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Functional Gastrointestinal Disorders and the Joint Hypermobility Syndrome

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Functional Gastrointestinal Disorders and the Joint Hypermobility Syndrome Functional Gastrointestinal Disorders and the Joint Hypermobility Syndrome Asma Fikree BMBCh, MA, MRCP St Bartholomew’s and the Royal London School of Medicine and Dentistry A Thesis submitted for the Degree of Doctor of Philosophy The University of London March 2013 Abstract Despite the fact that functional gastrointestinal disorders (FGID), such as irritable bowel syndrome, are common, our understanding of them is limited. The Joint Hypermobility Syndrome (JHS) is a common non-inflammatory connective tissue disorder which is thought to be associated with FGID although this has never been proven. Thus, further understanding of the link between JHS and GI symptoms is warranted. Our aim was to fully characterise the gastrointestinal (GI) manifestations of JHS, to determine if there is a true association between GI symptoms in JHS and FGID, and to determine the factors that are involved in this association. Using a cross-sectional design I demonstrate in the first study that patients with a known diagnosis of JHS who are referred from rheumatologists to gastroenterologists have significantly increased gastro-oesophageal symptoms, alternating bowel habit, bloating and abdominal pain compared to other patients referred to the GI clinics. Autonomic factors, and to a lesser extent, somatic hypersensitivity factors appear to mediate the association between JHS and gastro-oesophageal symptoms. In the second study, I demonstrate that healthy university students with JHS are more likely to experience postprandial dyspeptic symptoms compared to those without JHS. Although autonomic and somatic symptoms are increased in JHS their presence does not seem to confound the association with GI symptoms in this group of healthy individuals. In a case-control study of patients attending secondary care GI clinics, I demonstrate that JHS is overrepresented in patients with FGID and reflux disease but not in those with organic disease. Furthermore, the association with FGID is specifically with postprandial distress syndrome and this association is dependent on autonomic factors. In the final chapter, I confirm that abnormalities in GI physiology are common in JHS patients with GI symptoms attending a physiology unit. 60% of JHS patients with reflux symptoms have non-erosive pathological acid reflux, 56% with dysphagia have oesophageal hypomotility, and 87% with dyspeptic symptoms have gastroparesis. My studies suggest that there is overlap between JHS, gastro-oeosphageal symptoms, FGID and GI dysmotility. Understanding the mechanisms underlying GI involvement in JHS may further our understanding of FGID. 2 Acknowledgements I am indebted to my supervisors, Professor Qasim Aziz and Professor Charles Knowles, for their motivation, support and encouragement over the last 4 years. I would like to pay a special tribute to Miss Rubina Aktar, a colleague and friend, without whom none of this work would have been possible. I will be forever grateful for all the support she gave me as my research assistant, particularly with all the administrative aspects of the study and with the database management. I am very grateful to the Pseudo-Obstruction Research Trust and Bowel and Cancer Research for funding me during this PhD. I would also like to thank the following: Professor Daniel Sifrim for supervising the GI physiology studies. Dr Jafar Jafari for patiently teaching me how to analyse physiology data. Professor Rodney Grahame, Dr Hana Kazkaz and Dr Alan Hakim for training me to confidently diagnose Hypermobility Conditions and Fibromyalgia. The doctors and reception staff at the Mission Practice, Lawson Practice and Chrisp Street Practice, from where the GP control patients were recruited. Wout Rohof who provided me with the healthy control data for the Endoflip study. Neel Sharma, Malik Magrabi, Mike Kulska, Charlotte O'Brien, Georgina Wellstead, Katherine Gillespie, Lucy Glasgow, and Moheen Ahmed who helped with data management, particularly with the transcription of questionnaires to an electronic format. David Annan, Esther Woo, Priyanga Balasinga and Jon Choi for creation of the GI phsyiology database. Finally I would like to thank my family, particularly my sister, for always being supportive, encouraging and loving. Last but not least, my most heartfelt and sincere thanks goes to my wonderful husband, who is always a calm source of inspiration, and whose support during the final stages of the PhD no words can describe. 3 Declaration This work was carried out during my tenure as a research fellow in the Wingate Institute of Neurogastroenterology, Barts and the London School of Medicine and Dentistry between April 2009 and December 2012. I designed and wrote the ethics applications for all the studies. All the studies were performed and analysed by myself except as stated below: The skin stretch tests were performed by my research assistant, Miss Rubina Aktar. The GI physiology studies in non-JHS patients presented in Chapter 5 were performed collectively by all the fellows working in the upper GI physiology unit, but the data was collated and analysed by myself. The gastric emptying breath tests were performed by Dr Jafari, Dr Shaub, and Dr Yu Tien, all research fellows in the upper GI physiology unit. The endoflip data for healthy volunteers was obtained and analysed by Dr W Rohof in the Netherlands. The administrative tasks including the transcription of data to electronic format, and contacting patients were performed jointly by myself and by my research assistant, Miss Rubina Aktar. I believe that this work represents a new contribution to medical knowledge. The work in this thesis has not already been accepted in substance for any degree and is not being concurrently submitted in candidature for any degree. The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without the prior written consent of the author. Dr Asma Fikree BMBCh, MA, MRCP 4 To my late father, who was fond of asking questions and even fonder of finding answers 5 Table of contents Abstract ………………………………………………………………………………...2 Acknowledgements …………………………………………………………………...3 Declaration ...…………………………………………………………………………..4 Table of Contents ……………………………………………………………………..6 List of Tables ………………………………………………………………………...14 List of Figures .……………………………………………………………………….16 List of Abbreviations …………………………………………………………………19 Publications related to thesis………………………………………………………..22 Reviews ......................................................................................................... 22 Case reports .................................................................................................. 22 Abstracts ........................................................................................................ 23 Presentations………………………………………………………………………....25 Chapter 1 Introduction, literature review and aims .......................................... 26 1.1 Functional Gastrointestinal Disorders ................................................... 26 1.1.1 Epidemiology of Functional Gastrointestinal Disorders .................. 28 1.1.2 The burden of FGID ........................................................................ 28 1.1.3 Associated features and disorders in FGID .................................... 31 1.1.4 Aetiology of FGID ............................................................................ 33 1.1.5 Biopsychosocial model for FGID ..................................................... 40 1.1.6 Limitations of FGID research .......................................................... 42 1.2 Connective tissue .................................................................................. 43 1.2.1 Connective tissue components ....................................................... 43 1.2.2 Connective tissue and the GI tract in health ................................... 44 6 1.2.3 Connective tissue and the GI tract in GI disease ............................ 45 1.3 Joint hypermobility ................................................................................. 49 1.3.1 Assessment of Generalised Joint Hypermobility ............................. 51 1.3.2 Generalised Joint Hypermobility and connective tissue disorders .. 53 1.4 Ehlers-Danlos Syndrome ...................................................................... 53 1.4.1 Ehlers-Danlos Syndrome Hypermobility Type ............................... 55 1.5 Joint Hypermobility Syndrome ............................................................... 58 1.5.1 Epidemiology .................................................................................. 58 1.5.2 Classical features in JHS ................................................................ 59 1.5.3 Aetiology ......................................................................................... 60 1.5.4 Diagnosis ........................................................................................ 61 1.5.5 Extra-articular associations of JHS ................................................. 66 1.5.6 Functional somatic symptoms, JHS and FGID ............................... 73 1.6 Joint Hypermobility and the GI tract ...................................................... 74 1.6.1 Joint Hypermobility and abnormal GI anatomy ............................... 74 1.6.2 Joint hypermobility and abnormal GI physiology ........................... 75 1.6.3 Association between JHS and GI symptoms .................................. 76 1.6.4 Joint hypermobility and organic GI disorders .................................
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