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Kaizuka M, Tatsuta T, Kawaguchi S, Yoshizawa T, Yoshida S, Tateda T, Sawada Y, Ota S, Hayamizu S, Hasui K, Kikuchi H, Hiraga H, Chinda D, Muroya T, Hakamada K, Kijima H, Mikami T, Fukuda S, Sakuraba H. Toll-Like Receptor 7-Expressed Macrophages Are Involved in the Pathogenesis of Esophageal Achalasia and Esophagogastric Junction Outflow Obstruction. Digestion 2024; 105:436-447. [PMID: 39102805 PMCID: PMC11633874 DOI: 10.1159/000540693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
INTRODUCTION Esophageal achalasia is a typical esophageal motility disorder (EMD). Although viral infections have been hypothesized to play a role in the pathogenesis of esophageal achalasia, its etiology remains unclear. This study used esophageal muscle layer specimens collected during per-oral endoscopic myotomy (POEM) procedures to investigate the association between esophageal achalasia and esophagogastric junction outflow obstruction (EGJOO) and pattern recognition receptors. METHODS Patients with esophageal achalasia and EGJOO who underwent POEM were allocated to the EMD group. Biopsies of the inner circular muscle were conducted during the POEM procedure. The control group comprised individuals diagnosed with esophageal squamous cell carcinoma who underwent surgical resection. Expression of pattern recognition receptors, including Toll-like receptor (TLR) 7, was examined by polymerase chain reaction. Immunohistochemical staining was performed to determine TLR7 expression sites in the esophageal muscle layer, and the relationship between TLR7 mRNA expression and clinical score was investigated. RESULTS Our analysis revealed a notable upregulation of TLR7 mRNA levels within the muscle layer of esophageal achalasia and EGJOO, in contrast to those of control specimens. In contrast, the correlation between TLR7 and clinical score was not significant. Immunohistochemical staining revealed increased numbers of TLR7-expressing macrophages between the muscle layers. CONCLUSIONS TLR7-expressing macrophages are involved in the innate immune response underlying esophageal achalasia and EGJOO. This result will lead to the elucidation of new pathogenetic mechanisms and the development of novel therapeutic targets.
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Affiliation(s)
- Masatoshi Kaizuka
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan,
| | - Tetsuya Tatsuta
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shogo Kawaguchi
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Department of Vascular and Inflammatory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tadashi Yoshizawa
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shukuko Yoshida
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Shibata Irika Co., Hirosaki, Japan
| | - Tetsuyuki Tateda
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Yohei Sawada
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shinji Ota
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shiro Hayamizu
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Keisuke Hasui
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hidezumi Kikuchi
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Department of Community Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hiroto Hiraga
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Daisuke Chinda
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Division of Endoscopy, Hirosaki University Hospital, Hirosaki, Japan
| | - Takahiro Muroya
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Kenichi Hakamada
- Department of Gastroenterological Surgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Hiroshi Kijima
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Tatsuya Mikami
- Department of Preemptive Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Shinsaku Fukuda
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
- Hirosaki University, Hirosaki, Japan
| | - Hirotake Sakuraba
- Department of Gastroenterology, Hematology, and Clinical Immunology,,Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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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.
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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
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Parkinson's Disease and Current Treatments for Its Gastrointestinal Neurogastromotility Effects. ACTA ACUST UNITED AC 2018; 16:489-510. [PMID: 30361854 DOI: 10.1007/s11938-018-0201-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
PURPOSE OF REVIEW Gastrointestinal disturbances are seen in nearly all patients with Parkinson's disease and lead to impaired quality of life, affect drug pharmacodynamics, and potentially worsen patient's existing motor fluctuations, leading to further disability. Recent evidence links abnormal accumulations of α-synuclein aggregates in the periphery (gut) as seen in the cortex which causes dysfunctions impacting every level of the gastrointestinal tract from the esophagus, to the stomach, small bowel, colon, and rectum and can even predate the onset of the central neurologic disorder itself. Many treatments exist for the clinical phenotypes that result from the autonomic dysfunction and neuropathy involved in this neurodegenerative disorder. The treatments for the gut dysfunction seen in Parkinson's disease (PD) depend on the specific area of the gastrointestinal tract affected. For dysphagia, behavioral therapies with speech pathology, neuromuscular electrical stimulation, or botulinum toxin injection may be helpful. For gastroparesis, domperidone may serve as an antiemetic while also blunting the hypotensive potential of Levodopa while new treatments such as ghrelin agonists may prove beneficial to help appetite, satiety, gastric emptying in those with constipation, and even improve constipation. Antibiotics such as rifaximin with poor systemic absorption may be used to treat small bacterial overgrowth also found in those with PD while the benefits of probiotics is yet to be determined. Finally, constipation in PD can be a reflection of pelvic floor dyssynergia, slow transit constipation, or both, thus treatments targeting the specific anorectal dysfunction is necessary for better outcomes.
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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).
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Affiliation(s)
| | - Radu Tutuian
- Gastroenterology Department, Tiefenauspital, Inselgruppe, Bern, Switzerland
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Wollmer E, Klein S. A review of patient-specific gastrointestinal parameters as a platform for developing in vitro models for predicting the in vivo performance of oral dosage forms in patients with Parkinson’s disease. Int J Pharm 2017; 533:298-314. [DOI: 10.1016/j.ijpharm.2017.08.126] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 08/25/2017] [Accepted: 08/31/2017] [Indexed: 02/06/2023]
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Ding X, Gao J, Xie C, Xiong B, Wu S, Cen Z, Lou Y, Lou D, Xie F, Luo W. Prevalence and clinical correlation of dysphagia in Parkinson disease: a study on Chinese patients. Eur J Clin Nutr 2017; 72:82-86. [DOI: 10.1038/ejcn.2017.100] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 04/23/2017] [Accepted: 05/09/2017] [Indexed: 11/09/2022]
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Comprehensive epidemiological and genotype-phenotype analyses in a large European sample with idiopathic achalasia. Eur J Gastroenterol Hepatol 2016; 28:689-95. [PMID: 26882171 DOI: 10.1097/meg.0000000000000602] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Although an eight-residue insertion in HLA-DQβ1 has been recently identified as a genetic risk factor for idiopathic achalasia, other risk factors are still unknown. In the present study, we carried out an epidemiological survey and a genotype-phenotype (G×P) analysis to gain further insights into the etiology of achalasia. METHODS We obtained medical data from 696 achalasia patients and 410 controls, as well as their first-degree relatives (2543 of patients and 1497 of controls). For the G×P analysis, we stratified the patients into HLA-DQβ1 insertion carriers and noncarriers. RESULTS Our data show that patients are more often affected by viral infections before achalasia onset (P<0.0001, most significantly for varicella zoster virus infections). In addition, allergic (P=0.0005) and autoimmune disorders (P=0.0007, most significantly for psoriasis and Sjögren's syndrome) represent comorbid disease conditions. First-degree relatives of patients also show higher prevalence rates of allergic disorders (P=0.0007) and psoriasis (P=0.016) compared with control relatives. Moreover, the G×P analysis reveals that achalasia is triggered by pregnancies in female HLA-DQβ1 insertion carriers (P=0.031). CONCLUSION Our data point to a role of viral infections in the development of achalasia. In addition, they provide evidence for a relationship between achalasia and allergic, as well as autoimmune, disorders. Furthermore, pregnancy seems to be a disease-triggering factor in female HLA-DQβ1 insertion carriers, which points to hormonal and/or immunosuppressive factors influencing disease development.
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Presentation, diagnosis, and management of achalasia. Clin Gastroenterol Hepatol 2013; 11:887-97. [PMID: 23395699 DOI: 10.1016/j.cgh.2013.01.032] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Revised: 01/17/2013] [Accepted: 01/24/2013] [Indexed: 02/07/2023]
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Kaufmann H, Goldstein DS. Autonomic dysfunction in Parkinson disease. HANDBOOK OF CLINICAL NEUROLOGY 2013; 117:259-78. [DOI: 10.1016/b978-0-444-53491-0.00021-3] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Ghoshal UC, Daschakraborty SB, Singh R. Pathogenesis of achalasia cardia. World J Gastroenterol 2012; 18:3050-7. [PMID: 22791940 PMCID: PMC3386318 DOI: 10.3748/wjg.v18.i24.3050] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2011] [Revised: 10/11/2011] [Accepted: 04/28/2012] [Indexed: 02/06/2023] Open
Abstract
Achalasia cardia is one of the common causes of motor dysphagia. Though the disease was first described more than 300 years ago, exact pathogenesis of this condition still remains enigmatic. Pathophysiologically, achalasia cardia is caused by loss of inhibitory ganglion in the myenteric plexus of the esophagus. In the initial stage, degeneration of inhibitory nerves in the esophagus results in unopposed action of excitatory neurotransmitters such as acetylcholine, resulting in high amplitude non-peristaltic contractions (vigorous achalasia); progressive loss of cholinergic neurons over time results in dilation and low amplitude simultaneous contractions in the esophageal body (classic achalasia). Since the initial description, several studies have attempted to explore initiating agents that may cause the disease, such as viral infection, other environmental factors, autoimmunity, and genetic factors. Though Chagas disease, which mimics achalasia, is caused by an infective agent, available evidence suggests that infection may not be an independent cause of primary achalasia. A genetic basis for achalasia is supported by reports showing occurrence of disease in monozygotic twins, siblings and other first-degree relatives and occurrence in association with other genetic diseases such as Down’s syndrome and Parkinson’s disease. Polymorphisms in genes encoding for nitric oxide synthase, receptors for vasoactive intestinal peptide, interleukin 23 and the ALADIN gene have been reported. However, studies on larger numbers of patients and controls from different ethnic groups are needed before definite conclusions can be obtained. Currently, the disease is believed to be multi-factorial, with autoimmune mechanisms triggered by infection in a genetically predisposed individual leading to degeneration of inhibitory ganglia in the wall of the esophagus.
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Awad RA. Neurogenic bowel dysfunction in patients with spinal cord injury, myelomeningocele, multiple sclerosis and Parkinson’s disease. World J Gastroenterol 2011; 17:5035-48. [PMID: 22171138 PMCID: PMC3235587 DOI: 10.3748/wjg.v17.i46.5035] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2011] [Revised: 06/20/2011] [Accepted: 06/27/2011] [Indexed: 02/06/2023] Open
Abstract
Exciting new features have been described concerning neurogenic bowel dysfunction, including interactions between the central nervous system, the enteric nervous system, axonal injury, neuronal loss, neurotransmission of noxious and non-noxious stimuli, and the fields of gastroenterology and neurology. Patients with spinal cord injury, myelomeningocele, multiple sclerosis and Parkinson’s disease present with serious upper and lower bowel dysfunctions characterized by constipation, incontinence, gastrointestinal motor dysfunction and altered visceral sensitivity. Spinal cord injury is associated with severe autonomic dysfunction, and bowel dysfunction is a major physical and psychological burden for these patients. An adult myelomeningocele patient commonly has multiple problems reflecting the multisystemic nature of the disease. Multiple sclerosis is a neurodegenerative disorder in which axonal injury, neuronal loss, and atrophy of the central nervous system can lead to permanent neurological damage and clinical disability. Parkinson's disease is a multisystem disorder involving dopaminergic, noradrenergic, serotoninergic and cholinergic systems, characterized by motor and non-motor symptoms. Parkinson's disease affects several neuronal structures outside the substantia nigra, among which is the enteric nervous system. Recent reports have shown that the lesions in the enteric nervous system occur in very early stages of the disease, even before the involvement of the central nervous system. This has led to the postulation that the enteric nervous system could be critical in the pathophysiology of Parkinson's disease, as it could represent the point of entry for a putative environmental factor to initiate the pathological process. This review covers the data related to the etiology, epidemiology, clinical expression, pathophysiology, genetic aspects, gastrointestinal motor dysfunction, visceral sensitivity, management, prevention and prognosis of neurogenic bowel dysfunction patients with these neurological diseases. Embryological, morphological and experimental studies on animal models and humans are also taken into account.
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Johansen KK, White LR, Farrer MJ, Aasly JO. Subclinical signs in LRRK2 mutation carriers. Parkinsonism Relat Disord 2011; 17:528-32. [PMID: 21641848 DOI: 10.1016/j.parkreldis.2011.04.014] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Revised: 03/18/2011] [Accepted: 04/21/2011] [Indexed: 11/19/2022]
Abstract
BACKGROUND Several non-motor features have been reported to precede the motor signs of Parkinson's disease (PD) by several years. However, the time of onset of non-motor and motor symptoms is still debated. Healthy individuals carrying a PD-related mutation are candidates for studying the earliest disease signs. OBJECTIVES To describe clinically healthy family members of PD patients carrying a LRRK2 mutation (LRRK2-PD). METHODS A total of 47 family members of LRRK2-PD patients were included in the present study and were screened for the p.G2019S and p.N1437H substitutions in the LRRK2 gene. A standardized case report form was filled out in each case, including general medical evaluation, neurological examination with UPDRS, an olfaction test, mood, sleep and cognitive questionnaires. RESULTS Thirty-two study participants were positive, and 15 were negative for a LRRK2 mutation. Higher UPDRS motor scores, more frequent reports of urinary problems, and fewer hours of sleep were found in mutation carriers compared to non-carriers. The mutation carriers with UPDRS ≥8 were all aged over 50 years, had shorter overall sleeping hours, more frequent urinary and constipation problems, higher mood scores and body mass index. Deterioration of olfaction was not detected in either group. CONCLUSION Healthy LRRK2 mutation carriers presented subclinical parkinsonian motor and non-motor signs in the apparent absence of olfactory loss. Longitudinal studies will determine whether these changes precede alterations detectable by neuroimaging.
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Gockel HR, Schumacher J, Gockel I, Lang H, Haaf T, Nöthen MM. Achalasia: will genetic studies provide insights? Hum Genet 2010. [PMID: 20700745 DOI: 10.1007/s00439-010-0874-8.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
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Affiliation(s)
- Henning R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
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Gockel HR, Schumacher J, Gockel I, Lang H, Haaf T, Nöthen MM. Achalasia: will genetic studies provide insights? Hum Genet 2010; 128:353-64. [PMID: 20700745 DOI: 10.1007/s00439-010-0874-8] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Accepted: 08/02/2010] [Indexed: 12/15/2022]
Abstract
Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research.
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Affiliation(s)
- Henning R Gockel
- Department of General and Abdominal Surgery, Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
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15
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de León AR, de la Serna JP, Santiago JL, Sevilla C, Fernández-Arquero M, de la Concha EG, Nuñez C, Urcelay E, Vigo AG. Association between idiopathic achalasia and IL23R gene. Neurogastroenterol Motil 2010; 22:734-8, e218. [PMID: 20367798 DOI: 10.1111/j.1365-2982.2010.01497.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Idiopathic achalasia is a primary esophageal motor disorder of unknown etiology. Different evidences have been reported in support of achalasia as the result of an autoimmune and inflammatory process leading to neuronal cell loss. According to this, idiopathic achalasia has been significantly associated with specific alleles of the human leukocyte antigen system class II, although few reports studying association with other loci can be found in the literature. Recent studies have shown association of a non-synonymous polymorphism within the IL23R gene with different chronic inflammatory disorders, including Barrett's esophagus. The purpose of this study was to assess whether the IL23R coding variant Arg381Gln polymorphism is involved in susceptibility to idiopathic achalasia. METHODS We performed a case-control study including 262 patients with idiopathic achalasia and 802 healthy subjects, all of them white Spaniards. Achalasia patients were diagnosed on the basis of clinical, radiographic, endoscopic, and manometric criteria. All samples were genotyped for the IL23R Arg381Gln polymorphism using TaqMan technology. KEY RESULTS The minor allele of the Arg381Gln polymorphism was significantly increased in patients compared with healthy controls (OR = 1.46, 95% CI = 1.01-2.11, P = 0.036). This association seems to be specific to male patients with disease onset after 40 years (OR = 2.33, 95% CI = 1.29-4.16, P = 0.002). CONCLUSIONS & INFERENCES Our results suggest a role of IL23R in idiopathic achalasia predisposition and extend the evidence of the general influence of this gene in autoimmune and inflammatory diseases.
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Affiliation(s)
- A R de León
- Gastroenterology Department, Hospital Clínico San Carlos, Madrid, Spain
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Abstract
In recent years, there has been increasing recognition of the presence of gastrointestinal (GI) dysfunction in the setting of neurologic diseases. Parkinson's disease is a particularly well-known example, but GI dysfunction also may occur in multiple sclerosis, stroke, and in various myopathic and peripheral neuropathic processes. There is much less awareness, however, that primary GI diseases may also display neurologic dysfunction as part of their clinical picture. This article focuses on some of those disease processes. Illnesses primarily targeting the GI tract are addressed and examples of primary esophageal, gastric, and intestinal disease processes are described.
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Affiliation(s)
- Ronald F Pfeiffer
- Department of Neurology, University of Tennessee Health Science Center, 855 Monroe Avenue, Memphis, TN 38163, USA.
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17
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Jankovic J. Disease-oriented approach to botulinum toxin use. Toxicon 2009; 54:614-23. [DOI: 10.1016/j.toxicon.2008.11.013] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2008] [Accepted: 11/28/2008] [Indexed: 11/26/2022]
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Cersosimo MG, Benarroch EE. Neural control of the gastrointestinal tract: implications for Parkinson disease. Mov Disord 2008; 23:1065-75. [PMID: 18442139 DOI: 10.1002/mds.22051] [Citation(s) in RCA: 137] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Disorders of swallowing and gastrointestinal motility are prominent nonmotor manifestations of Parkinson disease (PD). Motility of the gut is controlled both by extrinsic inputs from the dorsal motor nucleus of the vagus (DMV) and paravertebral sympathetic ganglia and by local reflexes mediated by intrinsic neurons of the enteric nervous system (ENS). Both the ENS and the DMV are affected by Lewy body pathology at early stages of PD. This early involvement provides insights into the pathophysiology of gastrointestinal dysmotility in this disorder and may constitute an important step in the etiopathogenesis of Lewy body disease.
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Affiliation(s)
- Maria G Cersosimo
- Parkinson's Disease and Movement Disorder Unit, Hospital de Clínicas, University of Buenos Aires, Argentina
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Kaphan E, Pellissier JF, Rey M, Robert D, Auphan M, Ali Chérif A. [Esophageal achalasia, sleep disorders and chorea in a tauopathy without ophthalmoplegia, parkinsonian syndrome, nor dementia (progressive supranuclear palsy?): clinicopathological study]. Rev Neurol (Paris) 2008; 164:377-83. [PMID: 18439931 DOI: 10.1016/j.neurol.2007.09.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2007] [Revised: 08/15/2007] [Accepted: 09/26/2007] [Indexed: 12/12/2022]
Abstract
CONTEXT Progressive supranuclear palsy (PSP) is classically characterized by supranuclear ophthalmoplegia, paroxysmal imbalance with backward falling, axial dystonia, rigidity, pseudobulbar palsy and cognitive dysfunction. However, incomplete or atypical clinical presentation has been previously reported, but in all these cases, the patients had at least one of the main clinical features of the disease (ophthalmoplegia, parkinsonian syndrome or cognitive dysfunction). CASE REPORT A 60-year-old woman presented with nocturnal agitation and choreiform movements. A few months later she developed severe swallowing disorders, caused by achalasia of the upper esophageal sphincter, and responsible for recurrent acute respiratory distress and pneumonia, prevailing to tracheotomy and gastrostomy. She died suddenly two years after the onset of the symptoms. RESULTS Postmortem examination of brain revealed a tauopathy, with deposition of abnormal phosphorylated tau in threads and in coiled-shaped as well as globose tangles in the brainstem, subthalamic nuclei and hippocampus. Nuclei of the medulla, including the vagus/solitarius complex and the region of the nucleus ambiguous were especially rich in tau positive inclusions. Ultrastructural analysis of globoid-shaped tangles in the brainstem revealed the presence of straight and paired helicoidal filaments compatible with a PSP. CONCLUSIONS This case contributes to improve knowledge of the clinical phenotypic range of PSP. In this case, the neuropathological lesions accounted for most of the symptoms. However, the early death of the patient was probably related to the particular distribution of the neuropathological lesions. This case suggests that the initial neuropathological changes in PSP is located in the dorsal brainstem.
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Affiliation(s)
- E Kaphan
- Pôle de neurosciences cliniques, Assistance publique-Hôpitaux de Marseille, université de la Méditerranée, CHU Timone, 264, Rue St-Pierre, 13005 Marseille, France.
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Abstract
AIM: To investigate some possible etiologies of achalasia by screening patients with achalasia for some autoimmune diseases such as thyroid disease.
METHODS: We examined 30 known cases of achalasia (20 females, 10 males). Their age ranged 15-70 years. All of them were referred to our institute for treatment. Their sera were evaluated to detect some possible associations with rheumatoid disease, thyroid disease, inflammatory process, anemia, etc.
RESULTS: Seven out of 30 patients (23%) had thyroid disease including four patients with hypothyroidism (13.3%), two patients with hyperthyroidism (6.6%), and one had only thyroid nodule but was in euthyroid state (3.3%). Two of these hypothyroid patients had no related clinical symptoms (subclinical) and two had clinical manifestations of hypothyroidism. There were no correlations between the intensity of thyroid diseases and the severity of achalasia symptoms.
CONCLUSION: The etiology of achalasia is unknown although autoimmunity has been implicated and is supported by several studies. Thyroid disease presents concomitantly with achalasia in about one fourth of our patients who may have a common etiology.
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Affiliation(s)
- Mohammad Hassan Emami
- Isfahan University of Medical Sciences, Poursina Hakim Research Institution, Isfahan, Iran
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Mearin F, García-González MA, Strunk M, Zárate N, Malagelada JR, Lanas A. Association between achalasia and nitric oxide synthase gene polymorphisms. Am J Gastroenterol 2006; 101:1979-84. [PMID: 16848803 DOI: 10.1111/j.1572-0241.2006.00762.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Our group previously reported the absence of nitric oxide synthase (NOS) in the gastroesophageal junction of patients with achalasia. NOS exists in three distinct isoforms: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible isoform (iNOS). Some studies have shown that NO production is regulated by NOS polymorphisms. AIM To assess whether some functional polymorphisms in the nNOS, iNOS, or eNOS genes are involved in susceptibility to suffer from achalasia. METHODS Genomic DNA from 80 unrelated Spanish Caucasian patients with sporadic achalasia and 144 healthy subjects matched for age (+/-5 yr) and gender was typed by PCR and RFLP methods for the 27-bp variable number of tandem repeat (VNTR) polymorphism in intron 4 of the eNOS gene, a CA microsatellite repeat and a Nla III (C-->T) restriction fragment length polymorphism (RFLP) in exon 29 of the nNOS gene, and two nucleotide substitutions located in exon 16 (C-->T) and exon 22 (G-->A) of the iNOS gene. RESULTS No significant differences in carriage, genotype, and allele frequencies of the nNOS, iNOS, or eNOS gene polymorphisms were found between patients with achalasia and controls. Individuals homozygous for genotype iNOS22*A/A tended to be more frequent in achalasia (20%vs 11%, odds ratio [OR] 1.79, 95% confidence interval [CI] 0.89-3.59, p= 0.09) as were those homozygous for the rare eNOS*4a allele (6.2%vs 1.4%, OR 4.5, 95% CI 0.89-22.67, p= 0.1) although the difference did not reach statistical significance. No differences in genotype and allele distribution were found with respect to epidemiological and clinical characteristics of patients with achalasia. CONCLUSION Our data suggest that NOS gene polymorphisms are not involved in the susceptibility to and nature of the clinical course of sporadic achalasia. However, studies in a greater number of patients are required to analyze the tendency toward a higher prevalence of genotypes iNOS22*A/A and eNOS*4a4a.
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Affiliation(s)
- Fermín Mearin
- Institute of Functional and Motor Digestive Disorders, Centro Médico Teknon, Barcelona, Spain
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Latiano A, De Giorgio R, Volta U, Palmieri O, Zagaria C, Stanghellini V, Barbara G, Mangia A, Andriulli A, Corinaldesi R, Annese V. HLA and enteric antineuronal antibodies in patients with achalasia. Neurogastroenterol Motil 2006; 18:520-525. [PMID: 16771767 DOI: 10.1111/j.1365-2982.2006.00772.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The aetiopathogenesis of primary achalasia is largely unknown, although an immunogenetic predisposition is suspected. To establish whether a correlation exists among possible aetiological factors, including class II human leucocyte antigen (HLA) alleles and autoantibodies to enteric neurones, and clinical features of patients with achalasia, a total of 60 patients and 200 healthy subjects were typed by high-resolution HLA-DQ and HLA-DR alleles. Circulating antineuronal antibodies were investigated by using indirect immunofluorescence on enteric neurones of rat ileum and colon and immunoblotting assay in a subset of achalasic patients and in all controls. The DQB1*0502 and DQB1*0601 alleles were significantly increased in patients with achalasia compared with controls (P < 0.03, P < 0.001, respectively). Moreover a negative correlation with the DQB1*0201 allele was found (P = 0.016). As a whole, 14 of 60 (23.3%) achalasia patients were carriers of HLA risk alleles, and 10 of 41 (24.4%) presented antineuronal antibodies. No significant correlation among HLA risk alleles, antineuronal antibodies and clinical features was found. In achalasia, no correlation exists among HLA alleles, antineuronal antibodies and clinical features. However, given the association between achalasia and HLA-DQ1, further research is needed to clarify the role of HLA antigens and antineuronal antibodies in this disease.
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Affiliation(s)
- A Latiano
- U.O. Gastroenterologia, Ospedale CSS-IRCCS, San Giovanni Rotondo, Italy
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Abstract
Idiopathic achalasia is an inflammatory disease of unknown etiology characterized by esophageal aperistalsis and failure of LES relaxation due to loss of inhibitory nitrinergic neurons in the esophageal myenteric plexus. Proposed causes of achalasia include gastroesophageal junction obstruction, neuronal degeneration, viral infection, genetic inheritance, and autoimmune disease. Current evidence suggests that the initial insult to the esophagus, perhaps a viral infection or some other environmental factor, results in myenteric plexus inflammation. The inflammation then leads to an autoimmune response in a susceptible population who may be genetically predisposed. Subsequently, chronic inflammation leads to destruction of the inhibitory myenteric ganglion cells resulting in the clinical syndrome of idiopathic achalasia. Further studies are needed to better understand the etiology and pathogenesis of achalasia-such an understanding will be important in developing safe, effective, and possibly curative therapy for achalasia.
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Affiliation(s)
- Woosuk Park
- Department of Gastroenterology and Hepatology, Center for Swallowing and Esophageal Disorders, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
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Kountouras J, Zavos C, Chatzopoulos D. Apoptosis and autoimmunity as proposed pathogenetic links between Helicobacter pylori infection and idiopathic achalasia. Med Hypotheses 2005; 63:624-9. [PMID: 15325006 DOI: 10.1016/j.mehy.2004.04.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2004] [Accepted: 04/06/2004] [Indexed: 12/14/2022]
Abstract
Achalasia is a disorder of the oesophagus characterised by increased lower oesophageal sphincter (LOS) tone, lack of LOS relaxation with swallowing and aperistalsis of the body of the oesophagus. The aetiology and pathogenesis of idiopathic achalasia are still unclear, although a viral cause, genetic influences (associations with HLA loci) and autoimmune processes have been postulated. Degeneration and significant loss of nerve fibres, associated with an inflammatory infiltrate of the myenteric plexus in idiopathic achalasia, provide evidence of an immune mediated destruction of the myenteric plexus, possibly through apoptotic process. This concept is reinforced by the concomitant appearance of achalasia and Guillain-Barré syndrome (GBS) and/or Parkinson's disease, where inappropriate initiation of apoptosis has been proposed to underlie the neuronal attrition. In the same respect, Helicobacter pylori (H. pylori) infection has been associated with gastric autoimmunity, and patients infected with H. pylori have been shown to possess autoantibodies that cross-react with antigens expressed on the gastric mucosa. Furthermore, H. pylori is thought to be associated with the development of autoimmune sequelae observed in peripheral neuropathies and GBS, where autoantibodies to specific neural targets have been found to impair native neural function by inducing nerve tissue damage, possibly by apoptosis. Taken together, we assume that H. pylori infection might be a pathogenetic factor of achalasia through induction of autoimmunity and apoptosis. Whether eradication of H. pylori infection may indirectly offer benefit to the pathophysiology of idiopathic achalasia by ameliorating the apoptotic loss of ganglion cells and their axons in the oesophageal wall remains to be elucidated.
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Affiliation(s)
- Jannis Kountouras
- Department of Gastroenterology, 2nd Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
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Gosney M, Punekar S, Playfer JR, Bilsborrow PK, Martin MV. The incidence of oral Gram-negative bacteria in patients with Parkinson's disease. Eur J Intern Med 2003; 14:484-487. [PMID: 14962700 DOI: 10.1016/j.ejim.2003.09.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2003] [Accepted: 09/30/2003] [Indexed: 11/16/2022]
Abstract
Background: Parkinson's disease is a common neurodegenerative disorder that affects an increasing number of older people every year. Dysphagia is not only a common feature, but one that results in poor nutrition and an increased risk of bronchopneumonia. Previous work has suggested that the oral flora is altered in patients with oral pathology. Methods: Fifty patients were assessed to quantify the incidence of oral Gram-negative bacteria. Results: Sixteen of the patients with Parkinson's disease were found to have six different Gram-negative bacilli in their oral cavities. The 20 different Gram-negative bacteria present were Escherichia coli (n=7), Klebsiella spp. (n=3), Kluyvera spp. (n=3), Serratia spp. (n=3), Proteus spp. (n=2) and Enterobacter spp. (n=2). We found that the oral cavity of 16 (32%) of the patients with Parkinson's disease was abnormally colonised with Gram-negative bacteria and that Gram-negative bacteria were more likely to occur in those patients in whom oromuscular dysfunction was present (88% vs. 21%; p<0.05). Conclusion: Further work is required to determine the association between oral flora and the pathogenic organisms found in aspiration pneumonia as well as work on innovative treatments to reduce oral Gram-negative bacteria in those patients at particular risk of aspiration pneumonia.
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Affiliation(s)
- Margot Gosney
- School of Food Biosciences, University of Reading, Whiteknights, Reading RG6 6AP, UK
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Abstract
There is growing recognition that gastrointestinal dysfunction is common in Parkinson's disease (PD). Virtually all parts of the gastrointestinal tract can be affected, in some cases early in the disease course. Weight loss is common but poorly understood in people with PD. Dysphagia can result from dysfunction at the mouth, pharynx, and oesophagus and may predispose individuals to aspiration (accidental inhalation of food or liquid). Gastroparesis can produce various symptoms in patients with PD and may cause erratic absorption of drugs given to treat the disorder. Bowel dysfunction can consist of both slowed colonic transit with consequent reduced bowel-movement frequency, and difficulty with the act of defecation itself with excessive straining and incomplete emptying. Recognition of these gastrointestinal complications can lead to earlier and potentially more effective therapeutic intervention.
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