Rome IV functional gastrointestinal disorders and health impairment in subjects with hypermobility spectrum disorders or hypermobile Ehlers-Danlos syndrome

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

Functional gastrointestinal disorders are increased in joint hypermobility-related disorders with concomitant postural orthostatic tachycardia syndrome

Background: Individuals with hypermobility spectrum disorders/hypermobile Ehlers-Danlos syndrome (HSD/hEDS) frequently fulfill criteria for Rome IV functional gastrointestinal disorders (FGIDs). Postural orthostatic tachycardia syndrome (POTS) is also commonly reported in HSD/hEDS and may impact on co-morbidity with and severity of FGIDs, although this remains to be studied. We determined the impact of concomitant POTS and HSD/hEDS on their association with Rome IV FGIDs. Methods: With the help of the charity organization Ehlers-Danlos Support UK, an online cross-sectional health survey was completed by individuals with HSD/hEDS. The survey enquired for (a) self-reported doctor diagnosis of POTS, chronic fatigue syndrome, and fibromyalgia, (b) the presence and symptom frequency of Rome IV FGIDs, and (c) anxiety and depression scores. Key Results: Of 616 subjects with HSD/hEDS, 37.5% reported a doctor diagnosis of POTS. POTS-positive individuals were significantly younger than POTS-negative subjects (37 vs 40 years, P = 0.002), more likely to report chronic fatigue syndrome (44% vs 31%, P < 0.0001), and showed a trend toward increased prevalence of fibromyalgia (44% vs 37%, P = 0.06) and higher depression score (P = 0.07). POTS-positive subjects were also more likely to fulfill criteria for Rome IV FGIDs across various organ domains and experienced both upper and lower gastrointestinal symptoms significantly more frequently. The increased associations for FGIDs and GI symptom frequency remained unchanged in HSD/hEDS subjects with POTS following adjustments for age, chronic fatigue syndrome, fibromyalgia, and depression scores. Conclusions and Inferences: The high FGID burden in HSD/hEDS is further amplified in the presence of POTS. Future studies should elucidate the mechanism by which POTS arises in HSD/hEDS and is associated with increased GI symptoms

Chlamydia trachomatis antigens in enteroendocrine cells and macrophages of the small bowel in patients with severe irritable bowel syndrome

<p>Abstract</p> <p>Background</p> <p>Inflammation and immune activation have repeatedly been suggested as pathogentic factors in irritable bowel syndrome (IBS). The driving force for immune activation in IBS remains unknown. The aim of our study was to find out if the obligate intracellular pathogen <it>Chlamydia </it>could be involved in the pathogenesis of IBS.</p> <p>Methods</p> <p>We studied 65 patients (61 females) with IBS and 42 (29 females) healthy controls in which IBS had been excluded. Full thickness biopsies from the jejunum and mucosa biopsies from the duodenum and the jejunum were stained with a monoclonal antibody to <it>Chlamydia </it>lipopolysaccharide (LPS) and species-specific monoclonal antibodies to <it>C. trachomatis </it>and <it>C. pneumoniae</it>. We used polyclonal antibodies to chromogranin A, CD68, CD11c, and CD117 to identify enteroendocrine cells, macrophages, dendritic, and mast cells, respectively.</p> <p>Results</p> <p><it>Chlamydia </it>LPS was present in 89% of patients with IBS, but in only 14% of healthy controls (p < 0.001) and 79% of LPS-positive biopsies were also positive for <it>C. trachomatis </it>major outer membrane protein (MOMP). Staining for <it>C. pneumoniae </it>was negative in both patients and controls. <it>Chlamydia </it>LPS was detected in enteroendocrine cells of the mucosa in 90% of positive biopsies and in subepithelial macrophages in 69% of biopsies. Biopsies taken at different time points in 19 patients revealed persistence of <it>Chlamydia </it>LPS up to 11 years. The odds ratio for the association of <it>Chlamydia </it>LPS with presence of IBS (43.1; 95% CI: 13.2-140.7) is much higher than any previously described pathogenetic marker in IBS.</p> <p>Conclusions</p> <p>We found <it>C. trachomatis </it>antigens in enteroendocrine cells and macrophages in the small bowel mucosa of patients with IBS. Further studies are required to clarify if the presence of such antigens has a role in the pathogenesis of IBS.</p

Impaired leukocyte influx in cervix of postterm women not responding to prostaglandin priming

<p>Abstract</p> <p>Background</p> <p>Prolonged pregnancies are associated with increased rate of maternal and fetal complications. Post term women could be divided into at least two subgroups, one where parturition is possible to induce by prostaglandins and one where it is not. Our aim was to study parameters in cervical biopsies in women with spontaneous delivery at term (controls) and compare to those that are successfully induced post term (responders), and those that are not induced (non-responders), by local prostaglandin treatment.</p> <p>Methods</p> <p>Stromal parameters examined in this study were the accumulation of leukocytes (CD45, CD68), mRNAs and/or proteins for the extracellular matrix degrading enzymes (matrix metalloproteinase (MMP)-2, MMP-8 and MMP-9), their inhibitors (tissue inhibitor of MMP (TIMP)-1 and TIMP-2), interleukin-8 (IL-8), the platelet activating factor-receptor (PAF-R), syndecan-1 and estrogen binding receptors (estrogen receptor (ER)α, ERβ and G-coupled protein receptor (GPR) 30) as well as the proliferation marker Ki-67.</p> <p>Results</p> <p>The influx of leukocytes as assessed by CD45 was strongest in the responders, thereafter in the controls and significantly lower in the non-responders. IL-8, PAF-R and MMP-9, all predominantly expressed in leukocytes, showed significantly reduced immunostaining in the group of non-responders, while ERα and GPR30 were more abundant in the non-responders, as compared to the controls.</p> <p>Conclusion</p> <p>The impaired leukocyte influx, as reflected by the reduced number of CD45 positive cells as well as decreased immunostaining of IL-8, PAF-R and MMP-9 in the non-responders, could be one explanation of the failed ripening of the cervix in post term women. If the decreased leukocyte influx is a primary explanation to absent ripening or secondary, as a result of other factors, is yet to be established.</p

Empirical estimates of prostate cancer overdiagnosis by age and prostate-specific antigen

Background: Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA.Methods: Estimates of the effects of age on overdiagnosis were based on population based incidence data from the US Surveillance, Epidemiology and End Results database. To investigate the relationship between PSA and overdiagnosis, we used two separate cohorts subject to PSA testing in clinical trials (n = 1,577 and n = 1,197) and a population-based cohort of Swedish men not subject to PSA-screening followed for 25 years (n = 1,162).Results: If PSA testing had been restricted to younger men, the number of excess cases associated with the introduction of PSA in the US would have been reduced by 85%, 68% and 42% for age cut-offs of 60, 65 and 70, respectively. The risk that a man with screen-detected cancer at age 60 would not subsequently lead to prostate cancer morbidity or mortality decreased exponentially as PSA approached conventional biopsy thresholds. For PSAs below 1 ng/ml, the risk of a positive biopsy is 65 (95% CI 18.2, 72.9) times greater than subsequent prostate cancer mortality.Conclusions: Prostate cancer overdiagnosis has a strong relationship to age and PSA level. Restricting screening in men over 60 to those with PSA above median (>1 ng/ml) and screening men over 70 only in selected circumstances would importantly reduce overdiagnosis and change the ratio of benefits to harms of PSA-screening

Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barrett's Esophagus, and Gastroesophageal Reflux

Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett’s esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA

Gut microbiota and sirtuins in obesity-related inflammation and bowel dysfunction

Obesity is a chronic disease characterized by persistent low-grade inflammation with alterations in gut motility. Motor abnormalities suggest that obesity has effects on the enteric nervous system (ENS), which controls virtually all gut functions. Recent studies have revealed that the gut microbiota can affect obesity and increase inflammatory tone by modulating mucosal barrier function. Furthermore, the observation that inflammatory conditions influence the excitability of enteric neurons may add to the gut dysfunction in obesity. In this article, we discuss recent advances in understanding the role of gut microbiota and inflammation in the pathogenesis of obesity and obesity-related gastrointestinal dysfunction. The potential contribution of sirtuins in protecting or regulating the circuitry of the ENS under inflamed states is also considered

Psychological factors selectively upregulate rectal pain perception in hypersensitive patients with irritable bowel syndrome

BACKGROUND: Visceral hypersensitivity and psychological symptoms are frequent features in irritable bowel syndrome (IBS). Exploring mechanistic pathways leading to visceral hypersensitivity is of importance to direct future studies and treatment options. In this study, we evaluated the contribution of psychological factors to the perception of painful and non-painful rectal sensations in hyper- vs normosensitive IBS patients. METHODS: We included 138 IBS patients (Rome II criteria) who underwent an ascending method of limited rectal balloon distension paradigm. At the end of each distension step, subjects rated the perceived intensity of non-painful ('unpleasantness') and painful rectal sensations on visual analog scales. Sensitivity status was determined based on pain thresholds. Anxiety, depression and somatization were assessed by questionnaires. Mixed models were used to test the relationship between sensitivity status, psychological variables, and pain & unpleasantness ratings upon increasing distension. KEY RESULTS: Hypersensitive IBS patients had lower sensory thresholds for pain, first perception, urge to defecate, and discomfort (p < 0.0001). Upon increasing distension, they rated both painful and non-painful sensations as more intense than normosensitive patients (p < 0.0001). Psychological factors were associated with higher pain ratings during distension in hypersensitive (p < 0.006-0.0001), but not in normosensitive patients. Anxiety, but not depression or somatization, was associated with increased intensity ratings of non-painful sensations (p < 0.001), independent of sensitivity status. CONCLUSIONS & INFERENCES: Hypersensitive IBS patients are characterized by increased perception of pain, but also of non-painful sensations. Psychological factors increase the perception of painful sensations in hypersensitive patients only, whereas non-painful visceral sensations were exaggerated in anxious patients regardless of the sensitivity status.status: publishe