalsis. Nitric oxide (NO), produced by NO synthase (NOS), plays an important role in peristalsis and LES relaxation. Therefore, we evaluated genetic polymorphisms of NOS gene isoforms (endothelial NOS [eNOS], inducible NOS [iNOS], and neuronal NOS [nNOS]) in patients with achalasia and healthy subjects (HS). Methods Consecutive patients with achalasia (diagnosed using esophageal manometry) and HS were genotyped for 27-base pair (bp) eNOS variable number of tandem repeats (VNTR), iNOS22G/A (rs1060826), nNOS C/T (rs2682826) polymorphisms by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (RFLP), respectively. Results Among 183 patients (118 [64.5%] male, age 39.5 ± 13.0 years) with achalasia and 366 HS (254 [69.4%] male, age 40.8 ± 11.0 years), eNOS4a4a genotype of 27-bp VNTR was more common among achalasia than HS (20 [10.9%] vs 13 [3.6%]; P < 0.001; OR, 3.72; 95% CI, 1.8–7.7). Patients with achalasia had iNOS22GA genotypes more often than HS (95 [51.9%] vs 93 [25.4%]; P < 0.001; OR, 3.0; 95% CI, 2.1–4.4). Frequency of genotypes GA + AA was higher in patients than HS (97 [53%] vs 107 [29.2%]; P < 0.001; OR, 2.7; 95% CI, 1.8–3.9). Also, nNOS29TT variant genotype in rs2682826 was more common among patients compared to HS (14 [7.7%] vs 6 [1.6%]; P < 0.001; OR, 5.91; 95% CI, 2.2–15.8). Conclusions Achalasia is associated with eNOS4a4a, iNOS22GA, and nNOS29TT genotypes. This may suggest that polymorphisms of eNOS, iNOS, and nNOS genes are risk factors for achalasia.
Collapse
Affiliation(s)
- Rajan Singh
- Departments of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Uday C Ghoshal
- Departments of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Asha Misra
- Departments of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| | - Balraj Mittal
- Departments of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
| |
Collapse
|
37
|
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.
Collapse
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:
| | | | | | | | | | | | | |
Collapse
|
38
|
Hernández-Mondragón OV, González-Martínez MA, Blancas-Valencia JM, Altamirano-Castañeda ML, Muñoz-Bautista A. Peroral endoscopic myotomy in achalasia: Report on the first case performed in Mexico. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2015; 80:165-6. [PMID: 26112371 DOI: 10.1016/j.rgmx.2015.01.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 12/19/2014] [Accepted: 01/09/2015] [Indexed: 10/23/2022]
Affiliation(s)
- O V Hernández-Mondragón
- Departamento de Endoscopía, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México.
| | - M A González-Martínez
- Departamento de Endoscopía, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México
| | - J M Blancas-Valencia
- Departamento de Endoscopía, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México
| | - M L Altamirano-Castañeda
- Departamento de Endoscopía, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México
| | - A Muñoz-Bautista
- Departamento de Endoscopía, Hospital de Especialidades del Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México D.F., México
| |
Collapse
|
39
|
Kaths JM, Foltys DB, Scheuermann U, Strempel M, Niebisch S, Ebert M, Jansen-Winkeln B, Gockel I, Lang H. Achalasia with megaesophagus and tracheal compression in a young patient: A case report. Int J Surg Case Rep 2015. [PMID: 26209755 PMCID: PMC4573207 DOI: 10.1016/j.ijscr.2015.06.020] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
This report emphasizes that physicians should be alert and consider airway obstruction and signs of dyspnea as severe and threatening symptoms in extensive cases of achalasia with megaesophagus. Early surgical treatment provides a therapeutic option to obviate the occurrence of acute respiratory distress and consecutive complications. In particular, difficulties in intubation prior to surgery must be considered. Due to potential tracheomalacia, the status of “bull frog neck” in achalasia, including severe tracheal compression caused by megaesophagus with concomitant cervical swelling, may also lead to extubation problems and deserves special care in the postoperative period. Introduction Achalasia is one of the most common causes of dysphagia. Typical symptoms include difficulties in controlling the swallowing process, regurgitation, weight loss, and chest pain. A megaesophagus rarely causes tracheal compression with consecutive acute dyspnea or similar respiratory symptoms. Presentation of case A 23-year-old male patient presented with difficulties in swallowing, a consecutive massive weight loss over the past three years, and minor respiratory ailments. Further diagnostics revealed a megaesophagus caused by achalasia leading to a severe compression of the trachea. A laparoscopic Heller myotomy with anterior semi-fundoplication 180° according to Dor was performed. Discussion Acute dyspnea and similar respiratory symptoms are rarely observed in patients with achalasia, especially in young patients. Early diagnosis and timely, proper treatment are the hallmarks of restoring esophageal and tracheobronchial function and of successful prevention of severe long-lasting complications of the disease. When not treated properly, the disease may have progressed rapidly, leading to distinct respiratory symptoms such as stridor and acute dyspnea Conclusion This report emphasizes that physicians should be alert and consider airway obstruction and signs of dyspnea as severe and threatening symptoms in extensive cases of achalasia with megaesophagus. Early surgical treatment provides a therapeutic option to obviate the occurrence of acute respiratory distress and consecutive complications. In particular, difficulties in intubation prior to surgery must be considered.
Collapse
Affiliation(s)
- J Moritz Kaths
- Department of General-, Visceral- and Transplant Surgery, University Medical Centre, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany.
| | - Daniel B Foltys
- Department of General-, Visceral- and Transplant Surgery, University Medical Centre, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Uwe Scheuermann
- Department of Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Leipzig, Germany
| | - Mari Strempel
- Deutsche Stiftung Organtransplantation, Region Mitte, Frankfurt, Germany
| | - Stefan Niebisch
- Department of Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Leipzig, Germany
| | - Maren Ebert
- Department of Diagnostic and Interventional Radiology, University Medical Centre, Johannes Gutenberg-University Mainz, Germany
| | - Boris Jansen-Winkeln
- Department of Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Leipzig, Germany
| | - Ines Gockel
- Department of Visceral, Transplantation, Vascular and Thoracic Surgery, University Hospital of Leipzig, Germany
| | - Hauke Lang
- Department of General-, Visceral- and Transplant Surgery, University Medical Centre, Johannes Gutenberg-University Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| |
Collapse
|
40
|
Hernández-Mondragón O, González-Martínez M, Blancas-Valencia J, Altamirano-Castañeda M, Muñoz-Bautista A. Peroral endoscopic myotomy in achalasia: Report on the first case performed in Mexico. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2015. [DOI: 10.1016/j.rgmxen.2015.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
|
41
|
Shteyer E, Edvardson S, Wynia-Smith SL, Pierri CL, Zangen T, Hashavya S, Begin M, Yaacov B, Cinamon Y, Koplewitz BZ, Vromen A, Elpeleg O, Smith BC. Truncating mutation in the nitric oxide synthase 1 gene is associated with infantile achalasia. Gastroenterology 2015; 148:533-536.e4. [PMID: 25479138 DOI: 10.1053/j.gastro.2014.11.044] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2014] [Revised: 11/23/2014] [Accepted: 11/20/2014] [Indexed: 12/23/2022]
Abstract
Nitric oxide is thought to have a role in the pathogenesis of achalasia. We performed a genetic analysis of 2 siblings with infant-onset achalasia. Exome analysis revealed that they were homozygous for a premature stop codon in the gene encoding nitric oxide synthase 1. Kinetic analyses and molecular modeling showed that the truncated protein product has defects in folding, nitric oxide production, and binding of cofactors. Heller myotomy had no effect in these patients, but sildenafil therapy increased their ability to drink. The finding recapitulates the previously reported phenotype of nitric oxide synthase 1-deficient mice, which have achalasia. Nitric oxide signaling appears to be involved in the pathogenesis of achalasia in humans.
Collapse
Affiliation(s)
- Eyal Shteyer
- Pediatric Gastroenterology Unit, Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
| | - Simon Edvardson
- Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Sarah L Wynia-Smith
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ciro Leonardo Pierri
- Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy
| | - Tzili Zangen
- Pediatric Gastroenterology Unit, E Wolfson Medical Center, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
| | - Saar Hashavya
- Emergency Medicine Department of Pediatrics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Michal Begin
- Neuropediatric Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Barak Yaacov
- Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yuval Cinamon
- Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Benjamin Z Koplewitz
- Department of Medical Imaging, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Amos Vromen
- Department of Pediatric Surgery, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Orly Elpeleg
- Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Brian C Smith
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin
| |
Collapse
|
42
|
Yang SH, Procaccia S, Jung HJ, Nobumori C, Tatar A, Tu Y, Bayguinov YR, Hwang SJ, Tran D, Ward SM, Fong LG, Young SG. Mice that express farnesylated versions of prelamin A in neurons develop achalasia. Hum Mol Genet 2015; 24:2826-40. [PMID: 25652409 DOI: 10.1093/hmg/ddv043] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 02/02/2015] [Indexed: 12/15/2022] Open
Abstract
Neurons in the brain produce lamin C but almost no lamin A, a consequence of the removal of prelamin A transcripts by miR-9, a brain-specific microRNA. We have proposed that miR-9-mediated regulation of prelamin A in the brain could explain the absence of primary neurological disease in Hutchinson-Gilford progeria syndrome, a genetic disease caused by the synthesis of an internally truncated form of farnesyl-prelamin A (progerin). This explanation makes sense, but it is not entirely satisfying because it is unclear whether progerin-even if were expressed in neurons-would be capable of eliciting neuropathology. To address that issue, we created a new Lmna knock-in allele, Lmna(HG-C), which produces progerin transcripts lacking an miR-9 binding site. Mice harboring the Lmna(HG-C) allele produced progerin in neurons, but they had no pathology in the central nervous system. However, these mice invariably developed esophageal achalasia, and the enteric neurons and nerve fibers in gastrointestinal tract were markedly abnormal. The same disorder, achalasia, was observed in genetically modified mice that express full-length farnesyl-prelamin A in neurons (Zmpste24-deficient mice carrying two copies of a Lmna knock-in allele yielding full-length prelamin A transcripts lacking a miR-9 binding site). Our findings indicate that progerin and full-length farnesyl-prelamin A are toxic to neurons of the enteric nervous system.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Yulia R Bayguinov
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
| | - Sung Jin Hwang
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
| | | | - Sean M Ward
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
| | | | - Stephen G Young
- Department of Medicine, Molecular Biology Institute and Department of Human Genetics, University of California, Los Angeles, CA 90095, USA and
| |
Collapse
|
43
|
von Rahden BHA, Filser J, Reimer S, Inoue H, Germer CT. [Peroral endoscopic myotomy for treatment of achalasia. Literature review and own initial experience]. Chirurg 2015; 85:420-32. [PMID: 24352827 DOI: 10.1007/s00104-013-2639-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Peroral endoscopic myotomy (POEM) is a new, purely endoscopic procedure for treatment of achalasia. Due to the lack of incisions POEM can be regarded as a true NOTES procedure. With POEM a myotomy is created in a similar fashion to the previous standard treatment, laparoscopic Heller myotomy (LHM). The relatively free choice of length and localization of the myotomy may be regarded as advantages of POEM. The procedure starts with a mucosal incision (mucosal entry) followed by preparation of a submucosal tunnel crossing the esophagogastric junction and creation of a myotomy in an antegrade direction before the mucosal access is closed with endoscopic clip placement. Since the first description of the application of POEM in humans in 2010 by the pioneer Haruhiro Inoue, Yokohama, Japan, it has been used increasingly and investigated in some centers in Asia, the U.S.A. and also Europe. The results are very promising. Although the procedure is technically demanding it can be performed safely with low complication rates. The POEM procedure achieves very good control of dysphagia and gastroesophageal reflux witch is only a rare side-effect witch is well-controllable with proton pump inhibitors (PPI). We review the currently available data from the literature and present our own initial series of 14 patients treated with POEM.
Collapse
Affiliation(s)
- B H A von Rahden
- Klinik für Allgemein-, Visceral-, Gefäß- und Kinderchirurgie, Zentrum für operative Medizin (ZOM), Universitätsklinikum Würzburg, Oberdürrbacherstr. 6, 97080, Würzburg, Deutschland,
| | | | | | | | | |
Collapse
|
44
|
Noe E, Tabeling C, Doehn JM, Naujoks J, Opitz B, Hippenstiel S, Witzenrath M, Klopfleisch R. Juvenile megaesophagus in PKCα-deficient mice is associated with an increase in the segment of the distal esophagus lined by smooth muscle cells. Ann Anat 2014; 196:365-71. [DOI: 10.1016/j.aanat.2014.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Revised: 03/31/2014] [Accepted: 04/01/2014] [Indexed: 12/29/2022]
|
45
|
Pescarus R, Shlomovitz E, Swanstrom LL. Per-oral endoscopic myotomy (POEM) for esophageal achalasia. Curr Gastroenterol Rep 2014; 16:369. [PMID: 24362953 DOI: 10.1007/s11894-013-0369-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Per-oral endoscopic myotomy (POEM) is a new minimally invasive endoscopic treatment for achalasia. Since the first modern human cases were published in 2008, around 2,000 cases have been performed worldwide. This technique requires advanced endoscopic skills and a learning curve of at least 20 cases. POEM is highly successful with over 90 % improvement in dysphagia while offering patients the advantage of a low impact endoscopic access. The main long-term complication is gastroesophageal reflux (GER) with an estimated incidence of 35 %, similar to the incidence of GER post-laparoscopic Heller with fundoplication. Although POEM represents a paradigm shift in the treatment of achalasia, more long-term data are clearly needed to further define its role in the treatment algorithm of this rare disease.
Collapse
Affiliation(s)
- Radu Pescarus
- Providence Cancer Center, Division of Gastrointestinal and Minimally Invasive Surgery, The Oregon Clinic, Portland, OR, USA
| | | | | |
Collapse
|
46
|
Gockel I, Becker J, Wouters MM, Niebisch S, Gockel HR, Hess T, Ramonet D, Zimmermann J, Vigo AG, Trynka G, de León AR, de la Serna JP, Urcelay E, Kumar V, Franke L, Westra HJ, Drescher D, Kneist W, Marquardt JU, Galle PR, Mattheisen M, Annese V, Latiano A, Fumagalli U, Laghi L, Cuomo R, Sarnelli G, Müller M, Eckardt AJ, Tack J, Hoffmann P, Herms S, Mangold E, Heilmann S, Kiesslich R, von Rahden BHA, Allescher HD, Schulz HG, Wijmenga C, Heneka MT, Lang H, Hopfner KP, Nöthen MM, Boeckxstaens GE, de Bakker PIW, Knapp M, Schumacher J. Common variants in the HLA-DQ region confer susceptibility to idiopathic achalasia. Nat Genet 2014; 46:901-4. [PMID: 24997987 DOI: 10.1038/ng.3029] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2014] [Accepted: 06/11/2014] [Indexed: 12/15/2022]
Abstract
Idiopathic achalasia is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. This ultimately leads to massive dilatation and an irreversibly impaired megaesophagus. We performed a genetic association study in 1,068 achalasia cases and 4,242 controls and fine-mapped a strong MHC association signal by imputing classical HLA haplotypes and amino acid polymorphisms. An eight-residue insertion at position 227-234 in the cytoplasmic tail of HLA-DQβ1 (encoded by HLA-DQB1*05:03 and HLA-DQB1*06:01) confers the strongest risk for achalasia (P=1.73×10(-19)). In addition, two amino acid substitutions in the extracellular domain of HLA-DQα1 at position 41 (lysine encoded by HLA-DQA1*01:03; P=5.60×10(-10)) and of HLA-DQβ1 at position 45 (glutamic acid encoded by HLA-DQB1*03:01 and HLA-DQB1*03:04; P=1.20×10(-9)) independently confer achalasia risk. Our study implies that immune-mediated processes are involved in the pathophysiology of achalasia.
Collapse
Affiliation(s)
- Ines Gockel
- 1] Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany. [2]
| | - Jessica Becker
- 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3]
| | - Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium
| | - Stefan Niebisch
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Henning R Gockel
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Timo Hess
- 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany
| | - David Ramonet
- Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany
| | - Julian Zimmermann
- Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany
| | - Ana González Vigo
- Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Gosia Trynka
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Antonio Ruiz de León
- Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Julio Pérez de la Serna
- Department of Gastroenterology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Elena Urcelay
- Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Vinod Kumar
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Lude Franke
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Harm-Jan Westra
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Daniel Drescher
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Werner Kneist
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Jens U Marquardt
- First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany
| | - Peter R Galle
- First Department of Internal Medicine, University Medical Center, University of Mainz, Mainz, Germany
| | - Manuel Mattheisen
- 1] Department of Biomedicine, Aarhus University, Aarhus, Denmark. [2] Centre for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark
| | - Vito Annese
- Department of Gastroenterology, Careggi Hospital, University of Florence, Florence, Italy
| | - Anna Latiano
- Division of Gastroenterology, Istituto di Ricovero e Cura a Carattere Scientifico, Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Uberto Fumagalli
- Department of Surgery, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
| | - Luigi Laghi
- Department of Gastroenterology, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
| | - Rosario Cuomo
- Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy
| | - Giovanni Sarnelli
- Department of Clinical Medicine and Surgery, Division of Gastroenterology, Federico II University Hospital School of Medicine, Naples, Italy
| | - Michaela Müller
- Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany
| | - Alexander J Eckardt
- Department of Gastroenterology, German Diagnostic Clinic, Wiesbaden, Germany
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium
| | - Per Hoffmann
- 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3] Division of Medical Genetics, University Hospital, Basel, Switzerland. [4] Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Stefan Herms
- 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3] Division of Medical Genetics, University Hospital, Basel, Switzerland. [4] Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Elisabeth Mangold
- 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany
| | - Stefanie Heilmann
- 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany
| | - Ralf Kiesslich
- Department of Internal Medicine, Hospital St. Marien, Frankfurt, Germany
| | - Burkhard H A von Rahden
- Department of General, Visceral, Vascular and Pediatric Surgery, University of Würzburg, Würzburg, Germany
| | - Hans-Dieter Allescher
- Center of Internal Medicine, Hospital Garmisch-Partenkirchen, Garmisch-Partenkirchen, Germany
| | - Henning G Schulz
- Department of General and Abdominal Surgery, Protestant Hospital Castrop-Rauxel, Castrop-Rauxel, Germany
| | - Cisca Wijmenga
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Michael T Heneka
- Department of Neurology, Division of Clinical Neurosciences, University of Bonn, Bonn, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany
| | - Karl-Peter Hopfner
- 1] Department of Biochemistry, Gene Center, Ludwig Maximilians University, Munich, Germany. [2] Center for Integrated Protein Sciences, Munich, Germany
| | - Markus M Nöthen
- 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders, Catholic University of Leuven, Leuven, Belgium
| | - Paul I W de Bakker
- 1] Department of Epidemiology, University Medical Center Utrecht, Utrecht, the Netherlands. [2] Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Michael Knapp
- 1] Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany. [2]
| | - Johannes Schumacher
- 1] Institute of Human Genetics, University of Bonn, Bonn, Germany. [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany. [3]
| |
Collapse
|
47
|
Inoue H, Santi EG, Onimaru M, Kudo SE. Submucosal endoscopy: from ESD to POEM and beyond. Gastrointest Endosc Clin N Am 2014; 24:257-64. [PMID: 24679236 DOI: 10.1016/j.giec.2013.12.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Peroral endoscopic myotomy (POEM) is an evolving minimally invasive endoscopic surgical procedure, with no skin incision, intended for long-term recovery from symptoms of esophageal achalasia. POEM was developed based on both the already established surgical principles of esophageal myotomy and the advanced techniques of endoscopic submucosal dissection. This article relates how POEM was developed, and its use in practice is reported and discussed. As an extension of the POEM technique, submucosal endoscopic tumor resection is introduced.
Collapse
Affiliation(s)
- Haruhiro Inoue
- Digestive Disease Center, Showa University Koto-Toyosu Hospital, Yokohama, Japan.
| | - Esperanza Grace Santi
- Section of Gastroenterology, Department of Internal Medicine, De La Salle University Medical Center, Manila, Philippines
| | - Manabu Onimaru
- Digestive Disease Center, Showa University Koto-Toyosu Hospital, Yokohama, Japan
| | - Shin-ei Kudo
- Digestive Disease Center, Showa University Koto-Toyosu Hospital, Yokohama, Japan
| |
Collapse
|
48
|
Latiano A, Palmieri O, Bossa F, Latiano T, Corritore G, De Santo E, Martino G, Merla A, Valvano MR, Cuttitta A, Mazza T, Annese V, Andriulli A. Impact of genetic polymorphisms on the pathogenesis of idiopathic achalasia: Association with IL33 gene variant. Hum Immunol 2014; 75:364-9. [PMID: 24468584 DOI: 10.1016/j.humimm.2014.01.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 01/03/2014] [Accepted: 01/14/2014] [Indexed: 02/06/2023]
|
49
|
Hervé D, Philippi A, Belbouab R, Zerah M, Chabrier S, Collardeau-Frachon S, Bergametti F, Essongue A, Berrou E, Krivosic V, Sainte-Rose C, Houdart E, Adam F, Billiemaz K, Lebret M, Roman S, Passemard S, Boulday G, Delaforge A, Guey S, Dray X, Chabriat H, Brouckaert P, Bryckaert M, Tournier-Lasserve E. Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia. Am J Hum Genet 2014; 94:385-94. [PMID: 24581742 DOI: 10.1016/j.ajhg.2014.01.018] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 01/31/2014] [Indexed: 12/09/2022] Open
Abstract
Moyamoya is a cerebrovascular condition characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICAs) and the compensatory development of abnormal "moyamoya" vessels. The pathophysiological mechanisms of this condition, which leads to ischemic and hemorrhagic stroke, remain unknown. It can occur as an isolated cerebral angiopathy (so-called moyamoya disease) or in association with various conditions (moyamoya syndromes). Here, we describe an autosomal-recessive disease leading to severe moyamoya and early-onset achalasia in three unrelated families. This syndrome is associated in all three families with homozygous mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for nitric oxide (NO). Platelet analysis showed a complete loss of the soluble α1β1 guanylate cyclase and showed an unexpected stimulatory role of sGC within platelets. The NO-sGC-cGMP pathway is a major pathway controlling vascular smooth-muscle relaxation, vascular tone, and vascular remodeling. Our data suggest that alterations of this pathway might lead to an abnormal vascular-remodeling process in sensitive vascular areas such as ICA bifurcations. These data provide treatment options for affected individuals and strongly suggest that investigation of GUCY1A3 and other members of the NO-sGC-cGMP pathway is warranted in both isolated early-onset achalasia and nonsyndromic moyamoya.
Collapse
|
50
|
Pang J, Borjeson TM, Muthupalani S, Ducore RM, Carr CA, Feng Y, Sullivan MP, Cristofaro V, Luo J, Lindstrom JM, Fox JG. Megaesophagus in a line of transgenic rats: a model of achalasia. Vet Pathol 2014; 51:1187-200. [PMID: 24457157 DOI: 10.1177/0300985813519136] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Megaesophagus is defined as the abnormal enlargement or dilatation of the esophagus, characterized by a lack of normal contraction of the esophageal walls. This is called achalasia when associated with reduced or no relaxation of the lower esophageal sphincter (LES). To date, there are few naturally occurring models for this disease. A colony of transgenic (Pvrl3-Cre) rats presented with megaesophagus at 3 to 4 months of age; further breeding studies revealed a prevalence of 90% of transgene-positive animals having megaesophagus. Affected rats could be maintained on a total liquid diet long term and were shown to display the classic features of dilated esophagus, closed lower esophageal sphincter, and abnormal contractions on contrast radiography and fluoroscopy. Histologically, the findings of muscle degeneration, inflammation, and a reduced number of myenteric ganglia in the esophagus combined with ultrastructural lesions of muscle fiber disarray and mitochondrial changes in the striated muscle of these animals closely mimic that seen in the human condition. Muscle contractile studies looking at the response of the lower esophageal sphincter and fundus to electrical field stimulation, sodium nitroprusside, and L-nitro-L-arginine methyl ester also demonstrate the similarity between megaesophagus in the transgenic rats and patients with achalasia. No primary cause for megaesophagus was found, but the close parallel to the human form of the disease, as well as ease of care and manipulation of these rats, makes this a suitable model to better understand the etiology of achalasia as well as study new management and treatment options for this incurable condition.
Collapse
Affiliation(s)
- J Pang
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - T M Borjeson
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - S Muthupalani
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - R M Ducore
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - C A Carr
- The Picower Institute for Learning and Memory, RIKEN-MIT Center for Neural Circuit Genetics, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Y Feng
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - M P Sullivan
- VA Boston Healthcare System, Harvard Medical School, West Roxbury, MA, USA
| | - V Cristofaro
- VA Boston Healthcare System, Harvard Medical School, West Roxbury, MA, USA
| | - J Luo
- Department of Neuroscience, Medical School of the University of Pennsylvania, Philadelphia, PA, USA
| | - J M Lindstrom
- Department of Neuroscience, Medical School of the University of Pennsylvania, Philadelphia, PA, USA
| | - J G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| |
Collapse
|