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Sanders KM, Drumm BT, Cobine CA, Baker SA. Ca 2+ dynamics in interstitial cells: foundational mechanisms for the motor patterns in the gastrointestinal tract. Physiol Rev 2024; 104:329-398. [PMID: 37561138 PMCID: PMC11281822 DOI: 10.1152/physrev.00036.2022] [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] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 06/29/2023] [Accepted: 08/06/2023] [Indexed: 08/11/2023] Open
Abstract
The gastrointestinal (GI) tract displays multiple motor patterns that move nutrients and wastes through the body. Smooth muscle cells (SMCs) provide the forces necessary for GI motility, but interstitial cells, electrically coupled to SMCs, tune SMC excitability, transduce inputs from enteric motor neurons, and generate pacemaker activity that underlies major motor patterns, such as peristalsis and segmentation. The interstitial cells regulating SMCs are interstitial cells of Cajal (ICC) and PDGF receptor (PDGFR)α+ cells. Together these cells form the SIP syncytium. ICC and PDGFRα+ cells express signature Ca2+-dependent conductances: ICC express Ca2+-activated Cl- channels, encoded by Ano1, that generate inward current, and PDGFRα+ cells express Ca2+-activated K+ channels, encoded by Kcnn3, that generate outward current. The open probabilities of interstitial cell conductances are controlled by Ca2+ release from the endoplasmic reticulum. The resulting Ca2+ transients occur spontaneously in a stochastic manner. Ca2+ transients in ICC induce spontaneous transient inward currents and spontaneous transient depolarizations (STDs). Neurotransmission increases or decreases Ca2+ transients, and the resulting depolarizing or hyperpolarizing responses conduct to other cells in the SIP syncytium. In pacemaker ICC, STDs activate voltage-dependent Ca2+ influx, which initiates a cluster of Ca2+ transients and sustains activation of ANO1 channels and depolarization during slow waves. Regulation of GI motility has traditionally been described as neurogenic and myogenic. Recent advances in understanding Ca2+ handling mechanisms in interstitial cells and how these mechanisms influence motor patterns of the GI tract suggest that the term "myogenic" should be replaced by the term "SIPgenic," as this review discusses.
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Affiliation(s)
- Kenton M Sanders
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada-Reno, Reno, Nevada, United States
| | - Bernard T Drumm
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland
| | - Caroline A Cobine
- Smooth Muscle Research Centre, Dundalk Institute of Technology, Dundalk, Ireland
| | - Salah A Baker
- Department of Physiology and Cell Biology, School of Medicine, University of Nevada-Reno, Reno, Nevada, United States
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Chan EEH, Merchant K, Othman MY, Laksmi NK. Diagnostic dilemma and challenges in management: Hirschsprung's disease, anal stenosis and reduced interstitial cells of Cajal enteric mesenchymopathy. BMJ Case Rep 2023; 16:e252484. [PMID: 37185243 PMCID: PMC10151910 DOI: 10.1136/bcr-2022-252484] [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] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Hirschsprung's disease (HD) is one of the most well-known gastrointestinal motility disorders. Diagnosis and management of other lesser-known motility disorders are often challenging and tedious. We describe a teenager who was severely constipated from birth and needed intensive care admissions for life-threatening enterocolitis. She also had concomitant anal stenosis. Several rectal biopsies were unable to yield a conclusive diagnosis. Surgical level of resection had to be identified based on the motility of the bowel as determined by transit studies using oral ingestion of a milk feed labelled with Technetium-99m colloid. After completion of all operative stages, histopathological examination of the excised specimens concluded that she had short-segment HD associated with reduced interstitial cells of Cajal in the large bowel. She is currently continent, evacuating voluntarily approximately four times a day and is relieved of all her symptoms.
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Affiliation(s)
| | - Khurshid Merchant
- Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, Singapore
| | - Mohd Yusran Othman
- Department of Paediatric Surgery, Hospital Tunku Azizah (Kuala Lumpur Women's and Children's Hospital), Kuala Lumpur, Malaysia
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Li YW, Yu YJ, Fei F, Zheng MY, Zhang SW. High-resolution colonic manometry and its clinical application in patients with colonic dysmotility: A review. World J Clin Cases 2019; 7:2675-2686. [PMID: 31616684 PMCID: PMC6789394 DOI: 10.12998/wjcc.v7.i18.2675] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 07/26/2019] [Accepted: 08/20/2019] [Indexed: 02/05/2023] Open
Abstract
The detailed process and mechanism of colonic motility are still unclear, and colonic motility disorders are associated with numerous clinical diseases. Colonic manometry is considered to the most direct means of evaluating colonic peristalsis. Colonic manometry has been studied for more than 30 years; however, the long duration of the examination, high risk of catheterization, huge amount of real-time data, strict catheter sterilization, and high cost of disposable equipment restrict its wide application in clinical practice. Recently, high-resolution colonic manometry (HRCM) has rapidly developed into a major technique for obtaining more effective information involved in the physiology and/or pathophysiology of colonic contractile activity in colonic dysmotility patients. This review focuses on colonic motility, manometry, operation, and motor patterns, and the clinical application of HRCM. Furthermore, the limitations, future directions, and potential usefulness of HRCM in the evaluation of clinical treatment effects are also discussed.
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Affiliation(s)
- Yu-Wei Li
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300071, China
| | - Yong-Jun Yu
- Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin 300071, China
| | - Fei Fei
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300071, China
- Nankai University School of Medicine, Nankai University, Tianjin 300071, China
| | - Min-Ying Zheng
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300071, China
| | - Shi-Wu Zhang
- Department of Pathology, Tianjin Union Medical Center, Tianjin 300071, China
- Nankai University School of Medicine, Nankai University, Tianjin 300071, China
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Keller J, Bassotti G, Clarke J, Dinning P, Fox M, Grover M, Hellström PM, Ke M, Layer P, Malagelada C, Parkman HP, Scott SM, Tack J, Simren M, Törnblom H, Camilleri M. Expert consensus document: Advances in the diagnosis and classification of gastric and intestinal motility disorders. Nat Rev Gastroenterol Hepatol 2018; 15:291-308. [PMID: 29622808 PMCID: PMC6646879 DOI: 10.1038/nrgastro.2018.7] [Citation(s) in RCA: 155] [Impact Index Per Article: 22.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Disturbances of gastric, intestinal and colonic motor and sensory functions affect a large proportion of the population worldwide, impair quality of life and cause considerable health-care costs. Assessment of gastrointestinal motility in these patients can serve to establish diagnosis and to guide therapy. Major advances in diagnostic techniques during the past 5-10 years have led to this update about indications for and selection and performance of currently available tests. As symptoms have poor concordance with gastrointestinal motor dysfunction, clinical motility testing is indicated in patients in whom there is no evidence of causative mucosal or structural diseases such as inflammatory or malignant disease. Transit tests using radiopaque markers, scintigraphy, breath tests and wireless motility capsules are noninvasive. Other tests of gastrointestinal contractility or sensation usually require intubation, typically represent second-line investigations limited to patients with severe symptoms and are performed at only specialized centres. This Consensus Statement details recommended tests as well as useful clinical alternatives for investigation of gastric, small bowel and colonic motility. The article provides recommendations on how to classify gastrointestinal motor disorders on the basis of test results and describes how test results guide treatment decisions.
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Affiliation(s)
- Jutta Keller
- Israelitic Hospital, Academic Hospital University of Hamburg, Orchideenstieg 14, 22297 Hamburg, Germany
| | - Gabrio Bassotti
- University of Perugia, Piazza dell’Università, 1, 06121 Perugia, Italy
| | - John Clarke
- Stanford University, 900 Blake Wilbur Dr, Palo Alto, CA 94304, USA
| | - Phil Dinning
- Flinders Medical Centre, GPO Box 2100, Adelaide 5001, Australia
| | - Mark Fox
- University Hospital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland, and St. Claraspital, Kleinriehenstrasse 30, 4058 Basel, Switzerland
| | | | - Per M. Hellström
- Uppsala University Hospital, Building 40, SE‑75185, Uppsala, Sweden
| | - Meiyun Ke
- Peking Union Medical College Hospital, No.1 Shuaifuyuan Wangfujing Dongcheng District, Beijing, 100730, China
| | - Peter Layer
- Israelitic Hospital, Academic Hospital University of Hamburg, Orchideenstieg 14, 22297 Hamburg, Germany
| | - Carolina Malagelada
- University of Barcelona, Passeig de la Vall d’Hebron, 119–129, 08035 Barcelona, Spain
| | - Henry P. Parkman
- Temple University Hospital, 3401 N Broad St, Philadelphia, PA 19140, USA
| | - S. Mark Scott
- Queen Mary University of London, The Wingate Institute, 26 Ashfield Street, Whitechapel, London E1 2AJ, UK
| | - Jan Tack
- University Hospital Gasthuisberg, University of Leuven, Herestraat 49, 3000 Leuven, Belgium
| | - Magnus Simren
- Sahlgrenska Academy, University of Gothenburg, Blå stråket 5, 41345 Gothenburg, Sweden
| | - Hans Törnblom
- Sahlgrenska Academy, University of Gothenburg, Blå stråket 5, 41345 Gothenburg, Sweden
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Endoscopic muscle biopsy sampling of the duodenum and rectum: a pilot survival study in a porcine model to detect myenteric neurons. Gastrointest Endosc 2018; 87:600-606. [PMID: 28734992 PMCID: PMC5775930 DOI: 10.1016/j.gie.2017.07.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2017] [Accepted: 07/10/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Small bowel and colorectal muscle biopsy sampling requires a surgical approach. Advancing our understanding of the pathophysiology of motility disorders, such as functional bowel disorders, intestinal pseudo-obstruction, and slow-transit constipation, is hindered by our inability to noninvasively obtain muscularis propria (MP) for evaluation of multiple cell types, including myenteric neurons. The aims of this study were to determine (1) technical feasibility, reproducibility, and safety of performing duodenal endoscopic muscle biopsy sampling (dEMB) and rectal endoscopic muscle biopsy sampling (rEMB) using a clip-assist technique and (2) the presence of myenteric neurons in tissue samples. METHODS Five 40-kg pigs were studied. Each animal underwent a dEMB and rEMB procedure. dEMB was performed using a single resection clip-assist technique. An over-the-scope clip was advanced to the duodenum. Tissue was suctioned into the cap and the clip deployed. The pseudopolyp of the duodenal wall created was then resected using snare electrocautery. rEMB was performed using a double resection clip-assist technique. EMR was initially performed to uncover the underlying MP using a band ligation technique. An over-the-scope clip was then advanced to the exposed MP. The MP was retracted and suctioned into the cap and the clip deployed. The pseudopolyp of the MP was resected using snare electrocautery. An antibody to protein gene product 9.5 was used to determine the presence of myenteric neurons in the samples. Animals were kept alive for 2 weeks, at which time an upper endoscopy and necropsy were performed. RESULTS dEMB and rEMB were successfully performed in all animals with no procedural adverse events using this "no hole" (close then cut) approach. Mean procedure times for dEMB and rEMB were 23.7 ± 2.5 minutes and 13.25 ± 2.8 minutes, respectively. Mean length of resected full-thickness duodenal wall was 13.25 ± 4.3 mm and rectal MP was 12.5 ± 1.7 mm. Hematoxylin and eosin stain and antibody to protein gene product 9.5 confirmed the presence of MP with inner circular, outer longitudinal, and intermuscular layers, including myenteric neurons, in all samples. Clinical course was uneventful in all animals. Repeat upper endoscopy at 2 weeks showed well-healed dEMB sites. Necropsy in all animals showed no perforation, fluid collection, or abscess at the dEMB and rEMB sites. CONCLUSIONS Based on this preclinical study, dEMB and rEMB appear to be technically feasible, reproducible, and safe. Sufficient MP tissue was obtained to identify myenteric neurons. These promising results are a step toward successful and safe implementation of these techniques into clinical practice for tissue diagnosis of muscle-based pathologies.
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Lu C, Hou G, Liu C, Geng Q, Xu X, Zhang J, Chen H, Tang W. Single-stage transanal endorectal pull-through procedure for correction of Hirschsprung disease in neonates and nonneonates: A multicenter study. J Pediatr Surg 2017; 52:1102-1107. [PMID: 28185631 DOI: 10.1016/j.jpedsurg.2017.01.061] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 12/28/2016] [Accepted: 01/30/2017] [Indexed: 12/16/2022]
Abstract
PURPOSE The outcomes of single-stage transanal endorectal pull-through (SSTEPT) for Hirschsprung disease (HSCR) in young patients are favorable; however, reports have shown that diagnosis and surgery at young ages increase the risk for postoperative enterocolitis and slows postoperative recovery. The present study was primarily designed to evaluate the outcomes of SSTEPT in a multi-institutional cohort of neonates and nonneonates with HSCR. METHODS Between August 2005 and May 2012, a total of 650 children with HSCR were divided into the following two groups: group A (neonatal group, operative age<28days [n=186]); and group B (nonneonatal group, operative age>28days [n=464]). The short-term outcomes were postoperative enterocolitis, perianal excoriation, and anastomotic stricture and leakage rates. The midterm outcomes were incomplete continence and constipation rates based on multi-institutional chart review. Statistical analyses were performed using chi-square (χ2) tests. RESULTS Follow-up was completed in 112 neonates and 303 nonneonates. Short-term outcomes indicated a higher incidence of perianal excoriation (27.6% vs. 6.6%, χ2=33.70, p<0.05), anastomotic strictures (14.3% vs. 6.0%, χ2=27.18, p<0.05), anastomotic leakage (8.0% vs. 1.7%, χ2=8.36, p<0.05), and postoperative enterocolitis (40.2% vs. 10.2%, χ2=49.05, p<0.05) in group A compared to group B. Midterm outcomes indicated a higher incidence of incomplete continence (35.7% vs. 14.9%, χ2=21.85, p<0.05) in group A compared to group B. CONCLUSION Performing single-stage transanal endorectal pull-through in the nonneonatal period may be more appropriate than the neonatal period. There were higher rates of perianal excoriation, anastomotic strictures and leakage, postoperative enterocolitis, and incomplete continence postoperatively in neonates than nonneonates.
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Affiliation(s)
- Changgui Lu
- Department of Pediatric Surgery, Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China, 210008
| | - Guangjun Hou
- Department of Pediatric Surgery, Zhengzhou Children's Hospital, Zhengzhou, China, 450053
| | - Chunyi Liu
- Department of Pediatric Surgery, Hebei Provincial Children's Hospital, Shijiazhuang, China, 050030
| | - Qiming Geng
- Department of Pediatric Surgery, Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China, 210008
| | - Xiaoqun Xu
- Department of Pediatric Surgery, Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China, 210008
| | - Jie Zhang
- Department of Pediatric Surgery, Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China, 210008
| | - Huan Chen
- Department of Pediatric Surgery, Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China, 210008
| | - Weibing Tang
- Department of Pediatric Surgery, Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China, 210008.
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Rodriguez L, Sood M, Di Lorenzo C, Saps M. An ANMS-NASPGHAN consensus document on anorectal and colonic manometry in children. Neurogastroenterol Motil 2017; 29. [PMID: 27723185 DOI: 10.1111/nmo.12944] [Citation(s) in RCA: 92] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Accepted: 08/18/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Over the last few years, the study of the colon and anorectal function has experienced great technical advances that have facilitated the performance of the tests and have allowed a more detailed characterization of reflexes and motor patterns. As a result, we have achieved a much better understanding of the pathophysiology of children with defecation problems. Anorectal and colonic manometry are now commonly used in all major pediatric referral centers as diagnostic tools and to guide the management of children with intractable constipation and fecal incontinence, particularly when a surgical intervention is being considered. PURPOSE This review highlights some of the recent advances in pediatric colon and anorectal motility testing including indications and preparation for the studies, and how to perform and interpret the tests. This update has been endorsed by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN).
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Affiliation(s)
- L Rodriguez
- Department of Gastroenterology, Hepatology and Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - M Sood
- Department of Pediatric Gastroenterology, Children's Hospital of Wisconsin, Milwaukee, WI, USA
| | - C Di Lorenzo
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
| | - M Saps
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children's Hospital, Columbus, OH, USA
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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.
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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
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Uyttebroek L, Shepherd IT, Vanden Berghe P, Hubens G, Timmermans JP, Van Nassauw L. The zebrafish mutant lessen: an experimental model for congenital enteric neuropathies. Neurogastroenterol Motil 2016; 28:345-57. [PMID: 26685876 DOI: 10.1111/nmo.12732] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 10/22/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Congenital enteric neuropathies of the distal intestine (CEN) are characterized by the partial or complete absence of enteric neurons. Over the last decade, zebrafish has emerged as a leading model organism in experimental research. Our aim was to demonstrate that the mutant zebrafish, lessen, expressing CEN characteristics, is an equally valuable animal model alongside mammalian models for CEN, by studying its enteric phenotype. METHODS The effect of the lessen mutation on the development of the enteric nervous system (ENS), interstitial cells of Cajal (ICC), and intestinal motility in each intestinal region of mutant and wild-type (wt) zebrafish embryos at 3-6 dpf, was analyzed by immunofluorescent detection of neurochemical markers and motility assays. KEY RESULTS Development of intestinal motility in the mutant was delayed and the majority of the observed contractions were disturbed. A significant disturbance in ENS development resulted in a distal intestine that was almost free of neuronal elements, in reduced neuronal density in the proximal and mid-intestine, and in a defect in the expression of neurochemical markers. Furthermore, markedly disturbed development of ICC gave rise to a less dense network of ICC. CONCLUSIONS & INFERENCES The observed alterations in intestinal motility, intrinsic innervation and ICC network of the mutant in comparison with the wt zebrafish, are similar to those seen in the oligo- and aganglionic regions of the intestine of CEN patients. It is concluded that the zebrafish mutant lessen is an appropriate animal model to investigate CEN.
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Affiliation(s)
- L Uyttebroek
- Laboratory of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium
| | - I T Shepherd
- Department of Biology, Emory University, Atlanta, GA, USA
| | - P Vanden Berghe
- Laboratory for Enteric NeuroScience (LENS), Translational Research in GastroIntestinal Disorders (TARGID), Department of Clinical and Experimental Medicine, University of Leuven, Leuven, Belgium
| | - G Hubens
- Laboratory of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium
| | - J-P Timmermans
- Laboratory of Cell Biology and Histology, Department of Veterinary Sciences, University of Antwerp, Antwerpen, Belgium
| | - L Van Nassauw
- Laboratory of Human Anatomy and Embryology, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerpen, Belgium
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Gfroerer S, Rolle U. Pediatric intestinal motility disorders. World J Gastroenterol 2015; 21:9683-9687. [PMID: 26361414 PMCID: PMC4562951 DOI: 10.3748/wjg.v21.i33.9683] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 05/07/2015] [Accepted: 07/03/2015] [Indexed: 02/06/2023] Open
Abstract
Pediatric intestinal motility disorders affect many children and thus not only impose a significant impact on pediatric health care in general but also on the quality of life of the affected patient. Furthermore, some of these conditions might also have implications for adulthood. Pediatric intestinal motility disorders frequently present as chronic constipation in toddler age children. Most of these conditions are functional, meaning that constipation does not have an organic etiology, but in 5% of the cases, an underlying, clearly organic disorder can be identified. Patients with organic causes for intestinal motility disorders usually present in early infancy or even right after birth. The most striking clinical feature of children with severe intestinal motility disorders is the delayed passage of meconium in the newborn period. This sign is highly indicative of the presence of Hirschsprung disease (HD), which is the most frequent congenital disorder of intestinal motility. HD is a rare but important congenital disease and the most significant entity of pediatric intestinal motility disorders. The etiology and pathogenesis of HD have been extensively studied over the last several decades. A defect in neural crest derived cell migration has been proven as an underlying cause of HD, leading to an aganglionic distal end of the gut. Numerous basic science and clinical research related studies have been conducted to better diagnose and treat HD. Resection of the aganglionic bowel remains the gold standard for treatment of HD. Most recent studies show, at least experimentally, the possibility of a stem cell based therapy for HD. This editorial also includes rare causes of pediatric intestinal motility disorders such as hypoganglionosis, dysganglionosis, chronic intestinal pseudo-obstruction and ganglioneuromatosis in multiple endocrine metaplasia. Underlying organic pathologies are rare in pediatric intestinal motility disorders but must be recognized as early as possible.
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O'Dwyer RH, Acosta A, Camilleri M, Burton D, Busciglio I, Bharucha AE. Clinical Features and Colonic Motor Disturbances in Chronic Megacolon in Adults. Dig Dis Sci 2015; 60:2398-407. [PMID: 25868630 PMCID: PMC4499849 DOI: 10.1007/s10620-015-3645-5] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Accepted: 03/26/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND Chronic megacolon is a rare disease of the colonic motor function characterized by a permanent increase in colonic diameter. METHODS We reviewed electronic medical records of all patients diagnosed with chronic megacolon from 1999 to 2014 at Mayo Clinic. Our aim was to summarize clinical and motility features, including colonic compliance and tone measured by colonic barostat-controlled 10-cm-long infinitely compliant balloon. Colonic compliance curves were compared to healthy control (40) and disease (47) control groups. RESULTS Among 24 identified patients, the mean maximal colonic diameter on abdominal radiograph was 12.7 ± 0.8 cm. The cause of megacolon was idiopathic in 16 of 24 and secondary in 8 of 24. A relatively high prevalence (10/24) of comorbid pelvic floor dyssynergia was identified. At the time of this report, 16 patients had undergone colectomy. In general, megacolon presented high fasting colonic volume at relatively low pressures (16-20 mmHg), suggesting high colonic compliance; similarly, volumes at operating pressures that ensured apposition of the balloon to the colonic wall suggested low colonic tone. Median balloon volume at 44 mmHg distension was 584 mL (IQR 556.5-600) in patients with megacolon compared to 251 mL (212-281) in healthy, 240 mL (207-286) in functional constipation, and 241 mL (210.8-277.5) in diarrhea-predominant irritable bowel syndrome controls. Colon's tonic response to feeding was generally intact, and there was frequently maintained phasic contractile response to feeding. CONCLUSIONS Chronic megacolon is a severe colonic dysmotility, manifesting radiologically with increased colonic diameter; it can be proven by measuring colonic compliance and typically requires colectomy because of failed medical therapy.
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Role of the enteric nervous system in the elongated sigmoid colon of patients with sigmoid volvulus. Int Surg 2014; 99:699-704. [PMID: 25437573 DOI: 10.9738/intsurg-d-13-00198.1] [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: 11/17/2022] Open
Abstract
To clarify the physiologic function of the enteric nervous system (ENS) in the elongated sigmoid colon (ESC) of patients with sigmoid volvulus (SV), we examined the enteric nerve responses in lesional and normal longitudinal muscle strips (LMS) derived from patients with ESC and patients who underwent colon resection for colonic cancers. Thirty preparations of LMS were taken from the lesional sigmoid colons of 10 ESC patients with SV (8 men and 2 women, aged 53 to 80 years, mean 66.2 years). Forty preparations of LMS were taken from the normal sigmoid colons (NSC) of 20 patients with colonic cancer (12 men and 8 women, aged 55 to 76 years, mean 62.3 years). A mechanographic technique was used to evaluate in vitro muscle responses to electrical field stimulation (EFS) before and after treatment with various autonomic nerve blockers. Response to EFS before blockade of the adrenergic and cholinergic nerves was as follows: NSC and ESC significantly demonstrated relaxation reaction rather than contraction reaction (P = 0.0253, P < 0.0001, respectively). ESC showed relaxation reaction more than NSC (P = 0.1138). Response to EFS after blockade of the adrenergic and cholinergic nerves was as follows: NSC and ESC significantly demonstrated relaxation reaction via nonadrenergic noncholinergic (NANC) inhibitory nerves rather than contraction reaction via NANC excitatory nerves (P < 0.0001, P < 0.0001, respectively). ESC with SV significantly showed relaxation reaction more than NSC (P = 0.0092). An increased response of relaxation mediated NANC inhibitory nerves may play a role in impaired motility in the ESC of patients with SV.
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Abstract
OBJECTIVES Colonic manometry is a test used in the evaluation of children with defecation disorders unresponsive to conventional treatment. The most commonly reported protocol in pediatrics consists of a study that lasts approximately 4 hours. Given the wide physiological variations in colonic motility throughout the day, longer observation may detect clinically relevant information. The aim of the present study was to compare prolonged colonic manometry studies in children referred for colonic manometry with the more traditional short water-perfused technology. METHODS Colonic manometry studies of 19 children (8 boys, mean age 9.4 ± 0.9, range 3.9-16.3) with severe defecation disorders were analyzed. First, a "standard test" was performed with at least 1-hour fasting, 1-hour postprandial, and 1-hour postbisacodyl provocation recording. Afterwards, recordings continued until the next day. RESULTS In 2 of the 19 children, prolonged recording gave us extra information. In 1 patient with functional nonretentive fecal incontinence who demonstrated no abnormalities in the short recording, 2 long clusters of high-amplitude contractions were noted in the prolonged study, possibly contributing to the fecal incontinence. In another patient evaluated after failing use of antegrade enemas through a cecostomy, short recordings showed colonic activity only in the most proximal part of the colon, whereas the prolonged study showed normal motility over a larger portion of the colon. CONCLUSIONS Prolonged colonic measurement provides more information regarding colonic motor function and allows detection of motor events missed by the standard shorter manometry study.
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Jabari S, da Silveira ABM, de Oliveira EC, Quint K, Wirries A, Neuhuber W, Brehmer A. Interstitial cells of Cajal: crucial for the development of megacolon in human Chagas' disease? Colorectal Dis 2014; 15:e592-8. [PMID: 23810202 DOI: 10.1111/codi.12331] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 03/02/2013] [Indexed: 02/08/2023]
Abstract
AIM Megacolon, chronic dilation of a colonic segment,is accompanied by extensive myenteric neuron loss. However, this fails to explain unequivocally the formation of megacolon. We aimed to study further enteric structures that are directly or indirectly involved in colonic motility. METHOD From surgically removed megacolon segments of seven Chagasic patients, three sets of cryosections from oral, megacolonic and anal zones were immunohistochemically quadruple-stained for smooth-muscle actin (SMA), synaptophysin (SYN, for nerve fibres), S100 (glia) and c-Kit (interstitial cells of Cajal, ICCs). Values of area measurements were related to the appropriate muscle layer areas and these proportions were compared with those of seven non-Chagasic control patients. RESULTS Whereas nerve and glia profile proportions did not mirror unequivocally the changes of Chagasic colon calibre (nondilation/dilation/nondilation), the proportions of SMA (i.e. muscle tissue density) and c-Kit (i.e. ICC density) did so: they decreased from the oral to the megacolonic segment but increased to the anal zones (muscle tissue density: control 68.3%, oral 54.3%, mega 42.1%, anal 47.6%; ICC-density: control 1.8%, oral 1.1%, mega 0.4, anal 0.8%). CONCLUSION Of the parameters evaluated, muscle tissue and ICC densities may be involved in the formation of Chagasic megacolon, although the mechanism of destruction cannot be deduced.
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Affiliation(s)
- S Jabari
- Institute of Anatomy I, University of Erlangen-Nuremberg, Erlangen, Germany
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15
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Abstract
Megacolon, the irreversible dilation of a colonic segment, is a structural sign associated with various gastrointestinal disorders. In its hereditary, secondary form (e.g. in Hirschsprung's disease), dilation occurs in an originally healthy colonic segment due to an anally located, aganglionic zone. In contrast, in chronic Chagas' disease, the dilated segment itself displays pathohistological changes, and the earliest and most prominent being found was massive loss of myenteric neurons. This neuron loss was partial and selective, i.e. some neurons containing neuronal nitric oxide synthase and/or vasoactive intestinal peptide (VIP) were spared from neuron death. This disproportionate survival of inhibitory neurons, however, did not completely correlate with the calibre change along the surgically removed, megacolonic segments. A better correlation was observed as to potentially contractile muscle tissue elements and the interstitial cells of Cajal. Therefore, the decreased densities of α-smooth muscle actin- and c-kit-immunoreactive profiles were estimated along resected megacolonic segments. Their lowest values were observed in the megacolonic zones itself, whereas less pronounced decreases were found in the non-dilated, transitional zones (oral and anal to dilation). In contrast to the myenteric plexus, the submucosal plexus displayed only a moderate neuron loss. Neurons co-immunoreactive for VIP and calretinin survived disproportionately. As a consequence, these neurons may have contributed to maintain the epithelial barrier and allowed the chagasic patients to survive for decades, despite their severe disturbance of colonic motility. Due to its neuroprotective and neuroeffectory functions, VIP may play a key role in the development and duration of chagasic megacolon.
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Abstract
The enteric nervous system is vulnerable to a range of congenital and acquired disorders that disrupt the function of its neurons or lead to their loss. The resulting enteric neuropathies are some of the most challenging clinical conditions to manage. Neural stem cells offer the prospect of a cure given their potential ability to replenish missing or dysfunctional neurons. This article discusses diseases that might be targets for stem cell therapies and the barriers that could limit treatment application. We explore various sources of stem cells and the proof of concept for their use. The critical steps that remain to be addressed before these therapies can be used in patients are also discussed. Key milestones include the harvesting of neural stem cells from the human gut and the latest in vivo transplantation studies in animals. The tremendous progress in the field has brought experimental studies exploring the potential of stem cell therapies for the management of enteric neuropathies to the cusp of clinical application.
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Affiliation(s)
- Alan J Burns
- Neural Development and Gastroenterology Units, Birth Defects Research Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
| | - Nikhil Thapar
- 1] Neural Development and Gastroenterology Units, Birth Defects Research Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. [2] Division of Neurogastroenterology and Motility, Department of Paediatric Gastroenterology, Great Ormond Street Hospital, Great Ormond Street, London WC1N 3JH, UK
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17
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Abstract
BACKGROUND Interstitial cells of Cajal, expressing the proto-oncogene c-kit, have been shown to regulate the spontaneous activity of the gastrointestinal tract. They have been described in the human internal anal sphincter; however, their function is still unclear. OBJECTIVE We examined the effects of the c-kit tyrosine kinase inhibitor imatinib mesylate on sphincter strips to investigate the function of the interstitial cells. DESIGN This was a case series study. SETTIGS This was a single-center study conducted at the University of Oxford. PATIENTS Internal anal sphincter strips were collected from 10 patients undergoing abdominoperineal resection or proctectomy and mounted in organ bath. Responses to electrical field stimulation and chemical agents were monitored in the absence of drugs and after the administration of increasing doses of imatinib mesylate. Immunohistochemistry was performed to identify interstitial cells. MAIN OUTCOME MEASURES The role of the interstitial cells in the internal anal sphincter was assessed. RESULTS Imatinib mesylate significantly reduced the tone and the spontaneous activity of the strips. In the absence of drugs, the tone generated was 147.7 ± 33.0 mg/mg of tissue. Administration of ≥5 μM of imatinib mesylate caused a dose-dependent reduction in the tone. Strips exhibited spontaneous activity characterized by intermittent low-amplitude contractions superimposed on basal tone (135.6 ± 4.6 contractions in 10 minutes). Imatinib mesylate significantly reduced the number of contractions at concentration >5 μM. No differences were observed in the responses to electrical field stimulation, carbachol, or phenylephrine. Immunohistochemistry showed c-kit-positive cells. LIMITATIONS This study was limited by the relatively small number of patients enrolled and thus the difficulty of finding human tissue for laboratory studies. CONCLUSIONS Our results suggest that the interstitial cells modulate the tone and the spontaneous activity of the internal anal sphincter. This provides a foundation for new approaches to preclinical and clinical research. Moreover, these cells may represent a target for drugs inhibiting the c-kit receptor and provide a new approach for treating anorectal diseases.
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Evaluation and treatment of functional constipation in infants and children: evidence-based recommendations from ESPGHAN and NASPGHAN. J Pediatr Gastroenterol Nutr 2014; 58:258-74. [PMID: 24345831 DOI: 10.1097/mpg.0000000000000266] [Citation(s) in RCA: 626] [Impact Index Per Article: 56.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Constipation is a pediatric problem commonly encountered by many health care workers in primary, secondary, and tertiary care. To assist medical care providers in the evaluation and management of children with functional constipation, the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition were charged with the task of developing a uniform document of evidence-based guidelines. METHODS Nine clinical questions addressing diagnostic, therapeutic, and prognostic topics were formulated. A systematic literature search was performed from inception to October 2011 using Embase, MEDLINE, the Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, and PsychInfo databases. The approach of the Grading of Recommendations Assessment, Development and Evaluation was applied to evaluate outcomes. For therapeutic questions, quality of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation system. Grading the quality of evidence for the other questions was performed according to the classification system of the Oxford Centre for Evidence-Based Medicine. During 3 consensus meetings, all recommendations were discussed and finalized. The group members voted on each recommendation, using the nominal voting technique. Expert opinion was used where no randomized controlled trials were available to support the recommendation. RESULTS This evidence-based guideline provides recommendations for the evaluation and treatment of children with functional constipation to standardize and improve their quality of care. In addition, 2 algorithms were developed, one for the infants <6 months of age and the other for older infants and children. CONCLUSIONS This document is intended to be used in daily practice and as a basis for further clinical research. Large well-designed clinical trials are necessary with regard to diagnostic evaluation and treatment.
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Chapman TP, Hadley G, Fratter C, Cullen SN, Bax BE, Bain MD, Sapsford RA, Poulton J, Travis SP. Unexplained gastrointestinal symptoms: think mitochondrial disease. Dig Liver Dis 2014; 46:1-8. [PMID: 23768727 DOI: 10.1016/j.dld.2013.04.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Revised: 04/06/2013] [Accepted: 04/14/2013] [Indexed: 02/08/2023]
Abstract
Defects in mitochondrial function are increasingly recognised as central to the pathogenesis of many diseases, both inherited and acquired. Many of these mitochondrial defects arise from abnormalities in mitochondrial DNA and can result in multisystem disease, with gastrointestinal involvement common. Moreover, mitochondrial disease may present with a range of non-specific symptoms, and thus can be easily misdiagnosed, or even considered to be non-organic. We describe the clinical, histopathological and genetic findings of six patients from three families with gastrointestinal manifestations of mitochondrial disease. In two of the patients, anorexia nervosa was considered as an initial diagnosis. These cases illustrate the challenges of both diagnosing and managing mitochondrial disease and highlight two important but poorly understood aspects, the clinical and the genetic. The pathophysiology of gastrointestinal involvement in mitochondrial disease is discussed and emerging treatments are described. Finally, we provide a checklist of investigations for the gastroenterologist when mitochondrial disease is suspected.
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Affiliation(s)
- Thomas P Chapman
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
| | - Gina Hadley
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
| | - Carl Fratter
- Oxford Medical Genetics Laboratories, Churchill Hospital, Oxford, UK
| | - Sue N Cullen
- Buckinghamshire Hospitals NHS Trust, Department of Gastroenterology, Level 6, Queen Alexandra Road, High Wycombe, UK
| | - Bridget E Bax
- Division of Clinical Sciences, St. George's University of London, London, UK
| | - Murray D Bain
- Division of Clinical Sciences, St. George's University of London, London, UK
| | | | - Joanna Poulton
- Nuffield Dept Obstetrics and Gynaecology, University of Oxford, The Women's Centre, Oxford, UK
| | - Simon P Travis
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK.
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20
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Abstract
Hirschsprung disease (HD) is the most prevalent congenital gastrointestinal motility disorder. The pathogenesis of HD is defined as a functional intestinal obstruction resulting from a defect in the intrinsic innervation of the distal bowel. In addition to the enteric nervous system, the interstitial cells of Cajal (ICC) play an important role in the generation of coordinated gastrointestinal peristalsis. The major function of the ICCs is the generation of slow waves that allow these cells to act as specialised pacemaker cells within various tissues. ICCs have additional functions in the gastrointestinal tract as regulators of mechanical activity and neurotransmission. Due to the central role of ICCs in gastrointestinal peristalsis, it has been suggested that defects or impairments of the ICCs may contribute to motility dysfunction in several gastrointestinal motility disorders. This review describes the distribution and functions of ICCs in the normal gut and in Hirschsprung disease.
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Affiliation(s)
- Stefan Gfroerer
- Department of Paediatric Surgery, University Hospital, Goethe University Frankfurt/M, 60596 Frankfurt/M, Germany,
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21
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Bassotti G, Villanacci V, Creƫoiu D, Creƫoiu SM, Becheanu G. Cellular and molecular basis of chronic constipation: taking the functional/idiopathic label out. World J Gastroenterol 2013; 19:4099-4105. [PMID: 23864772 PMCID: PMC3710411 DOI: 10.3748/wjg.v19.i26.4099] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Revised: 05/16/2013] [Accepted: 05/18/2013] [Indexed: 02/06/2023] Open
Abstract
In recent years, the improvement of technology and the increase in knowledge have shifted several strongly held paradigms. This is particularly true in gastroenterology, and specifically in the field of the so-called "functional" or "idiopathic" disease, where conditions thought for decades to be based mainly on alterations of visceral perception or aberrant psychosomatic mechanisms have, in fact, be reconducted to an organic basis (or, at the very least, have shown one or more demonstrable abnormalities). This is particularly true, for instance, for irritable bowel syndrome, the prototype entity of "functional" gastrointestinal disorders, where low-grade inflammation of both mucosa and myenteric plexus has been repeatedly demonstrated. Thus, researchers have also investigated other functional/idiopathic gastrointestinal disorders, and found that some organic ground is present, such as abnormal neurotransmission and myenteric plexitis in esophageal achalasia and mucosal immune activation and mild eosinophilia in functional dyspepsia. Here we show evidence, based on our own and other authors' work, that chronic constipation has several abnormalities reconductable to alterations in the enteric nervous system, abnormalities mainly characterized by a constant decrease of enteric glial cells and interstitial cells of Cajal (and, sometimes, of enteric neurons). Thus, we feel that (at least some forms of) chronic constipation should no more be considered as a functional/idiopathic gastrointestinal disorder, but instead as a true enteric neuropathic abnormality.
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Singh S, Heady S, Coss-Adame E, Rao SS. Clinical utility of colonic manometry in slow transit constipation. Neurogastroenterol Motil 2013; 25:487-95. [PMID: 23384415 PMCID: PMC3764651 DOI: 10.1111/nmo.12092] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2012] [Accepted: 01/08/2013] [Indexed: 02/06/2023]
Abstract
BACKGROUND The clinical significance of colorectal sensorimotor evaluation in patients with slow transit constipation (STC) is unclear. We investigated whether colonic manometric evaluation is useful for characterizing colonic sensorimotor dysfunction and for guiding therapy in STC. METHODS 24-h ambulatory colonic manometry was performed in 80 patients (70 females) with STC by placing a six sensor solid-state probe, along with assessment of colonic sensation with barostat. Anorectal manometry was also performed. Manometrically, patients were categorized as having colonic neuropathy or myopathy based on gastrocolonic response, waking response and high amplitude propagated contractions (HAPC); and based on colonic sensation, as colonic hyposensitivity or hypersensitivity. Clinical response to pharmacological, biofeedback, and surgical treatment was assessed at 1 year and correlated with manometric findings. KEY RESULTS Forty seven (59%) patients who had abnormal colonic manometry, with features suggestive of neuropathy (26%), and myopathy (33%); 41% had normal colonic manometry. Patients who had abnormal colonic sensation were 74% and 61% had overlapping dyssynergic defecation. Patients with neuropathy were more likely to have colonic hyposensitivity. Sixty-four percent of patients with colonic myopathy or normal manometry improved with medical/biofeedback therapy when compared to 15% with colonic neuropathy (P < 0.01). Selected patients with colonic neuropathy had excellent response to surgery, but many developed bacterial overgrowth. CONCLUSIONS & INFERENCES Colonic manometry demonstrates significant colonic sensorimotor dysfunction in STC patients and reveals considerable pathophysiological heterogeneity. It can be useful for characterizing the underlying pathophysiology and for guiding clinical management in STC, especially surgery.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology and Hepatology, University of Iowa Hospitals and Clinics, Iowa City, IA
| | - Sarah Heady
- Division of Gastroenterology and Hepatology, University of Iowa Hospitals and Clinics, Iowa City, IA
| | - Enrique Coss-Adame
- Section of Gastroenterology, Department of Internal Medicine, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA
| | - Satish S.C. Rao
- Division of Gastroenterology and Hepatology, University of Iowa Hospitals and Clinics, Iowa City, IA,Section of Gastroenterology, Department of Internal Medicine, Medical College of Georgia, Georgia Health Sciences University, Augusta, GA
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Russo M, Martinelli M, Sciorio E, Botta C, Miele E, Vallone G, Staiano A. Stool consistency, but not frequency, correlates with total gastrointestinal transit time in children. J Pediatr 2013; 162:1188-92. [PMID: 23312678 DOI: 10.1016/j.jpeds.2012.11.082] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2012] [Revised: 10/23/2012] [Accepted: 11/29/2012] [Indexed: 12/12/2022]
Abstract
OBJECTIVES To evaluate the correlation between stool characteristics (consistency and frequency) and gut transit time in children and to determine whether the Bristol Stool Form Scale is a reliable method of assessing intestinal transit rate in children. STUDY DESIGN From March 2011 to March 2012, 44 children (25 boys and 19 girls, mean age 7.8 years) with a diagnosis of functional constipation and 36 healthy, nonconstipated children (17 boys and 19 girls, mean age 7.6 years) were enrolled. All participants maintained a 1-week stool diary, recording the time and date of every bowel movement and stool form, and then completed a validated questionnaire on functional constipation according to Rome III criteria. Whole gut transit time (WGTT) was then assessed using the radiopaque markers test. RESULTS There was a significant correlation between stool form and WGTT in both constipated and nonconstipated children (correlation coefficient -0.84, P<.001). By contrast, there was no correlation between either stool frequency and WGTT or stool frequency and stool form. Multivariate logistic regression analysis, using WGTT as a dependent variable, showed that the sole variable significantly associated with WGTT was stool form (regression coefficient 2.9, OR 18.4, 95% CI 5.4-62.5, P<.001). CONCLUSION In this prospective, observational, case-control study, we show that stool form, as measured by the Bristol Stool Form Scale, rather than stool frequency, correlates with WGTT in both constipated and nonconstipated children.
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Affiliation(s)
- Marina Russo
- Department of Pediatrics, University of Naples Federico II, Naples, Italy
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Knowles CH, Lindberg G, Panza E, De Giorgio R. New perspectives in the diagnosis and management of enteric neuropathies. Nat Rev Gastroenterol Hepatol 2013; 10:206-18. [PMID: 23399525 DOI: 10.1038/nrgastro.2013.18] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Chronic disturbances of gastrointestinal function encompass a wide spectrum of clinical disorders that range from common conditions with mild-to-moderate symptoms to rare diseases characterized by a severe impairment of digestive function, including chronic pain, vomiting, bloating and severe constipation. Patients at the clinically severe end of the spectrum can have profound changes in gut transit and motility. In a subset of these patients, histopathological analyses have revealed abnormalities of the gut innervation, including the enteric nervous system, termed enteric neuropathies. This Review discusses advances in the diagnosis and management of the main clinical entities--achalasia, gastroparesis, intestinal pseudo-obstruction and chronic constipation--that result from enteric neuropathies, including both primary and secondary forms. We focus on the various evident neuropathologies (degenerative and inflammatory) of these disorders and, where possible, present the specific implications of histological diagnosis to contemporary treatment. This knowledge could enable the future development of novel targeted therapeutic approaches.
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Affiliation(s)
- Charles H Knowles
- Centre for Digestive Diseases, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, London E1 2AD, UK
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Bernardini N, Ippolito C, Segnani C, Mattii L, Bassotti G, Villanacci V, Blandizzi C, Dolfi A. Histopathology in gastrointestinal neuromuscular diseases: methodological and ontological issues. Adv Anat Pathol 2013; 20:17-31. [PMID: 23232568 DOI: 10.1097/pap.0b013e31827b65c0] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Gastrointestinal neuromuscular diseases (GINMDs) comprise a heterogenous group of chronic conditions associated with impaired gut motility. These gastrointestinal (GI) disorders, differing for etiopathogenic mechanisms, pathologic lesions, and region of gut involvement, represent a relevant matter for public health, because they are very common, can be disabling, and determine major social and economic burdens. GINMDs are presumed or proven to arise as a result of a dysfunctioning GI neuromuscular apparatus, which includes myenteric ganglia (neurons and glial cells), interstitial cells of Cajal and smooth muscle cells. Despite the presence of symptoms related to gut dysmotility in the clinical phenotype of these patients, in the diagnostic setting scarce attention is usually paid to the morphologic pattern of the GI neuromuscular apparatus. It is also objectively difficult to collect full-thickness gut tissue samples from patients with GINMDs, because their disease, which can be only functional in nature, may not justify invasive diagnostic procedures as a first-line approach. As a consequence, whenever available, bioptic gut specimens, retrieved from these patients, must be regarded as a unique chance for obtaining relevant diagnostic information. On the basis of these arguments, there is an urgent need of standardized and validated histopathologic methods, aiming at overcoming the discrepancies affecting current approaches, which usually lead to conflicting definitions of normality and hamper the identification of disease-specific pathologic patterns. This review article intends to address current methodological and ontological issues in the histopathologic diagnosis of GINMDs, to foster the debate on how to discriminate normal morphology from abnormalities.
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Affiliation(s)
- Nunzia Bernardini
- Unit of Histology, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
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Giorgio V, Borrelli O, Smith VV, Rampling D, Köglmeier J, Shah N, Thapar N, Curry J, Lindley KJ. High-resolution colonic manometry accurately predicts colonic neuromuscular pathological phenotype in pediatric slow transit constipation. Neurogastroenterol Motil 2013; 25:70-8.e8-9. [PMID: 23030503 DOI: 10.1111/nmo.12016] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Severe pediatric slow transit constipation (STC) is commonly due to intrinsic colonic neuromuscular disease. We sought to correlate neuromuscular histological phenotypes in pediatric STC with colonic manometric phenotypes using high-resolution manometry (HRM). We tested the hypothesis that failure of motor quiescence (FQ) between bisacodyl-induced high amplitude propagating sequences (HAPSs) might predict neuromuscular pathology. METHODS Eighteen children (10 males, median age: 7.5 years) with refractory STC underwent stationary colonic HRM before segmental colonic resection. Six age-matched constipated children with normal colonic transit served as controls. Colonic resection specimens underwent histopathological analysis. Conventional manometric parameters and area under the curve (AUC) during a 1-min period following bisacodyl-induced HAPSs [PBAUC(1) ], as measure of FQ, were calculated. KEY RESULTS Numbers of postbisacodyl HAPSs in descending and sigmoid segments were lower in patients than controls (P < 0.01, respectively). Low amplitude propagating sequences (LAPSs) were common prebisacodyl in controls and rare in STC (P < 0.001), whereas postbisacodyl LAPS were more common in STC (P < 0.001). Postbisacodyl, both retrograde propagating contractions and bursts of contractions were present in STC patients only (P < 0.001 and P < 0.01). Postbisacodyl simultaneous pressurization was seen only in STC (P < 0.05 and P < 0.001, in descending and rectosigmoid segments). Histological abnormalities were present in 17/18. Fourteen were neurogenic, one neuro-myogenic, and two myogenic. In segments with HAPS, PBAUC(1) was predictive of colonic neuropathy using a cutoff of 205 mmHg.s(-1) (Sensitivity 100%, specificity 86%, PPV92%, NPV100%). CONCLUSIONS & INFERENCES PBAUC(1) is increased in multiple colonic segments in neuropathic pediatric STC and constitutes a sensitive and specific biomarker of neuropathy.
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Affiliation(s)
- V Giorgio
- Division of Neurogastroenterology & Motility, Department of Pediatric Gastroenterology, Great Ormond Street Hospital and UCL, London, UK
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Lemos SPP, Martins JL, Lemos PVRB, Silva SRGE, Santos FLD, Silva Júnior VAD. Abnormalities of digestive tract innervation in rat fetus treated with ethylenethiourea. Acta Cir Bras 2012; 27:244-50. [DOI: 10.1590/s0102-86502012000300007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Accepted: 01/20/2012] [Indexed: 09/13/2023] Open
Abstract
PURPOSE: The pathophysiology of abnormalities associated with myenteric plexus lesions remains imperfectly understood. Such abnormalities have been correlated with subocclusive intestinal conditions in children with Hirschsprung's disease, cases of chronic constipation and, postoperatively, in cases of anorectal anomalies. This study evaluated abnormalities of the myenteric plexus in fetus from female rats that received ethylenethiourea. METHODS: Female rats were exposed to ethylenethiourea on the 11th day of pregnancy (experimental group) or to 0.9% physiological solution (control group). Abnormalities were only found in the experimental group. The digestive tract muscle layer was analyzed morphometrically and changes to the frequencies of nerve plexus cells and interstitial cells of Cajal were evaluated, using hematoxylin-eosin, S-100 protein, neuron-specific enolase and C-Kit, respectively. RESULTS: Muscle and skeletal abnormalities were observed in 100%, anorectal anomalies in 86%, absent tail in 71%, short tail in 29%, duodenal atresia in 5%, esophageal atresia in 5% and persistent omphalomesenteric duct in 5%. Histopathological analysis showed a thinner muscle layer associated with lower frequencies of ganglion cells and interstitial cells of Cajal, in all gastrointestinal tract. CONCLUSION: Severe nerve plexus abnormalities associated with muscle layer atrophy were observed throughout the gastrointestinal tract in newborn rats exposed to ethylenethiourea.
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Abstract
Constipation in children is an often long-lasting pediatric functional gastrointestinal disorder with a worldwide prevalence varying between 0.7% and 29.6%, and estimated health-care costs of US$3.9 billion per year in the USA alone. The pathophysiology of childhood constipation is multifactorial and remains incompletely understood; however, withholding of stools, starting after an experience of a hard, painful, or frightening bowel movement is the most common cause found in children. A thorough medical history and physical examination, including a rectal examination in combination with a bowel diary, is sufficient in the majority of cases to diagnose constipation. The current standard treatment consists of education, toilet training, disimpaction, maintenance therapy and long-term follow-up. In the past decade, well-designed treatment trials in the pediatric population have emerged and long-term outcome studies have been completed. This Review summarizes the current knowledge of the clinical aspects of childhood constipation, including pathogenesis, diagnosis and treatment, with particular emphasis on the latest available data.
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Knowles CH, Farrugia G. Gastrointestinal neuromuscular pathology in chronic constipation. Best Pract Res Clin Gastroenterol 2011; 25:43-57. [PMID: 21382578 PMCID: PMC4175481 DOI: 10.1016/j.bpg.2010.12.001] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 12/15/2010] [Indexed: 01/31/2023]
Abstract
Some patients with chronic constipation may undergo colectomy yielding tissue appropriate to diagnosis of underlying neuromuscular pathology. The analysis of such tissue has, over the past 40 years, fueled research that has explored the presence of neuropathy, myopathy and more recently changes in interstitial cells of Cajal (ICC). In this chapter, the data from these studies have been critically reviewed in the context of the significant methodological and interpretative issues that beset the field of gastrointestinal neuromuscular pathology. On this basis, reductions in ICC appear to a consistent finding but one whose role as a primary cause of slow-transit constipation requires further evaluation. Findings indicative of significant neuropathy or myopathy are variable and in many studies subject to considerable methodological bias. Methods with practical diagnostic utility in the individual patient have rarely been employed and require further validation in respect of normative data.
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Affiliation(s)
| | - Gianrico Farrugia
- Enteric NeuroScience Program, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA
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Dinning PG, Di Lorenzo C. Colonic dysmotility in constipation. Best Pract Res Clin Gastroenterol 2011; 25:89-101. [PMID: 21382581 DOI: 10.1016/j.bpg.2010.12.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 11/23/2010] [Accepted: 12/13/2010] [Indexed: 01/31/2023]
Abstract
Constipation is a common and distressing condition with major morbidity, health care burden, and impact on quality of life. Colonic motor dysfunction remains the leading hypothesis to explain symptom generation in the most severe cases of chronic constipation and physiological testing plays a role in identifying the colonic dysmotility and the subsequent patient management. Measurement of colonic motor patterns and transit has enhanced our knowledge of normal and abnormal colonic motor physiology. The scope of this review encompasses the latest findings that improve our understanding of the motility disorders associated with colonic dysfunction in both the paediatric and adult population suffering from constipation.
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Affiliation(s)
- Philip G Dinning
- Department of Gastroenterology, University of New South Wales, St George Hospital, Gray St, Kogarah, NSW 2217, Sydney, Australia.
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Chronic constipation: lessons from animal studies. Best Pract Res Clin Gastroenterol 2011; 25:59-71. [PMID: 21382579 DOI: 10.1016/j.bpg.2010.12.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Revised: 11/23/2010] [Accepted: 12/15/2010] [Indexed: 01/31/2023]
Abstract
Chronic constipation is a highly debilitating condition, affecting a significant proportion of the community. The burden to the health care system and impact on individual patients quality of life is immense. Unfortunately, the aetiology underlying chronic constipation is poorly understood and animal models are being used increasingly to investigate possible intrinsic neurogenic and myogenic mechanisms leading to relevant colonic sensori-motor dysfunction. Recently, major advances have been made in our understanding of the mechanisms that underlie propagating contractions along the large intestine, such as peristalsis and colonic migrating motor complexes in laboratory animals, particularly in guinea-pigs and mice. The first recordings of cyclical propagating contractions along the isolated whole human colon have now also been made. This review will highlight some of these advances and how impairments to these motility patterns may contribute to delayed colonic transit, known to exist in a proportion of patients with chronic constipation.
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Dinning PG, Benninga MA, Southwell BR, Scott SM. Paediatric and adult colonic manometry: A tool to help unravel the pathophysiology of constipation. World J Gastroenterol 2010; 16:5162-72. [PMID: 21049550 PMCID: PMC2975087 DOI: 10.3748/wjg.v16.i41.5162] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colonic motility subserves large bowel functions, including absorption, storage, propulsion and defaecation. Colonic motor dysfunction remains the leading hypothesis to explain symptom generation in chronic constipation, a heterogeneous condition which is extremely prevalent in the general population, and has huge socioeconomic impact and individual suffering. Physiological testing plays a crucial role in patient management, as it is now accepted that symptom-based assessment, although important, is unsatisfactory as the sole means of directing therapy. Colonic manometry provides a direct method for studying motor activities of the large bowel, and this review provides a contemporary understanding of how this technique has enhanced our knowledge of normal colonic motor physiology, as well as helping to elucidate pathophysiological mechanisms underlying constipation. Methodological approaches, including available catheter types, placement technique and recording protocols, are covered, along with a detailed description of recorded colonic motor activities. This review also critically examines the role of colonic manometry in current clinical practice, and how manometric assessment may aid diagnosis, classification and guide therapeutic intervention in the constipated individual. Most importantly, this review considers both adult and paediatric patients. Limitations of the procedure and a look to the future are also addressed.
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Demirogullari B, Sari S, Egritas O, Karakus C, Ozen I, Sonmez K, Dalgic B, Kale N, Basaklar AC. Colonic phasic motor activity is stronger in patients with repaired anorectal malformations than patients with severe colonic dismotility. Pediatr Rep 2010; 2:e18. [PMID: 21589831 PMCID: PMC3093997 DOI: 10.4081/pr.2010.e18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Accepted: 10/21/2010] [Indexed: 11/23/2022] Open
Abstract
In this study, colonic manometry studies of the patients with repaired anorectal malformations (ARM) were compared with those of patients with severe colonic dismotility due to chronic constipation (CC) and acute pseudo-obstruction (PSO). The patients with repaired ARM were accepted as group #1 (n=10). The patients with CC and acute PSO composed group #2 (n=10). Eight-channel water perfused catheter was inserted into the colon under sedation. Colonic activity was recorded in three phases including fasting, after meal and after bisacodyl installation. The results were assessed by Pearson χ(2) test, P<.05 was considered statistically significant. Mean age was 9.6 and 12.1 in groups #1 and #2, respectively. Ninety-five per cent of all patients had propagated contractions (PCs) and 20% and 40% of the patients in group #1 had PCs during fasting and after meal, respectively. These contractions were seen 30% and 70% of the patients in group #2, but no statistical difference was found between the groups. PCs after bisacodyl were observed 90% and 40% of the patients in groups #1 and #2, respectively, and this difference was statistically significant (P=.019). In this study, the prominent difference between the groups was found in response to intraluminal stimulation. This finding may indicate that the colon of the patients with ARM has more capacity to develop PCs by peripheral stimuli and more regular enteric nervous integrity.
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Affiliation(s)
- Billur Demirogullari
- Gazi University Medical Faculty Departments of Pediatric Surgery and Pediatric Gastroenterology, Ankara, Turkey
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Bongers MEJ, van Wijk MP, Reitsma JB, Benninga MA. Long-term prognosis for childhood constipation: clinical outcomes in adulthood. Pediatrics 2010; 126:e156-62. [PMID: 20530072 DOI: 10.1542/peds.2009-1009] [Citation(s) in RCA: 146] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
OBJECTIVES This study examines long-term prognoses for children with constipation in adulthood and identifies prognostic factors associated with clinical outcomes. METHODS In a Dutch tertiary hospital, children (5-18 years of age) who were diagnosed as having functional constipation were eligible for inclusion. After a 6-week treatment protocol, prospective follow-up evaluations were conducted at 6 and 12 months and annually thereafter. Good clinical outcomes were defined as > or =3 bowel movements per week for > or =4 weeks, with < or =2 fecal incontinence episodes per month, irrespective of laxative use. RESULTS A total of 401 children (260 boys; median age: 8 years [interquartile range: 6-9 years]) were included, with a median follow-up period of 11 years (interquartile range: 9-13 years). The dropout rate during follow-up was 15%. Good clinical outcomes were achieved by 80% of patients at 16 years of age. Thereafter, this proportion remained constant at 75%. Poor clinical outcomes at adult age were associated with: older age at onset (odds ratio [OR]: 1.15 [95% confidence interval [CI]: 1.02-1.30]; P = .04), longer delay between onset and first visit to our outpatient clinic (OR: 1.24 [95% CI: 1.10-1.40]; P = .001), and lower defecation frequency at study entry (OR: 0.92 [95% CI: 0.84-1.00]; P = .03). CONCLUSIONS One-fourth of children with functional constipation continued to experience symptoms at adult age. Certain risk factors for poor clinical outcomes in adulthood were identified. Referral to a specialized clinic should be considered at an early stage for children who are unresponsive to first-line treatment.
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Affiliation(s)
- Marloes E J Bongers
- Department of Pediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam, Netherlands
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Dudding TC, Vaizey CJ. Current Concepts in Evaluation and Testing of Posterior Pelvic Floor Disorders. SEMINARS IN COLON AND RECTAL SURGERY 2010. [DOI: 10.1053/j.scrs.2009.10.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Abstract
Gastrointestinal motility disorders in their most severe forms may directly lead to intestinal failure. Abnormal motor function may also contribute to the overall gut dysfunction of children who have other underlying gastrointestinal diseases, such as Hirschsprung disease or gastroschisis. Understanding the extent and the severity of the dysmotile segments has direct therapeutic and prognostic implications. Our ability to study gastrointestinal motility has greatly improved in the past few years, with the development of less-invasive diagnostic tests. Optimal treatment of children with intestinal motility disorders relies on a multidisciplinary approach, which focuses on optimizing nutrition, improving gastrointestinal motility, and reducing psychosocial disability. Patient education is important to avoid aggravations of symptoms caused by dietary indiscretions.
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Affiliation(s)
- Carlo Di Lorenzo
- Division of Pediatric Gastroenterology, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
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Abstract
PURPOSE OF REVIEW Disorders of colonic motor and sensory function are common among children and adults and pose significant diagnostic and therapeutic challenges; the purpose of this review, therefore, was to critically assess the recent literature on this topic. RECENT FINDINGS Considerable progress has been made at the ultrastructural, molecular and electrophysiological level in understanding the normal functions of the muscles, nerves and interstitial cells that generate and control colonic motility. Furthermore, abnormalities in these cell types and in the interstitial cells of Cajal, in particular, have been identified in a number of disease states. Testing of colonic motor and sensory function in clinical practice continues to be a challenge due, in part, not only to the technical issues presented by accessing the organ but also to the intrinsic variability of its physiology. These have not been auspicious times for advances in the therapy of disturbed colonic motility; new agents or new applications for 'old' agents continue to be explored as are more innovative approaches such as those based on neural stimulation and cell therapy. SUMMARY Considerable progress has been made in understanding the basic pathophysiology of colonic dysmotility; clinical diagnostics and therapeutics continue to lag behind.
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