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Barbara G, Aziz I, Ballou S, Chang L, Ford AC, Fukudo S, Nurko S, Olano C, Saps M, Sayuk G, Siah KTH, Van Oudenhove L, Simrén M. Rome Foundation Working Team Report on overlap in disorders of gut-brain interaction. Nat Rev Gastroenterol Hepatol 2025; 22:228-251. [PMID: 39870943 DOI: 10.1038/s41575-024-01033-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/29/2025]
Abstract
In patients with disorders of gut-brain interaction (DGBI), overlapping non-gastrointestinal conditions such as fibromyalgia, headaches, gynaecological and urological conditions, sleep disturbances and fatigue are common, as is overlap among DGBI in different regions of the gastrointestinal tract. These overlaps strongly influence patient management and outcome. Shared pathophysiology could explain this scenario, but details are not fully understood. This overlap has been shown to be of great relevance for DGBI. In addition, symptoms considered to be caused by a DGBI could have a detectable organic cause, and in patients with a diagnosed organic gastrointestinal disease, symptoms not clearly explained by the pathology defining this organic disease are common. Thus, the aims of this Rome Foundation Working Team Report were to review the literature on overlapping conditions among patients with paediatric and adult DGBI and, based on the available epidemiological and clinical evidence, make recommendations for the current diagnostic and therapeutic approach, and for future research. Specifically, we focused on other DGBI in the same or different gastrointestinal anatomical region(s), DGBI overlap with organic bowel diseases in remission, and DGBI overlap with non-gastrointestinal, non-structural conditions.
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Affiliation(s)
- Giovanni Barbara
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Imran Aziz
- Academic Department of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, UK
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| | - Sarah Ballou
- Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Lin Chang
- Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, UK
- Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Shin Fukudo
- Department of Psychosomatic Medicine, Japanese Red Cross Ishinomaki Hospital, Research Center for Accelerator and Radioisotope Science, Tohoku University, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Samuel Nurko
- Center for Motility and Functional Gastrointestinal Disorders, Boston Children's Hospital, Boston, MA, USA
| | - Carolina Olano
- Gastroenterology Department. Universidad de la República, Montevideo, Uruguay
| | - Miguel Saps
- Division of Gastroenterology, Hepatology, and Nutrition, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Gregory Sayuk
- Gastroenterology Division, Washington University School of Medicine, St. Louis, MO, USA
- St. Louis Veterans Affairs Medical Center, St. Louis, MO, USA
| | - Kewin T H Siah
- NUS Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore
| | - Lukas Van Oudenhove
- Laboratory for Brain-Gut Axis Studies (LaBGAS), Translational Research in Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Leuven Brain Institute, KU Leuven, Leuven, Belgium
- Consultation-Liaison Psychiatry, University Psychiatric Centre KU Leuven, Leuven, Belgium
| | - Magnus Simrén
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
- Center for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Choudhary A, Fikree A, Ruffle JK, Takahashi K, Palsson OS, Aziz I, Aziz Q. A machine learning approach to stratify patients with hypermobile Ehlers-Danlos syndrome/hypermobility spectrum disorders according to disorders of gut brain interaction, comorbidities and quality of life. Neurogastroenterol Motil 2025; 37:e14957. [PMID: 39543811 DOI: 10.1111/nmo.14957] [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: 04/16/2024] [Revised: 10/06/2024] [Accepted: 10/21/2024] [Indexed: 11/17/2024]
Abstract
BACKGROUND A high prevalence of disorders of gut-brain interaction (DGBI) exist in patients with hypermobile Ehlers-Danlos Syndrome (hEDS) and hypermobility spectrum disorders (HSD). However, it is unknown if clusters of hEDS/HSD patients exist which overlap with different DGBIs and whether this overlap influences presence of comorbidities and quality of life. We aimed to study these knowledge gaps. METHODS A prospectively collected hEDS/HSD cohort of 1044 individuals were studied. We undertook Uniform Manifold Approximation and Projection-enabled (UMAP) dimension reduction to create a representation of nonlinear interactions between hEDS/HSD and DGBIs, from which individuals were stratified into clusters. Somatization, Postural Tachycardia Syndrome (PoTS), autonomic symptoms, psychological factors and quality of life were statistically compared between clusters. KEY RESULTS The mean age of patients was 40 ± 13.2 years; 87.8% were female. Patients segregated into three clusters: Cluster 0 (n = 466): hEDS/HSD+ functional foregut disorders (FFD) + irritable bowel syndrome (IBS); Cluster 1 (n = 180): hEDS/HSD+ IBS and Cluster 2 (n = 337): hEDS/HSD alone. In cluster 0, we demonstrated increased somatization (p <0.0001), anxiety (p <0.0001), depression (p <0.0001), PoTS prevalence (p = 0.003), autonomic symptoms (p <0.0001) and reduced quality of life (p <0.0001) compared to cluster 2. Cluster 0 had greater comorbidity burden than cluster 1. CONCLUSIONS Within hEDS/HSD, subgroups exist with a high prevalence of FFD and IBS. These subgroups have a higher prevalence of psychological disorders, dysautonomia and poorer quality of life compared with hEDS/HSD alone. Further research should focus on healthcare utilization, management and prognosis in hEDS/HSD and DGBI overlap.
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Affiliation(s)
- Anisa Choudhary
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Asma Fikree
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - James K Ruffle
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- High Dimensional Neurology Group, UCL Queen Square Institute of Neurology, University College London, London, UK
| | - Kazuya Takahashi
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Olafur S Palsson
- Centre for Functional GI and Motility Disorders, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Imran Aziz
- Academic Department of Gastroenterology, Sheffield Teaching Hospitals and University of Sheffield, Sheffield, UK
| | - Qasim Aziz
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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Pasricha PJ, McKnight M, Villatoro L, Barahona G, Brinker J, Hui K, Polydefkis M, Burns R, McMahan ZH, Gould N, Goodman B, Hentz J, Treisman G. Joint Hypermobility, Autonomic Dysfunction, Gastrointestinal Dysfunction, and Autoimmune Markers: Clinical Associations and Response to Intravenous Immunoglobulin Therapy. Am J Gastroenterol 2024; 119:2298-2306. [PMID: 38912927 PMCID: PMC11524627 DOI: 10.14309/ajg.0000000000002910] [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: 11/09/2023] [Accepted: 05/30/2024] [Indexed: 06/25/2024]
Abstract
INTRODUCTION We examined autoimmunity markers (AIM) and autonomic dysfunction in patients with chronic neurogastroenterological symptoms and their relationship to joint hypermobility/hypermobility spectrum disorder (JH/HSD). METHODS AIM positivity was defined as a diagnosis of known autoimmune/autoinflammatory disorder with at least 1 positive seromarker of autoimmunity or at least 2 positive seromarkers by themselves. Three cohorts were studied: (i) retrospective (n = 300), (ii) prospective validation cohort (n = 133), and (iii) treatment cohort (n = 40), administered open-label intravenous immunoglobulin (IVIG). RESULTS AIM positivity was found in 40% and 29% of the retrospective and prospective cohorts, the majority of whom (71% and 69%, respectively) had autoinflammatory disorder. Significantly more patients with AIM had elevations of C-reactive protein (31% vs 15%, P < 0.001) along with an increased proportion of cardiovascular autonomic dysfunction (48% vs 29%; P < 0.001), small fiber neuropathy (20% vs 9%; P = 0.002), and HLADQ8 positivity (24% vs 13%, P = 0.01). Patients with JH/HSD were more likely to have AIM (43% vs 15%, P = 0.001) along with more severe autonomic and gastrointestinal (GI) symptom scores. IVIG treatment was associated with robust improvement in pain, GI, and autonomic symptoms, but adverse events were experienced by 62% of patients. DISCUSSION Autoimmune markers and autonomic dysfunction are common in patients with unexplained GI symptoms, especially in those with JH/HSD. Many patients seem to respond to IVIG treatment, but this needs to be confirmed by controlled trials. These results highlight the need for vigilance for autoimmune and autonomic factors and JH/HSD in patients with neurogastroenterological disorders. Clinicaltrials.gov , NCT04859829.
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Affiliation(s)
| | - Megan McKnight
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
| | | | | | - Jeffrey Brinker
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
| | - Ken Hui
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
| | | | - Robert Burns
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
| | | | - Neda Gould
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
| | | | | | - Glenn Treisman
- Johns Hopkins University School of Medicine, Baltimore, Maryland, USA;
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Penny HA, Aziz I, Lam C. Mast cell activation and nutritional disorders in patients with hypermobility. Curr Opin Gastroenterol 2024; 40:225-232. [PMID: 38393310 DOI: 10.1097/mog.0000000000001008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/25/2024]
Abstract
PURPOSE OF REVIEW Individuals with joint hypermobility disorders are increasingly referred to gastroenterology services for support with the investigation and management of gastrointestinal complaints. Individuals can present with a myriad of complex coexisting diagnoses, the inter-relationship of which is unclear. This review discusses the proposed association between hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorder (HSD) with disorders of mast cell activation and provides an overview of gastrointestinal symptoms and nutritional outcomes in this patient cohort. RECENT FINDINGS It is unclear whether a true association between hEDS/HSD and mast cell activation disorders exists. There is a high prevalence of nonspecific gastrointestinal symptoms in individuals with hEDS/HSD and patients may be at risk of macro-nutrient and micro-nutrient deficiencies, although the current evidence base is limited. SUMMARY We advocate a pragmatic approach to the investigation and management of gastrointestinal symptoms in patients with hEDS/HSD. This centres on excluding organic pathology, discussing the overlap with disorders of gut-brain interactions, trialling evidence-based therapies targeting individual symptoms, and supporting nutritional deficiencies where present via the least invasive approach. Engagement with a broad multidisciplinary team is also important to support the holistic needs of this patient cohort.
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Affiliation(s)
- Hugo A Penny
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals Foundation Trust
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| | - Imran Aziz
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals Foundation Trust
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| | - Ching Lam
- Academic Unit of Gastroenterology, Sheffield Teaching Hospitals Foundation Trust
- Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
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Silvernale C, Garcia-Fischer I, Staller K. Relationship Between Psychological Trauma and Irritable Bowel Syndrome and Functional Dyspepsia in a Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome Patient Population. Dig Dis Sci 2024; 69:870-875. [PMID: 38112834 DOI: 10.1007/s10620-023-08201-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 10/04/2023] [Indexed: 12/21/2023]
Abstract
BACKGROUND There is frequent overlap between and the connective tissue diseases Joint Hypermobility Syndrome/Ehlers-Danlos Syndrome (JHS/EDS) and disorders of the gut-brain interaction (DGBIs). AIMS Because not all JHS/EDS patients develop DGBIs, we sought to determine whether secondary environmental triggers may lead to development of irritable bowel syndrome (IBS) and functional dyspepsia (FD) in patients with JHS/EDS. METHODS We sent electronic surveys to 253 patients from a JHS/EDS support group, with responses collected over one year. IBS and FD were diagnosed by the Rome IV criteria, with additional validated assessments of adverse childhood experiences (ACEs) and traumatic stressors according to DSM-V criteria. We compared clinical and psychological characteristics of JHS/EDS patients with and without DGBIs using univariable and multivariable analyses. RESULTS We enrolled 193 JHS/EDS patients, of whom 67.9% met Rome IV criteria for IBS. The IBS and JHS/EDS overlap group reported significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without IBS. FD was found in 35.2% of patients and was associated with significantly more traumatic exposures (P < 0.001) and were more likely to have experienced greater than 3 ACEs (P < 0.001) than JHS/EDS patients without FD. CONCLUSIONS We found that JHS/EDS patients with IBS and FD overlap reported significantly more traumatic exposures and ACEs compared to JHS/EDS patients without overlapping IBS or FD. JHS/EDS patients may have increased susceptibility to DGBIs, with traumatic life experiences and/or ACEs acting a secondary environmental trigger driving the subsequent development of DGBIs.
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Affiliation(s)
- Casey Silvernale
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Sidney Kimmel Medical College, Jefferson University Hospital, 1025 Walnut St #100, Philadelphia, PA, 19107, USA.
| | - Isabelle Garcia-Fischer
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Kyle Staller
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Neurointestinal Health, Massachusetts General Hospital, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA
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Börsch N, Mücke M, Maier A, Conrad R, Pantel JT, Sellin J, Mani K, Chopra P. Treating pain in patients with Ehlers-Danlos syndrome : Multidisciplinary management of a multisystemic disease. Schmerz 2024; 38:12-18. [PMID: 38189943 DOI: 10.1007/s00482-023-00778-7] [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: 11/24/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND The clinical picture of people with Ehlers-Danlos syndromes (EDS) is complex and involves a variety of potential causes of pain. This poses major challenges to patients and healthcare professionals alike in terms of diagnosis and management of the condition. OBJECTIVES The aim of the article was to provide an overview of the specific pain management needs of patients with EDS and address their background. MATERIAL AND METHODS A selective literature search was performed to highlight the current state of research on pain management in EDS patients. RESULTS Affected patients require multimodal pain management considering their individual needs, disease-specific features, and comorbidities. CONCLUSION Medical awareness and evidence need to be further improved to enhance the medical care situation of these patients with complex needs.
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Affiliation(s)
- Natalie Börsch
- Institute for Digitalization and General Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany.
- Center for Rare Diseases (ZSEA), Medical Faculty, RWTH Aachen University, Aachen, Germany.
| | - Martin Mücke
- Institute for Digitalization and General Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Rare Diseases (ZSEA), Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Andrea Maier
- Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Rupert Conrad
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Muenster, Muenster, Germany
| | - Jean Tori Pantel
- Institute for Digitalization and General Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Rare Diseases (ZSEA), Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Julia Sellin
- Institute for Digitalization and General Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Rare Diseases (ZSEA), Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Kyros Mani
- Institute for Digitalization and General Medicine, Medical Faculty, RWTH Aachen University, Aachen, Germany
- Center for Rare Diseases (ZSEA), Medical Faculty, RWTH Aachen University, Aachen, Germany
| | - Pradeep Chopra
- Center for Complex Conditions, Brown Medical School, Providence, RI, USA
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Loganathan P, Herlihy D, Gajendran M, Gonzalez Z, Chavez LO, Espino K, McCallum RW. The spectrum of gastrointestinal functional bowel disorders in joint hypermobility syndrome and in an academic referral center. J Investig Med 2024; 72:162-168. [PMID: 37858959 DOI: 10.1177/10815589231210486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2023]
Abstract
Joint hypermobility syndrome (JHS) is a non-inflammatory hereditary disorder of connective tissue with varied clinical presentations, including frequent joint dislocations, hyperextensible skin, easy bruising, and abnormal paper-thin scar formation. Many of these patients have unexplained gastrointestinal (GI) symptoms. Our aim was to evaluate the prevalence of JHS in a tertiary gastroenterology motility clinic and the spectrum of functional bowel disorders in JHS patients. In this retrospective case series, we screened the medical records of 277 patients seen over 4 years at an academic GI Motility Center. The patients who met the criteria for JHS by Beighton hypermobility score were evaluated for the presence of functional GI disorders by Rome IV criteria. They also underwent gastric emptying study and glucose breath testing for small intestinal bacterial overgrowth. The prevalence of JHS in the study population was 9.7%. The mean age was 27 years, and 92.5% were female. The symptoms experienced by these patients include nausea/vomiting (89%), abdominal pain (70%), constipation (48%), and bloating (18.5%). The disorders associated with JHS include gastroparesis (52%), irritable bowel syndrome (55.5%), and gastroesophageal reflux disease (30%). Also, 10 patients (37%) were diagnosed with postural hypotension tachycardia syndrome secondary to autonomic dysfunction. Approximately 10% of patients with suspected functional bowel disorders have hypermobility syndrome. Hence, it is crucial to familiarize gastrointestinal practitioners with the criteria utilized to diagnose JHS and the methods to identify physical examination findings related to this condition.
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Affiliation(s)
| | - Daniel Herlihy
- Department of Gastroenterology, Bethany Medical Center, Winston-Salem, NC, USA
| | - Mahesh Gajendran
- Division of Gastroenterology, Texas Tech University Health Sciences Center, El Paso, TX, USA
| | - Zorisadday Gonzalez
- Department of Gastroenterology, University of New Mexico School of Medicine, Albuquerque, NM, USA
| | - Luis O Chavez
- Paul L. Foster School of Medicine (PLFSOM), Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Karina Espino
- Paul L. Foster School of Medicine (PLFSOM), Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Richard W McCallum
- Paul L. Foster School of Medicine (PLFSOM), Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
- Department of Gastroenterology, University of Texas Health Science Center at San Antonio, TX, USA
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Lim J, Rezaie A. Irritable Bowel Syndrome-Like Symptoms in Quiescent Inflammatory Bowel Disease: A Practical Approach to Diagnosis and Treatment of Organic Causes. Dig Dis Sci 2023; 68:4081-4097. [PMID: 37695549 PMCID: PMC10570178 DOI: 10.1007/s10620-023-08095-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 08/23/2023] [Indexed: 09/12/2023]
Abstract
BACKGROUND Despite achieving remission in inflammatory bowel disease (IBD), persistent gastrointestinal symptoms are common in quiescent IBD. While irritable bowel syndrome (IBS) is commonly diagnosed in IBD, IBS-like symptoms of recurrent abdominal pain and altered bowel habits can also be attributed to a wide range of overlapping gastrointestinal (GI) etiologies and systemic disorders with GI manifestations that often do not respond to conventional IBS therapies. Delay in diagnosis of these conditions can lead to ongoing patient suffering, reduced quality of life, repetition of invasive testing, increased healthcare utilization, and potentially unnecessary empirical escalation of IBD-related treatments. AIMS This review provides a practical approach for the evaluation and diagnosis of IBS mimickers in IBD. We summarize the definition, pathophysiology, diagnosis and treatment of the potential etiologies causing unexplained GI symptoms. CONCLUSION Overlapping conditions can co-exist with IBD and explain IBS-like symptoms. The diagnostic work-up in this population should be individualized and tailored to the predominant symptom pattern, associated clinical signs and symptoms and predisposing conditions that can be obtained from a detailed history and physical examination.
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Affiliation(s)
- Jane Lim
- GI Motility Program, Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, 8730 Alden Drive, Thalians Bldg, #E203, Los Angeles, CA, 90048, USA.
| | - Ali Rezaie
- GI Motility Program, Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, 8730 Alden Drive, Thalians Bldg, #E203, Los Angeles, CA, 90048, USA
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Lindberg G, Mohammadian G. Loose ends in the differential diagnosis of IBS-like symptoms. Front Med (Lausanne) 2023; 10:1141035. [PMID: 37484861 PMCID: PMC10357384 DOI: 10.3389/fmed.2023.1141035] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 05/30/2023] [Indexed: 07/25/2023] Open
Abstract
Two thirds of the patients we believed to have IBS in the 1970's have since been possible to diagnose with treatable conditions like bile acid diarrhea, inflammatory bowel disease, microscopic colitis, celiac disease, disaccharide malabsorption, exocrine pancreatic insufficiency, or rare genetic variants. Despite advances in diagnostic techniques a substantial proportion of patients continue suffering from IBS-like symptoms that cannot be explained by current knowledge. Although it is likely that further research will reveal small but important subgroups of patients with treatable mechanisms for IBS-like symptoms, we propose that only two large groups remain for being addressed in the clinic: those with connective tissue disorders such as Ehlers-Danlos syndrome or hypermobility spectrum disorders and those with autism spectrum disorders. Patients with connective tissue disorders exhibit identifiable disturbances of gut motor function and possibly increased gut permeability as underlying mechanisms for IBS-like symptoms. Autism spectrum disorders pose a much more difficult problem in the clinic. Disturbances of perception combined with anxiety and excessive worry about signals from the gut can lead to an endless but futile search for something being wrong. The search can involve large numbers of care givers, no one understanding the patient's suffering. Others may try to change their diet to lessen symptoms, only to find that almost all foods may cause worrying perceptions from the gut. Early recognition of autism spectrum disorders is essential for finding better ways to help patients with gastrointestinal and, as is often the case, extraintestinal symptoms.
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Affiliation(s)
- Greger Lindberg
- Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden
- Neurogastroenterology Unit, Division of Gastroenterology, Department of Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Ghazaleh Mohammadian
- Department of Medicine at Huddinge, Karolinska Institutet, Stockholm, Sweden
- Neurogastroenterology Unit, Division of Gastroenterology, Department of Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
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Guerrieri V, Polizzi A, Caliogna L, Brancato AM, Bassotti A, Torriani C, Jannelli E, Mosconi M, Grassi FA, Pasta G. Pain in Ehlers-Danlos Syndrome: A Non-Diagnostic Disabling Symptom? Healthcare (Basel) 2023; 11:936. [PMID: 37046863 PMCID: PMC10094213 DOI: 10.3390/healthcare11070936] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/18/2023] [Accepted: 03/23/2023] [Indexed: 04/14/2023] Open
Abstract
Ehlers-Danlos syndrome (EDS) is a phenotypically and genetically heterogeneous group of connective tissue disorders. Currently, diagnosis of EDS is based on a series of clinical and genetic tools. On the other hand, the hypermobile form has not yet been characterized from a genetic point of view: it is considered a part of a continuous spectrum of phenotypes, ranging from isolated non syndromic joint hypermobility, through to the recently defined hypermobility spectrum disorders (HSD). The aim of this study is to characterize the pain symptom that is not considered among the diagnostic criteria but is relevant to what concerns the quality of life of patients with EDS. (2) Methods: A review of the literature was performed on two medical electronic databases (PubMed and Embase) on 20 December 2022. Study selection and data extraction were achieved independently by two authors and the following inclusion criteria were determined a priori: published in the English language and published between 2000 and 2022. (3) Results: There were fifty eligible studies obtained at the end of the search and screen process. Pain is one of the most common symptoms found in Ehlers-Danlos (ED) patients. Different causes seem to be recognized in different phases of the syndrome. (4) Conclusions: Pain is a nonspecific symptom and cannot be considered among the diagnostic criteria, but it is a negative predictive factor in the quality of life of patients with EDS. Therefore, proper evaluation and treatment is mandatory.
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Affiliation(s)
- Viviana Guerrieri
- Department of Othopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy
| | - Alberto Polizzi
- Department of Othopaedics and Traumatology, Fondazione Poliambulanza Istituto Ospedaliero, 25124 Brescia, Italy
| | - Laura Caliogna
- Department of Othopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy
| | - Alice Maria Brancato
- Department of Othopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy
| | - Alessandra Bassotti
- Regional Center of Ehlers-Danlos Syndrome, IRCCS Ca’Granda Foundation Ospedale Maggiore Policlinico, 20122 Milan, Italy
| | - Camilla Torriani
- Department of Othopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy
| | - Eugenio Jannelli
- Department of Othopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy
| | - Mario Mosconi
- Department of Othopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy
| | - Federico Alberto Grassi
- Department of Othopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy
| | - Gianluigi Pasta
- Department of Othopaedics and Traumatology, Fondazione Policlinico IRCCS San Matteo, University of Pavia, 27100 Pavia, Italy
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11
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The concomitant diagnosis of fibromyalgia and connective tissue disorders: A systematic review. Semin Arthritis Rheum 2023; 58:152127. [PMID: 36462303 DOI: 10.1016/j.semarthrit.2022.152127] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 10/04/2022] [Accepted: 10/24/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Anecdotally, fibromyalgia syndrome (FMS) and connective tissue disorders (hypermobile Ehlers-Danlos Syndrome (hEDS), Hypermobility Spectrum disorders (HSD) and Generalized Joint Hypermobility (GJH)) manifest overlap in their diagnostic approach and symptomatic features. Understanding this overlap is important for accurate diagnosis and the success of subsequent management. This study therefore aimed to identify the prevalence of concomitant diagnosis of FMS and hEDS/HSD/GJH in adults and their shared symptomatic manifestations using a systematic review. METHODS MEDLINE (via EBSCO host) was systematically searched. Observational research (case-control or single group) studies were considered for inclusion, where adults screened for hEDS/HSD/GJH and FMS were compared in terms of diagnostic prevalence, and musculoskeletal and non-musculoskeletal manifestations. Studies on pediatric populations were excluded. The quality of the included studies was assessed using the National Institute of Health Quality Assessment of Case-Control Studies and Jonna Briggs Critical Appraisal checklist for prevalence studies. The review was registered prospectively in PROSPERO (CRD42020216283). FINDINGS The review included eleven studies: nine case-control studies and two single group studies. The prevalence of concomitant diagnosis of hEDS/HSD and FMS ranged from 68%-88.9% and from 8.0 to 64.2% for GJH and FMS. The prevalence and severity of a range of objective and patient-reported features were similar between hEDS/HSD and FMS, including joint pain (duration, persistence, SF-36-pain component score); joint swelling; muscle weakness; neurological problems; multidimensional pain inventory-activity; dysautonomia and total autonomic symptoms burden (including orthostatic intolerance, reflex syncope, vasomotor, gastrointestinal, diarrhea, constipation and pupillomotor domains); function; and quality of life. Shared symptomatic features between GJH and FMS were mean pain level, tender points count, total myalgia score and psychological impact. INTERPRETATION There may be overlapping symptomatology and diagnostic prevalence of FMS and hEDS/HSD/GJH. Clinicians should consider both diagnoses to ensure appropriate diagnosis and management.
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12
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Thwaites PA, Gibson PR, Burgell RE. Hypermobile Ehlers-Danlos syndrome and disorders of the gastrointestinal tract: What the gastroenterologist needs to know. J Gastroenterol Hepatol 2022; 37:1693-1709. [PMID: 35750466 PMCID: PMC9544979 DOI: 10.1111/jgh.15927] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 05/11/2022] [Accepted: 06/14/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Hypermobile Ehlers-Danlos syndrome (hEDS) and the hypermobility spectrum disorders (HSD) can be challenging to diagnose and manage. Gastrointestinal symptoms and disorders of gut-brain interaction are common in this cohort and multifactorial in origin. The primary aim of this review is to arm the gastroenterologist with a clinically useful understanding of HSD/hEDS, by exploring the association of gastrointestinal disorders with HSD/hEDS, highlighting current pathophysiological understanding and providing a pragmatic approach to managing these patients. METHODS Literature relevant to the gastrointestinal system and hypermobile Ehlers-Danlos syndrome was systematically searched, critically appraised, and summarized. RESULTS Diagnosis is based upon clinical criteria and a genetic basis is yet to be defined. The prevalence of many gut symptoms, including abdominal pain (69% vs 27%, P < 0.0001), postprandial fullness (34% vs 16%, P = 0.01), constipation (73% vs 16%, P < 0.001), and diarrhea (47% vs 9%, P < 0.001) are significantly higher in HSD/hEDS compared with non-HSD/hEDS individuals. Disorders of gut-brain interaction are also common, particularly functional dyspepsia. The pathophysiology of gut symptoms is poorly understood but may involve effects of connective tissue laxity and its functional consequences, and the influence of autonomic dysfunction, medication and comorbid mental health disorders. Awareness is the key to early diagnosis. Management is limited in evidence-base but ideally should include an integrated multidisciplinary approach. CONCLUSIONS HSD/hEDS is a multisystemic disorder in which gastrointestinal symptoms, particularly related to disorders of gut-brain interaction are common. Deficiencies in knowledge regarding the pathophysiological processes limit evidence-based interventions and remain important areas for future research.
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Affiliation(s)
- Phoebe A Thwaites
- Department of Gastroenterology, Central Clinical SchoolMonash University and Alfred HealthMelbourneVictoriaAustralia
| | - Peter R Gibson
- Department of Gastroenterology, Central Clinical SchoolMonash University and Alfred HealthMelbourneVictoriaAustralia
| | - Rebecca E Burgell
- Department of Gastroenterology, Central Clinical SchoolMonash University and Alfred HealthMelbourneVictoriaAustralia
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13
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Monaco A, Choi D, Uzun S, Maitland A, Riley B. Association of mast-cell-related conditions with hypermobile syndromes: a review of the literature. Immunol Res 2022; 70:419-431. [PMID: 35449490 PMCID: PMC9022617 DOI: 10.1007/s12026-022-09280-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 04/11/2022] [Indexed: 11/26/2022]
Abstract
Ehlers-Danlos syndrome (EDS) is a group of related connective tissue disorders consisting of 13 subtypes, each with its own unique phenotypic and genetic variation. The overlap of symptoms and multitude of EDS variations makes it difficult for patients to achieve a diagnosis early in the course of their disease. The most common form, hypermobile type EDS (hEDS) and its variant, hypermobile spectrum disorder (HSD), are correlated with rheumatologic and inflammatory conditions. Evidence is still needed to determine the pathophysiology of hEDS; however, the association among these conditions and their prevalence in hEDS/HSD may be explained through consideration of persistent chronic inflammation contributing to a disruption of the connective tissue. Aberrant mast cell activation has been shown to play a role in disruption of connective tissue integrity through activity of its mediators including histamine and tryptase which affects multiple organ systems resulting in mast cell activation disorders (MCAD). The overlap of findings associated with MCAD and the immune-mediated and rheumatologic conditions in patients with hEDS/HSD may provide an explanation for the relationship among these conditions and the presence of chronic inflammatory processes in these patients. It is clear that a multidisciplinary approach is required for the treatment of patients with EDS. However, it is also important for clinicians to consider the summarized symptoms and MCAD-associated characteristics in patients with multiple complaints as possible manifestations of connective tissue disorders, in order to potentially aid in establishing an early diagnosis of EDS.
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Affiliation(s)
- Ashley Monaco
- Department of Family Medicine, NYIT College of Osteopathic Medicine, Northern Boulevard, Old Westbury, NY, 11568, USA.
| | - Diane Choi
- Department of Family Medicine, NYIT College of Osteopathic Medicine, Northern Boulevard, Old Westbury, NY, 11568, USA
| | - Serife Uzun
- Department of Family Medicine, NYIT College of Osteopathic Medicine, Northern Boulevard, Old Westbury, NY, 11568, USA
| | - Anne Maitland
- Division of Medicine, Icahn School of Medicine at Mount Sinai, Gustave L. Levy Place, New York, NY, 10029, USA
| | - Bernadette Riley
- Department of Family Medicine, NYIT College of Osteopathic Medicine, Northern Boulevard, Old Westbury, NY, 11568, USA
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14
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Coffin B, Duboc H. Review article: diagnostic and therapeutic approach to persistent abdominal pain beyond irritable bowel syndrome. Aliment Pharmacol Ther 2022; 56:419-435. [PMID: 35656644 DOI: 10.1111/apt.17064] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/01/2021] [Accepted: 05/18/2022] [Indexed: 01/30/2023]
Abstract
BACKGROUND Persistent abdominal pain (PAP) poses substantial challenges to patients, physicians and healthcare systems. The possible aetiologies of PAP vary widely across organ systems, which leads to extensive and repetitive diagnostic testing that often fails to provide satisfactory answers. As a result, widely recognised functional disorders of the gut-brain interaction, such as irritable bowel syndrome and functional dyspepsia, are often diagnosed in patients with PAP. However, there are a number of less well-known differential diagnoses that deserve consideration. AIM To provide a comprehensive update on causes of PAP that are relatively rare in occurrence. METHODS A literature review on the diagnosis and management of some less well-known causes of PAP. RESULTS Specific algorithms for the diagnostic work-up of PAP do not exist. Instead, appropriate investigations tailored to patient medical history and physical examination findings should be made on a case-by-case basis. After a definitive diagnosis has been reached, some causes of PAP can be effectively treated using established approaches. Other causes are more complex and may benefit from a multidisciplinary approach involving gastroenterologists, pain specialists, psychologists and physiotherapists. This list is inclusive but not exhaustive of all the rare or less well-known diseases potentially associated with PAP. CONCLUSIONS Persistent abdominal pain (PAP) is a challenging condition to diagnose and treat. Many patients undergo repeated diagnostic testing and treatment, including surgery, without achieving symptom relief. Increasing physician awareness of the various causes of PAP, especially of rare diseases that are less well known, may improve patient outcomes.
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Affiliation(s)
- Benoit Coffin
- Université de Paris-Cité, équipe PIMS, Paris, France.,AP-HP, DMU Esprit, Gastroenterology Unit, Hôpital Louis Mourier, Colombes, France
| | - Henri Duboc
- Université de Paris-Cité, équipe PIMS, Paris, France.,AP-HP, DMU Esprit, Gastroenterology Unit, Hôpital Louis Mourier, Colombes, France
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15
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Lam C, Amarasinghe G, Zarate-Lopez N, Fikree A, Byrne P, Kiani-Alikhan S, Gabe S, Paine P. Gastrointestinal symptoms and nutritional issues in patients with hypermobility disorders: assessment, diagnosis and management. Frontline Gastroenterol 2022; 14:68-77. [PMID: 36561778 PMCID: PMC9763642 DOI: 10.1136/flgastro-2022-102088] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/20/2022] [Indexed: 02/04/2023] Open
Abstract
Patients diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobile spectrum disorders are increasingly presenting to secondary and tertiary care centres with gastrointestinal (GI) symptoms and nutritional issues. Due to the absence of specific guidance, these patients are investigated, diagnosed and managed heterogeneously, resulting in a growing concern that they are at increased risk of iatrogenic harm. This review aims to collate the evidence for the causes of GI symptoms, nutritional issues and associated conditions as well as the burden of polypharmacy in this group of patients. We also describe evidence-based strategies for management, with an emphasis on reducing the risk of iatrogenic harm and improving multidisciplinary team care.
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Affiliation(s)
- Ching Lam
- Gastroenterology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Gehanjali Amarasinghe
- Gastroenterology, St Marks Hospital, London North West University Healthcare NHS Trust, Harrow, UK
| | - Natalia Zarate-Lopez
- Gastoenterology and GI physiology, University College London Hospitals NHS Foundation Trust, London, UK
| | - Asma Fikree
- Gastroenterology, Barts Health NHS Trust, London, UK
| | - Peter Byrne
- Psychiatry, East London NHS Foundation Trust, London, UK
| | | | - Simon Gabe
- Gastroenterology, St Marks Hospital, London North West University Healthcare NHS Trust, Harrow, UK
- Intestinal Failure Unit, St Mark's Hospital and Academic Institute, Harrow, UK
| | - Peter Paine
- Gastroenterology, Salford Royal NHS Foundation Trust, Salford, UK
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16
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Ceulemans M, Jacobs I, Wauters L, Vanuytsel T. Immune Activation in Functional Dyspepsia: Bystander Becoming the Suspect. Front Neurosci 2022; 16:831761. [PMID: 35557605 PMCID: PMC9087267 DOI: 10.3389/fnins.2022.831761] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/25/2022] [Indexed: 11/13/2022] Open
Abstract
Disorders of gut-brain interaction (DGBI), formerly termed functional gastrointestinal disorders (FGID), are highly prevalent although exact pathophysiological mechanisms remain unclear. Intestinal immune activation has been recognized, but increasing evidence supports a pivotal role for an active inflammatory state in these disorders. In functional dyspepsia (FD), marked eosinophil and mast cell infiltration has been repeatedly demonstrated and associations with symptoms emphasize the relevance of an eosinophil-mast cell axis in FD pathophysiology. In this Review, we highlight the importance of immune activation in DGBI with a focus on FD. We summarize eosinophil biology in both homeostasis and inflammatory processes. The evidence for immune activation in FD is outlined with attention to alterations on both cellular and molecular level, and how these may contribute to FD symptomatology. As DGBI are complex and multifactorial conditions, we shed light on factors associated to, and potentially influencing immune activation, including bidirectional gut-brain interaction, allergy and the microbiota. Crucial studies reveal a therapeutic benefit of treatments targeting immune activation, suggesting that specific anti-inflammatory therapies could offer renewed hope for at least a subset of DGBI patients. Lastly, we explore the future directions for DGBI research that could advance the field. Taken together, emerging evidence supports the recognition of FD as an immune-mediated organic-based disorder, challenging the paradigm of a strictly functional nature.
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Affiliation(s)
- Matthias Ceulemans
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
| | - Inge Jacobs
- Allergy and Clinical Immunology Research Group, Department of Microbiology, Immunology and Transplantation, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Lucas Wauters
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Tim Vanuytsel
- Department of Chronic Diseases and Metabolism, Translational Research Center for Gastrointestinal Disorders (TARGID), Katholieke Universiteit Leuven, Leuven, Belgium
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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17
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Kilgore AL, Hawa JT, Liu E, Belkind-Gerson J, Santucci KK. EDS-related Feeding Difficulties: Preventing the Placement of a Surgical Feeding Tube. JPGN REPORTS 2022; 3:e147. [PMID: 37168755 PMCID: PMC10158406 DOI: 10.1097/pg9.0000000000000147] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 07/21/2021] [Indexed: 05/13/2023]
Abstract
Feeding difficulties due to functional gastrointestinal (GI) symptoms (i.e., nausea, pain, and bloating) are well described in patients with hypermobile-type Ehlers-Danlos Syndrome. These symptoms are particularly difficult to treat when there is comorbid dysautonomia, usually manifesting as postural orthostatic tachycardia syndrome. Here, we describe a successful trial of multidisciplinary rehabilitative interventions to avoid placement of a surgical feeding tube in such a patient. Main components of intervention were intensive pelvic floor physiotherapy and biofeedback, occupational therapy focused on coping with feeding-related symptoms, psychology support, and medications targeting histamine blockade and enhancing intestinal motility.
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Affiliation(s)
- Alexandra L. Kilgore
- From the Neurogastroenterology Program, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Juliette T. Hawa
- Department of Physical Therapy, Children’s Hospital Colorado, Aurora, CO
| | - Edwin Liu
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
- Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO
| | - Jaime Belkind-Gerson
- From the Neurogastroenterology Program, Digestive Health Institute, Children’s Hospital Colorado, Aurora, CO
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
| | - Kourtney Kuss Santucci
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO
- Ehlers-Danlos Center of Excellence, Children’s Hospital Colorado, Aurora, CO
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18
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Masterclass: Hypermobility and hypermobility related disorders. Musculoskelet Sci Pract 2022; 57:102465. [PMID: 34808594 DOI: 10.1016/j.msksp.2021.102465] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 08/27/2021] [Accepted: 10/10/2021] [Indexed: 01/24/2023]
Abstract
INTRODUCTION Hypermobile joints display a range of movement that is considered excessive, taking into consideration the age, gender and ethnic background of the individual. Joint hypermobility may present in a single joint, a few joints or in multiple joints and may be congenital or acquired with training, disease or injury. Hypermobile joints may be asymptomatic or may be associated with pain, fatigue, multisystemic complaints and significant disability. Furthermore, joint hypermobility may be a sign of an underlying hereditary disorder of connective tissue. PURPOSE This masterclass aims to provides a state-of-the-art review of the aetiology, epidemiology, clinical presentation, assessment and management of joint hypermobility and hypermobility related disorders using an evidence based and biopsychosocial approach. The new framework for classifying the spectrum of joint hypermobility disorders along with new diagnostic criteria for the hypermobile Ehlers Danlos syndrome, published by an international consortium of clinical experts and researchers in 2017 is integrated into the paper. IMPLICATIONS FOR PRACTICE People with joint hypermobility related disorders present to healthcare professionals with a wide range of symptoms which extend beyond the musculoskeletal system. Early recognition and treatment are key to effective management. A biopsychosocial and patient empowerment approach to functional restoration is recommended.
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19
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Laszkowska M, Ludvigsson JF. Comment on: Prevalence of gastrointestinal, cardiovascular, autonomic and allergic manifestations in hospitalized patients with Ehlers-Danlos syndrome: a case-control study. Rheumatology (Oxford) 2021; 61:e105-e106. [PMID: 34918051 DOI: 10.1093/rheumatology/keab908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
- Monika Laszkowska
- Department of Medicine, Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.,Department of Pediatrics, Örebro University Hospital, 701 85 Örebro, Sweden.,Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK
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20
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Kolacz J, Kovacic K, Lewis GF, Sood MR, Aziz Q, Roath OR, Porges SW. Cardiac autonomic regulation and joint hypermobility in adolescents with functional abdominal pain disorders. Neurogastroenterol Motil 2021; 33:e14165. [PMID: 33991431 DOI: 10.1111/nmo.14165] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 04/01/2021] [Accepted: 04/15/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Joint hypermobility (JH) is associated with autonomic nervous system dysregulation and functional abdominal pain disorders (FAPDs). Understanding the neurophysiological processes linking these conditions can inform clinical interventions. Autonomic activity regulates gastrointestinal (GI) sensorimotor function and may be a key mechanism. The aims of this study were to examine the relation of JH with dynamic autonomic activity and parasympathetic regulation in adolescents with FAPDs and identify optimal JH cutoff scores that best index autonomic regulation in FAPDs. METHODS A total of 92 adolescents with FAPDs and 27 healthy controls (age 8-18 years; 80% female) were prospectively enrolled. JH was assessed by Beighton scores. ECG recordings were conducted during supine, sitting, and standing posture challenges. ECG-derived variables-heart period (HP), respiratory sinus arrhythmia (RSA), and vagal efficiency (VE)-were analyzed using linear regression and mixed effects modeling. KEY RESULTS Beighton scores of ≥4 optimally distinguished autonomic function. Adolescents with FAPD and JH had reduced VE compared to adolescents with FAPDs without JH (B = 18.88, SE = 6.25, p = 0.003) and healthy controls (B = 17.56, SE = 8.63, p = 0.044). These subjects also had lower and less dynamic RSA and HP values during posture shifts, with strongest differences in supine position and using the VE metric. CONCLUSIONS & INFERENCES Suboptimal autonomic regulation indexed by reduced vagal efficiency may be a mechanism of symptoms in hypermobile FAPD patients with Beighton score ≥ 4. Autonomic disturbance may serve as potential intervention target for patients with JH and functional GI disorders.
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Affiliation(s)
- Jacek Kolacz
- Socioneural Physiology Laboratory, Kinsey Institute, Indiana University, Bloomington, IN, USA.,Traumatic Stress Research Consortium, Kinsey Institute, Indiana University, Bloomington, IN, USA
| | - Katja Kovacic
- Department of Pediatrics, University of Illinois College of Medicine, Chicago, IL, USA
| | - Gregory F Lewis
- Socioneural Physiology Laboratory, Kinsey Institute, Indiana University, Bloomington, IN, USA.,Intelligent Systems Engineering, Indiana University, Bloomington, IN, USA
| | - Manu R Sood
- Department of Pediatrics, University of Illinois College of Medicine, Chicago, IL, USA
| | - Qasim Aziz
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Olivia R Roath
- Socioneural Physiology Laboratory, Kinsey Institute, Indiana University, Bloomington, IN, USA
| | - Stephen W Porges
- Traumatic Stress Research Consortium, Kinsey Institute, Indiana University, Bloomington, IN, USA.,Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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21
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Micale L, Fusco C, Castori M. Ehlers-Danlos Syndromes, Joint Hypermobility and Hypermobility Spectrum Disorders. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1348:207-233. [PMID: 34807421 DOI: 10.1007/978-3-030-80614-9_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Ehlers-Danlos syndrome is an umbrella term for a clinically and genetically heterogeneous group of hereditary soft connective tissue disorders mainly featuring abnormal cutaneous texture (doughy/velvety, soft, thin, and/or variably hyperextensible skin), easy bruising, and joint hypermobility. Currently, musculoskeletal manifestations related to joint hypermobility are perceived as the most prevalent determinants of the quality of life of affected individuals. The 2017 International Classification of Ehlers-Danlos syndromes and related disorders identifies 13 clinical types due to deleterious variants in 19 different genes. Recent publications point out the possibility of a wider spectrum of conditions that may be considered members of the Ehlers-Danlos syndrome community. Most Ehlers-Danlos syndromes are due to inherited abnormalities affecting the biogenesis of fibrillar collagens and other components of the extracellular matrix. The introduction of next-generation sequencing technologies in the diagnostic setting fastened patients' classification and improved our knowledge on the phenotypic variability of many Ehlers-Danlos syndromes. This is impacting significantly patients' management and family counseling. At the same time, most individuals presenting with joint hypermobility and associated musculoskeletal manifestations still remain without a firm diagnosis, due to a too vague clinical presentation and/or the lack of an identifiable molecular biomarker. These individuals are currently defined with the term "hypermobility spectrum disorders". Hence, in parallel with a continuous update of the International Classification of Ehlers-Danlos syndromes, the scientific community is investing efforts in offering a more efficient framework for classifying and, hopefully, managing individuals with joint hypermobility.
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Affiliation(s)
- Lucia Micale
- Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Carmela Fusco
- Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Marco Castori
- Division of Medical Genetics, Fondazione IRCCS-Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
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22
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Choudhary A, Fikree A, Aziz Q. Overlap between irritable bowel syndrome and hypermobile Ehlers-Danlos syndrome: An unexplored clinical phenotype? AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS 2021; 187:561-569. [PMID: 34741491 DOI: 10.1002/ajmg.c.31938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/18/2021] [Accepted: 10/22/2021] [Indexed: 12/11/2022]
Abstract
Irritable bowel syndrome (IBS) is common, but its cause remains unknown. IBS patients present with gastrointestinal (GI) symptoms such as abdominal pain with altered bowel habits; however, some patients also have non-GI symptoms including muscle and joint pains. It is thus plausible that within large IBS cohorts, subgroups exist with distinct clinical phenotypes. Yet, these subgroups have not been clearly identified or characterized. Due to lack of segmentation, treatment-focused symptomatic management is similar for all with IBS and follows indiscriminate algorithms regardless of possible differing clinical phenotype. This universal approach to IBS management may account for the reported lack of efficacy of treatment. One emerging subgroup receiving increasing attention is that with overlap IBS and the underlying heritable connective tissue disorder, hypermobile Ehlers-Danlos syndrome (hEDS). Current evidence suggests that up to 62% of patients with hEDS suffer from IBS. However, despite recognition of the presence of IBS in hEDS, this overlap IBS/hEDS group has not been characterized and these patients are managed in a similar way to those with IBS alone. Future studies are required to characterize and deep phenotype in this overlap IBS/hEDS group.
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Affiliation(s)
- Anisa Choudhary
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Asma Fikree
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Qasim Aziz
- Centre for Neuroscience, Surgery and Trauma, Blizard Institute, Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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23
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Burns GL, Hoedt EC, Walker MM, Talley NJ, Keely S. Physiological mechanisms of unexplained (functional) gastrointestinal disorders. J Physiol 2021; 599:5141-5161. [PMID: 34705270 DOI: 10.1113/jp281620] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/20/2021] [Indexed: 12/13/2022] Open
Abstract
Functional gastrointestinal disorders (FGIDs) encompass a range of complex conditions with similar clinical characteristics and no overt pathology. Recent recognition of sub-clinical pathologies in FGIDs, in conjunction with physiological and biochemical abnormalities including increased intestinal permeability, microbial profile alterations, differences in metabolites and extra-intestinal manifestations of disease, call into question the designation of these conditions as 'functional'. This is despite significant heterogeneity in both symptom profile and specifics of reported physiological abnormalities hampering efforts to determine defined mechanisms that drive onset and chronicity of symptoms. Instead, the literature demonstrates these conditions are disorders of homeostatic imbalance, with disruptions in both host and microbial function and metabolism. This imbalance is also associated with extraintestinal abnormalities including psychological comorbidities and fatigue that may be a consequence of gastrointestinal disruption. Given the exploitation of such abnormalities will be crucial for improved therapeutic selection, an enhanced understanding of the relationship between alterations in function of the gastrointestinal tract and the response of the immune system is of interest in identifying mechanisms that drive FGID onset and chronicity. Considerations for future research should include the role of sex hormones in regulating physiological functions and treatment responses in patients, as well as the importance of high-level phenotyping of clinical, immune, microbial and physiological parameters in study cohorts. There is opportunity to examine the functional contribution of the microbiota and associated metabolites as a source of mechanistic insight and targets for therapeutic modulation.
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Affiliation(s)
- Grace L Burns
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.,NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia
| | - Emily C Hoedt
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Marjorie M Walker
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Nicholas J Talley
- NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia.,School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia
| | - Simon Keely
- School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Newcastle, NSW, Australia.,NHMRC Centre for Research Excellence in Digestive Health, University of Newcastle, Newcastle, NSW, Australia.,New Lambton Heights, Hunter Medical Research Institute, Newcastle, NSW, Australia
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Sharp HEC, Critchley HD, Eccles JA. Connecting brain and body: Transdiagnostic relevance of connective tissue variants to neuropsychiatric symptom expression. World J Psychiatry 2021; 11:805-820. [PMID: 34733643 PMCID: PMC8546774 DOI: 10.5498/wjp.v11.i10.805] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/12/2021] [Accepted: 08/18/2021] [Indexed: 02/06/2023] Open
Abstract
The mind is embodied; thoughts and feelings interact with states of physiological arousal and physical integrity of the body. In this context, there is mounting evidence for an association between psychiatric presentations and the expression variant connective tissue, commonly recognised as joint hypermobility. Joint hypermobility is common, frequently under-recognised, significantly impacts quality of life, and can exist in isolation or as the hallmark of hypermobility spectrum disorders (encompassing joint hypermobility syndrome and hypermobile Ehlers-Danlos syndrome). In this narrative review, we appraise the current evidence linking psychiatric disorders across the lifespan, beginning with the relatively well-established connection with anxiety, to hypermobility. We next consider emerging associations with affective illnesses, eating disorders, alongside less well researched links with personality disorders, substance misuse and psychosis. We then review related findings relevant to neurodevelopmental disorders and stress-sensitive medical conditions. With growing understanding of mind-body interactions, we discuss potential aetiopathogenetic contributions of dysautonomia, aberrant interoceptive processing, immune dysregulation and proprioceptive impairments in the context of psychosocial stressors and genetic predisposition. We examine clinical implications of these evolving findings, calling for increased awareness amongst healthcare professionals of the transdiagnostic nature of hypermobility and related disorders. A role for early screening and detection of hypermobility in those presenting with mental health and somatic symptoms is further highlighted, with a view to facilitate preventative approaches alongside longer-term holistic management strategies. Finally, suggestions are offered for directions of future scientific exploration which may be key to further delineating fundamental mind-body-brain interactions.
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Affiliation(s)
- Harriet Emma Clare Sharp
- Department of Medical Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, East Sussex, United Kingdom
- Department of Psychiatry, Sussex Partnership NHS Foundation Trust, Worthing, BN13 3EP, West Sussex, United Kingdom
| | - Hugo D Critchley
- Department of Medical Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, East Sussex, United Kingdom
- Department of Psychiatry, Sussex Partnership NHS Foundation Trust, Worthing, BN13 3EP, West Sussex, United Kingdom
| | - Jessica A Eccles
- Department of Medical Neuroscience, Brighton and Sussex Medical School, University of Sussex, Brighton BN1 9PX, East Sussex, United Kingdom
- Department of Psychiatry, Sussex Partnership NHS Foundation Trust, Worthing, BN13 3EP, West Sussex, United Kingdom
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25
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Caliogna L, Guerrieri V, Annunziata S, Bina V, Brancato AM, Castelli A, Jannelli E, Ivone A, Grassi FA, Mosconi M, Pasta G. Biomarkers for Ehlers-Danlos Syndromes: There Is a Role? Int J Mol Sci 2021; 22:10149. [PMID: 34576312 PMCID: PMC8469247 DOI: 10.3390/ijms221810149] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 09/16/2021] [Accepted: 09/17/2021] [Indexed: 02/05/2023] Open
Abstract
Ehlers-Danlos syndromes (EDS) are an inherited heterogeneous group of connective tissue disorders characterized by an abnormal collagen synthesis affecting skin, ligaments, joints, blood vessels, and other organs. It is one of the oldest known causes of bruising and bleeding, and it was described first by Hippocrates in 400 BC. In the last years, multiple gene variants involved in the pathogenesis of specific EDS subtypes have been identified; moreover, new clinical diagnostic criteria have been established. New classification models have also been studied in order to differentiate overlapping conditions. Moreover, EDS shares many characteristics with other similar disorders. Although distinguishing between these seemingly identical conditions is difficult, it is essential in ensuring proper patient care. Currently, there are many genetic and molecular studies underway to clarify the etiology of some variants of EDS. However, the genetic basis of the hypermobile type of EDS (hEDS) is still unknown. In this review, we focused on the study of two of the most common forms of EDS-classic and hypermobile-by trying to identify possible biomarkers that could be of great help to confirm patients' diagnosis and their follow up.
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Affiliation(s)
- Laura Caliogna
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Viviana Guerrieri
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Salvatore Annunziata
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Valentina Bina
- Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy;
| | - Alice Maria Brancato
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Alberto Castelli
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Eugenio Jannelli
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Alessandro Ivone
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Federico Alberto Grassi
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Mario Mosconi
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
| | - Gianluigi Pasta
- Orthopedic and Traumatology Clinic, IRCCS Policlinico San Matteo Foundation, 27100 Pavia, Italy; (L.C.); (V.G.); (A.M.B.); (A.C.); (E.J.); (A.I.); (F.A.G.); (M.M.); (G.P.)
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26
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Brooks RS, Grady J, Lowder TW, Blitshteyn S. Prevalence of gastrointestinal, cardiovascular, autonomic and allergic manifestations in hospitalized patients with Ehlers-Danlos syndrome: a case-control study. Rheumatology (Oxford) 2021; 60:4272-4280. [PMID: 33410480 DOI: 10.1093/rheumatology/keaa926] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 11/30/2020] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE Previous observations suggest an association between Ehlers-Danlos syndrome (EDS) and gastrointestinal (GI), cardiovascular, immune, and autonomic nervous system dysfunction. We sought to determine whether a hospital diagnosis of EDS is associated with a higher prevalence of these manifestations vs hospitalized patients without EDS. We also evaluated hospital outcomes. METHODS A total of 6,021 cases and matched controls were acquired from the 2016 National Inpatient Sample. In total, 2,007 EDS patients were identified via ICD-10 code. After bivariate analyses, multivariate logistic regression models were used to adjust for potential confounders. RESULTS GI conditions were found in 44% of EDS patients vs 18% of controls [odds ratio (OR) = 3.57, 95% CI: 3.17, 4.02, P < 0.0001], with irritable bowel syndrome, gastroparesis and coeliac disease strongly associated with EDS. Autonomic dysfunction, including postural orthostatic tachycardia syndrome (POTS), neurocardiogenic syncope and orthostatic hypotension was found in 20% of EDS patients vs 6% of controls (OR = 4.45, 95% CI: 3.71, 5.32, P < 0.0001). EDS patients were more likely to have food allergy (OR = 3.88, 95% CI: 2.65, 5.66, P < 0.0001) and cardiovascular complications such as mitral valve disorders, aortic aneurysm and dysrhythmias (OR = 6.16, 95% CI: 4.60, 8.23, P < 0.0001). These conditions remained highly associated with EDS after considering confounders. EDS patients were 76% more likely to have longer than average hospitalizations (OR = 1.76, 95% CI: 1.54, 2.02, P < 0.0001). CONCLUSION GI, cardiovascular, autonomic and allergic manifestations are significantly more prevalent in EDS patients compared with hospitalized patients without EDS. Physicians should consider EDS in patients with unexplained GI, cardiovascular, autonomic and allergic conditions and exercise precautions when treating EDS patients in a hospital setting.
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Affiliation(s)
- Rachel S Brooks
- Connecticut Convergence Institute for Translation in Regenerative Engineering, School of Medicine, University of Connecticut, Farmington, CT
| | - James Grady
- Connecticut Convergence Institute for Translation in Regenerative Engineering, School of Medicine, University of Connecticut, Farmington, CT
| | - Thomas W Lowder
- Department of Exercise and Sport Science, University of Central Arkansas, Conway, AR
| | - Svetlana Blitshteyn
- Department of Neurology, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA
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27
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Chen G, Olver JS, Kanaan RA. Functional somatic syndromes and joint hypermobility: A systematic review and meta-analysis. J Psychosom Res 2021; 148:110556. [PMID: 34237584 DOI: 10.1016/j.jpsychores.2021.110556] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 06/17/2021] [Accepted: 06/18/2021] [Indexed: 11/29/2022]
Abstract
OBJECTIVE There have been multiple reports of increased joint hypermobility (JH) in functional somatic syndromes (FSS). We sought to evaluate the evidence for an association. METHODS A systematic search of the databases Medline and PsycINFO was conducted to identify all controlled studies from inception to February 2020 measuring the association of an FSS and JH. Records were identified and screened, and full-text articles assessed for eligibility by two independent authors. Meta-analysis was performed using random-effects modelling with the DerSimonian and Laird method. RESULTS We found 220 studies initially, which yielded 11 studies for inclusion in the qualitative review and 10 in the quantitative analysis - 5 studies on fibromyalgia, 3 on chronic fatigue syndrome and 3 on functional gastrointestinal disorder. Nine of the 11 studies found increased rates of JH in FSS compared to controls, though most studies were fair to poor in quality. Meta-analysis showed a weighted summary effect odds ratio of 3.27 (95% CI: 1.83, 5.84; p < 0.001) of JH in FSS, suggesting greater odds of FSS in individuals with JH than in those without. CONCLUSIONS There is some evidence for an association between FSS and JH, but this is limited by the generally poor quality of studies and the narrow range of FSS studied. Better research is needed to confirm these findings as well as evaluate causation using prospective cohort studies.
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Affiliation(s)
- Grant Chen
- University of Melbourne, Department of Psychiatry, Austin Health, Heidelberg, VIC 3084, Australia.
| | - James S Olver
- University of Melbourne, Department of Psychiatry, Austin Health, Heidelberg, VIC 3084, Australia; Fellow of the Royal Australian and New Zealand College of Psychiatrists, Australia
| | - Richard A Kanaan
- University of Melbourne, Department of Psychiatry, Austin Health, Heidelberg, VIC 3084, Australia; Fellow of the Royal Australian and New Zealand College of Psychiatrists, Australia; The Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC 3084, Australia; King's College London, Department of Psychological Medicine, Institute of Psychiatry, Weston Education Centre, Denmark Hill, London SE5 9RJ, UK
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28
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Martinez KL, Mauss C, Andrews J, Saboda K, Huynh JM, Sanoja AJ, Jesudas R, Byers PH, Laukaitis CM. Subtle differences in autonomic symptoms in people diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders. Am J Med Genet A 2021; 185:2012-2025. [PMID: 33826221 PMCID: PMC11841374 DOI: 10.1002/ajmg.a.62197] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 02/09/2021] [Accepted: 02/26/2021] [Indexed: 12/31/2022]
Abstract
The hypermobile Ehlers-Danlos syndrome (hEDS) GENE study is a multicenter, cohort study with the goal to identify genes associated with hypermobile EDS. Of the 148 people enrolled in the hEDS GENE study, 98 meet the 2017 hEDS criteria, 27 have a hypermobility spectrum disorder (HSD) and 23 are asymptomatic family members. More than 80% of participants are female with an average age of 41 years. Each participant has completed seven questionnaires to quantify disease-related symptomatology. People with hypermobility experience a variety of physical and somatic symptoms, especially in the areas of fatigue, kinesiophobia, gastrointestinal, and autonomic function. These cause a significant decrease in health-related quality of life. The frequency and severity of most symptoms were indistinguishable between participants with hEDS and HSD; however, there were significant differences in autonomic symptoms. Less than 20% of participants had autoantibodies known to be associated with dysautonomia. Subtle symptomatic differences in people meeting the 2017 diagnostic criteria suggest focusing further etiologic studies on autonomic pathways.
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Affiliation(s)
- Kiana L. Martinez
- Genetics Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona
| | - Corina Mauss
- Arizona Cancer Center, University of Arizona, Tucson, Arizona
- Department of Medicine, University of Arizona, Tucson, Arizona
- Department of Pediatrics, University of Arizona, Tucson, Arizona
| | - Jennifer Andrews
- Department of Pediatrics, University of Arizona, Tucson, Arizona
| | | | - Julie M. Huynh
- College of Medicine, University of Arizona, Tucson, Arizona
| | | | - Rohith Jesudas
- St. Jude’s Children’s Research Hospital, Memphis, Tennessee
| | - Peter H. Byers
- Departments of Pathology and Medicine, University of Washington, Seattle, Washington
| | - Christina M. Laukaitis
- Arizona Cancer Center, University of Arizona, Tucson, Arizona
- Department of Medicine, University of Arizona, Tucson, Arizona
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29
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Carbone F, Goelen N, Fikree A, Aziz Q, Tack J. Impact of joint hypermobility syndrome on gastric accommodation and nutrient tolerance in functional dyspepsia. Neurogastroenterol Motil 2021; 33:e14086. [PMID: 33528850 DOI: 10.1111/nmo.14086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/25/2020] [Accepted: 01/06/2021] [Indexed: 01/07/2023]
Abstract
UNLABELLED Functional dyspepsia (FD) is defined as the presence of gastroduodenal symptoms in the absence of organic disease that is likely to explain the symptoms. Joint hypermobility (JH) refers to the increased passive or active movement of a joint beyond its normal range and is characteristically present in patients with joint hypermobility syndrome (JHS), which is a hypermobile subtype of Ehlers-Danlos syndrome (EDS). Recent reports have highlighted the co-existence of FD with Ehlers-Danlos syndrome. Our aim was to study the prevalence of JHS in FD compared with healthy subjects and to study the impact of co-existing JHS on gastric motility, nutrient tolerance, and dyspeptic symptoms in FD. METHODS FD patients filled out a dyspepsia symptom severity score. Intragastric pressure (IGP) was measured with high-resolution manometry (HRM) during the intragastric infusion of nutrition drink (ND, 1.5 Kcal/ml, 60 ml/min) until maximal satiation in healthy subjects and FD. We compared IGP profiles and nutrient tolerance in HS and FD with or without JHS. RESULTS JHS was present in 54% of FD patients (n = 39, 41.2 ± 2.2 years old) and 7% of healthy subjects (n = 15, 27.3 ± 2.3 years old). IGP drop and nutrient tolerance were lower in non-JHS-FD compared with JHS-FD and HS (AUC JHS-FD: -17.9 ± 2.5 vs. non-JHS-FD: -13.0 ± 3.3 mmHg min, p = 0.2, HS:-19.6 ± 2.9 mmHg min; ND tolerance non-JHS-FD: 671.0 ± 96.0 vs. JHS-FD: 842.7 ± 105.7 Kcal, p = 0.25, HS: 980.0 ± 108.1 Kcal). CONCLUSION JHS often co-exists with FD. Non-JHS-FD was characterized by decreased accommodation and lower nutrient tolerance characterized compared with JHS-FD. Clinicaltrials.gov, reference number NCT04279990.
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Affiliation(s)
- Florencia Carbone
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Nick Goelen
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Asma Fikree
- Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Qasim Aziz
- Wingate Institute of Neurogastroenterology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
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30
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Dhingra R, Bascom R, Thompson E, Francomano CA, Schubart JR. Gastrointestinal medication burden among persons with the Ehlers-Danlos syndromes. Neurogastroenterol Motil 2021; 33:e14077. [PMID: 33393191 DOI: 10.1111/nmo.14077] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 11/04/2020] [Accepted: 12/14/2020] [Indexed: 12/20/2022]
Abstract
BACKGROUND The Ehlers-Danlos syndromes (EDSs) are a group of heritable disorders of connective tissue associated with an increased prevalence of both structural and functional GI conditions. METHODS We used 10 years (2005-2014) of administrative claims data comprised of 4294 people with clinician-diagnosed EDS, aged 5-62 years, and compared their frequency of GI drug prescription claims to their age-, sex-, state of residence-, and earliest claim date-matched controls. We categorized the GI medications into the following groups: acid suppressants, anti-emetics, irritable bowel syndrome drugs, and visceral hypersensitivity (VHS) medications. KEY RESULTS Compared to controls, a significantly higher proportion of persons with EDS had prescription claims for at least one GI drug group, as well as for drugs in each of the four GI drug groups included in our study. By age-group, 25.7% children and 45.1% adults with EDS had prescription claims for at least one GI drug group compared with only 7.4% and 21.0% of controls, respectively (p < 0.0001). By gender, 44.0% of women and 25.3% of men with EDS had prescription claims for at least one class of GI drugs compared with 19.2% and 9.6% of controls, respectively (p < 0.0001). CONCLUSIONS AND KEY INFERENCES Predominant medication burden occurs among women with EDS, beginning peri-pubertally for anti-emetics and VHS drugs. High GI medication burden underscores previous evidence that GI dysmotility is common among persons with EDS.
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Affiliation(s)
- Radha Dhingra
- Department of Public Health Sciences, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA
| | - Rebecca Bascom
- Department of Public Health Sciences, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA.,Department of Medicine, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA
| | - Elizabeth Thompson
- Department of Medicine, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA
| | - Clair A Francomano
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jane R Schubart
- Department of Public Health Sciences, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA.,Department of Surgery, Penn State Health Milton S Hershey Medical Center, Hershey, PA, USA
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Vasant DH, Lal S. Recent Advances in the Management of Severe Gastrointestinal Dysmotility. Clin Exp Gastroenterol 2021; 14:163-172. [PMID: 34007199 PMCID: PMC8121621 DOI: 10.2147/ceg.s249877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 04/15/2021] [Indexed: 11/23/2022] Open
Abstract
Severe gastrointestinal motility disorders with small bowel involvement continue to pose a major clinical challenge to clinicians, particularly because of the limitations of diagnostic tests and the lack of efficacious treatment options. In this article, we review current understanding and the utility of diagnostic modalities and therapeutic approaches, and describe how their limitations may potentially exacerbate prolonged suffering with debilitating symptoms, diagnostic delays, the risk of iatrogenic harm and increased healthcare utilisation in this group of patients. Moreover, observations from intestinal failure units worldwide suggest that this problem could be set to increase in the future, with reported trends of increasing numbers of patients presenting with nutritional consequences. Unfortunately, until recently, there has been a lack of consensus recommendations and guidance to support clinicians with their management approach. The aim of this narrative review is to summarise recent developments in this field following publication of an international census of experts, and subsequent clinical guidelines, which have emphasized the importance of holistic, multidisciplinary care. This is particularly important in achieving good clinical outcomes and ensuring the appropriate use of artificial nutritional support, in order to prevent iatrogenic harm. We discuss how these recent developments may impact clinical practice by supporting the development of specialised clinical services to deliver optimal care, and highlight areas where further research is needed.
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Affiliation(s)
- Dipesh H Vasant
- Neurogastroenterology Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, UK
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
| | - Simon Lal
- Division of Diabetes, Endocrinology and Gastroenterology, University of Manchester, Manchester, UK
- Intestinal Failure Unit, Salford Royal NHS Foundation Trust, Salford, UK
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32
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Lam CY, Palsson OS, Whitehead WE, Sperber AD, Tornblom H, Simren M, Aziz I. Rome IV Functional Gastrointestinal Disorders and Health Impairment in Subjects With Hypermobility Spectrum Disorders or Hypermobile Ehlers-Danlos Syndrome. Clin Gastroenterol Hepatol 2021; 19:277-287.e3. [PMID: 32109633 DOI: 10.1016/j.cgh.2020.02.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 01/14/2020] [Accepted: 02/14/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Individuals with hypermobility spectrum disorder or hypermobile Ehlers-Danlos Syndrome (HSD/hEDS) are increasingly encountered by gastroenterologists and pose complex clinical challenges. Uncontrolled studies have found functional gastrointestinal disorders (FGIDs) to be common in patients with HSD/hEDS. Some patients have somatic symptoms (medically unexplained symptoms) that might affect FGIDs. We performed a case-control study to determine the prevalence of and factors associated with Rome IV FGIDs in subjects with HSD/hEDS compared with age- and sex- matched population-based controls. METHODS An online general health survey was completed by 603 individuals with HSD/hEDS in October 2018 (cases) and 603 matched individuals from the population of the United Kingdom (controls) in 2015. The mean participant age was 39 yrs, and 96% were women. The survey included questions about Rome IV FGIDs, non-GI and non-musculoskeletal somatic symptoms (maximum number, 10), quality of life, medical history and healthcare use. The prevalence of FGIDs was compared between cases and controls, with subsequent logistic regression models - adjusting for the number of somatic symptoms - used to determine the associations for FGIDs in HSD/hEDS compared with controls. RESULTS Nearly all subjects (98%) with HSD/hEDS fulfilled symptom-based criteria for 1 or more Rome IV FGIDs, compared with 47% of controls (P < .0001). The gastrointestinal regions most commonly affected by FGIDs in individuals with HSD/hEDS and control subjects were the bowel (90% vs 40% of controls), gastroduodenal (70% vs 13% of controls), esophageal (56% vs 6% of controls), and anorectal (53% vs 9% of controls); P < .0001. A higher proportion of subjects with HSD/hEDS had FGIDs in 2 or more regions (84% vs 15% of controls; P < .0001). Subjects with HSD/hEDS also reported a significantly higher number of non-GI and non-musculoskeletal somatic symptoms (7.1 vs 3.3 in controls), lower quality of life, and greater healthcare use, including abdominal surgeries and medication use (for example, 84% used analgesics compared with 29% of controls). Almost 40% of subjects with HSD/hEDS reported a diagnosis of chronic fatigue syndrome and/or fibromyalgia. Following adjustments for somatic symptoms, the association for FGIDs in subjects with HSD/hEDS was reduced by as much as 4-fold and in some instances was eliminated. CONCLUSIONS In a large case-control study of persons with HSD/hEDS, almost all of the cases met criteria for Rome IV FGIDs, incurred considerable health impairment, and had high healthcare use. Patients with HSD/hEDS frequently have somatic symptoms that should be treated to reduce the high burden of gastrointestinal illness in this population.
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Affiliation(s)
- Ching Y Lam
- Academic Department of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, United Kingdom
| | - Olafur S Palsson
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina
| | - William E Whitehead
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina
| | - Ami D Sperber
- Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Hans Tornblom
- Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Simren
- Center for Functional Gastrointestinal and Motility Disorders, University of North Carolina, Chapel Hill, North Carolina; Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Imran Aziz
- Academic Department of Gastroenterology, Sheffield Teaching Hospitals, Sheffield, United Kingdom; Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, United Kingdom.
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Abstract
INTRODUCTION: The pathophysiology underlying functional dyspepsia (FD) is multifactorial and focuses on gastric sensorimotor dysfunction. Recent studies demonstrated that joint hypermobility syndrome (JHS) is strongly associated with unexplained dyspeptic symptoms in patients attending gastrointestinal clinics. We aimed to study the relationship between symptoms, gastric sensorimotor function, and JHS in FD patients. METHODS: Tertiary care FD patients who underwent a gastric barostat study and a gastric emptying breath test with 13C-octanoic acid were recruited for assessment of JHS. The presence of JHS was evaluated by a 2-phase interview and clinical examination that included major and minor criteria of the Brighton classification. RESULTS: A total of 62 FD patients (68% women, age 44 ± 1.8 years, and body mass index: 21.7 ± 0.7 kg/m2) accepted to participate in the study. JHS was diagnosed in 55% of FD patients. Assessed symptom profiles during the visit did not differ between the groups. Delayed gastric emptying was not significantly more common in JHS group compared with non-JHS group (JHS group 32% vs non-JHS group 16%, P = 0.31). Prevalence of hypersensitivity to distention (JHS group 24% vs non-JHS group 29%, P = 0.76) and impaired gastric accommodation (JHS group 38% vs non-JHS group 42%, P = 0.79) was similar in patients with or without JHS. No correlations were found between the Beighton hypermobility score and gastric compliance (r = 0.09). DISCUSSION: A large subset of this study cohort of tertiary care FD patients has coexisting JHS. We did not identify any specific differences in gastric sensorimotor function between patients with and without JHS. Further prospective research will be required to elucidate the relationship between JHS, a multisystemic disorder with widespread manifestations, and FD symptoms.
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Feldman ECH, Hivick DP, Slepian PM, Tran ST, Chopra P, Greenley RN. Pain Symptomatology and Management in Pediatric Ehlers-Danlos Syndrome: A Review. CHILDREN-BASEL 2020; 7:children7090146. [PMID: 32967103 PMCID: PMC7552757 DOI: 10.3390/children7090146] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 09/16/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022]
Abstract
Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders that manifest with hyperextensibility of joints and skin, and general tissue fragility. While not a major criterion for clinical diagnosis, pain is a frequently endorsed symptom across subtypes of EDS. As such, the present review aims to summarize research to date on pain characteristics and management, and the relationship between such pain symptomatology and quality of life in pediatric EDS. Characteristics of pain, including theorized etiology, relative intensity and extent of pain are described, as well as descriptions of frequently endorsed pain sites (musculoskeletal, and non-musculoskeletal). Interventions related to the management of musculoskeletal (e.g., pharmaceutical intervention, physical therapy) and non-musculoskeletal pain (e.g., pharmaceutical and psychological interventions) are discussed, highlighting the need for additional research related to pediatric pain management in the context of hypermobility syndromes. In addition, the relationship between pain in pediatric EDS and quality of life is described. Finally, limitations of literature to date are described and recommendations for future lines of research are outlined.
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Affiliation(s)
- Estée C. H. Feldman
- Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA;
- Correspondence:
| | - Daniel P. Hivick
- Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA;
| | - P. Maxwell Slepian
- Toronto General Hospital, University Health Network, Toronto, ON M5G 2C4, Canada;
| | - Susan T. Tran
- Department of Psychology, DePaul University, Chicago, IL 60614, USA;
| | - Pradeep Chopra
- Alpert Medical School, Brown University, Providence, RI 02903, USA;
| | - Rachel Neff Greenley
- Department of Psychology, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA;
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Beckers AB, Vork L, Fikree A, de Ridder R, Aziz Q, Masclee A, Keszthelyi D. Colonoscopy is safe and not associated with higher pain scores in patients with hypermobility spectrum disorder: results from an exploratory prospective study. Therap Adv Gastroenterol 2020; 13:1756284820927310. [PMID: 32733599 PMCID: PMC7370544 DOI: 10.1177/1756284820927310] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Patient perception of colonoscopy varies greatly. Young slender women and patients with irritable bowel syndrome (IBS) appear to be at risk for periprocedural pain. Recent evidence suggests a high prevalence of joint hypermobility related connective tissue disorders in this population. Therefore, we aimed to investigate whether hypermobility spectrum disorder (HSD) is associated with increased pain during colonoscopy. METHODS We prospectively included patients undergoing routine colonoscopy. Subjects were assessed for HSD using the 2017 criteria, and IBS and functional dyspepsia using the Rome III criteria. After colonoscopy and recovery from sedation, patients were asked to report pain scores on a 100-mm visual analogue scale (VAS). In addition, caecal intubation time was measured, endoscopists scored the difficulty of the procedure (100-mm VAS) and procedure-related adverse events were registered. RESULTS Of 200 included patients, 22 (11%) met criteria for HSD. A female predominance was observed in patients with HSD (86.4% versus 49.4%, p < 0.001). A crude linear regression model demonstrated that pain scores were 13.30 mm higher in patients with HSD versus non-HSD patients (95% CI 0.07 - 26.53, p = 0.049). When subsequently correcting for possible confounding factors, however, this difference in pain scores could be explained by a confounding effect of female gender. Caecal intubation time, perceived procedural difficulty and complication rate did not differ significantly between groups. CONCLUSION HSD does not seem to be a predictor of painful colonoscopy, probably due to female gender as a confounding factor. In addition, performing colonoscopy is not more complicated in patients with HSD versus non-HSD patients, nor is it associated with more adverse events.
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Affiliation(s)
- Abraham B. Beckers
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - Lisa Vork
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - Asma Fikree
- Gastroenterology Department, Royal London Hospital, London, UK
| | - Rogier de Ridder
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
| | - Qasim Aziz
- Wingate Institute of Neurogastroenterology, Queen Mary University of London, London, UK
| | - Ad Masclee
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Limburg, The Netherlands
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The Prevalence of Hypermobility in Children with Irritable Bowel Syndrome and Functional Abdominal Pain Is Similar to that in Healthy Children. J Pediatr 2020; 222:134-140.e2. [PMID: 32381468 PMCID: PMC7321879 DOI: 10.1016/j.jpeds.2020.03.033] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/25/2020] [Accepted: 03/16/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVES To test the hypothesis that the prevalence of joint hypermobility is greater in children with irritable bowel syndrome and functional abdominal pain than in healthy control children and is related to gastrointestinal symptoms and psychosocial distress (anxiety, depression, and somatization). STUDY DESIGN Children (irritable bowel syndrome, n = 109; functional abdominal pain, n = 31; healthy control, n = 69), 7-12 years of age completed prospective 2-week pain and stooling diaries and child- and parent-reported measures of anxiety, depression, and somatization. Joint hypermobility was determined using Beighton criteria (score of ≥4 or 6). We also examined possible relationships between Beighton score, race, body mass index, gastrointestinal symptoms, and psychosocial distress. RESULTS Beighton scores were similar between groups, as was the proportion with joint hypermobility. Scores were higher in girls (3.1 ± 2.4) than boys (2.3 ± 1.8; P = .004) and decreased with age (P < .001; r = -0.25). Race and body mass index did not impact joint hypermobility prevalence. Beighton scores were not related to abdominal pain or stooling characteristics. Participants with a score of ≥4 and ≥6 had greater somatization and depression by child report (P = .017 and P = .048, respectively). No association was seen for anxiety. There was no significant association between joint hypermobility and psychosocial distress measures per parent report. CONCLUSIONS Contrary to the adult literature, the prevalence of joint hypermobility does not differ among children with irritable bowel syndrome, functional abdominal pain, or healthy control children. The presence or severity of joint hypermobility does not correlate with abdominal pain or stooling characteristics. Somatization and depression by child report appear to have a relationship with joint hypermobility.
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Alomari M, Hitawala A, Chadalavada P, Covut F, Al Momani L, Khazaaleh S, Gosai F, Al Ashi S, Abushahin A, Schneider A. Prevalence and Predictors of Gastrointestinal Dysmotility in Patients with Hypermobile Ehlers-Danlos Syndrome: A Tertiary Care Center Experience. Cureus 2020; 12:e7881. [PMID: 32489735 PMCID: PMC7255528 DOI: 10.7759/cureus.7881] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Introduction Ehlers-Danlos syndrome (EDS), specifically the hypermobility type (hEDS), is associated with a variety of gastrointestinal (GI) conditions. This study aims to evaluate the prevalence of and factors associated with gut dysmotility in patients with hEDS. Methods This is a retrospective study of hEDS patients conducted at the Cleveland Clinic's Center for Personalized Genetic Healthcare between January 2007 and December 2017. Demographics, GI motility testing, endoscopic, and imaging data were extracted from the patients' charts. Results A total of 218 patients with hEDS were identified. Among them, 136 (62.3%) patients had at least one GI symptom at the time of EDS diagnosis. Motility testing was performed and reported in 42 (19.2%) patients. Out of them, five (11.9%) had esophageal dysmotility, 18 (42.8%) had gastroparesis, five (11.9%) had small bowel/colon altered transit time, and four (9.5%) had global dysmotility. In univariable analysis, patients with postural orthostatic tachycardia syndrome (POTS) [odds ratio (OR): 8.88, 95% CI: 3.69-24.9, p<0.0001], fibromyalgia (OR: 4.43, 95% CI: 2.04-10.1, p=0.0002), history of irritable bowel syndrome (OR: 5.01, 95% CI: 2.31-11.2, p<0.0001), and gastroesophageal reflux disease (OR: 3.33, 95% CI: 1.55-7.44, p=0.002) were more likely to be diagnosed with GI dysmotility. On multivariable analysis, only POTS (OR: 5.74, 95% CI: 2.25-16.7, p=0.0005) was significantly associated with an increased likelihood of GI dysmotility. Conclusions This study suggests that GI symptoms are relatively common among patients with hEDS. Of the patients tested for dysmotility, 76.2% were found to have some form of dysmotility. POTS was found to be an independent predictive factor for GI dysmotility.
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Affiliation(s)
| | - Asif Hitawala
- Internal Medicine, Cleveland Clinic - Fairview Hospital, Cleveland, USA
| | - Pravallika Chadalavada
- Internal Medicine, Cleveland Clinic - Fairview Hospital, Cleveland, USA.,Oncology, Cleveland Clinic - Fairview Hospital, Cleveland, USA
| | - Fahrettin Covut
- Internal Medicine, Cleveland Clinic - Fairview Hospital, Cleveland, USA
| | - Laith Al Momani
- Internal Medicine, East Tennessee State University, Johnson City, USA
| | | | - Falgun Gosai
- Internal Medicine, Cleveland Clinic - Fairview Hospital, Cleveland, USA
| | - Suleiman Al Ashi
- Internal Medicine, Cleveland Clinic - Fairview Hospital, Cleveland, USA
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Khorasgani SMF, Ramezani N, Varnousfaderani NE. Joint hypermobility in children with and without functional constipation. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2020; 25:28. [PMID: 32419785 PMCID: PMC7213011 DOI: 10.4103/jrms.jrms_881_19] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/07/2019] [Accepted: 12/24/2019] [Indexed: 12/14/2022]
Abstract
Background: Previous studies report an association between joint hypermobility (JH), as a hallmark of connective tissue disorder, and autonomic dysfunction, digestive problems, and irritable bowel syndrome. However, its association with functional constipation (FC) has not been evaluated. This study is run and implemented to justify this theme/topic. Materials and Methods: In this case–control study among 200 subjects, 100 were of FC according to the ROME III Criteria (case group) and each child was matched for age and gender with a healthy control that did not meet criteria for FC (control group). The demographic information and JH were assessed and compared in both groups, through a physical examination according to the Beighton score. Results: A total of 200 children with a mean age of 6.2 ± 2.2 years constituted the statistical population. The prevalence of JH was assessed to establish the Beighton score (≥4 was considered JH). There was no significant difference in JH between children with and without FC, odds ratio (OR) 1.13 (95% confidence interval [CI]: 0.65–1.98, P = 0.669). There was no significant difference in terms of gender and age between the two groups (P = 0.887, P = 0.396, respectively). JH was not significantly associated with gender (P = 0.445) while significantly associated with age (P = 0.041). Furthermore, there was no significant association between JH and FC (P = 0.669). Following multivariate logistic regression analysis between the presence of JH as the dependent variable and the measured variables as the independent variables, only age had significant independent predictive values in the development of JH (P = 0.041, OR =0.88 [0.77–1]). The obtained adjusted OR in this study indicated that at each year age increase the JH risk decreased by 12%. Conclusion: Here, it is revealed that the relative frequency of JH in this age range, with and without FC, is not significantly different, and it is not significantly associated with gender while significantly associated with age.
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Affiliation(s)
| | - Neda Ramezani
- Department of General Medicine, Islamic Azad University, Najaf Abad Branch, Isfahan, Iran
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Prevalence of Functional GI Diseases and Pelvic Floor Symptoms in Marfan Syndrome and Ehlers-Danlos Syndrome: A National Cohort Study. J Clin Gastroenterol 2019; 53:653-659. [PMID: 30672816 PMCID: PMC6642856 DOI: 10.1097/mcg.0000000000001173] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIMS Prior studies have shown a high prevalence of gastrointestinal (GI) symptoms, diagnoses of functional GI diseases (FGIDs), and pelvic floor symptoms associated with Ehlers-Danlos syndrome (EDS). It is unclear if Marfan syndrome (MFS), another common hereditary noninflammatory connective tissue disorder, is also associated these symptoms. This study evaluates the prevalence of and compares FGIDs and pelvic floor symptoms in a national cohort of EDS and MFS patients. METHODS A questionnaire was sent to members of local and national MFS and EDS societies. The questionnaire evaluated the presence of GI and pelvic floor symptoms and diagnoses. The presence of FGIDs was confirmed using Rome III criteria. Quality of life was evaluated and scored with the CDC quality of life. KEY RESULTS Overall, 3934 patients completed the questionnaire, from which 1804 reported that they had some form of EDS and 600 had MFS. In total, 93% of patients with EDS complained of GI symptoms and qualified for at least one FGID compared with 69.8% of patients with MFS. When comparing EDS prevalence of upper and lower GI symptoms as well as FGIDs, subjects with EDS reported significantly higher prevalence of Rome III FGIDs as compared with those with MFS. Irritable bowel syndrome (57.8% vs. 27.0%, P<0.001), functional dyspepsia (FD) (55.4% vs. 25.0%, P<0.001), postprandial distress (49.6% vs. 21.7%, P<0.001), heartburn (33.1% vs. 16.8%, P<0.001), dysphagia (28.5% vs. 18.3%, P<0.001), aerophagia (24.7% vs. 12.3%, P<0.001), and nausea (24.7% vs. 7.2%, P<0.001) were all significantly greater in the EDS population compared with MFS population. The prevalence of FGIDs was similar across subtypes of EDS. In general, participants with EDS were more likely to have nearly all pelvic floor symptoms as compared with participants with MFS. CONCLUSIONS The prevalence of FGIDs and pelvic floor symptoms in EDS is higher than that found in MFS. The prevalence of FGIDs were similar across EDS subtypes. This study supports the mounting evidence for FGIDs in those with connective tissue diseases, but more specifically, in EDS.
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40
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Lindberg G. Pseudo-obstruction, enteric dysmotility and irritable bowel syndrome. Best Pract Res Clin Gastroenterol 2019; 40-41:101635. [PMID: 31594655 DOI: 10.1016/j.bpg.2019.101635] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Accepted: 07/18/2019] [Indexed: 02/06/2023]
Abstract
New diagnostic techniques have advanced our knowledge about the irritable bowel syndrome. The majority of patients that we believed to have a psychosomatic disorder have received other diagnoses explaining their symptoms. Endoscopy makes it possible to diagnose celiac disease before it leads to malnutrition and allows the detection of microscopic colitis as a cause of watery diarrhea. At the severe end of the symptom spectrum enteric dysmotility marks the border at which IBS ceases to be a functional disorder and becomes a genuine motility disorder. Joint hypermobility or Ehlers-Danlos syndrome is present in a substantial proportion of patients with enteric dysmotility. Chronic intestinal pseudo-obstruction is the end-stage of a large number of very rare disorders in which failed peristalsis is the common denominator. Nutritional needs and symptom control are essential in the management of pseudo-obstruction. Home parenteral nutrition is life saving in more than half of patients with chronic intestinal pseudo-obstruction.
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Affiliation(s)
- Greger Lindberg
- Karolinska Institutet, Department of Medicine, Huddinge and Karolinska University Hospital Huddinge, Patient Area Gastroenterology, Dermatology, and Rheumatology, SE-14186, Stockholm, Sweden.
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41
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Fragkos KC, Keetarut K, Cox A, Eady J, Emmanuel AV, Zarate-Lopez N. Joint Hypermobility Syndrome Affects Response to a Low Fermentable Oligosaccharide, Disaccharide, Monosaccharide and Polyol Diet in Irritable Bowel Syndrome Patients: A Retrospective Study. Gastroenterology Res 2019; 12:27-36. [PMID: 30834032 PMCID: PMC6396789 DOI: 10.14740/gr1133] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 01/16/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The low fermentable oligosaccharide, disaccharide, monosaccharide and polyol (FODMAP) diet causes significant clinical improvement in patients with irritable bowel syndrome (IBS). Joint hypermobility syndrome (JHS), defined as musculoskeletal symptoms in a hypermobile individual in the absence of systemic rheumatological disease, may be associated with functional gastrointestinal symptoms, including IBS. The aim of this study is to examine whether JHS can affect the response to the low FODMAP diet in patients with IBS. METHODS In this retrospective study, we included patients with IBS according to Rome III criteria who had followed a low FODMAP diet. Symptoms scores were measured before and after the low FODMAP diet. RESULTS A total of 165 patients (130 females, age 44 ± 14 years) were included. Diarrhea predominant IBS (IBS-D) was present in 40.6% of our patients while JHS was present in 21.2%. The score for abdominal pain was higher for JHS compared to non-JHS prior to intervention (P = 0.011). Symptoms improved in both groups of patients after a low FODMAP diet (P < 0.0001). The largest effects were shown with significant decreases of the average score and bloating. When broken down by JHS and IBS type, a low FODMAP diet significantly improved pain, bloating, diarrhea, constipation, and the average score with the largest effect in JHS/constipation predominant IBS (IBS-C), JHS/mixed IBS and unclassified IBS (IBS-M), JHS/IBS-D, non-JHS/IBS-C and JHS/IBS-M, respectively. CONCLUSIONS Our study suggests that a low FODMAP diet has a greater effect on IBS symptoms in JHS than non-JHS patients.
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Affiliation(s)
- Konstantinos C. Fragkos
- GI Physiology Unit, Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK
| | - Katie Keetarut
- Dietetics Department, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK
| | - Anna Cox
- GI Physiology Unit, Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK
| | - Johanna Eady
- Dietetics Department, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK
| | - Anton V. Emmanuel
- GI Physiology Unit, Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK
| | - Natalia Zarate-Lopez
- GI Physiology Unit, Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2PG, UK
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Loganathan P, Gajendran M, McCallum RW. Clinical Manifestation and Natural History of Gastroparesis. Gastrointest Endosc Clin N Am 2019; 29:27-38. [PMID: 30396526 DOI: 10.1016/j.giec.2018.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although gastroparesis was described more than 60 years ago, the natural history and the long-term outcome are still being clarified. The patients with more severe gastroparesis often seek health care treatment in university medical centers specializing in gastrointestinal motility disorders and hence reports in the literature tend to be based on this population and may not be representative of the entire spectrum. The clinical manifestations of gastroparesis are heterogeneous but a significant proportion of patients end up with substantially poorer quality of life. In this article, the focus is on the clinical presentation and natural history of gastroparesis.
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Affiliation(s)
- Priyadarshini Loganathan
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905, USA
| | - Mahesh Gajendran
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905, USA
| | - Richard W McCallum
- Division of Gastroenterology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine, 4800 Alberta Avenue, El Paso, TX 79905, USA.
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Zylberberg HM, Lebwohl B, Green PHR. Celiac Disease-Musculoskeletal Manifestations and Mechanisms in Children to Adults. Curr Osteoporos Rep 2018; 16:754-762. [PMID: 30350261 DOI: 10.1007/s11914-018-0488-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW We aim to review the current literature on the association of musculoskeletal disorders and celiac disease that is a common disorder, affecting about 1% of the population. Extra-intestinal symptoms and presentations predominate. RECENT FINDINGS While the literature supports an association with reduced bone mineral density and increased fracture risk and celiac disease, there is little evidence supporting associations with other rheumatological conditions. Patients frequently report musculoskeletal symptoms; however, studies of specific disease entities suffer from a lack of standardization of testing for celiac disease and a lack of control groups. Well-controlled, preferably population-based studies are required to further explore a relationship between celiac disease and musculoskeletal disorders.
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Affiliation(s)
- Haley M Zylberberg
- Celiac Disease Center, Columbia University Medical Center, 180 Fort Washington Ave, New York, NY, 10032, USA
| | - Benjamin Lebwohl
- Celiac Disease Center, Columbia University Medical Center, 180 Fort Washington Ave, New York, NY, 10032, USA
| | - Peter H R Green
- Celiac Disease Center, Columbia University Medical Center, 180 Fort Washington Ave, New York, NY, 10032, USA.
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DiBaise JK, Harris LA, Goodman B. Postural Tachycardia Syndrome (POTS) and the GI Tract: A Primer for the Gastroenterologist. Am J Gastroenterol 2018; 113:1458-1467. [PMID: 30072778 DOI: 10.1038/s41395-018-0215-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/16/2018] [Indexed: 12/11/2022]
Abstract
Postural tachycardia syndrome (POTS) is one of the most common causes of orthostatic intolerance and is being increasingly recognized in clinical practice. Gastrointestinal (GI) symptoms are reported commonly in patients with POTS and pose a considerable management challenge, making it imperative that gastroenterologists be aware of this condition and its GI comorbidities. Although the evidence presented herein does not prove causation, it does support an association between GI symptoms, GI dysmotility, and POTS. At present, the evaluation and treatment of GI symptoms in patients with POTS remains largely empirical. General measures to treat POTS may lead to improvement in both GI and non-GI symptoms. GI symptoms refractory to these measures should prompt further diagnostic evaluation of gastrointestinal dysmotility and appropriate dietary and pharmacologic management. This review focuses its attention on the involvement of the GI tract in POTS including a discussion of GI symptoms and conditions associated with POTS, followed by an analysis of abnormalities in gut physiology described in POTS, and concluding with an overview of management and suggestions for research directions.
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Affiliation(s)
- John K DiBaise
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, 85259, USA. Department of Neurology, Mayo Clinic, Scottsdale, AZ, 85259, USA
| | - Lucinda A Harris
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, 85259, USA. Department of Neurology, Mayo Clinic, Scottsdale, AZ, 85259, USA
| | - Brent Goodman
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, 85259, USA. Department of Neurology, Mayo Clinic, Scottsdale, AZ, 85259, USA
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Gastrointestinal Symptoms in Marfan Syndrome and Hypermobile Ehlers-Danlos Syndrome. Gastroenterol Res Pract 2018; 2018:4854701. [PMID: 30151001 PMCID: PMC6087563 DOI: 10.1155/2018/4854701] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 07/08/2018] [Indexed: 12/19/2022] Open
Abstract
Objective Marfan syndrome (MS) is a multisystem disorder caused by a mutation in FBN1 gene. It shares some phenotypic features with hypermobile Ehlers-Danlos syndrome (EDS) such as joint hypermobility. EDS is a group of inherited heterogenous multisystem disorders characterized by skin hyperextensibility, atrophic scarring, joint hypermobility, and generalized tissue fragility. Hypermobile EDS (hEDS) is thought to be the most common type. Recent studies have suggested an association between connective tissue hypermobility and functional gastrointestinal disorders (FGDs). The aim of this study is to determine the prevalence of gastrointestinal symptoms in patients with Marfan syndrome and hypermobile EDS. Method Patients with a diagnosis of either MS or hEDS attending cardiology or rheumatology outpatients at our hospital were asked to complete SF36 RAND and Rome IV Diagnostic questionnaires. Questionnaires were also completed by patients who are members of Marfan Association UK. The same questionnaires were also completed by age- and gender-matched controls attending fracture clinic without existing diagnoses of MS or hEDS. Results Data were collected from 45 MS patients (12 males and 33 females, age range 19-41 years, mean 28 years) and 45 hEDS patients (6 males and 39 females, age range 18-32 years, mean 24 years). None had a previous organic gastrointestinal diagnosis. The control group was matched for age and sex (18 males and 72 females, age range 18-45, mean 29 years). Both MS and hEDS groups showed a higher prevalence of abdominal symptoms compared to the control group; however, the hEDS group not only showed a higher prevalence but more frequent and severe symptoms meeting Rome IV criteria for diagnosis of FGIDs. Nearly half of the hEDS patients met the criteria for more than one FGID. The hEDS group also scored lower on quality of life (QOL) scores in comparison to either of the other groups with a mean score of 48.6 as compared to 54.2 in the Marfan group and 78.6 in the control group. Conclusion FGIDs are reported in both Marfan syndrome and hypermobile Ehlers-Danlos syndrome but appear to be more common and severe in hEDS. These patients score lower on quality of life scores as well despite hypermobility being a common feature of both conditions. Further work is needed to understand the impact of connective tissue disorders on gastrointestinal symptoms.
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Aktar R, Peiris M, Fikree A, Cibert-Goton V, Walmsley M, Tough IR, Watanabe P, Araujo EJA, Mohammed SD, Delalande JM, Bulmer DC, Scott SM, Cox HM, Voermans NC, Aziz Q, Blackshaw LA. The extracellular matrix glycoprotein tenascin-X regulates peripheral sensory and motor neurones. J Physiol 2018; 596:4237-4251. [PMID: 29917237 PMCID: PMC6117562 DOI: 10.1113/jp276300] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/11/2018] [Indexed: 12/15/2022] Open
Abstract
KEY POINTS Tenascin-X (TNX) is an extracellular matrix glycoprotein with anti-adhesive properties in skin and joints. Here we report the novel finding that TNX is expressed in human and mouse gut tissue where it is exclusive to specific subpopulations of neurones. Our studies with TNX-deficient mice show impaired defecation and neural control of distal colonic motility that can be rescued with a 5-HT4 receptor agonist. However, colonic secretion is unchanged. They are also susceptible to internal rectal intussusception. Colonic afferent sensitivity is increased in TNX-deficient mice. Correspondingly, there is increased density of and sensitivity of putative nociceptive fibres in TNX-deficient mucosa. A group of TNX-deficient patients report symptoms highly consistent with those in the mouse model. These findings suggest TNX plays entirely different roles in gut to non-visceral tissues - firstly a role in enteric motor neurones and secondly a role influencing nociceptive sensory neurones Studying further the mechanisms by which TNX influences neuronal function will lead to new targets for future treatment. ABSTRACT The extracellular matrix (ECM) is not only an integral structural molecule, but is also critical for a wide range of cellular functions. The glycoprotein tenascin-X (TNX) predominates in the ECM of tissues like skin and regulates tissue structure through anti-adhesive interactions with collagen. Monogenic TNX deficiency causes painful joint hypermobility and skin hyperelasticity, symptoms characteristic of hypermobility Ehlers Danlos syndrome (hEDS). hEDS patients also report consistently increased visceral pain and gastrointestinal (GI) dysfunction. We investigated whether there is a direct link between TNX deficiency and GI pain or motor dysfunction. We set out first to learn where TNX is expressed in human and mouse, then determine how GI function, specifically in the colon, is disordered in TNX-deficient mice and humans of either sex. In human and mouse tissue, TNX was predominantly associated with cholinergic colonic enteric neurones, which are involved in motor control. TNX was absent from extrinsic nociceptive peptidergic neurones. TNX-deficient mice had internal rectal prolapse and a loss of distal colonic contractility which could be rescued by prokinetic drug treatment. TNX-deficient patients reported increased sensory and motor GI symptoms including abdominal pain and constipation compared to controls. Despite absence of TNX from nociceptive colonic neurones, neuronal sprouting and hyper-responsiveness to colonic distension was observed in the TNX-deficient mice. We conclude that ECM molecules are not merely support structures but an integral part of the microenvironment particularly for specific populations of colonic motor neurones where TNX exerts functional influences.
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Affiliation(s)
- Rubina Aktar
- Blizard Institute, Queen Mary University of London, London, UK
| | - Madusha Peiris
- Blizard Institute, Queen Mary University of London, London, UK
| | - Asma Fikree
- Blizard Institute, Queen Mary University of London, London, UK
| | | | - Maxim Walmsley
- Blizard Institute, Queen Mary University of London, London, UK
| | - Iain R Tough
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
| | - Paulo Watanabe
- Blizard Institute, Queen Mary University of London, London, UK.,Department of Histology, Centre for Biological Sciences, State University of Londrina, Brazil
| | - Eduardo J A Araujo
- Blizard Institute, Queen Mary University of London, London, UK.,Department of Histology, Centre for Biological Sciences, State University of Londrina, Brazil
| | | | | | - David C Bulmer
- Blizard Institute, Queen Mary University of London, London, UK
| | - S Mark Scott
- Blizard Institute, Queen Mary University of London, London, UK
| | - Helen M Cox
- Institute of Psychiatry, Psychology and Neuroscience, Kings College London, London, UK
| | - Nicol C Voermans
- Department of Neurology, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Qasim Aziz
- Blizard Institute, Queen Mary University of London, London, UK
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Botrus G, Baker O, Borrego E, Ngamdu KS, Teleb M, Gonzales Martinez JL, Maldonado G, Hussein AM, McCallum R. Spectrum of Gastrointestinal Manifestations in Joint Hypermobility Syndromes. Am J Med Sci 2018; 355:573-580. [DOI: 10.1016/j.amjms.2018.03.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 02/20/2018] [Accepted: 03/01/2018] [Indexed: 10/17/2022]
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Koduru P, Irani M, Quigley EMM. Definition, Pathogenesis, and Management of That Cursed Dyspepsia. Clin Gastroenterol Hepatol 2018; 16:467-479. [PMID: 28899670 DOI: 10.1016/j.cgh.2017.09.002] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 08/28/2017] [Accepted: 09/05/2017] [Indexed: 02/07/2023]
Abstract
Dyspepsia is an umbrella term used to encompass a number of symptoms thought to originate from the upper gastrointestinal tract. These symptoms are relatively nonspecific; not surprisingly, therefore, a myriad of conditions may present with any one or a combination of these symptoms. Therein lays the clinician's first challenge: detecting the minority who may have a potentially life-threatening disorder, such as gastric cancer, from a population whose symptoms are, for the most part, considered functional in origin. The second challenge lies in the definition and management of those individuals with functional dyspepsia (FD); the major focus of this review. The Rome process has addressed the issue of FD definition and a look back at the evolution of Rome criteria for this disorder illustrates the complexities that have so frustrated us. There has been no shortage of hypotheses to explain symptom pathogenesis in FD; initially focused on gastric sensorimotor dysfunction, these have now strayed well into the duodenum and have come to entertain such factors as immune responses and the microbiome. FD has proven to be an equally challenging area for therapeutics; while the staple approaches of acid suppression and eradication of Helicobacter pylori have some limited efficacy in select populations, strategies to ameliorate symptoms in the majority of sufferers based on presumed pathophysiology have largely foundered. Lacking a validated biomarker(s) FD continues to be an elusive target and is likely to remain so until we can better define the various phenotypes that it must surely contain.
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Affiliation(s)
- Pramoda Koduru
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
| | - Malcolm Irani
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
| | - Eamonn M M Quigley
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas.
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Buhner S, Hahne H, Hartwig K, Li Q, Vignali S, Ostertag D, Meng C, Hörmannsperger G, Braak B, Pehl C, Frieling T, Barbara G, De Giorgio R, Demir IE, Ceyhan GO, Zeller F, Boeckxstaens G, Haller D, Kuster B, Schemann M. Protease signaling through protease activated receptor 1 mediate nerve activation by mucosal supernatants from irritable bowel syndrome but not from ulcerative colitis patients. PLoS One 2018. [PMID: 29529042 PMCID: PMC5846775 DOI: 10.1371/journal.pone.0193943] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background & aims The causes of gastrointestinal complaints in irritable bowel syndrome (IBS) remain poorly understood. Altered nerve function has emerged as an important pathogenic factor as IBS mucosal biopsy supernatants consistently activate enteric and sensory neurons. We investigated the neurally active molecular components of such supernatants from patients with IBS and quiescent ulcerative colitis (UC). Method Effects of supernatants from 7 healthy controls (HC), 20 IBS and 12 UC patients on human and guinea pig submucous neurons were studied with neuroimaging techniques. We identify differentially expressed proteins with proteome analysis. Results Nerve activation by IBS supernatants was prevented by the protease activated receptor 1 (PAR1) antagonist SCHE79797. UC supernatants also activated enteric neurons through protease dependent mechanisms but without PAR1 involvement. Proteome analysis of the supernatants identified 204 proteins, among them 17 proteases as differentially expressed between IBS, UC and HC. Of those the four proteases elastase 3a, chymotrypsin C, proteasome subunit type beta-2 and an unspecified isoform of complement C3 were significantly more abundant in IBS compared to HC and UC supernatants. Of eight proteases, which were upregulated in IBS, the combination of elastase 3a, cathepsin L and proteasome alpha subunit-4 showed the highest prediction accuracy of 98% to discriminate between IBS and HC groups. Elastase synergistically potentiated the effects of histamine and serotonin–the two other main neuroactive substances in the IBS supernatants. A serine protease inhibitor isolated from the probiotic Bifidobacterium longum NCC2705 (SERPINBL), known to inhibit elastase-like proteases, prevented nerve activation by IBS supernatants. Conclusion Proteases in IBS and UC supernatants were responsible for nerve activation. Our data demonstrate that proteases, particularly those signalling through neuronal PAR1, are biomarker candidates for IBS, and protease profiling may be used to characterise IBS.
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Affiliation(s)
- Sabine Buhner
- Human Biology, Technische Universität München, Freising, Germany
| | - Hannes Hahne
- Proteomics and Bioanalytics, Technische Universität München, Freising, Germany
| | - Kerstin Hartwig
- Human Biology, Technische Universität München, Freising, Germany
| | - Qin Li
- Human Biology, Technische Universität München, Freising, Germany
- Department of Physiology, Shangdong University, Shangdong, China
| | - Sheila Vignali
- Human Biology, Technische Universität München, Freising, Germany
| | - Daniela Ostertag
- Human Biology, Technische Universität München, Freising, Germany
| | - Chen Meng
- Proteomics and Bioanalytics, Technische Universität München, Freising, Germany
| | | | - Breg Braak
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | | | | | - Giovanni Barbara
- Department of Medical and Surgical Sciences, St. Orsola Hospital, Bologna, Italy
| | - Roberto De Giorgio
- Department of Clinical Sciences, Nuovo Arcispedale S. Anna, University of Ferrara, Ferrara, Italy
| | - Ihsan Ekin Demir
- Department of General Surgery, University Hospital Rechts der Isar, Technische Universität München, Germany
| | - Güralp Onur Ceyhan
- Department of General Surgery, University Hospital Rechts der Isar, Technische Universität München, Germany
| | | | - Guy Boeckxstaens
- Translational Research Centre for Gastrointestinal Disorders, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium
| | - Dirk Haller
- Nutrition and Immunology, Technische Universität München, Freising, Germany
| | - Bernhard Kuster
- Proteomics and Bioanalytics, Technische Universität München, Freising, Germany
| | - Michael Schemann
- Human Biology, Technische Universität München, Freising, Germany
- * E-mail:
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Abstract
The aim of the study was to assess the prevalence of joint hypermobility (JH) among school children with and without functional gastrointestinal disorders (FGIDs). School children completed validated Rome III questionnaires to diagnose FGID. Each child diagnosed with an FGID was matched for age and sex with a healthy control. The prevalence of JH in both groups was compared. A total of 654 school children participated in the study. One hundred forty-eight (22.6%) children were diagnosed with an FGID. Data from 136 FGIDs and 136 healthy controls were analyzed. Joint laxity was assessed to establish the Beighton score (≥4 was considered JH). There was no significant difference in JH between children with and without diagnoses of FGIDs odds ratio (OR) 1.03 (95% confidence interval [CI]: 0.59-1.81, P = 0.89). Multivariate analysis showed that younger age OR 2.31 (95% CI: 1.30-4.10, P = 0.004) and female sex OR 2.27 (95% CI: 1.22-4.24, P = 0.009) were significantly associated with JH. JH is equally prevalent in school children with and without FGIDs.
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