Introduction

Patients with inflammatory bowel disease (IBD) have an increased risk of developing intestinal and extra-intestinal cancers. Specific therapies used to control inflammation in IBD may have a different impact on cancer risk. However, there are no long-term studies investigating cancer risk in patients with IBD.

Aims & Methods

In the present study we aimed to quantify the overall risk for of developing cancer and to identify specific risk factors for the occurrence of intestinal and extra-intestinal cancers in 560 consecutive patients with Crohn's disease (CD, N=310) or ulcerative colitis (UC, N=250) referred to our outpatient department between January 2021 and February 2022. Demographic data, smoking status, alcohol consumption, age at IBD diagnosis, disease location and course, therapies, and cancer development after IBD diagnosis were recorded. Odds ratios (OR) were estimated by logistic regression analysis. Standardized Incidence Ratios (SIRs) were estimated compared with the general population.

Results

During a median follow-up interval or time of 10 years (range 1-26 years), 6.6% of patients (37/550, female 65 %, mean age 51 years) developed cancer (SIR 1.94, 95%CI 1.4-2.6). The most common cancers were colorectal (12.3%), skin (8.2%), and breast cancer (7.2%). Female patients had an increased risk for all cancers (SIR 3.11, 95%CI 2.06-4.3), melanoma (SIR 5.6, 95%CI 1.14-16.2) and colorectal cancer (SIR 7.59, 95%CI 3-15.4). Male patients had an increased risk of lymphoma (SIR 26.15, 95%CI 3.2-95.7). Younger age at diagnosis of CD (A1 Montreal classification, OR 37.9, 95%CI 10-14), immunosuppressive monotherapy (OR 5.5, 95%CI 2.65- 11) or in combination with anti-TNFα (OR 9.9, 95%CI 3.3-29.09) were associated with an increased risk of cancer in the study population.

Conclusion

We have identified subgroups of IBD patients who would particularly benefit from screening programs. Our findings need to be validated in independent cohorts.

Introduction

High-resolution manometry (HRM) is routinely performed in an outpatient clinic setting. If intubation is not tolerated or if the LOS is not traversed, the test is often abandoned with no viable alternative option, thus impacting on therapeutic decisions. This study explores the option of intubating the catheter during endoscopy under the comfort of sedation and direct vision.

Aims & Methods

All patients who had HRM catheter insertion during endoscopy at a tertiary referral centre in London between Jan 2020 and April 2023 were collated and analysed. A consecutive equivalent number of standard unsedated HRM studies, as well as patients having standard diagnostic endoscopy at the same centre between Nov and Dec 2022 were included for comparison. Demographic data, symptom presentation, endoscopic technique and manometry diagnosis were analysed. All HRM studies attempted a full protocol of single water swallows and rice meal, undertaken only after confirmation that sedation had abated. The median integrated relaxation pressure (IRP) of single water swallows was used to categorise patients into those with and without a disorder of outflow. Oesophageal body function was defined according to the Chicago Classification of motility disorders¹.

Results

Of the 47 patients (68.1% F; 17-86 yrs) who were referred for endoscopic insertion (EI) of the HRM catheter, 42 (89.3%) were successfully intubated to the stomach. Of those, 33 (78.6%) were observed to pass through the pharynx and LOS with the endoscope, 4 (9.5%) required manual guidance through the oesophagus and LOS, whilst 5 (11.9%) required only observation of catheter passage through the pharynx. Overall, 41 (87.2%) patients completed the full swallow protocol. Indications for referral for EI included intolerance to standard insertion through the nares (52.4%), inability to breach the LOS resulting in a curled catheter (26.2%) and other reasons including septal deviation and psychiatric burden (21.4%). Similarly, of the contemporaneous 47 patients who had standard insertion (SI) of the HRM catheter in the outpatient setting (67.3% F, 23-80 yrs), 39 (82.9%) were successfully intubated and 33 (67.3%) completed the full swallow protocol. Symptoms were reproduced during the test protocol in both cohorts similarly (69.0% EI, n=42; 59.0% SI, n=39). EI patients required higher doses of sedation compared to a consecutive cohort of patients who attended for routine diagnostic endoscopy; mean Fentanyl 112.5µg (n=36) vs 78.7µg (n=47) p<.001, and Midazolam 4.9mg vs 3.4mg p<.001, respectively. The IRP was not significantly different between EI and SI regardless of LOS morphology; mean IRP in patients with no LOS outflow disorder (8.01mmHg, n=28 vs 6.05mmHg, n=35; p=.08), compared to those with an outflow obstruction (28.0mmHg, n=12 vs 23.1mmHg, n=5; p=.35). Overall motility diagnoses between the two cohorts are presented in Table 1.

Table 1: Diagnoses for HRM

Conclusion

Inserting the HRM catheter during endoscopy under sedation and direct vision enables oesophageal physiology testing for patients who might not have otherwise been able to receive motility assessment. The procedure is safe, feasible and is associated with no complications or adverse risk to date. Just as wireless pH monitoring can be a salvage for those who are unable to tolerate the pH catheter, this technique can fill an important gap in the investigation algorithm where motility testing would have otherwise been abandoned.

References

¹Yadlapati, Rena et al. “Esophageal motility disorders on high-resolution manometry: Chicago classification version 4.0^©.” Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society vol. 33,1 (2021): e14058. doi:10.1111/nmo.14058

Introduction

Gastro-oesophageal reflux disease (GERD), caused by reflux of stomach contents into the oesophagus, results in discomfort and pain. Evidence suggests reflux- induced oxidative stress in oesophageal epithelial cells may have a role in GERD pathogenesis and symptom development. High mobility group box 1 (HMGB1), a nuclear protein found in most cell types, is actively released in response to oxidative stress. HMGB1 binds to TLR2, TLR4, and RAGE, leading to downstream inflammatory signalling.

Aims & Methods

Our aim was to investigate the potential role of epithelial-derived HMGB1 in the context of GERD.
Oesophageal biopsy tissue was obtained from consented healthy volunteers (N=10) and GERD patients categorised as functional heartburn (FH; N=7), non-erosive reflux disease (NERD; N=13), and erosive reflux disease (ERD; N=11) based on clinical assessment. Oesophageal HMGB1 mRNA was assessed by RT-qPCR. Tissue was used to assess protein expression of HMGB1, TLR2, TLR4, and RAGE using immunohistochemistry (IHC). Healthy oesophageal biopsies were used to assess HMGB1 release ex vivo following synthetic refluxate challenge (pH2, 1mM deoxycholate (DCA), 1mg/mL pepsin). Cellular translocation of HMGB1 was assessed using immunofluorescence in NE-1 cells in response to acidic bile salts (pH4, 1mM DCA).

Results

HMGB1 mRNA and epithelial protein expression were consistent between healthy control and GERD patients. TLR2 and TLR4 were expressed primarily on epithelial cells with cell quantification revealing TLR4 to be the predominantly expressed epithelial receptor. The proportion of TLR4+ cells was higher in ERD compared to healthy controls (1.4% ± 0.43 vs 7.2% ± 2.567; p<0.05). In contrast, RAGE was expressed exclusively on CD45+ leukocytes – predominantly in GERD phenotypes. Many RAGE+ immune cells in GERD tissue were in close apposition to sensory CGRP+ nerve fibres. Incubating NE-1 cells with acidic bile salts (10mins), but not acid alone, induced HMGB1 translocation to the cytosol (nuclear:cytosolic HMGB1 ratios: pH7 = 2.42 ± 0.19; pH4 = 2.66 ± 0.07; pH4 + DCA = 1.416 ± 0.06; p=0.0003). Challenging oesophageal biopsies with synthetic refluxate (5mins) led to release of HMGB1 over 18 hours compared to paired biopsies (218 ± 57 vs 586 ± 220 pg/mL/mg; p<0.05).

Conclusion

HMGB1 released by oesophageal epithelial cells following reflux may contribute to inflammatory pathways in GERD, particularly via TLR4 and RAGE on epithelial and immune cells, respectively. This is of particular interest in PPI-refractory GERD, due to the exaggerated role of bile salts in HMGB1 release. Further, the close proximity of RAGE+ leukocytes and CGRP+ nerve fibres may represent a cross-talk between epithelial cells, immune cells, and sensory nerves. HMGB1 may therefore be a potential new treatment target for GERD.

Introduction

Psychiatric comorbidity, most commonly measured as severity of anxiety and depression symptoms, has been found to be associated with IBS symptom severity. However, available studies have rarely assessed the importance of formal psychiatric diagnoses on disease burden in IBS. In this analysis from a pan-European project (DISCOvERIE) focusing on the relevance of comorbid mental (anxiety, depression) and/or somatic (fibromyalgia, chronic fatigue syndrome) diagnoses in patients with IBS, we aimed to assess whether presence of psychiatric diagnoses according to the DSM-5 criteria has an impact on overall symptom severity in IBS.

Aims & Methods

We included patients with IBS according to the Rome IV criteria from nine different European centers. Exclusion criteria included the presence of severe psychiatric disease (i.e. bipolar disorder, schizophrenia, autism spectrum disorder, schizoaffective disorder, or organic psychiatric disorder demanding psychopharmacotherapy, psychiatric day-care or inpatient treatment). The patients underwent The Mini International Neuropsychiatric Interview (MINI) to diagnose major psychiatric diagnoses (a total of 17). Fibromyalgia and chronic fatigue were diagnosed by current diagnostic criteria. They also filled in questionnaires assessing Severity of IBS symptoms (IBS-SSS), depression (PHQ-9), anxiety (GAD-7), somatic symptoms (PHQ-15), and fibromyalgia symptoms (FIQ). Severity of symptoms were compared between groups with increasing number of psychiatric diagnoses using One-Way Between-Groups ANOVA with linear trend analysis.

Results

In total, 617 patients with IBS (median age 44 years, 80% females) were included. Among the IBS patients, 269 (44%) had none of the mental (anxiety, depression) or somatic (fibromyalgia, chronic fatigue syndrome) comorbidities (median age 44 y, 75% females), whereas 174 (28%) had comorbid mental disorder only (median age 38 y, 82% females), 49 (8%) had comorbid somatic disorder only (median age 50 y, 86% females) and 124 patients (20%) had mental and somatic comorbidities (median age 47 y, 86% females). The most common psychiatric diagnoses among the IBS patients were depression (n=284), generalized anxiety disorder (n=145) and panic disorder (n=38) followed by agoraphobia (n=23) and social anxiety (n=19). Participants were divided into four groups according to the number of psychiatric diagnoses (0, 1, 2, and ≥3). The severity of IBS, depression, anxiety, somatic, and fibromyalgia symptoms all increased gradually with increasing number of psychiatric diagnoses. The effect sizes (partial eta squared) were small for IBS symptoms, medium for somatic symptoms and large for the other severity measures (Table 1).

Table 1: Symptom severity in groups with increasing number of psychiatric diagnoses

Conclusion

This multicenter pan-European study shows that psychiatric diagnoses are common among IBS patients and that the overall disease burden in IBS is associated with psychiatric comorbidity. These findings highlight the importance of taking psychiatric comorbidity into consideration and to acknowledge the relevance of gut-brain axis interactions when managing patients with IBS.

Disclosure

Hans Törnblom: Consultant or advisory board member for Allergan, Cinclus Pharma, Medifactia, and VIPUN and as a speaker for Tillotts, Takeda, and Shire.
Daisy Jonkers: Part of the work of DJ, outside the submitted work has been financed by public-private partnership grants of Top Knowledge Institute (TKI) Agri&Food and Health Holland, by the Carbokinetics program as part of the NWO-CCC Partnership Program, by Organic A2BV/Mothersfinest BV.

Clinical Case Summary

A 28-year-old patient presented with recurrent episodes of overt gastrointestinal bleeding, requiring multiple blood transfusions over the past two months (5 units of packed red blood cells). Despite undergoing UGI endoscopy and colonoscopy twice at other medical centers, no abnormalities were detected. CT enterography with CT angiography yielded normal results. To further investigate, the patient underwent antegrade and retrograde power spiral enteroscopy, revealing gross active bleeding from a site of hookworm bite in the jejunum. Following the procedure, the patient was discharged with antihelminthic therapy. However, a week later, he experienced abdominal pain, difficulty passing stools, intermittent rectal bleeding again, and low-grade fever. A relook sigmoidoscopy revealed a large hematoma with intraluminal compression in the sigmoid colon. CT scan confirmed a localized sealed-off perforation along with the hematoma. Management included percutaneous aspiration of the hematoma, intravenous antibiotics, and repeat blood transfusion. Anti-helminthic therapy continued, and the patient recovered completely after approximately four weeks which was confirmed by sigmoidoscopy. The mechanism of this sigmoid colon hematoma involves potential mechanical injury by the overtube's spiral tip during insertion or manipulation. Although the localized perforation was sealed off in this case, the preceding bleeding and drop in hemoglobin complicated the initial treatment plan. Considering such technical challenges, the equipment and technology have now been withdrawn globally by the manufacturer. Close monitoring of patient symptoms, and vital signs, and prompt discontinuation of the procedure in case of discomfort or pain are crucial in preventing such complications. As advanced endoscopic techniques become more prevalent, maintaining a cautious approach towards technology and addressing complications promptly is essential for ensuring patient safety and effective care

Introduction

Irritable bowel syndrome (IBS) is a complex multifactorial disorder characterized by recurrent abdominal pain associated with defecation or a change in bowel habits. Patients with IBS often complain of extra-intestinal symptoms resulting in impaired related quality of life. Growing evidence support the hypothesis that intestinal barrier dysfunction has a central role in the pathophysiology of IBS being the interface between the gut lumen and the deeper intestinal layers as well as the brain.

Aims & Methods

The aims of this study were: to characterize the epithelial and vascular barriers; to correlate molecular, morphological and functional aspects of epithelial and vascular barriers with IBS symptoms. 66 healthy subjects (AC) and 223 patients with IBS (112 IBS-D, 58 IBS-C and 53 IBS-M) were enrolled in the study. Rome IV criteria, Bowel disease questionnaire, Short Form 36, Hospital Anxiety Depression Scale were used to phenotype patients. Sugar test was used to evaluate in vivo permeability. The vascular barrier was characterized by using immunohistochemistry, western blot and electron microscopy. Vascular permeability was evaluated by assessing two markers: plasmalemma vesicle–associated protein-1 (PV1) and vascular endothelial cadherin (VEC). A translational model based on Caco-2 cells or HUVEC was used to evaluate permeability changes induced by mediators spontaneously released by mucosal biopsies and to highlight the underlying molecular mechanisms. Correlation analyses have been performed among experimental and clinical data.

Results

Compared to AC, lactulose (P<0.05), sucralose (P<0.01), sucrose (P<0.01) excretion and the L/M ratio (P<0.01) were significantly increased in IBS patients. Soluble mediators released by mucosal biopsies of IBS patients increased Caco-2 permeability compared to AC mediators (P<0.05) via a down-regulation of tight junction gene expression. Blood vessels were significantly increased by 1.5 fold in the colonic mucosa of IBS patients compared to AC (P<0.01). PV1 expression was increased (P<0.01) while VEC expression was decreased in the colonic mucosa of IBS group compared to AC (P<0.05). IBS mucosal mediators increased HUVEC permeability compared to AC mediators. The HUVEC changes associated with IBS samples were mediated by a protease-activated receptor (PAR)2 dependent mechanism resulting in VEC down-regulation. Significant correlations emerged among permeability changes and intestinal, extra-intestinal symptoms and health-related quality of life reported by IBS patients.

Conclusion

Epithelial and vascular barriers are compromised in IBS and are likely involved in symptom development.

Disclosure

Nothing to disclose