Rubina Aktar

A Prospective Evaluation of Undiagnosed Joint Hypermobility Syndrome in Patients With Gastrointestinal Symptoms

BACKGROUND & AIMS The Joint Hypermobility Syndrome (JHS) is a common connective tissue disorder characterized by joint hyperflexibility, dysautonomia, and chronic pain. Gastrointestinal (GI) symptoms are reported in JHS patients attending rheumatology clinics, but the prevalence and symptom pattern of previously undiagnosed JHS in GI clinics are unknown. METHODS By using validated questionnaires, a prospective cross-sectional study in secondary care GI clinics estimated the prevalence of JHS in new consecutively referred patients, compared GI symptoms in patients with and without JHS, and by using multiple regression determined whether the burden of GI symptoms in JHS patients was dependent on chronic pain, autonomic, psychological, and medication related factors. A positive control group consisted of JHS patients referred from rheumatology clinics with GI symptoms (JHS-Rh). RESULTS From 552 patients recruited, 180 (33%) had JHS (JHS-G) and 372 did not (non-JHS-G). Forty-four JHS-Rh patients were included. JHS-G patients were more likely to be younger, female with poorer quality of life (P = .02) than non-JHS-G patients. After age and sex matching, heartburn (odds ratio [OR], 1.66; confidence interval [CI], 1.1-2.5; P = .01), water brash (OR, 2.02; CI, 1.3-3.1; P = .001), and postprandial fullness (OR, 1.74; CI, 1.2-2.6; P = .006) were more common in JHS-G vs non-JHS-G. Many upper and lower GI symptoms increased with increasing severity of JHS phenotype. Upper GI symptoms were dependent on autonomic and chronic pain factors. CONCLUSIONS JHS is common in GI clinics, with increased burden of upper GI and extraintestinal symptoms and poorer quality of life. Recognition of JHS will facilitate multidisciplinary management of GI and extra-GI manifestations.

Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case–control study

The overlap of unexplained gastrointestinal (GI) and somatic symptoms is well established in patients with functional gastrointestinal disorders (FGID). Joint hypermobility syndrome (JHS) is a non‐inflammatory connective tissue disorder associated with GI and somatic symptoms. We aimed to determine whether there is an association between diagnosis of JHS and FGID and the impact of this association on comorbidities and quality of life (QOL).

Distinct afferent innervation patterns within the human proximal and distal esophageal mucosa.

Little is known about the mucosal phenotype of the proximal human esophagus. There is evidence to suggest that the proximal esophagus is more sensitive to chemical and mechanical stimulation compared with the distal. This may have physiological relevance (e.g., in prevention of aspiration of gastroesophageal refluxate), but also pathological relevance (e.g., in reflux perception or dysphagia). Reasons for this increased sensitivity are unclear but may include impairment in mucosal barrier integrity or changes in sensory innervation. We assessed mucosal barrier integrity and afferent nerve distribution in the proximal and distal esophagus of healthy human volunteers. In 10 healthy volunteers baseline proximal and distal esophageal impedance was measured in vivo. Esophageal mucosal biopsies from the distal and proximal esophagus were taken, and baseline transepithelial electrical resistance (TER) was measured in Ussing chambers. Biopsies were examined immunohistochemically for presence and location of calcitonin gene-related peptide (CGRP)-immunoreactive nerve fibers. In a further four healthy volunteers we investigated for colocalization of CGRP and protein gene product (PGP) 9.5 immunoreactivity in nerve fibers. Baseline impedance was higher in the proximal than in the distal esophagus [2,936 Ω (SD578) vs. 2,229 Ω (SD821); P = 0.03], however, baseline TER was not significantly different between them. Mucosal CGRP-immunoreactive nerves were found in the epithelium of both proximal and distal esophagus, but were located more superficially in the proximal mucosa compared with the distal [11.5 (SD7) vs. 21.7 (SD5) cell layers from lumen, P = 0.002] 19% of proximal, and 10% of distal mucosal PGP-immunoreactive fibers colocalized with CGRP. PGP-immunoreactive fibers were also significantly closer to the luminal surface in the proximal compared with the distal esophagus (P < 0.001). We conclude that mucosal barrier integrity is similar in proximal and distal esophagus, but proximal mucosal afferent nerves are in a more superficial location. The enhanced sensitivity to reflux-evoked symptoms of the proximal esophagus most likely has an anatomical basis.

Zinc accumulation in heterozygous mutants of fumble, the pantothenate kinase homologue of Drosophila

Coenzyme A (CoA) functions in the intracellular trafficking of acetyl groups. In humans, mutations in the pantothenate kinase‐2 gene, which encodes a key enzyme in CoA biosynthesis, are associated with neurodegeneration and premature death. Diagnosis is based on iron accumulation in the globus pallidus observed by magnetic resonance imaging. We investigated the elemental composition of the fumble mutant, a model of the human disease. Surprisingly, flies carrying a fumble loss‐of‐function allele had a three‐fold increase in total zinc levels per dry weight when compared to control strains, but no change in total iron, copper or manganese levels. Accordingly, zinc supplementation had an adverse impact on the development of fumble mutant larvae, but zinc chelation failed to protect.

The association between Ehlers-Danlos syndrome-hypermobility type and gastrointestinal symptoms in university students: a cross-sectional study.

Patients with Ehlers‐Danlos syndrome—hypermobility type (EDS‐HT) have increased prevalence of gastrointestinal (GI) symptoms, particularly reflux and dyspepsia. EDS‐HT is associated with dysautonomia, psychopathology, and chronic pain which can be associated with GI symptoms. The association between GI symptoms and EDS‐HT in a ‘non‐patient’ population and the effect of the above‐mentioned factors has never been studied.

The extracellular matrix glycoprotein tenascin‐X regulates peripheral sensory and motor neurones

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.

Effects of Obesity and Gastric Bypass Surgery on Nutrient Sensors, Endocrine Cells, and Mucosal Innervation of the Mouse Colon

Background: Nutrient-sensing receptors located on enteroendocrine (EEC) cells modulate appetite via detection of luminal contents. Colonic ‘tasting’ of luminal contents may influence changes to appetite observed in obesity and after weight loss induced by bariatric surgery. We assessed the effects of obesity and gastric bypass-induced weight loss on expression of nutrient-sensing G-protein coupled receptors (GPCRs), EEC and enterochromaffin (EC) cells and mucosal innervation. Methods: qPCR and immunohistochemistry were used to study colonic tissue from (a) chow-fed/lean, (b) high-fat fed/obese, (c) Roux-en-Y gastric bypass surgery (RYGB), and (d) calorie restriction-induced weight loss mice. Results: Expression of GPR41, GPR43, GPR40, GPR120, GPR84, GPR119, GPR93 and T1R3 was increased in obese mice. Obesity-induced overexpression of GPR41, 40, 84, and 119 further increased after RYGB whereas GPR120 and T1R3 decreased. RYGB increased TGR5 expression. L-cells, but not EC cells, were increased after RYGB. No differences in mucosal innervation by protein gene product (PGP) 9.5 and GLP-1R-positive nerve fibers were observed. Stimulation of colonic mucosa with GPR41, GPR40, GPR85, GPR119, and TGR5 agonists increased cell activation marker expression. Conclusions: Several nutrient-sensing receptors induced activation of colonic EEC. Profound adaptive changes to the expression of these receptors occur in response to diet and weight loss induced by RYGB or calorie restriction.

PWE-160 The Joint Hypermobility Syndrome Is Associated With Functional Dyspepsia And Reflux And Identifies A Subgroup With Somatisation, Chronic Pain And Worse Quality Of Life

Introduction The Joint hypermobility syndrome (JHS) is a non-inflammatory connective tissue disorder with a prevalence of 20%. It is characterised by joint hypermobility,chronic pain, fibromyalgia (FM) and dysautonomia. Gastrointestinal (GI) symptoms e.g., dyspepsia, reflux, bloating and constipation are present in up to 80% of affected individuals. Small studies suggest that FGID are common in these patients yet no controlled studies have systematically investigated if JHS is associated with particular GI diagnoses nor explored the effect of JHS on non-GI symptom presentation and quality of life (QOL). Methods Using a nested case-control double-blind study in secondary care GI clinics, consecutive new referrals (without prior GI diagnosis), aged 18–70, completed validated questionnaires for GI, somatic, psychological and autonomic symptoms and QOL, and were assessed for JHS and FM. They then consulted a gastroenterologist, underwent investigations and received a GI diagnosis. ROME III criteria were used to categorise FGID. A control group of patients, aged 18–70, who were referred to secondary care for non-GI related problems, were similarly assessed. The prevalence of JHS in various GI diagnoses and in controls,adjusted for age and gender,was compared. Non-GI characteristics and QOL was compared in JHS and non-JHS patients. Results 688 GI patients [254 organic: (55% F, 43y); 341 FGID: (65% F, 40y); 53 reflux: (40% F, 46y)] and 93 non-GI controls (67% F, 43y) were included. JHS prevalence was higher in FGID (38%) and reflux (40%) compared to organic disorders (26%) and controls (26%) (p = 0.003). JHS was significantly associated with FGID (ORadj: 1.7, CI:1.02–2.88), specifically postprandial distress syndrome (ORadj 2.2, CI: 1.2–2.2), and with reflux disorders (ORadj 2.2, CI: 1.1–4.7), but not with organic disorders (ORadj: 1.0, CI:0.6–1.8). FGID patients with JHS had significantly more FM (12.6 vs. 4.9%, p = 0.02), chronic pain (23.2 vs. 11.7%, p = 0.01), somatisation scores (13 vs. 10, p < 0.01), anxiety scores (0.5 vs. 0.36, p = 0.02) and urinary autonomic symptoms (30.5% vs 19.6%, p = 0.047), and worse pain related QOL scores (45 vs. 63.5, p < 0.01). Conclusion JHS is associated with functional dyspepsia, and non-erosive reflux disease, and with FM, chronic pain, somatisation and anxiety. Clinical assessment for JHS in GI clinics is indicated in those with a combination of functional upper GI symptoms and extra-intestinal symptoms as this may help earlier identification of a more ‘challenging’ group of patients with multiple somatic symptoms and worse QOL. These may benefit from early multidisciplinary approach involving rheumatologists and pain specialists. Disclosure of Interest None Declared.

OC-067 Enhanced Perception Of Proximal Gastro-oesophageal Reflux: Impaired Mucosal Integrity Or Distinct Sensory Innervation?

Introduction In patients with GORD, including refractory disease, reflux events reaching the proximal oesophagus are more likely to be perceived than those only reaching the distal oesophagus. There is also experimental data suggesting an increased sensitivity of the proximal oesophagus relative to the distal. As such, the proximal oesophagus is likely to be highly significant in the pathogenesis of GORD symptoms. Reasons for this proximal oesophageal sensitivity are not clear, but may include reflux volume, impairment in mucosal integrity or changes in sensory innervation. It has recently been shown that distal mucosal integrity (its ability to perform a protective barrier function) is more vulnerable to acid exposure in GORD than in controls. The integrity of the proximal oesophagus has not been tested. To our knowledge, there are no studies evaluating mucosal afferent innervation of the distal and proximal oesophagus. We aimed to compare mucosal integrity and afferent nerve distribution in the proximal and distal oesophagus in patients with heartburn without oesophagitis. Methods In 23 patients with heartburn and 10 healthy volunteers baseline proximal and distal oesophageal impedance was measured in vivo. Oesophageal mucosal biopsies from the distal and proximal oesophagus were taken and baseline transepithelial electrical resistance (TER) was measured in Ussing chambers. Biopsies were examined immunohistochemically for presence and location of calcitonin gene-related peptide (CGRP) immunoreactive nerve fibres. Results Baseline impedance was higher in the proximal than in the distal oesophagus in healthy volunteers (2935 ± 204 Ω vs. 2234 ± 290 Ω, p < 0.05) and in patients (2949 ± 183Ω vs.1945 ± 235Ω, p < 0.001). However, baseline TER was not significantly different between proximal and distal oesophagus, or between patients with heartburn and healthy volunteers. Mucosal CGRP-immunoreactive nerves were located more superficially in the proximal oesophagus compared to the distal oesophagus in healthy controls (12.3 ± 0.9 vs. 23.8 ± 1.2 cells from lumen, p < 0.001) and in patients (5.7 ± 0.7 vs. 22.2 ± 2.7 cells from lumen, p < 0.0001). Moreover, these nerves were located closer to the lumen in patients with heartburn compared to asymptomatic controls (5.7 ± 0.7 vs. 12.3 ± 0.9, p < 0.001). Conclusion The baseline mucosal integrity of the proximal oesophagus is not more impaired than that of the distal, nor is it more impaired in patients with heartburn symptoms versus healthy controls. Increased sensitivity of the proximal oesophagus in GORD may instead be associated with a more superficial location of mucosal afferent nerves. Topical protection of the proximal oesophageal mucosa is a potential treatment strategy to reduce this sensitivity. Disclosure of Interest None Declared.

PTU-124 The Association of the Joint Hypermobility Syndrome with Functional Gastrointestinal Disorders – an Interesting New finding that may Explain Aetiology

Introduction Functional Gastrointestinal Disorders (FGID) are common, but their cause is unknown. Joint hypermobility syndrome (JHS) is a common non-inflammatory connective tissue disorder characterised by joint hyperflexibility. It is associated with gastrointestinal (GI) symptoms (1), in particular unexplained symptoms (2). The association between JHS and FGID has never been studied. Methods A nested case control study in patients aged 18–70 attending secondary care was performed. 694 consecutive new referrals to GI clinics were assessed for JHS using the Brighton criteria, prior to their outpatient consultation. Subsequent investigation by their gastroenterologist led to a diagnosis that was functional, organic or gastrooesophageal reflux (GOR); the latter were excluded due to the mixed aetiology of reflux. The control group consisted of 92 patients referred to secondary care for non-GI symptoms-those with diabetes, pregnancy, neuromuscular disorders or inflammatory arthritis were excluded. Controls were similarly assessed for JHS. JHS prevalence was compared in patients with FGID, organic GI disorders, and controls. Results Of the 694 GI patients, 26 had GOR and 52 had not received a diagnosis–these were excluded. Thus 616 GI patients were included in the study: 363 had FGID, 253 had organic disorders. There were no significant age or gender differences between FGID and controls (age: 40.3 ± 0.69 vs 42.7 ± 1.5; 64% vs 67% females). Compared to FGID patients, organic patients were older (43.9 ± 0.92 vs 40.3 ± 0.69, p:0.002) and less likely to be female (54% vs 64%, p:0.008).The prevalence of JHS in FGID patients in secondary care was 40.5%. This was significantly higher than in organic GI patients (26.9%, p:0.000) and in controls (25%, p:0.006). Even after adjusting for age and gender differences, JHS was significantly associated with FGID (p:0.005). Conclusion This is the first study that demonstrates a strong association between JHS and FGID, as compared to both organic GI and non-GI conditions. This suggests a potential connective tissue aetiology for 40% of FGID patients in secondary care. Furthermore, the high prevalence of JHS in FGID suggests that this common diagnosis is often overlooked. Our results have implications for future FGID research and efforts must now be focused to determine the mechanism of symptoms and identification of appropriate treatments for this subgroup of patients. Disclosure of Interest None Declared References Castori, M., et al., Am J Med Genet A, 2010. 152A(3): p. 556–64. Zarate, N., et al., Neurogastroenterol Motil, 2010. 22(3):252-e78.