|
1
|
Basilisco G, Marchi M, Coletta M. Chronic intestinal pseudo-obstruction in adults: A practical guide to identify patient subgroups that are suitable for more specific treatments. Neurogastroenterol Motil 2024; 36:e14715. [PMID: 37994282 DOI: 10.1111/nmo.14715] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Revised: 11/06/2023] [Accepted: 11/10/2023] [Indexed: 11/24/2023]
Abstract
Chronic intestinal pseudo-obstruction is a rare and heterogeneous syndrome characterized by recurrent symptoms of intestinal obstruction with radiological features of dilated small or large intestine with air/fluid levels in the absence of any mechanical occlusive lesion. Several diseases may be associated with chronic intestinal pseudo-obstruction and in these cases, the prognosis and treatment are related to the underlying disease. Also, in its "primary or idiopathic" form, two subgroups of patients should be determined as they require a more specific therapeutic approach: patients whose chronic intestinal pseudo-obstruction is due to sporadic autoimmune/inflammatory mechanisms and patients whose neuromuscular changes are genetically determined. In a context of a widely heterogeneous adult population presenting chronic intestinal pseudo-obstruction, this review aims to summarize a practical diagnostic workup for identifying definite subgroups of patients who might benefit from more specific treatments, based on the etiology of their underlying condition.
Collapse
Affiliation(s)
- Guido Basilisco
- Gastroenterology and Endoscopic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Margherita Marchi
- Neuroalgology Unit, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy
| | - Marina Coletta
- Gastroenterology and Endoscopic Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| |
Collapse
|
|
2
|
Baseline Characteristics and Predictive Factors of Intravenous Immunoglobulin Response in Drug and Device Refractory Gastroparesis Symptoms. J Clin Gastroenterol 2023; 57:172-177. [PMID: 34974494 DOI: 10.1097/mcg.0000000000001655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 11/12/2021] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Intravenous immunoglobulin (IVIG) has been shown in a small pilot series to be helpful for some patients with gastroparesis that is refractory to drugs, devices, and surgical therapies. Many but not all patients have serologic neuromuscular markers. We hypothesize that those patients with serologic markers and/or longer duration of therapy would have better responses to IVIG. MATERIALS AND METHODS We studied 47 patients with a diagnosis of gastroparesis and gastroparesis-like syndrome that had all failed previous therapies including available and investigational drugs, devices, and/or pyloric therapies. Patients had a standardized 12-week course of IVIG, dosed as 400 mg/kg per week intravenously. Symptom assessment was done with Food and Drug Administration (FDA) compliant traditional patient-reported outcomes. Success to IVIG was defined as 20% or greater reduction in average symptom scores from baseline to the latest evaluation. RESULTS Fourteen patients (30%) had a response, and 33 (70%) had no response per our definition. Patients responding had a higher glutamic acid decarboxylase 65 positivity (64% vs. 30%, P =0.049, missing=3) and longer duration of therapy (>12 wk/continuous: 86% vs. 48%, P =0.09). CONCLUSIONS In this moderately sized open-label series of refractory patients with gastroparesis symptoms treated with IVIG, 30% of patients responded. While serologic markers and extended therapies show a trend to greater response, neither was statistically significant, except for glutamic acid decarboxylase 65 which showed a higher positivity rate in responders. We conclude that a clinical trial of IVIG may be warranted in severely refractory patients with gastroparesis symptoms.
Collapse
|
|
3
|
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
|
|
4
|
Annaházi A, Schemann M. Contribution of the Enteric Nervous System to Autoimmune Diseases and Irritable Bowel Syndrome. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1383:1-8. [PMID: 36587141 DOI: 10.1007/978-3-031-05843-1_1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Anti-neuronal autoantibodies can lead to subacute gastrointestinal dysmotility, presenting with various symptoms typical of intestinal pseudoobstruction, achalasia, gastroparesis, or slow intestinal transit, among others. Such autoantibodies may be produced in response to a remote tumor and accelerate the diagnosis of malignancy, but in other cases they appear without an identifiable underlying cause. One example is the type I anti-neuronal nuclear antibody (ANNA-1 otherwise known as anti-Hu), which is usually linked to small cell-lung carcinoma. Anti-Hu can directly activate enteric neurons and visceral sensory nerve fibers and has a cytotoxic effect. Various other anti-neuronal antibodies have been described, targeting different ion channels or receptors on nerve cells of the central or the enteric nervous system. Autoimmune processes targeting enteric neurons may also play a role in more common disorders such as esophageal achalasia, celiac disease, or multiple sclerosis. Furthermore, anti-enteric neuronal antibodies have been found more abundant in the common functional gastrointestinal disorder, irritable bowel syndrome (IBS), than in controls. The pathogenesis of IBS is very complex, involving the release of various mediators from immune cells in the gut wall. Products of mast cells, such as histamine and tryptase, excite visceral afferents and enteric neurons, which may contribute to symptoms like abdominal pain and disturbed motility. Elevated serine- and cysteine-protease activity in stool of IBS-D and IBS-C patients, respectively, can be a factor leading to leaky gut and visceral hypersensitivity. More knowledge on these mediators in IBS may facilitate the development of novel diagnostic methods or therapies.
Collapse
Affiliation(s)
- Anita Annaházi
- Human Biology, Technical University of Munich, Freising, Germany
| | - Michael Schemann
- Human Biology, Technical University of Munich, Freising, Germany.
| |
Collapse
|
|
5
|
Holland AM, Bon-Frauches AC, Keszthelyi D, Melotte V, Boesmans W. The enteric nervous system in gastrointestinal disease etiology. Cell Mol Life Sci 2021; 78:4713-4733. [PMID: 33770200 PMCID: PMC8195951 DOI: 10.1007/s00018-021-03812-y] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 02/20/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023]
Abstract
A highly conserved but convoluted network of neurons and glial cells, the enteric nervous system (ENS), is positioned along the wall of the gut to coordinate digestive processes and gastrointestinal homeostasis. Because ENS components are in charge of the autonomous regulation of gut function, it is inevitable that their dysfunction is central to the pathophysiology and symptom generation of gastrointestinal disease. While for neurodevelopmental disorders such as Hirschsprung, ENS pathogenesis appears to be clear-cut, the role for impaired ENS activity in the etiology of other gastrointestinal disorders is less established and is often deemed secondary to other insults like intestinal inflammation. However, mounting experimental evidence in recent years indicates that gastrointestinal homeostasis hinges on multifaceted connections between the ENS, and other cellular networks such as the intestinal epithelium, the immune system, and the intestinal microbiome. Derangement of these interactions could underlie gastrointestinal disease onset and elicit variable degrees of abnormal gut function, pinpointing, perhaps unexpectedly, the ENS as a diligent participant in idiopathic but also in inflammatory and cancerous diseases of the gut. In this review, we discuss the latest evidence on the role of the ENS in the pathogenesis of enteric neuropathies, disorders of gut-brain interaction, inflammatory bowel diseases, and colorectal cancer.
Collapse
Affiliation(s)
- Amy Marie Holland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium
| | - Ana Carina Bon-Frauches
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Daniel Keszthelyi
- Department of Internal Medicine, Division of Gastroenterology-Hepatology, NUTRIM-School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Veerle Melotte
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - Werend Boesmans
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
- Biomedical Research Institute (BIOMED), Hasselt University, Diepenbeek, Belgium.
| |
Collapse
|
|
6
|
Wu XY, Liu ZQ, Wang Y, Chen WF, Gao PT, Li QL, Zhou PH. The etiology of achalasia: An immune-dominant disease. J Dig Dis 2021; 22:126-135. [PMID: 33583137 DOI: 10.1111/1751-2980.12973] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 02/09/2021] [Accepted: 02/10/2021] [Indexed: 02/06/2023]
Abstract
There is accumulating evidence suggesting that an autoimmune component is involved in esophageal achalasia. An increase in immune cells, cytokines, chemokines, and autoimmune antibodies in serum and infiltration of immune cells in tissues support the view that immune-mediated inflammation is a crucial pathogenesis of inhibitory neuron degeneration in the lower esophageal sphincter. Infection of viruses such as the herpes virus family has been suspected of provoking the autoimmune reaction. Meanwhile, previous reports on immunogenetics have proposed that specific risk alleles on the human leukocyte antigen complex define the susceptible population to achalasia. In this study we reviewed current knowledge regarding the immune-related factors of achalasia, including immunology, viral infection and immunogenetic variations.
Collapse
Affiliation(s)
- Xing Yue Wu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China.,Shanghai Medical College, Fudan University, Shanghai, China
| | - Zu Qiang Liu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yun Wang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei Feng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Ting Gao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Quan Lin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping Hong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
7
|
Bassi R, Saeed Y. A Rare Case of a Life-Threatening Massive Upper Gastrointestinal Bleed and Airway Obstruction in a Patient With a Megaesophagus Secondary to Longstanding Achalasia. Cureus 2021; 13:e13204. [PMID: 33717744 PMCID: PMC7943396 DOI: 10.7759/cureus.13204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Achalasia is a relatively rare motor disorder characterized by esophageal aperistalsis and incomplete relaxation of the lower esophageal sphincter. In only 10% of patients, untreated or poorly managed achalasia can progress to esophageal dilation and eventual loss of total functionality resulting in a characteristic sigmoid dolichomegaesopahagus. In extremely rare instances, this sigmoid dolichomegaesopahagus can present clinically as acute airway obstruction or a fatal, life-threatening hemorrhage requiring immediate intervention. We present the case of a 65-year-old female with a past medical history of long-standing achalasia who had complaints of shortness of breath, chest pain, and two episodes of life-threatening hematemesis requiring a blood transfusion. An angiography illustrated significant distention of the esophagus occupying most of the right hemithorax and non-specific intraluminal fluid with a small amount of gas. Emergent esophagogastroduodenoscopy showed fibrosis and necrosis of the esophageal mucosa with food debris, suggesting that the bleeding was likely coming from an ulcer caused by pressure necrosis. The patient was hemodynamically unstable after the procedure and was transferred to another facility the next day for an esophagectomy. Patients with achalasia have an increased susceptibility to develop pressure ulcers due to increased shear force on the esophageal wall, increased moisture of the esophageal wall from prolonged contact of food boluses, and underlying malnutrition and weight loss from the indigestion of food causing atrophy of the mucosal barriers. The management of these ulcers is to treat and manage the underlying cause. Although there are no curative treatments for achalasia, symptomatic relief through both surgical and medical therapies are the mainstay of management, with an esophagectomy reserved for refractory cases or in patients who develop end-stage complications.
Collapse
Affiliation(s)
- Raghav Bassi
- Internal Medicine, Lincoln Medical and Mental Health Center, New York, USA
| | - Yasir Saeed
- Internal Medicine, Lincoln Medical and Mental Health Center, New York, USA
| |
Collapse
|
|
8
|
Sara C, Marcella P, Martina C, Marta A, Eleonora E, Giovanni A, Marco M, Paola DV, Domenico DPG, Giovanni S. Clinical correlation and disease phenotype in patients with esophageal achalasia and comorbid autoimmune diseases. Dis Esophagus 2021; 34:5882160. [PMID: 32766709 DOI: 10.1093/dote/doaa072] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 05/12/2020] [Accepted: 06/20/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND There is evidence that idiopathic achalasia has an autoimmune component and a significant association with several autoimmune comorbidities has been described. However, data regarding the prevalence of autoimmune diseases in achalasia are not well established, and few studies have explored this association. OBJECTIVE Our primary aim was to prospectively investigate the type and frequency of autoimmune comorbidities in a large cohort of consecutive achalasia patients. Our secondary aim was to investigate the effects of autoimmune comorbidities on achalasia phenotype (clinical features and manometric pattern). METHODS The study population consisted of 375 consecutive patients (215 females-median age 55 ± 17 years), referred at our tertiary referral center from January 2008 to January 2018, with clinical and instrumental (EGDS, barium esophagogram, and manometry) diagnosis of idiopathic achalasia. Gender- and age-matched subjects undergoing manometry and pH-impedance monitoring for typical gastroesophageal reflux (GERD) complaints served as controls. In all patients a detailed history taking was carried out, recording the presence and type of autoimmune comorbidities. RESULTS The overall prevalence of autoimmune comorbidities was two times higher in achalasia than in control patients (12.3 vs. 5%, respectively). The presence of comorbidities did not significantly affect disease's phenotype, as the age of disease onset was similar in achalasia patients with and without comorbidities (50.13 ± 14.47 and 48.3 ± 18.71, respectively, P = NS). CONCLUSIONS Although larger epidemiologic studies are needed to confirm our data, our findings likely suggest that achalasia has a complex multifactorial pathophysiology with an autoimmune component.
Collapse
Affiliation(s)
- Cassarano Sara
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| | - Pesce Marcella
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| | - Cargiolli Martina
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| | - Andreozzi Marta
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| | - Efficie Eleonora
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| | - Aprea Giovanni
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| | - Milone Marco
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| | - Dinuzzi Vincenza Paola
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| | | | - Sarnelli Giovanni
- Department of Clinical Medicine and Surgery, 'Federico II' University of Naples, 80131 Naples, Italy
| |
Collapse
|
|
9
|
Kesserwani H. Glutamic Acid Decarboxylase (GAD-65) Autoimmunity Associated With Profound Daytime Hypersomnia, Nighttime Insomnia, Mild Autonomic Neuropathy and Axonal Sensori-Motor Polyneuropathy: A Case Report on a New Phenotype. Cureus 2020; 12:e11112. [PMID: 33240708 PMCID: PMC7682535 DOI: 10.7759/cureus.11112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
We describe the case of a 74-year-old fit and healthy man who developed a profound sleep disorder characterized by mid-day hypersomnia and debilitating insomnia. A wide range of therapies, including a large number of stimulants and hypnotics with multiple different mechanisms of action, failed to improve his condition. Trials with oral prosthetic devices and a wide range of face masks with positive pressure assistance and multiple continuous positive airway pressure (CPAP) titration studies failed to help. Along with his sleep disorder, our patient developed a slowly evolving axonal sensorimotor polyneuropathy with a subtle autonomic neuropathy. Due to the latter two conditions, a comprehensive paraneoplastic panel was obtained and revealed extremely high titer glutamic acid decarboxylase (GAD-65) autoantibodies. This was confirmed by three independent laboratories and by cerebrospinal fluid staining of rat hippocampus, revealing the classic tram-track lines along the dentate gyrus. Our patient was treated empirically with intravenous immunoglobulin. We believe that our case reveals a unique syndrome related to GAD-65 autoantibodies and adds to the growing list of GAD-65 associated diseases. This case is particularly provocative as it raises the idea to check for GAD-65 autoimmunity in patients who suffer from a profound sleep disorder resistant to conventional treatment.
Collapse
|
|
10
|
Suprapto B, Aswin A. Achalasia in a woman presenting with vitiligo: A case report. Int J Surg Case Rep 2020; 75:252-257. [PMID: 32971447 PMCID: PMC7516064 DOI: 10.1016/j.ijscr.2020.09.052] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 08/29/2020] [Accepted: 09/05/2020] [Indexed: 02/07/2023] Open
Abstract
Achalasia is a rare motor disorder of the oesophagus. Achalasia is thought to arise from organ-specific autoimmunity due to vitiligo that present in the patient. Clinical awareness is imperative when approaching an achalasia due to its similar symptom to GERD and respiratory disease, and must always be considered in autoimmune patient. We performed Laparoscopic Heller’s myotomy and repaired with Dor’s fundoplication. Background Achalasia is a rare motor disorder of the oesophagus that typically characterized by the absence of oesophagus peristalsis and failure of swallow induced relaxation of oesophagus sphincter (LOS). The prevalence of achalasia is eight cases per million population. Presentation of case A 35-year-old woman presented with progressive dysphagia for 6 years. Her symptoms worsened in the last 14 days followed by vomiting undigested and retained food. She was previously diagnosed with a variant respiratory problem but her symptoms did not improve with medication. Clinical evaluation and investigation revealed features of multiple depigmented patches with sharply defined borders and leucotrichia on the neck, abdomen, hand, knee, and lateral malleolus. The patient had vitiligo for 18 years. The upper gastrointestinal endoscopy showed the dilatation from distal oesophagus (38 cm from incisors) with retained food. The diagnosis of achalasia was given. After laparoscopic Heller’s myotomy was performed and the opening of the oesophagus was repaired with Dor’s fundoplication, her symptoms were much improved. Discussion and conclusion We hereby report on a rare case of achalasia in a woman presenting with vitiligo which may suggest an autoimmune disorder in the onset of achalasia. Achalasia must be considered in vitiligo or any autoimmune disease presenting with the oesophagus-related problem.
Collapse
Affiliation(s)
- Bambang Suprapto
- Division of Digestive Surgery, Department of Surgery, Abdul Wahab Sjahranie General Hospital/Faculty of Medicine, Mulawarman University, Samarinda, Indonesia
| | - Amalia Aswin
- Faculty of Medicine, Mulawarman University, Samarinda, Indonesia.
| |
Collapse
|
|
11
|
Sanchez JMS, McNally JS, Cortez MM, Hemp J, Pace LA, Clardy SL. Neuroimmunogastroenterology: At the Interface of Neuroimmunology and Gastroenterology. Front Neurol 2020; 11:787. [PMID: 32849234 PMCID: PMC7412790 DOI: 10.3389/fneur.2020.00787] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 06/25/2020] [Indexed: 12/11/2022] Open
Abstract
The central nervous system (CNS) is an important regulator of the gastrointestinal tract, and CNS dysfunction can result in significant and disabling gastrointestinal symptom manifestation. For patients with neuroimmunologic and neuroinflammatory conditions, the recognition of gastrointestinal symptoms is under-appreciated, yet the gastrointestinal manifestations have a dramatic impact on quality of life. The current treatment strategies, often employed independently by the neurologist and gastroenterologist, raise the question of whether such patients are being treated optimally when siloed in one specialty. Neuroimmunogastroenterology lies at the borderlands of medical specialties, and there are few resources to guide neurologists in this area. Here, we provide an overview highlighting the potential mechanisms of crosstalk between immune-mediated neurological disorders and gastrointestinal dysfunction.
Collapse
Affiliation(s)
- John Michael S. Sanchez
- Division of Microbiology and Immunology, Department of Pathology, University of Utah, Salt Lake City, UT, United States
| | - J. Scott McNally
- Department of Radiology, Utah Center for Advanced Imaging Research, University of Utah, Salt Lake City, UT, United States
| | - Melissa M. Cortez
- Department of Neurology, Imaging and Neurosciences Center, University of Utah, Salt Lake City, UT, United States
| | - James Hemp
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Laura A. Pace
- Division of Gastroenterology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States
| | - Stacey L. Clardy
- Department of Neurology, Imaging and Neurosciences Center, University of Utah, Salt Lake City, UT, United States
- George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT, United States
| |
Collapse
|
|
12
|
Nakane S, Mukaino A, Ihara E, Ogawa Y. Autoimmune gastrointestinal dysmotility: the interface between clinical immunology and neurogastroenterology. Immunol Med 2020; 44:74-85. [DOI: 10.1080/25785826.2020.1797319] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Shunya Nakane
- Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, Kumamoto, Japan
| | - Akihiro Mukaino
- Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, Kumamoto, Japan
| | - Eikichi Ihara
- Department of Gastroenterology and Metabolism, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| |
Collapse
|
|
13
|
Chen WF, Liu ZQ, Pu ZN, Xu JQ, Yao L, Wu XY, Xu XY, Xu JX, Zhu Y, Wang Y, Cheng J, Zhu L, Zhou PH, Li QL. Multiplex immunoassays reveal increased serum cytokines and chemokines associated with the subtypes of achalasia. Neurogastroenterol Motil 2020; 32:e13832. [PMID: 32134545 DOI: 10.1111/nmo.13832] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 02/15/2020] [Accepted: 02/18/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND Achalasia is an esophageal motility disorder with unknown etiology. Previous findings indicate that immune-mediated inflammatory process causes inhibitory neuronal degeneration. This study was designed to evaluate levels of serological cytokines and chemokines in patients with achalasia. METHODS We collected information from forty-seven patients with achalasia who underwent peroral endoscopic myotomy. Control samples were collected from forty-seven age- and sex-matched healthy people. The concentrations of serological cytokines and chemokines were analyzed by Luminex xMAP immunoassay. Serological and clinical data were compared between groups. KEY RESULTS Compared with healthy controls, achalasia patients had significantly increased concentrations of eleven cytokines and chemokines, namely, TGF-ß1 (P < .001), TGF-ß2 (P < .001), TGF-ß3 (P < .001), IL-1ra (P < .001), IL-17 (P = .005), IL-18 (P < .001), IFN-γ (P < .001), MIG (P < .001), PDGF-BB (P < .001), IP-10 (P = .003), and SCGF-B (P < .001). Gene ontology (GO) and network functional enrichment analysis revealed regulation of signaling receptor activity and receptor-ligand activity were the most related pathways of these cytokines and chemokines. Levels of twelve cytokines and chemokines were significantly increased in type III compared with I/II achalasia, namely, TGF-ß2, IL-1ra, IL-2Ra, IL-18, MIG, IFN-γ, SDF-1a, Eotaxin, PDGF-BB, IP-10, MCP-1, and TRAIL. CONCLUSIONS AND INFERENCES Patients with achalasia exhibited increased levels of serological cytokines and chemokines. Levels of cytokines and chemokines were significantly increased in type III than in type I/II achalasia. Cytokines and chemokines might contribute to the inflammatory development of achalasia.
Collapse
Affiliation(s)
- Wei-Feng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zu-Qiang Liu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Zhe-Ning Pu
- Center of Clinical Research, Wuxi People's Hospital of Nanjing Medical University, Wuxi, China
| | - Jia-Qi Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lu Yao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | | | - Xiao-Yue Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Xin Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yan Zhu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yun Wang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jing Cheng
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Liang Zhu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping-Hong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Quan-Lin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
14
|
Hoshikawa Y, Hoshino S, Kawami N, Tanabe T, Hanada Y, Takenouchi N, Goto O, Kaise M, Iwakiri K. Possible new endoscopic finding in patients with achalasia: "Gingko leaf sign". Esophagus 2020; 17:208-213. [PMID: 31227944 DOI: 10.1007/s10388-019-00684-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 06/16/2019] [Indexed: 02/03/2023]
Abstract
BACKGROUND The diagnosis of achalasia can occasionally be difficult because of the low prevalence of apparent endoscopic abnormal findings, such as dilation and food residue, and lack of "esophageal rosette" in some patients. We have found a new endoscopic finding "Gingko leaf sign", which consists of not being able to see the full extent of the esophageal palisade vessels and a Gingko leaf-shaped morphology of a longitudinal section of the esophagogastric junction at the end of a deep inspiration, in some achalasia patients without "esophageal rosette". The aim of the study was to investigate the prevalence of "Gingko leaf sign" in these patients. METHODS We retrospectively compared the prevalence of "Gingko leaf sign" between 11 achalasia patients without "esophageal rosette" and 22 age-/gender-matched healthy subjects. The diagnoses of achalasia were based on the results of high-resolution manometry. We also investigated the characteristics of the patients with "Gingko leaf sign". RESULTS All the patients had "Gingko leaf sign", in contrast to none of the healthy subjects (p < 0.001). Four of 11 patients did not require any therapy. Six of seven patients did not relapse after balloon dilatation, but one patient required per-oral endoscopic myotomy 8 months after balloon dilatation. CONCLUSION All our achalasia patients without "esophageal rosette" had "Gingko leaf sign". It is possibly a useful endoscopic finding in achalasia patients without "esophageal rosette".
Collapse
Affiliation(s)
- Yoshimasa Hoshikawa
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Shintaro Hoshino
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Noriyuki Kawami
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Tomohide Tanabe
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Yuriko Hanada
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Nana Takenouchi
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Osamu Goto
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Mitsuru Kaise
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan
| | - Katsuhiko Iwakiri
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8603, Japan.
| |
Collapse
|
|
15
|
Nakane S, Umeda M, Kawashiri SY, Mukaino A, Ichinose K, Higuchi O, Maeda Y, Nakamura H, Matsuo H, Kawakami A. Detecting gastrointestinal manifestations in patients with systemic sclerosis using anti-gAChR antibodies. Arthritis Res Ther 2020; 22:32. [PMID: 32085768 PMCID: PMC7035754 DOI: 10.1186/s13075-020-2128-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/12/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. To clarify the pathogenesis of gastrointestinal manifestations, we aimed to demonstrate the association among the clinical features of SSc, the serological markers, the autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR). METHODS Fifty patients were enrolled and divided into two groups according to the presence or absence of gastrointestinal manifestations, and the characteristics were analyzed between these two groups. We measured biomarkers and the autoantibodies against two gAChRα3 and β4 subunits to test sera samples. Furthermore, patients were classified based on the presence or absence of anti-gAChR autoantibodies, and their clinical features were compared. RESULTS In patients with SSc and gastrointestinal manifestations, digital ulcers were more frequent (p = 0.050) and VEGF expression was significantly higher (p = 0.038). Seven subjects with SSc were seropositive for α3 subunit, whereas one patient was seropositive for β4 subunit. The mean level of anti-gAChRα3 autoantibodies in SSc patients with gastrointestinal manifestations was significantly higher than that in SSc patients without gastrointestinal manifestations (p = 0.001). The group of patients with SSc and gAChR autoantibodies had significantly higher endostatin levels (p = 0.046). CONCLUSIONS This study is the first to demonstrate that clinical characteristics of SSc patients with seropositivity for gAChR autoantibodies. Patients with SSc have circulating autoantibodies against gAChR, which may contribute to gastrointestinal manifestations associated with this disease, suggesting that gAChR-mediated autonomic neurotransmission may provide a pathomechanism for gastrointestinal dysmotility in SSc.
Collapse
Affiliation(s)
- Shunya Nakane
- Department of Neuroimmunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Nagasaki, Japan
- Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan
- Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, 1-1-1, Honjo, Chuouku, Kumamoto-shi, Kumamoto, 860-8556 Japan
| | - Masataka Umeda
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Shin-ya Kawashiri
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Akihiro Mukaino
- Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital, 1-1-1, Honjo, Chuouku, Kumamoto-shi, Kumamoto, 860-8556 Japan
- Department of Neurology and Strokology, Nagasaki University Hospital, Nagasaki, Japan
| | - Kunihiro Ichinose
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Osamu Higuchi
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Nagasaki, Japan
| | - Yasuhiro Maeda
- Department of Neuroimmunology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Department of Clinical Research, Nagasaki Kawatana Medical Center, Nagasaki, Japan
- Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan
| | - Hideki Nakamura
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hidenori Matsuo
- Department of Neurology, Nagasaki Kawatana Medical Center, Nagasaki, Japan
| | - Atsushi Kawakami
- Department of Immunology and Rheumatology, Unit of Translational Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| |
Collapse
|
|
16
|
López-Verdugo F, Furuzawa-Carballeda J, Romero-Hernández F, Coss-Adame E, Valdovinos MA, Priego-Ranero A, Olvera-Prado H, Narváez-Chavez S, Peralta-Figueroa J, Torres-Villalobos G. Hematological indices as indicators of silent inflammation in achalasia patients: A cross-sectional study. Medicine (Baltimore) 2020; 99:e19326. [PMID: 32118763 PMCID: PMC7478540 DOI: 10.1097/md.0000000000019326] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Complete blood count (CBC)-derived parameters such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), eosinophil-to-lymphocyte (ELR) ratio, and platelet-to-lymphocyte ratio (PLR) are sensitive markers of occult inflammation and disease activity for systemic lupus erythematosus, rheumatoid arthritis, psoriasis, esophageal cancer, etc. We assessed NLR, PLR, MLR, and ELR as indicators of inflammation in achalasia patients.This cross-sectional study included 103 achalasia patients and 500 healthy blood donor volunteers (HD). Demographic, clinical and laboratory information was collected. NLR, MLR, ELR and PLR were calculated. Peripheral Th22, Th17, Th2 and Th1 subsets were determined by flow cytometry. Correlation between hematologic indices and clinical questionnaires scores, HRM parameters and CD4+ T-cells were assessed. Hematologic parameters associated with the different achalasia subtypes were evaluated by logistic regression analysis.Hemoglobin, leukocytes, lymphocytes, monocytes, and platelets counts were significantly lower in achalasia patients vs controls. NLR (P = .006) and ELR (P < .05) were higher in achalasia patients vs controls. NLR was significantly associated with achalasia in multivariate analysis (P < .001). Compared to HD, the achalasia group was 1.804 times more likely to have higher NLR (95% CI 1.287-2.59; P < .001). GERD-HRQL score had statistically significant correlations with PLR (Pearson's rho:0.318, P = .003), and ELR (Pearson's rho:0.216; P = .044). No correlation between CD4+ T-cells and hematologic indices were determined. NLR with a cut-off value of ≥2.20 and area under the curve of 0.581 yielded a specificity of 80% and sensitivity of 40%, for the diagnosis of achalasia.NLR is increased in achalasia patients vs HD. Sensitivity and specificity achieved by NLR may contribute to a clinical and manometric evaluation. We suggest these indices as potential indicators of silent inflammation and disease activity.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | | | - Gonzalo Torres-Villalobos
- Department of Experimental Surgery
- Department of Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| |
Collapse
|
|
17
|
Cappell MS, Stavropoulos SN, Friedel D. Updated Systematic Review of Achalasia, with a Focus on POEM Therapy. Dig Dis Sci 2020; 65:38-65. [PMID: 31451984 DOI: 10.1007/s10620-019-05784-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Accepted: 08/07/2019] [Indexed: 02/06/2023]
Abstract
AIM To systematically review clinical presentation, diagnosis, and therapy of achalasia, focusing on recent developments in high-resolution esophageal manometry (HREM) for diagnosis and peroral endoscopic myotomy (POEM) for therapy. METHODS Systematic review of achalasia using computerized literature search via PubMed and Ovid of articles published since 2005 with keywords ("achalasia") AND ("high resolution" or "HREM" or "peroral endoscopic myotomy" or "POEM"). Two authors independently performed literature searches and incorporated articles into this review by consensus according to prospectively determined criteria. RESULTS Achalasia is an uncommon esophageal motility disorder, usually manifested by dysphagia to solids and liquids, and sometimes manifested by chest pain, regurgitation, and weight loss. Symptoms often suggest more common disorders, such as gastroesophageal reflux disease (GERD), thus often delaying diagnosis. Achalasia is a predominantly idiopathic chronic disease. Diagnosis is typically suggested by barium swallow showing esophageal dilation; absent distal esophageal peristalsis; smoothly tapered narrowing ("bird's beak") at esophagogastric junction; and delayed passage of contrast into stomach. Diagnostic findings at high-resolution esophageal manometry (HREM) include: distal esophageal aperistalsis and integrated relaxation pressure (trough LES pressure during 4 s) > 15 mmHg. Achalasia is classified by HREM into: type 1 classic; type 2 compartmentalized high pressure in esophageal body, and type 3 spastic. This classification impacts therapeutic decisions. Esophagogastroduodenoscopy is required before therapy to assess esophagus and esophagogastric junction and to exclude distal esophageal malignancy. POEM is a revolutionizing achalasia therapy. POEM creates a myotomy via interventional endoscopy. Numerous studies demonstrate that POEM produces comparable, if not superior, results compared to standard laparoscopic Heller myotomy (LHM), as determined by LES pressure, dysphagia frequency, Eckardt score, hospital length of stay, therapy durability, and incidence of GERD. Other therapies, including botulinum toxin injection and pneumatic dilation, have moderately less efficacy and much less durability than POEM. CONCLUSION This comprehensive review suggests that POEM is equivalent or perhaps superior to LHM for achalasia in terms of cost efficiency, hospital length of stay, and relief of dysphagia, with comparable side effects. The data are, however, not conclusive due to sparse long-term follow-up and lack of randomized comparative clinical trials. POEM therapy is currently limited by a shortage of trained endoscopists.
Collapse
Affiliation(s)
- Mitchell S Cappell
- Division of Gastroenterology and Hepatology, MOB #602, William Beaumont Hospital, 3535 W. Thirteen Mile Rd, Royal Oak, MI, 48073, USA.
- Oakland University William Beaumont School of Medicine, MOB #602, William Beaumont Hospital, 3535 W. Thirteen Mile Rd, Royal Oak, MI, 48073, USA.
| | | | - David Friedel
- Division of Gastroenterology, New York University Winthrop Medical Center, Mineola, NY, 11501, USA
| |
Collapse
|
|
18
|
Nakane S. [Autoimmune autonomic ganglionopathy]. Rinsho Shinkeigaku 2019; 59:783-790. [PMID: 31761837 DOI: 10.5692/clinicalneurol.cn-001354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder of widespread autonomic failure. Approximately half of the patients with AAG have the autoantibodies against the neuronal nicotinic acetylcholine receptor (AChR) in autonomic ganglia. These ganglionic AChR antibodies have the potential to mediate the synaptic transmission in sympathetic, parasympathetic, and enteric ganglia. Therefore, seropositive AAG patients exhibit various autonomic symptoms. Extra-autonomic manifestations (coexistence with brain involvement, sensory disturbance, endocrine disorders, autoimmune diseases and tumors) are present in many patients with AAG. The nicotinic AChRs comprise a family of abundantly expressed ligand-gated cation channels found throughout the central and peripheral nervous systems. Moreover, limited manifestations of autoimmune dysautonomia including autoimmune gastrointestinal dysmotility are newly recognized clinical entity. Although combined immunomodulatory therapy is beneficial for almost all patients with AAG, several case reports of some AAG patients with small benefit exist. This review focuses on the recent progress in the clinical approaches of AAG and its related disorders involving the role of autoantibodies and clinical practice.
Collapse
Affiliation(s)
- Shunya Nakane
- Department of Molecular Neurology and Therapeutics, Kumamoto University Hospital
| |
Collapse
|
|
19
|
Liu ZQ, Chen WF, Wang Y, Xu XY, Zeng YG, Lee Dillon D, Cheng J, Xu MD, Zhong YS, Zhang YQ, Yao LQ, Zhou PH, Li QL. Mast cell infiltration associated with loss of interstitial cells of Cajal and neuronal degeneration in achalasia. Neurogastroenterol Motil 2019; 31:e13565. [PMID: 30868687 DOI: 10.1111/nmo.13565] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 12/10/2018] [Accepted: 01/11/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Achalasia is a motility disorder of unknown etiology. Previous studies supported the hypothesis that autoimmune-mediated inflammatory responses produce inhibitory neuronal degeneration. This study was designed to explore the role of mast cells in achalasia. METHODS We collected information from 116 patients with achalasia who underwent peroral endoscopic myotomy between December 2016 and May 2017. Lower esophageal sphincter (LES) muscle biopsy was performed in all patients with achalasia, as well as 20 control subjects. The number of mast cells, interstitial cells of Cajal (ICCs), nNOS-positive cells, and S-100-positive cells in the LES were evaluated by immunohistochemistry. Pathological and clinical data were compared between groups. KEY RESULTS Compared with controls, the LES of patients with achalasia had significantly fewer ICCs, nNOS-positive cells, and S-100-positive cells and a higher number of mast cells (all P < 0.001). Furthermore, the increased mast cell infiltration was significantly associated with decreased ICCs, nNOS-positive cells, and S-100-positive cells in patients with achalasia (all P < 0.05). Clinically, the number of strongly positive mast cells was highest in patients with type I achalasia and lowest in those with type III achalasia (P < 0.001). In addition, patients with a history of autoimmune disease or viral infection had greater mast cell infiltration in the LES muscle (P = 0.040). CONCLUSIONS & INFERENCES In patients with achalasia, mast cell infiltration in the LES muscle is increased, in association with loss of ICCs and neuronal degeneration. Mast cells may thereby play a crucial role in the development of achalasia.
Collapse
Affiliation(s)
- Zu-Qiang Liu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Wei-Feng Chen
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yun Wang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Yue Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Gang Zeng
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dustin Lee Dillon
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California
| | - Jing Cheng
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mei-Dong Xu
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yun-Shi Zhong
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yi-Qun Zhang
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Li-Qing Yao
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ping-Hong Zhou
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Quan-Lin Li
- Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, China
| |
Collapse
|
|
20
|
Nguyen A, de Boysson H, Audrey F, Yameogo S, Aouba A. Chronic intestinal pseudo-obstruction with dilated biliary tract as a spectrum of stiff person syndrome in a nondiabetic patient. JOURNAL OF MUSCULOSKELETAL & NEURONAL INTERACTIONS 2019; 19:526-530. [PMID: 31789305 PMCID: PMC6944797] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Stiff person syndrome (SPS) is a rare and challenging neuromuscular junction disorder with typical musculoskeletal manifestations associated with anti-GAD65 antibodies, extra rheumatological manifestations, including neuropsychiatric symptoms and severe dysautonomic troubles. Chronic intestinal pseudo-obstruction (CIPO) is also a rare condition corresponding to a sub-occlusive syndrome, resulting from the functional or structural impairment of smooth neuromuscular tissues of the intestinal tract. In the clinical spectrum of SPS, CIPO has rarely been described and dilated biliary tract has never been described. This present report is therefore the first in the context of anti-GAD65 antibodies with the additional involvement of the biliary tract. Here, we report the case of a 44-year-old woman hospitalized for a rapidly progressive CIPO associated with dilated biliary tract, revealing a typical SPS with slowly progressive rheumatologic complaints relegated to the background. The concomitant improvement of the neuromuscular function on skeletal, intestinal and biliary tree systems with the good outcomes of anti-GAD65 titer under immunosuppressant drugs, allowed us to link all three organic involvements to the antibody pathogenicity on the respective neuromuscular junctions. Therefore, we discussed their common pathogeny based on our patient's treatment outcome.
Collapse
Affiliation(s)
- Alexandre Nguyen
- Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France
| | - Hubert de Boysson
- Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France
| | - Fohlen Audrey
- Department of Radiology, Caen University Hospital, France; Normandy University, Caen, France
| | - Seydou Yameogo
- Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France
| | - Achille Aouba
- Department of Internal Medicine, Caen University Hospital, France; Normandy University, Caen, France,Corresponding author: Achille Aouba, MD, PhD, Department of Internal Medicine, Caen University Hospital, Avenue de la Côte de Nacre, 14000 Caen, France E-mail:
| |
Collapse
|
|
21
|
Anti-ganglionic AChR antibodies in Japanese patients with motility disorders. J Gastroenterol 2018; 53:1227-1240. [PMID: 29766276 DOI: 10.1007/s00535-018-1477-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 05/08/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti-ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO). METHODS First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups. RESULTS In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia. CONCLUSIONS These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders.
Collapse
|
|
22
|
Nakane S, Mukaino A, Higuchi O, Watari M, Maeda Y, Yamakawa M, Nakahara K, Takamatsu K, Matsuo H, Ando Y. Autoimmune autonomic ganglionopathy: an update on diagnosis and treatment. Expert Rev Neurother 2018; 18:953-965. [PMID: 30352532 DOI: 10.1080/14737175.2018.1540304] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to autonomic failure. The disorder is associated with autoantibodies to the ganglionic nicotinic acetylcholine receptor (gAChR). We subsequently reported that AAG is associated with an overrepresentation of psychiatric symptoms, sensory disturbance, autoimmune diseases, and endocrine disorders. Area covered: The aim of this review was to describe AAG and highlight its pivotal pathophysiological aspects, clinical features, laboratory examinations, and therapeutic options. Expert commentary: AAG is a complex neuroimmunological disease, these days considered as an autonomic failure with extra-autonomic manifestations (and various limited forms). Further comprehension of the pathophysiology of this disease is required, especially the mechanisms of the extra-autonomic manifestations should be elucidated. There is the possibility that the co-presence of antibodies that were directed against the other subunits in both the central and peripheral nAChRs in the serum of the AAG patients. Some patients improve with immunotherapies such as IVIg and/or corticosteroid and/or plasma exchange. 123I-MIBG myocardial scintigraphy may be a useful tool to monitor the therapeutic effects of immunotherapies.
Collapse
Affiliation(s)
- Shunya Nakane
- a Department of Neurology, Graduate School of Medical Sciences , Kumamoto University , Kumamoto , Japan.,b Department of Molecular Neurology and Therapeutics , Kumamoto University Hospital , Kumamoto , Japan
| | - Akihiro Mukaino
- a Department of Neurology, Graduate School of Medical Sciences , Kumamoto University , Kumamoto , Japan.,b Department of Molecular Neurology and Therapeutics , Kumamoto University Hospital , Kumamoto , Japan
| | - Osamu Higuchi
- c Department of Neurology and Clinical Research , Nagasaki Kawatana Medical Center , Nagasaki , Japan
| | - Mari Watari
- a Department of Neurology, Graduate School of Medical Sciences , Kumamoto University , Kumamoto , Japan
| | - Yasuhiro Maeda
- c Department of Neurology and Clinical Research , Nagasaki Kawatana Medical Center , Nagasaki , Japan
| | - Makoto Yamakawa
- a Department of Neurology, Graduate School of Medical Sciences , Kumamoto University , Kumamoto , Japan
| | - Keiichi Nakahara
- a Department of Neurology, Graduate School of Medical Sciences , Kumamoto University , Kumamoto , Japan
| | - Koutaro Takamatsu
- a Department of Neurology, Graduate School of Medical Sciences , Kumamoto University , Kumamoto , Japan
| | - Hidenori Matsuo
- c Department of Neurology and Clinical Research , Nagasaki Kawatana Medical Center , Nagasaki , Japan
| | - Yukio Ando
- a Department of Neurology, Graduate School of Medical Sciences , Kumamoto University , Kumamoto , Japan
| |
Collapse
|
|
23
|
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
|
|
24
|
Ashat M, Lewis A, Liaquat H, Stocker A, McElmurray L, Vedanarayanan V, Soota K, Howell T, Kedar A, Obert J, Abell TL. Intravenous immunoglobulin in drug and device refractory patients with the symptoms of gastroparesis-an open-label study. Neurogastroenterol Motil 2018; 30. [PMID: 29205691 DOI: 10.1111/nmo.13256] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2017] [Accepted: 10/29/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gastroparesis is a complex clinical entity; many aspects of which remain unknown. Although most patients have idiopathic, diabetic, or postsurgical gastroparesis, many are thought to have measurable neuromuscular abnormalities. Immunotherapy has recently been utilized to treat suspected autoimmune gastrointestinal dysmotility. METHODS Fourteen patients with symptoms of gastroparesis (Gp) who were refractory to drug/device were selected from 443 Gp patients from 2013 to 2015 who were treated at the University of Louisville motility center. All patients underwent a structural and psychiatric evaluation along with detailed psychological and behavioral examination to rule out eating disorders. We performed detailed neuromuscular evaluation and all 14 patients received at least 12 weeks of intravenous immunoglobulin (400 mg/kg infusion weekly). Response was defined subjectively (symptomatic improvement) using standardized IDIOM score system. KEY RESULTS All 14 patients had serological evidence and/or tissue evidence of immunological abnormality. Post-IVIG therapy, there was a significant improvement in symptoms scores for nausea, vomiting, early satiety, and abdominal pain. CONCLUSIONS AND INFERENCES Although limited by the absence of placebo group, the data illustrate the role of autoimmunity and neuromuscular evaluation in patients with gastroparesis and support the utility of a diagnostic trial of immunotherapy in an effort to improve therapeutic outcomes for such patients.
Collapse
Affiliation(s)
- M Ashat
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Iowa, Iowa City, IA, USA
| | - A Lewis
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - H Liaquat
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - A Stocker
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - L McElmurray
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - V Vedanarayanan
- Division of Neuromuscular Medicine, University of Mississippi, Oxford, MS, USA
| | - K Soota
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Iowa, Iowa City, IA, USA
| | - T Howell
- GI Motility Clinic, Jewish Hospital, Louisville, KY, USA
| | - A Kedar
- Division of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - J Obert
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - T L Abell
- Division of Gastroenterology, Hepatology & Nutrition, Department of Medicine, Jewish Hospital GI Motility Clinic, University of Louisville, Louisville, KY, USA
| |
Collapse
|
|
25
|
Herzig MJ, Tutuian R. Focal achalasia - case report and review of the literature. ACTA ACUST UNITED AC 2018; 91:120-128. [PMID: 29440962 PMCID: PMC5808260 DOI: 10.15386/cjmed-867] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 08/30/2017] [Indexed: 12/22/2022]
Abstract
Esophageal achalasia is a primary smooth muscle motility disorder specified by aperistalsis of the tubular esophagus in combination with a poorly relaxing and occasionally hypertensive lower esophageal sphincter (LES). These changes occur secondary to the destruction of the neural network coordinating esophageal peristalsis and LES relaxation (plexus myentericus). There are limited data on segmental involvement of the esophagus in adults. We report on the case of a 54-year-old man who presented initially with complete aperistalsis limited to the distal esophagus. After a primary good response to BoTox-infiltration of the distal esophagus the patient relapsed two years later. The manometric recordings documented now a progression of the disease with a poorly relaxing hypertensive lower esophageal sphincter and complete aperistalsis of the tubular esophagus (type III achalasia according to the Chicago 3.0 classification system). This paper also reviews diagnostic findings (including high resolution manometry, CT scan, barium esophagram, upper endoscopy and upper endoscopic ultrasound data) in patients with achalasia and summarizes the therapeutic options (including pneumatic balloon dilatation, botulinum toxin injection, surgical or endoscopic myotomy).
Collapse
Affiliation(s)
| | - Radu Tutuian
- Gastroenterology Department, Tiefenauspital, Inselgruppe, Bern, Switzerland
| |
Collapse
|
|
26
|
Romero-Hernández F, Furuzawa-Carballeda J, Hernández-Molina G, Alejandro-Medrano E, Núñez-Álvarez CA, Hernández-Ramírez DF, Azamar-Llamas D, Olivares-Martínez E, Breña B, Palacios A, Valdovinos MA, Coss-Adame E, Ramos-Ávalos B, Torres-Landa S, Hernández-Ávila AA, Flores-Nájera A, Torres-Villalobos G. Autoimmune comorbidity in achalasia patients. J Gastroenterol Hepatol 2018; 33:203-208. [PMID: 28568312 DOI: 10.1111/jgh.13839] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 05/23/2017] [Accepted: 05/28/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Idiopathic achalasia is a rare esophageal motor disorder. The disease state manifests local and systemic inflammation, and it appears that an autoimmune component and specific autoantibodies participate in the pathogenesis. The study aims to determine the prevalence of autoimmune and chronic inflammatory diseases in patients with achalasia and compare the results with those from patients with gastroesophageal reflux disease (GERD). METHODS It was a cross-sectional and included 114 patients with idiopathic achalasia and 114 age-matched and sex-matched control patients with GERD. Data on the presence of autoimmune and inflammatory diseases, the time of presentation, and any family history of autoimmune disease were obtained from the hospital's medical records. RESULTS Seventy three (64%) were female patients (mean age: 42.3 ± 15.5; median disease duration: 12 months). We identified the presence of autoimmune disease in 19 patients with achalasia (16.7%), hypothyroidism was the main diagnosis, and it was present in 52.6% of patients compared with 4.2% in controls. Thirteen of the 19 achalasia patients (68.4%) with autoimmune disease had history of familial autoimmunity. We identified 11 achalasia (9.6%) and 5 GERD patients (4.16%) with an inflammatory condition. Compared with the GERD, the achalasia group was 3.8 times more likely to have an autoimmune disease (95% CI: 1.47-9.83), 3.0 times more likely to have thyroidopathies (95% CI: 1.00-9.03), and 3.02 times more likely to suffer from any chronic inflammatory disease (95% CI: 1.65-6.20). CONCLUSIONS The non-negligible number of patients with autoimmune diseases identified among the patients with idiopathic achalasia supports the hypothesis that achalasia has an autoimmune component.
Collapse
Affiliation(s)
- Fernanda Romero-Hernández
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Janette Furuzawa-Carballeda
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Gabriela Hernández-Molina
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Edgar Alejandro-Medrano
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Carlos A Núñez-Álvarez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Diego F Hernández-Ramírez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Daniel Azamar-Llamas
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Elizabeth Olivares-Martínez
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Blanca Breña
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Axel Palacios
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Miguel A Valdovinos
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Enrique Coss-Adame
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Bárbara Ramos-Ávalos
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Samuel Torres-Landa
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Axel A Hernández-Ávila
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Athenea Flores-Nájera
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Gonzalo Torres-Villalobos
- Department of Experimental Surgery, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| |
Collapse
|
|
27
|
Runggaldier D, Fried M, Pohl D. Recurrent episodes of esophageal candidiasis without dysphagia post-Guillain-Barré syndrome: an unusual presentation of achalasia. BMJ Case Rep 2017; 2017:bcr-2017-221751. [PMID: 29038193 DOI: 10.1136/bcr-2017-221751] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Here, we present a case of a 50-year-old male with a history of a Guillain-Barré-syndrome, who was referred to our clinic with recurrent esophageal candidiasis and long-standing intermittent retrosternal cramps for further evaluation. Other symptoms such as dysphagia, regurgitations and weight loss were denied, and prior repeated endoscopy was otherwise unremarkable. Using high resolution impedance manometry, we could demonstrate a panesophageal pressure increase on water swallows and complete aperistalsis of the tubular esophagus, indicating achalasia type II. However, due to the patient's extraordinary body height and resulting length of the esophagus, endoluminal functional lumen imaging probe analysis supplementary to high resolution impedance manometry needed to be used to assess distensibility of the esophagogastral junction and to secure the diagnosis of achalasia before appropriately treating the patient with pneumatic dilation.
Collapse
Affiliation(s)
- Daniel Runggaldier
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - Michael Fried
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | - Daniel Pohl
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| |
Collapse
|
|
28
|
Abstract
The pathophysiology of achalasia is largely unknown, and involves the destruction of ganglion cell in the esophageal myenteric plexus. High-resolution esophageal manometry is the key investigation. Endoscopic pneumodilatation and laparoscopic Heller myotomy have comparable short-term success rates, around 90%. The main complication after pneumodilatation is esophageal perforation, occurring in about 1% of cases. Peroral endoscopic myotomy is a promising treatment modality, however with frequent post-procedural gastroesophageal reflux.
Collapse
|
|
29
|
Tancredi A, Cuttitta A, Scaramuzzi R, Scaramuzzi G, Taurchini M. Esophageal Achalasia: Predictive Value of Preoperative Resting Pressure of LES Correlated with Type of Fundoplication. Eurasian J Med 2017; 49:1-6. [PMID: 28416923 DOI: 10.5152/eurasianjmed.2017.16151] [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: 11/22/2022] Open
Abstract
OBJECTIVE The aim of the present study is to show the predictive value of the preoperative resting pressure of the lower esophageal sphincter (LES) correlated with the type of fundoplication (Nissen or Dor) after Heller myotomy in our series. MATERIALS AND METHODS From January 1998 to June 2010, 88 patients affected by esophageal achalasia underwent surgery at our unit. However, our study focused on a sample of 36 patients, because many data were lost or was never recorded. Among these, 14 patients underwent laparoscopic Heller myotomy plus Nissen fundoplication (group N), whereas 22 patients underwent laparoscopic Heller myotomy plus Dor fundoplication (group D). Clinical evaluation was performed using a modified DeMeester symptom scoring system consisting of the assessment of three symptoms: dysphagia, regurgitation, and heartburn. To each symptom was assigned a score from 0 to 3, depending on its severity, and the reduction in the severity of each symptom after surgery was assessed. RESULTS The surgical treatment is considered to be effective (p<0.0001). The preoperative resting pressures of LES were compared by Student's t-test, and it was found that patients who reported a greater improvement in the dysphagia symptom had a preoperative average pressure of LES that was significantly higher than that in other patients in both group N (p=0.03) and group D (p=0.01; p=0.003; p=0.001). The Dor treatment was shown to be more effective than the Nissen treatment (p<0.0001). CONCLUSION The preoperative resting pressure of LES is a predictive factor of surgical success both before Dor fundoplication and before Nissen fundoplication, but its predictive power is influenced by the chosen type of fundoplication.
Collapse
Affiliation(s)
- Antonio Tancredi
- Department of General Surgery and Thoracic Surgery, IRCCS Casa Sollievo della Sofferenza Hospital, Foggia, Italy.,Department of Emergency, IRCCS Casa Sollievo della Sofferenza Hospital, Foggia, Italy
| | - Antonello Cuttitta
- Department of General Surgery and Thoracic Surgery, IRCCS Casa Sollievo della Sofferenza Hospital, Foggia, Italy
| | - Roberto Scaramuzzi
- Department of General Surgery and Thoracic Surgery, IRCCS Casa Sollievo della Sofferenza Hospital, Foggia, Italy.,Department of Emergency, IRCCS Casa Sollievo della Sofferenza Hospital, Foggia, Italy.,Department of Thoracic Surgery, Second University of Naples, Naples, Italy
| | - Gerardo Scaramuzzi
- Department of General Surgery and Thoracic Surgery, IRCCS Casa Sollievo della Sofferenza Hospital, Foggia, Italy
| | - Marco Taurchini
- Department of General Surgery and Thoracic Surgery, IRCCS Casa Sollievo della Sofferenza Hospital, Foggia, Italy
| |
Collapse
|
|
30
|
McKeon A, Tracy JA. GAD65 neurological autoimmunity. Muscle Nerve 2017; 56:15-27. [PMID: 28063151 DOI: 10.1002/mus.25565] [Citation(s) in RCA: 114] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 01/04/2017] [Indexed: 12/11/2022]
Abstract
The glutamic acid decarboxylase 65-kilodalton isoform (GAD65) antibody is a biomarker of autoimmune central nervous system (CNS) disorders and, more commonly, nonneurological autoimmune diseases. Type 1 diabetes, autoimmune thyroid disease, and pernicious anemia are the most frequent GAD65 autoimmune associations. One or more of these disorders coexists in approximately 70% of patients with GAD65 neurological autoimmunity. Neurological phenotypes have CNS localization and include limbic encephalitis, epilepsy, cerebellar ataxia, and stiff-person syndrome (SPS), among others. Classic SPS is a disorder on the spectrum of CNS hyperexcitability which also includes phenotypes that are either more restricted (stiff-limb syndrome) or more widespread (progressive encephalomyelitis with rigidity and myoclonus). GAD65 antibody is not highly predictive of a paraneoplastic cause for neurological disorders, but diverse cancer types have been occasionally reported. For all phenotypes, responses to immunotherapy are variable (approximately 50% improve). GAD65 autoimmunity is important to recognize for both coexisting nonneurological autoimmune associations and potential immunotherapy-response. Muscle Nerve 56: 15-27, 2017.
Collapse
Affiliation(s)
- Andrew McKeon
- Department of Neurology, College of Medicine, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, USA.,Department of Laboratory Medicine and Pathology, College of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Jennifer A Tracy
- Department of Neurology, College of Medicine, Mayo Clinic, 200 1st Street SW, Rochester, Minnesota, 55905, USA
| |
Collapse
|
|
31
|
Gockel I, Niebisch S, Becker J, Schumacher J, Müller M. [Current diagnosis and therapy of achalasia]. MMW Fortschr Med 2016; 158:80-83. [PMID: 27966122 DOI: 10.1007/s15006-016-9110-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Affiliation(s)
- Ines Gockel
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, AöR, Liebigstr. 20, D-04103, Leipzig, Deutschland.
| | - Stefan Niebisch
- Klinik für Viszeral-, Transplantations-, Thorax- und Gefäßchirurgie, Universitätsklinikum Leipzig, Leipzig, Deutschland
| | - Jessica Becker
- Institut für Humangenetik, Universität Bonn, Bonn, Deutschland
| | | | - Michaela Müller
- DKD Helios Klinik, Fachbereich Gastroenterologie, Wiesbaden, Deutschland
| |
Collapse
|
|
32
|
Furuzawa-Carballeda J, Torres-Landa S, Valdovinos M&A, Coss-Adame E, Martín del Campo LA, Torres-Villalobos G. New insights into the pathophysiology of achalasia and implications for future treatment. World J Gastroenterol 2016; 22:7892-7907. [PMID: 27672286 PMCID: PMC5028805 DOI: 10.3748/wjg.v22.i35.7892] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 07/06/2016] [Accepted: 08/05/2016] [Indexed: 02/06/2023] Open
Abstract
Idiopathic achalasia is an archetype esophageal motor disorder, causing significant impairment of eating ability and reducing quality of life. The pathophysiological underpinnings of this condition are loss of esophageal peristalsis and insufficient relaxation of the lower esophageal sphincter (LES). The clinical manifestations include dysphagia for both solids and liquids, regurgitation of esophageal contents, retrosternal chest pain, cough, aspiration, weight loss and heartburn. Even though idiopathic achalasia was first described more than 300 years ago, researchers are only now beginning to unravel its complex etiology and molecular pathology. The most recent findings indicate an autoimmune component, as suggested by the presence of circulating anti-myenteric plexus autoantibodies, and a genetic predisposition, as suggested by observed correlations with other well-defined genetic syndromes such as Allgrove syndrome and multiple endocrine neoplasia type 2 B syndrome. Viral agents (herpes, varicella zoster) have also been proposed as causative and promoting factors. Unfortunately, the therapeutic approaches available today do not resolve the causes of the disease, and only target the consequential changes to the involved tissues, such as destruction of the LES, rather than restoring or modifying the underlying pathology. New therapies should aim to stop the disease at early stages, thereby preventing the consequential changes from developing and inhibiting permanent damage. This review focuses on the known characteristics of idiopathic achalasia that will help promote understanding its pathogenesis and improve therapeutic management to positively impact the patient’s quality of life.
Collapse
|
|
33
|
Brosens E, Burns AJ, Brooks AS, Matera I, Borrego S, Ceccherini I, Tam PK, García-Barceló MM, Thapar N, Benninga MA, Hofstra RMW, Alves MM. Genetics of enteric neuropathies. Dev Biol 2016; 417:198-208. [PMID: 27426273 DOI: 10.1016/j.ydbio.2016.07.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 07/13/2016] [Accepted: 07/13/2016] [Indexed: 12/23/2022]
Abstract
Abnormal development or disturbed functioning of the enteric nervous system (ENS), the intrinsic innervation of the gastrointestinal tract, is associated with the development of neuropathic gastrointestinal motility disorders. Here, we review the underlying molecular basis of these disorders and hypothesize that many of them have a common defective biological mechanism. Genetic burden and environmental components affecting this common mechanism are ultimately responsible for disease severity and symptom heterogeneity. We believe that they act together as the fulcrum in a seesaw balanced with harmful and protective factors, and are responsible for a continuum of symptoms ranging from neuronal hyperplasia to absence of neurons.
Collapse
Affiliation(s)
- Erwin Brosens
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
| | - Alan J Burns
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands; Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Institute of Child Health, London, UK
| | - Alice S Brooks
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Ivana Matera
- UOC Medical Genetics, Istituto Giannina Gaslini, Genova, Italy
| | - Salud Borrego
- Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), Seville, Spain; Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain
| | | | - Paul K Tam
- Division of Paediatric Surgery, Department of Surgery, Li Ka Shing Faculty of Medicine of the University of Hong Kong, Hong Kong, China
| | - Maria-Mercè García-Barceló
- State Key Laboratory of Brain and Cognitive Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China; Centre for Reproduction, Development, and Growth, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Nikhil Thapar
- Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Institute of Child Health, London, UK
| | - Marc A Benninga
- Pediatric Gastroenterology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands
| | - Robert M W Hofstra
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands; Stem Cells and Regenerative Medicine, Birth Defects Research Centre, UCL Institute of Child Health, London, UK
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus University Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands
| |
Collapse
|
|
34
|
Maier A, Mannartz V, Wasmuth H, Trautwein C, Neumann UP, Weis J, Grosse J, Fuest M, Hilz MJ, Schulz JB, Haubrich C. GAD Antibodies as Key Link Between Chronic Intestinal Pseudoobstruction, Autonomic Neuropathy, and Limb Stiffness in a Nondiabetic Patient: A CARE-Compliant Case Report and Review of the Literature. Medicine (Baltimore) 2015; 94:e1265. [PMID: 26252289 PMCID: PMC4616576 DOI: 10.1097/md.0000000000001265] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Chronic intestinal pseudoobstruction (CIP) can be a severe burden and even a life-threatening disorder. Typically, several years of uncertainty are passing before diagnosis. We are reporting the case of a young woman with a decade of severe, progressive gastrointestinal dysmotility. Unusually, she had also developed an autonomic neuropathy, and a stiff limb syndrome.In addition to achalasia and CIP the young woman also developed neuropathic symptoms: orthostatic intolerance, urinary retention, a Horner syndrome, and lower limb stiffness. Careful interdisciplinary diagnostics excluded underlying infectious, rheumatoid, metabolic or tumorous diseases.The detection of GAD (glutamic acid decarboxylase) antibodies, however, seemed to link CIP, autonomic neuropathy, and limb stiffness and pointed at an autoimmune origin of our patient's complaints. This was supported by the positive effects of intravenous immunoglobulin. In response to this therapy the body weight had stabilized, orthostatic tolerance had improved, and limb stiffness was reversed.The case suggested that GAD antibodies should be considered in CIP also in nondiabetic patients. This may support earlier diagnosis and immunotherapy.
Collapse
Affiliation(s)
- Andrea Maier
- From the Department of Neurology (AM, VM, JBS, CH), University Hospital RWTH Aachen,; Department of Medicine (HW), Luisenhospital Aachen; Department of Gastroenterology (CT), University Hospital RWTH Aachen; Department of Visceral Surgery (U-PN), University Hospital RWTH Aachen; Institute of Neuropathology (JW), University Hospital RWTH Aachen; Department of Urology (JG), University Hospital RWTH Aachen; Department of Ophthalmology (MF), University Hospital RWTH Aachen); and Department of Neurology (M-JH), Erlangen University Hospital, Germany
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Achalasia--An Autoimmune Inflammatory Disease: A Cross-Sectional Study. J Immunol Res 2015; 2015:729217. [PMID: 26078981 PMCID: PMC4452860 DOI: 10.1155/2015/729217] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 03/24/2015] [Accepted: 04/14/2015] [Indexed: 02/08/2023] Open
Abstract
Idiopathic achalasia is a disease of unknown etiology. The loss of myenteric plexus associated with inflammatory infiltrates and autoantibodies support the hypothesis of an autoimmune mechanism. Thirty-two patients diagnosed by high-resolution manometry with achalasia were included. Twenty-six specimens from lower esophageal sphincter muscle were compared with 5 esophagectomy biopsies (control). Immunohistochemical (biopsies) and flow cytometry (peripheral blood) analyses were performed. Circulating anti-myenteric autoantibodies were evaluated by indirect immunofluorescence. Herpes simplex virus-1 (HSV-1) infection was determined by in situ hybridization, RT-PCR, and immunohistochemistry. Histopathological analysis showed capillaritis (51%), plexitis (23%), nerve hypertrophy (16%), venulitis (7%), and fibrosis (3%). Achalasia tissue exhibited an increase in the expression of proteins involved in extracellular matrix turnover, apoptosis, proinflammatory and profibrogenic cytokines, and Tregs and Bregs versus controls (P < 0.001). Circulating Th22/Th17/Th2/Th1 percentage showed a significant increase versus healthy donors (P < 0.01). Type III achalasia patients exhibited the highest inflammatory response versus types I and II. Prevalence of both anti-myenteric antibodies and HSV-1 infection in achalasia patients was 100% versus 0% in controls. Our results suggest that achalasia is a disease with an important local and systemic inflammatory autoimmune component, associated with the presence of specific anti-myenteric autoantibodies, as well as HSV-1 infection.
Collapse
|
|
36
|
Cuttitta A, Tancredi A, Andriulli A, De Santo E, Fontana A, Pellegrini F, Scaramuzzi R, Scaramuzzi G. Fundoplication after heller myotomy: a retrospective comparison between nissen and dor. Eurasian J Med 2015; 43:133-40. [PMID: 25610181 DOI: 10.5152/eajm.2011.31] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2011] [Accepted: 10/24/2011] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE A retrospective comparison between Nissen and Dor fundoplication after laparoscopic Heller myotomy for achalasia. MATERIALS AND METHODS From 1998 to 2004 a first group of 48 patients underwent Heller myotomy and Nissen fundoplication for idiopathic achalasia (H+N group). From 2004 to 2010 a second group of 40 patients underwent Heller myotomy followed by Dor fundoplication (H+D group). Some patients received a previous endoscopic treatment with pneumatic dilatation or endoscopic injection of botulinum toxin that provided them only a temporary clinical benefit. Changes in clinical and instrumental examinations from before to after surgery were evaluated in all patients. Clinical evaluation was carried out using a modified DeMeester symptom score system. RESULTS Dor fundoplication treatment reduced both dysphagia and regurgitation severity scores significantly more than Nissen fundoplication (p<0.0001). Indeed, the incidence of dysphagia was significantly higher in patients treated with floppy-Nissen than in those treated with Dor fundoplication: by defining dysphagia as a DeMeester score equal to 3 (arbitrary cut-off), at the end of follow-up dysphagia occurred in 17.65% and 0% (p=0.037) of patients belonging to the H+N and H+D groups, respectively. CONCLUSION Heller myotomy followed by Dor fundoplication is a safe and valuable treatment. The procedure showed a lower incidence of postoperative dysphagia versus Nissen fundoplication and a negligible incidence of postoperative GERD in a long-term postoperative follow-up.
Collapse
Affiliation(s)
- Antonello Cuttitta
- Unit of General Surgery 2 and Thoracic Surgery, IRCCS "Casa Sollievo della Soff erenza" Hospital, Viale Cappuccini, San Giovanni Rotondo, FG, Italy
| | - Antonio Tancredi
- Unit of General Surgery 2 and Thoracic Surgery, IRCCS "Casa Sollievo della Soff erenza" Hospital, Viale Cappuccini, San Giovanni Rotondo, FG, Italy ; PhD School in Internal Medicine and Medical Therapy, Department of Internal Medicine and Medical Therapy, University of Pavia, Piazzale Golgi, Pavia, PV, Italy
| | - Angelo Andriulli
- Unit of Gastroenterology, IRCCS "Casa Sollievo della Soff erenza" Hospital, Viale Cappuccini, San Giovanni Rotondo, FG, Italy
| | - Ermelinda De Santo
- Unit of Gastroenterology, IRCCS "Casa Sollievo della Soff erenza" Hospital, Viale Cappuccini, San Giovanni Rotondo, FG, Italy
| | - Andrea Fontana
- Unit of Biostatistics, IRCCS "Casa Sollievo della Soff erenza" Hospital-Viale Cappuccini, San Giovanni Rotondo, FG, Italy
| | - Fabio Pellegrini
- Unit of Biostatistics, IRCCS "Casa Sollievo della Soff erenza" Hospital-Viale Cappuccini, San Giovanni Rotondo, FG, Italy ; Laboratory of Clinical Epidemiology of Diabetes and Chronic Diseases, Consorzio Mario Negri Sud-Via Nazionale, Santa Maria Imbaro, CH, Italy
| | - Roberto Scaramuzzi
- Unit of General Surgery 2 and Thoracic Surgery, IRCCS "Casa Sollievo della Soff erenza" Hospital, Viale Cappuccini, San Giovanni Rotondo, FG, Italy ; Graduate School of Medicine, Catholic University of the Sacred Heart - Largo Francesco Vito, Rome, Italy
| | - Gerardo Scaramuzzi
- Unit of General Surgery 2 and Thoracic Surgery, IRCCS "Casa Sollievo della Soff erenza" Hospital, Viale Cappuccini, San Giovanni Rotondo, FG, Italy
| |
Collapse
|
|
37
|
Wouters MM, Lambrechts D, Becker J, Cleynen I, Tack J, Vigo AG, Ruiz de León A, Urcelay E, Pérez de la Serna J, Rohof W, Annese V, Latiano A, Palmieri O, Mattheisen M, Mueller M, Lang H, Fumagalli U, Laghi L, Zaninotto G, Cuomo R, Sarnelli G, Nöthen MM, Vermeire S, Knapp M, Gockel I, Schumacher J, Boeckxstaens GE. Genetic variation in the lymphotoxin-α (LTA)/tumour necrosis factor-α (TNFα) locus as a risk factor for idiopathic achalasia. Gut 2014; 63:1401-1409. [PMID: 24259423 DOI: 10.1136/gutjnl-2013-304848] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility. METHODS 391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r(2)>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran-Armitage trend test. RESULTS The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication. CONCLUSIONS Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.
Collapse
Affiliation(s)
- Mira M Wouters
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Diether Lambrechts
- Vesalius Research Center, VIB, Leuven University, Leuven, Belgium Laboratory for Translational Genetics, University of Leuven, Leuven, Belgium
| | - Jessica Becker
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Isabelle Cleynen
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Ana G Vigo
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Antonio Ruiz de León
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Elena Urcelay
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Julio Pérez de la Serna
- Immunology and Gastroenterology Departments, Instituto de Investigacion Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain
| | - Wout Rohof
- Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands
| | - Vito Annese
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy Unit of Gastroenterology SOD2, Azienda Ospedaliera Universitaria, Careggi, Firenze, Italy
| | - Anna Latiano
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy
| | - Orazio Palmieri
- Division of Gastroenterology, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo, Italy
| | - Manuel Mattheisen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany Institute for Genomic Mathematics, University of Bonn, Bonn, Germany Department of Biostatistics, Harvard School of Public Health, Boston, USA
| | - Michaela Mueller
- Department of Gastroenterology, German Clinic of Diagnostics, Wiesbaden, Germany
| | - Hauke Lang
- Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
| | - Uberto Fumagalli
- Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy
| | - Luigi Laghi
- Department of Gastroenterology, Humanitas Clinical and Research Center-Istituto Clinico Humanitas IRCCS, Milan, Italy
| | - Giovanni Zaninotto
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy
| | - Rosario Cuomo
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
| | - Giovanni Sarnelli
- Gastroenterology Unit, Department of Clinical and Experimental Medicine, Federico II University, Napoli, Italy
| | - Markus M Nöthen
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Séverine Vermeire
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Michael Knapp
- Institute for Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany
| | - Ines Gockel
- Department of General, Visceral and Transplant Surgery, University Medical Center of Mainz, Mainz, Germany
| | - Johannes Schumacher
- Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Guy E Boeckxstaens
- Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| |
Collapse
|
|
38
|
O’Neill OM, Johnston BT, Coleman HG. Achalasia: a review of clinical diagnosis, epidemiology, treatment and outcomes. World J Gastroenterol 2013; 19:5806-5812. [PMID: 24124325 PMCID: PMC3793135 DOI: 10.3748/wjg.v19.i35.5806] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 06/30/2013] [Accepted: 07/18/2013] [Indexed: 02/06/2023] Open
Abstract
Achalasia is a neurodegenerative motility disorder of the oesophagus resulting in deranged oesophageal peristalsis and loss of lower oesophageal sphincter function. Historically, annual achalasia incidence rates were believed to be low, approximately 0.5-1.2 per 100000. More recent reports suggest that annual incidence rates have risen to 1.6 per 100000 in some populations. The aetiology of achalasia is still unclear but is likely to be multi-factorial. Suggested causes include environmental or viral exposures resulting in inflammation of the oesophageal myenteric plexus, which elicits an autoimmune response. Risk of achalasia may be elevated in a sub-group of genetically susceptible people. Improvement in the diagnosis of achalasia, through the introduction of high resolution manometry with pressure topography plotting, has resulted in the development of a novel classification system for achalasia. This classification system can evaluate patient prognosis and predict responsiveness to treatment. There is currently much debate over whether pneumatic dilatation is a superior method compared to the Heller's myotomy procedure in the treatment of achalasia. A recent comparative study found equal efficacy, suggesting that patient preference and local expertise should guide the choice. Although achalasia is a relatively rare condition, it carries a risk of complications, including aspiration pneumonia and oesophageal cancer. The risk of both squamous cell carcinoma and adenocarcinoma of the oesophagus is believed to be significantly increased in patients with achalasia, however the absolute excess risk is small. Therefore, it is currently unknown whether a surveillance programme in achalasia patients would be effective or cost-effective.
Collapse
|
|
39
|
Quidute ARP, Freitas EVD, Lima TGD, Feitosa AML, Santos JPD, Correia JW. Achalasia and thyroid disease: possible autoimmune connection? ACTA ACUST UNITED AC 2013; 56:677-82. [PMID: 23329193 DOI: 10.1590/s0004-27302012000900013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2012] [Accepted: 10/02/2012] [Indexed: 02/14/2023]
Abstract
Many cases have been published showing a co-existence of autoimmune thyroid diseases (AITDs) and other autoimmune diseases. About a quarter of patients with achalasia have a concurrent thyroid disease, most commonly associated with hypothyroidism. Although relatively rare, the association of achalasia and hyperthyroidism requires attention. The physiopathology of Grave's Disease (GD) involves B- and T-mediator lymphocytes, which have an affinity for known thyroid antigens: thyroglobulin, thyroid-peroxidase, and thyrotrophin receptor. Currently, however, the real physiopathogenesis of achalasia continues to be unknown. Some important findings are suggestive of an autoimmune mechanism: significant infiltration of the myoenteric plexus by monocytes, presence of the class II-Human Histocompatibility Complex DQwl antigen and antibodies to myoenteric neurons. The present case reports a patient who, despite testing negative for Chagas' disease, had achalasia, progressed to developing significant wasting and worsening of his quality of life, was later diagnosed with hyperthyroidism. After endoscopic esophageal dilatation and radioiodine ablation of the thyroid gland, there was great improvement in the patient clinical condition.
Collapse
|
|
40
|
Meeusen JW, Haselkorn KE, Fryer JP, Kryzer TJ, Gibbons SJ, Xiao Y, Lennon VA. Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active immunization model in mice. Neurogastroenterol Motil 2013; 25:84-8.e10. [PMID: 23072523 PMCID: PMC3535544 DOI: 10.1111/nmo.12030] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Autoimmune gastrointestinal dysmotility (AGID) is a limited form of dysautonomia. The only proven effector to date is IgG specific for ganglionic nicotinic-acetylcholine receptors containing α3 subunits [α3*- nicotinic acetylcholine receptor (nAChR)]. Rabbits immunized with recombinant α3-polypeptide produce α3*-nAChR autoantibodies, and profound AGID ensues. Human and rabbit α3*-nAChR-specific-IgGs induce transient hypomotility when injected into mice. Here, we describe success and problems encountered inducing gastrointestinal hypomotility in mice by active immunization. METHODS We repeatedly injected young adult mice of seven different strains susceptible to autoimmunity (spontaneous diabetes or neural antigen immunization-induced myasthenia gravis or encephalomyelitis) with: (i) α3-polypeptide, intradermally or (ii) live α3*-nAChR-expressing xenogeneic cells, intraperitoneally. We measured serum α3*-nAChR-IgG twice monthly, and terminally assessed blue dye gastrointestinal transit, total small intestinal α3*-nAChR content (radiochemically) and myenteric plexus neuron numbers (immunohistochemically, ileal-jejunal whole-mount preparations). KEY RESULTS Standard cutaneous inoculation with α3-polypeptide was minimally immunogenic, regardless of dose. Intraperitoneally injected live cells were potently immunogenic. Self-reactive α3*-nAChR-IgG was induced only by rodent immunogen; small intestinal transit slowing and enteric α3*-nAChR loss required high serum levels. Ganglionic neurons were not lost. CONCLUSIONS & INFERENCES Autoimmune gastrointestinal dysmotility is inducible in mice by active immunization. Accompanying enteric α3*-nAChR reduction without neuronal death is consistent with an IgG-mediated rather than T cell-mediated pathogenesis, as is improvement of symptoms in patients receiving antibody-depleting therapies.
Collapse
Affiliation(s)
- Jeffrey W. Meeusen
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | | | - James P. Fryer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Thomas J. Kryzer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
| | - Simon J. Gibbons
- Department of Enteric Neuroscience Program, Mayo Clinic, Rochester, MN
| | - Yingxian Xiao
- Department of Pharmacology and Physiology, Georgetown University School of Medicine, Washington, DC
| | - Vanda A. Lennon
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN,Department of Immunology, Mayo Clinic, Rochester, MN,Department of Neurology, Mayo Clinic, Rochester, MN
| |
Collapse
|
|
41
|
Kallel-Sellami M, Karoui S, Romdhane H, Laadhar L, Serghini M, Boubaker J, Lahmar H, Filali A, Makni S. Circulating antimyenteric autoantibodies in Tunisian patients with idiopathic achalasia. Dis Esophagus 2012; 26:782-7. [PMID: 22947106 DOI: 10.1111/j.1442-2050.2012.01398.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The physiopathology of idiopathic achalasia is still unknown. The description of circulating antimyenteric autoantibodies (CAA), directed against enteric neurons in sera of patients, suggests an autoimmune process. Recent data showed controversies according to the existence and the significance of CAA. The aims of this study were to investigate whether CAA are detected in Tunisian patients with idiopathic achalasia and to look for associated clinical or manometrical factors with CAA positivity. Twenty-seven patients with idiopathic achalasia and 57 healthy controls were prospectively studied. CAA were assessed by indirect immunofluorescence on intestinal monkey tissue sections. Western blot on primate cerebellum protein extract and dot technique with highly purified recombinant neuronal antigens (Hu, Ri, and Yo) were further used to analyze target antigens of CAA. CAA were significantly increased in achalasia patients compared with controls when considering nuclear or cytoplasmic fluorescence patterns. (33% vs. 12%, P = 0.03 and 48% vs. 23%, P = 0.001 respectively). By immunoblot analysis, CAA did not target neuronal antigens, however 52/53 and 49 kDa bands were consistently detected. CAA positivity was not correlated to specific clinical features. The results are along with previous studies demonstrating high CAA prevalence in achalasia patients. When reviewing technical protocols and interpretation criteria, several discrepancies which could explain controversies between studies were noted.
Collapse
|
|
42
|
Hubball AW, Lang B, Souza MAN, Curran OD, Martin JE, Knowles CH. Voltage-gated potassium channel (K(v) 1) autoantibodies in patients with chagasic gut dysmotility and distribution of K(v) 1 channels in human enteric neuromusculature (autoantibodies in GI dysmotility). Neurogastroenterol Motil 2012; 24:719-e344. [PMID: 22591165 DOI: 10.1111/j.1365-2982.2012.01924.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Autoantibodies directed against specific neuronal antigens are found in a significant number of patients with gastrointestinal neuromuscular diseases (GINMDs) secondary to neoplasia. This study examined the presence of antineuronal antibodies in idiopathic GINMD and GINMD secondary to South American Trypanosomiasis. The GI distribution of voltage-gated potassium channels (VGKCs) was also investigated. METHODS Seventy-three patients were included in the study with diagnoses of primary achalasia, enteric dysmotility, chronic intestinal pseudo-obstruction, esophageal or colonic dysmotility secondary to Chagas' disease. Sera were screened for specific antibodies to glutamic acid decarboxylase, voltage-gated calcium channels (VGCCs; P/Q subtype), nicotinic acetylcholine receptors (nAChRs; α3 subtype), and voltage-gated potassium channels (VGKCs, K(V) 1 subtype) using validated immunoprecipitation assays. The distribution of six VGKC subunits (K(V) 1.1-1.6), including those known to be antigenic targets of anti-VGKC antibodies was immunohistochemically investigated in all main human GI tract regions. KEY RESULTS Three patients (14%) with chagasic GI dysmotility were found to have positive anti-VGKC antibody titers. No antibodies were detected in patients with idiopathic GINMD. The VGKCs were found in enteric neurons at every level of the gut in unique yet overlapping distributions. The VGKC expression in GI smooth muscle was found to be limited to the esophagus. CONCLUSIONS & INFERENCES A small proportion of patients with GI dysfunction secondary to Chagas' disease have antibodies against VGKCs. The presence of these channels in the human enteric nervous system may have pathological relevance to the growing number of GINMDs with which anti-VGKC antibodies have been associated.
Collapse
Affiliation(s)
- A W Hubball
- Wingate Institute for Neurogastroenterology, Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, London, UK
| | | | | | | | | | | |
Collapse
|
|
43
|
Quek AML, Britton JW, McKeon A, So E, Lennon VA, Shin C, Klein C, Watson RE, Kotsenas AL, Lagerlund TD, Cascino GD, Worrell GA, Wirrell EC, Nickels KC, Aksamit AJ, Noe KH, Pittock SJ. Autoimmune epilepsy: clinical characteristics and response to immunotherapy. ARCHIVES OF NEUROLOGY 2012; 69:582-93. [PMID: 22451162 PMCID: PMC3601373 DOI: 10.1001/archneurol.2011.2985] [Citation(s) in RCA: 237] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
OBJECTIVE To describe clinical characteristics and immunotherapy responses in patients with autoimmune epilepsy. DESIGN Observational, retrospective case series. SETTING Mayo Clinic Health System. PATIENTS Thirty-two patients with an exclusive (n=11) or predominant (n=21) seizure presentation in whom an autoimmune etiology was suspected (on the basis of neural autoantibody [91%], inflammatory cerebrospinal fluid [31%], or magnetic resonance imaging suggesting inflammation [63%]) were studied. All had partial seizures: 81% had failed treatment with 2 or more antiepileptic drugs and had daily seizures and 38% had seizure semiologies that were multifocal or changed with time. Head magnetic resonance imaging was normal in 15 (47%) at onset. Electroencephalogram abnormalities included interictal epileptiform discharges in 20; electrographic seizures in 15; and focal slowing in 13. Neural autoantibodies included voltage-gated potassium channel complex in 56% (leucine-rich, glioma-inactivated 1 specific, 14; contactin-associated proteinlike 2 specific, 1); glutamic acid decarboxylase 65 in 22%; collapsin response- mediator protein 5 in 6%; and Ma2, N-methyl-D-aspartate receptor, and ganglionic acetylcholine receptor in 1 patient each. INTERVENTION Immunotherapy with intravenous methylprednisolone; intravenous immune globulin; and combinations of intravenous methylprednisolone, intravenous immune globulin, plasmapheresis, or cyclophosphamide. MAIN OUTCOME MEASURE Seizure frequency. RESULTS After a median interval of 17 months (range, 3-72 months), 22 of 27 (81%) reported improvement postimmunotherapy; 18 were seizure free. The median time from seizure onset to initiating immunotherapy was 4 months for responders and 22 months for nonresponders (P<.05). All voltage-gated potassium channel complex antibody-positive patients reported initial or lasting benefit (P<.05). One voltage-gated potassium channel complex antibody-positive patient was seizure free after thyroid cancer resection; another responded to antiepileptic drug change alone. CONCLUSION When clinical and serological clues suggest an autoimmune basis for medically intractable epilepsy, early-initiated immunotherapy may improve seizure outcome.
Collapse
Affiliation(s)
- Amy M L Quek
- Department of Laboratory Medicine and Pathology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
44
|
Pittock SJ, Lennon VA, Dege CL, Talley NJ, Locke GR. Neural autoantibody evaluation in functional gastrointestinal disorders: a population-based case-control study. Dig Dis Sci 2011; 56:1452-9. [PMID: 21181442 PMCID: PMC3089890 DOI: 10.1007/s10620-010-1514-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2010] [Accepted: 11/22/2010] [Indexed: 12/17/2022]
Abstract
BACKGROUND Our goal is to investigate the serum profile of neural autoantibodies in community-based patients with irritable bowel syndrome (IBS) or functional dyspepsia. The pathogenesis of functional gastrointestinal (GI) disorders, including IBS and dyspepsia, are unknown. Theories range from purely psychological to autoimmune alterations in GI tract neuromuscular function. METHODS The study subjects, based in Olmsted County, MN, reported symptoms of functional dyspepsia or IBS (n = 69), or were asymptomatic controls (n = 64). Their coded sera were screened for antibodies targeting neuronal, glial, and muscle autoantigens. RESULTS The prevalence of neural autoantibodies with functional GI disorders did not differ significantly from controls (17% vs. 13%; P = 0.43). In no case was a neuronal or glial nuclear autoantibody or enteric neuronal autoantibody identified. Neuronal cation channel antibodies were identified in 9% of cases (voltage-gated potassium channel [VGKC] in one dyspepsia case and one IBS case, ganglionic acetylcholine receptor [AChR] in four IBS cases) and in 6% of controls (ganglionic AChR in one, voltage-gated calcium channel [VGCC], N-type, in two and VGKC in one; P = 0.36). The frequency of glutamic acid decarboxylase-65 (GAD65) autoantibodies was similar in cases (10%) and controls (5%; P = 0.23). CONCLUSIONS Our data do not support neural autoimmunity as the basis for most IBS or functional dyspepsia cases.
Collapse
Affiliation(s)
- Sean J Pittock
- Division of Multiple Sclerosis and Autoimmune Neurology, Department of Neurology, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905, USA.
| | | | | | | | | |
Collapse
|
|
45
|
Sadowski DC, Ackah F, Jiang B, Svenson LW. Achalasia: incidence, prevalence and survival. A population-based study. Neurogastroenterol Motil 2010; 22:e256-61. [PMID: 20465592 DOI: 10.1111/j.1365-2982.2010.01511.x] [Citation(s) in RCA: 241] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Studies of achalasia epidemiology are important as they often yield new insights into disease etiology. In this study, our objective was to carry out the first North American population-based study of achalasia epidemiology using a governmental administrative database. METHODS All residents in the province of Alberta, Canada receive universal healthcare coverage as a benefit. The provincial health ministry, Alberta Health and Wellness, maintains a central stakeholder database of patient demographic information and physician billing claims. We defined an achalasia case as a billing claim submitted for the years 1996-2007 with an ICD-9-CM code of 530.0 or 530 and a Canadian Classification of Procedure treatment code of 54.92A (endoscopic balloon dilation) or 54.6 (esophagomyotomy). A preliminary validation study of the case definition demonstrated a sensitivity of 85% and specificity of 99% for known cases and controls. KEY RESULTS A total of 463 achalasia cases were identified from 1995 to 2008 (59.6% males). Mean age at diagnosis was 53.1 years. In 2007, the achalasia incidence was 1.63/100,000 (95% CI 1.20, 2.06) and the prevalence was 10.82/100,000 (95% CI 9.70, 11.93). We observed a steady increase in the overall prevalence rate from 2.51/100,000 in 1996 to 10.82/100,000 in 2007. Survival of achalasia cases was significantly less than age-sex matched population controls (P < 0.0001). CONCLUSIONS & INFERENCES Using a population-based approach, the incidence and prevalence of treated achalasia is 1.63/100,000 and 10.82/100,000, respectively. The disease appears to have a stable incidence but a rising prevalence. Survival of achalasia cases is significantly less than age-matched healthy controls.
Collapse
Affiliation(s)
- D C Sadowski
- GI Motility Laboratory, Royal Alexandra Hospital, University of Alberta, Edmonton, AB, Canada.
| | | | | | | |
Collapse
|
|
46
|
Affiliation(s)
- Dawn L Francis
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA
| | | |
Collapse
|
|
47
|
Chamberlain JL, Pittock SJ, Oprescu AM, Dege C, Apiwattanakul M, Kryzer TJ, Lennon VA. Peripherin-IgG association with neurologic and endocrine autoimmunity. J Autoimmun 2010; 34:469-77. [PMID: 20061119 PMCID: PMC2902873 DOI: 10.1016/j.jaut.2009.12.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2009] [Revised: 11/12/2009] [Accepted: 12/06/2009] [Indexed: 11/17/2022]
Abstract
Peripherin-IgG has been reported a pertinent autoantibody in non-obese type 1 diabetic (NOD) mice. However, it has not previously been recognized in any human disease. In blinded evaluation of serum for markers of neurological autoimmunity in a high-volume diagnostic laboratory, we incidentally identified 26 patients (61% female) with an IgG that bound selectively to neural elements in enteric ganglia, sympathetic nerve trunks and discrete nerve tracts in mid-brain and hind-brain. The target antigen was identified as peripherin, a 55kDa - type III intermediate filament protein. Review of clinical histories revealed that 54% of seropositive patients had dysautonomia (predominantly gastrointestinal dysmotility), 30% had neuropathies with varied sensory symptoms and 35% had clinical or serological evidence of endocrinopathy (type 1 diabetes, thyroiditis or premature ovarian failure). Collectively, 73% had autonomic dysfunction or endocrinopathy. None of 173 healthy subjects was seropositive. Subsequent western blot evaluation of archival sera from patients with small fiber/autonomic neuropathies (with or without endocrinopathy) revealed a 33% seropositivity rate for peripherin-IgG. Our further demonstration that peripherin-immunoreactive autonomic fibers in pancreas, thyroid and ovary are juxtaposed to endocrine epithelium, complement our clinical observations in suggesting that neuronal elements may be a pertinent initial target for immune attack in multiple forms of endocrine autoimmunity (intermolecular epitope spreading). It remains to be determined whether or not peripherin-IgG is predictive for development of small fiber neuropathy (autonomic or somatic).
Collapse
Affiliation(s)
- Jayne L. Chamberlain
- Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
| | - Sean J. Pittock
- Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
| | - Anna-Maria Oprescu
- Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
| | - Carissa Dege
- Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
| | - Metha Apiwattanakul
- Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
| | - Thomas J. Kryzer
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
| | - Vanda A. Lennon
- Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
- Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, U.S.A
| |
Collapse
|