Introduction

Mastocytosis is a heterogeneous disorder characterized by abnormal mast cell proliferation in one or more organs that induces cutaneous and/or systemic symptoms. While gastrointestinal (GI) symptoms are frequently reported (prevalence ~60%), no surrogate markers have been investigated yet.

Aims & Methods

This study aimed to explore disease-specific markers and their link to gastrointestinal symptoms in mastocytosis. Plasma samples were collected from patients with mastocytosis, including patients with cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), and Advanced SM (AdvSM). The presence of GI symptoms was registered. Patients with polycythemia vera (PCV), a stem cell disorder characterized by sludging of blood, were included as controls. In total, 276 systemic proteins were analyzed by Proximity Extension Assay using the OLINK Target 96 Cardiovascular II and III, and Immune response panels. Relative protein concentrations, expressed in NPX (log₂ Normalized Protein eXpression), were analyzed using Principal Component Analysis (PCA), linear regression of protein adjusted values (for age and sex) and the Boruta algorithm (based on random forest) in R. Mann-Whitney U test, false discovery rate and Spearman correlation were applied for univariate analyses (GraphPad Prism 9).

Results

A PCA based on the systemic proteomic profile (SProtP, n=275 detected proteins) of mastocytosis patients revealed 1 cluster of CM (n=15) and ISM (n=81) patients that separated away from AdvSM (n=12) patients. A separate PCA confirmed the ISM and AdvSM centroid distance (p<0.001). Feature selection with boruta confirmed 29 markers to be relevant for the outcome ISM (vs AdvSM), the majority found in low levels such as the Interleukin 1 Receptor Type 1 (IL-1RT1) (FDR-adjusted p value (q)<0.001), and inhibitory receptor Lymphocyte Activating 3 (LAG3) (q<0.01). Both ISM and AdvSM groups showed a distinct SProtP against PCV patients, respectively, in separate PCAs (p<0.001). For the outcome ISM (vs PCV), high levels of the mast cell mediator Tryptase α/β 1 (TPSAB1) (q<0.0001) and Mast Cell Immunoglobulin Like Receptor 1 (MILR1) (q<0.0001) and low levels of Fibroblast Growth Factor 2 (FGF2) (q<0.0001) were confirmed among the 27 relevant markers. For the outcome AdvSM (vs PCV), 25 relevant markers were found in high levels, including MILR1 (q<0.001), IL-1RT1 (q<0.0001), and Granulin Precursor (GRN) (q<0.0001).
Upper and/or lower GI manifestations were often reported within the mastocytosis group: 53.3% (n=8) CM, 73.1% (n=57) ISM, and 58.3% (n=7) AdvSM. ISM patients that reported GI manifestations (/GI+) showed higher levels of MILR1 (4.3 (3.9-5.0) vs 4.07 (3.4-4.3), p<0.01) and Transferrin Receptor protein 1 (TR) (4.9 (4.3-5.3) vs 4.36 (4.0-4.9), p<0.05) than patients without GI symptoms (GR-). In contrast, AdvSM/GI+ patients weakly tended to show higher NPX values than patients GI- manifestations (p>0.05). In addition, plasma TPSAB1 levels of ISM/GI+ patients correlated with MILR1 levels (r=0.45; 95%CI (0.2-0.6), p<0.001), while in patients with ISM/GI- TPSAB1 correlated moderately with FGF2 (r=0.6; 95%CI (0.2-0.8), p<0.01). No correlations were found between the top confirmed markers and TPSAB1 in AdvSM, regardless of the presence of GI symptoms.

Conclusion

Distinct systemic proteomic profiles, and specific plasma markers, of ISM and AdvSM patients support different disease mechanisms. While some of these markers might be associated with the presence of GI symptoms, further investigations are needed.

Clinical Case Summary

Introduction: Mastocytosis is an uncommon hematopoietic neoplasm characterized by clonal proliferation of atypical mast cells. The clinical manifestations of mastocytosis are heterogeneous,ranging from limited cutanous involvement to aggressive disease with various levels of extra cutanous multi-organ involvement. Most cases of mastocytosis are indolent, usually cutanous or indolent systemic mastocytosis (SM). Aggressive SM is a rare and often fatal disease. Gastrointestinal involvement in aggressive SM presents with non specific symptoms and the final diagnosis depends on the pathology. Herein, we present a special case of colonic mastocytosis
Clinical case: We report a case of 66 years old female patient who presented with chronic abdominal pain not responding to treatment. On physical examination showed abnormal abdominal pigmentation and reported that skin biopsy previously revealed urticaria pigmentosa. Laboratory investigations were unremarkable. Colonscopy was planned and showed diffuse reddish mottling of cecum and ascending colon. Multiple biopsies were taken and histopathological examination revealed focal crypt architectural distortion. The lamina showed moderate inflammatory cellular infiltrate. These are formed of lymphocytes and plasma cells with excess eosinophils > 100/HPF. Esinophilic cryptitis is seen. Subtle population of scattered ovoid cells with rounded ovoid nuclei are seen. Slide stained for CD117 revealed positive reaction highlighting frequent mast cells. Moderate diffuse colitis with frequent mast cells and excess eosinophils > 100/HPF. Picture is suggestive of mastocytosis involving colon. The patient started imatinib and prednisone and long term follow up showed complete relieve of abdominal pain.

Introduction

Postural orthostatic tachycardia syndrome (POTS) is a disorder of cardiovascular autonomic dysfunction, characterized with heart rate (HR) acceleration and orthostatic intolerance upon standing. Gastrointestinal (GI) symptoms are common in POTS (1).

Aims & Methods

The aim of this study was to explore the prevalence and severity of GI-symptoms in a Swedish POTS-cohort, and to investigate whether previously tested HR acceleration correlates with GI-symptoms.
To this cross-sectional study, we included 43 patients with POTS (93% female, median age 30.6 years) and 74 healthy controls (78% female, median age 35.6 years), who completed a study questionnaire, including prevalence of GI symptoms (2). GI symptom severity was assessed by the IBS severity scoring system (IBS-SSS) (3) and the visual analog scale for IBS (VAS-IBS) (4), both measured in millimetres (0-100). Five items from the IBS-SSS were added, producing a total IBS-SSS (maximum score 500). In addition, extra-intestinal symptoms from the IBS-SSS were assessed. All patients were examined by head up tilt test during 2010-2021, which included monitoring of blood pressure and HR at supine position and after 1, 3 and 10 minutes in upright position (5). Also, the maximum HR was measured. ΔHR was calculated from supine position to each time point of upright position. All continuous variables on the IBS-SSS and VAS-IBS-scale were correlated to ΔHR at each time point and adjustments were made for psychological well-being.

Results

In patients with POTS, all variables on the GI questionnaire were significantly higher than in controls. The most prevalent symptoms were nausea (79,1%), abdominal fullness (69.8%) and bloating (66.7%). The most severe GI symptoms measured on the VAS-IBS scale, were bloating and flatulence and constipation (see table, values presented as median (IQR), measured in millimetres). Total IBS-SSS was 213 (135-319) in POTS. The most common self-reported comorbidities in POTS were IBS (n=12) and hypermobile spectrum disorders (n=12). Seven patients reported organic GI disorder. There was an inverse correlation between ΔHR_max and abdominal pain (r=-0.406, p=0.007). The same tendency was seen at ΔHR_10min (p=0.054). No positive correlations were found between ΔHR and any GI-symptom and no correlations were found between ΔHR and extraintestinal symptoms. When excluding patients with organic GI disorder, we saw significantly inverse correlations between ΔHR_10min and ΔHR_max and abdominal pain, constipation, GI symptom’s influence on daily life, and total-IBS-SSS, respectively. Adjustments for psychological well-being did not affect the results.

Conclusion

This study confirms that GI-symptoms are widespread in POTS, equivalent to moderate IBS. Nausea is the most prevalent symptom, whereas bloating and flatulence, and constipation are the symptoms that are reported as most severe. Higher HR acceleration at diagnosis upon tilt testing seems to be associated with less severe chronic GI-symptoms in POTS. This finding may reflect the heterogeneity and possibly different underlying pathophysiological mechanisms in POTS, but it may also reflect treatment bias.

References

1. DiBaise, J. K., et al. (2018). "Postural Tachycardia Syndrome (POTS) and the GI Tract: A Primer for the Gastroenterologist." Am J Gastroenterol 113(10): 1458-1467.
2. Faraj, J., et al. (2007). "Oesophageal dysmotility, delayed gastric emptying and gastrointestinal symptoms in patients with diabetes mellitus." Diabet Med 24(11): 1235-1239.
3. Francis, C. Y., et al. (1997). "The irritable bowel severity scoring system: a simple method of monitoring irritable bowel syndrome and its progress." Aliment Pharmacol Ther 11(2): 395-402.
4. Bengtsson, M., et al. (2007). "Development and psychometric testing of the Visual Analogue Scale for
Irritable Bowel Syndrome (VAS-IBS)." BMC Gastroenterol 7: 16.
5. Brignole, M., et al. (2018). "2018 ESC Guidelines for the diagnosis and management of syncope." Eur Heart J 39(21): 1883-1948.

Introduction

Due to long waiting lists and limited resources, referring patients for colonoscopy requires assessment of both need (indication) as well as urgency of performing the procedure. Symptomatic patients are usually perceived as more urgent when compared to asymptomatic individuals sent for screening.

Aims & Methods

Our aim was to explore if indication for colonoscopy had any association with colon cancer or colon polyp incidence, size and number. We hypothesised that patients with most common symptoms (rectal bleeding, change in bowel movements, abdominal pain) were more likely to have pathological colonoscopy findings when compared to asymptomatic individuals sent for screening or due to positive faecal occult blood test (FOBT).
We performed a retrospective analysis of prospectively collected data included 7701 colonoscopies performed between January 2017 and December 2021 in Sestre Milosrdnice University hospital, Zagreb, Croatia. We included patients undergoing first-time colonoscopy due to history of either rectal bleeding, change in bowel movements or abdominal pain, as well as asymptomatic individuals without family history screened with colonoscopy (with or without positive guaiac-based FOBT). Exclusion criteria were all other indications for colonoscopy and a repeated procedure. Final dataset included 2321 patients. Statistical analysis was done in Python 3.2 with statsmodels module for creating logistic regression models to analyse relationships within data.

Results

Mean age in the cohort was 59 +\- 15 years, with 56.8% being female. When comparing symptomatic to asymptomatic individuals, adenomas were found in 30.1% vs. 40.6% and carcinomas in 4.0% vs. 4.2% respectively.
After adjusting for age and sex there was however no significant difference between these two groups regarding polyps or carcinoma findings. For polyp detection OR was 0.61 (95% CI 0.41- 1.09); for polyp size >2cm OR 0.68 (95% CI 0.38-1.2) and for carcinoma detection 1.15 (95% CI 0.56 -2.33). Age was the only factor that was consistently associated with pathological colonoscopy findings, as follows: for every year of age odds of finding an adenoma increased by 1.027 (95% CI 1.021-1.033), having >5 adenomas increased by 1.04 (95% CI 1.016-1.065), and finding a carcinoma by 1.057 (95% CI 1.039-1.075). None of the investigated factors were associated with polyp size.

Conclusion

Presence of most common symptoms/causes for sending patients to colonoscopy does not seem to increase the odds of pathological findings and therefore should not raise the urgency of performing the endoscopy. Increasing age is the only consistent risk factor for colonic neoplasia in these patients.

Introduction

Bowel, bladder and sexual dysfunction symptoms in patients with Inflammatory Bowel Disease (IBD) are common. Treatment with biofeedback, medication, neuromodulation or surgery can improve quality of life. Unfortunately, few patients proactively report symptoms for reasons including: embarrassment, lack of awareness of associations / treatment options or concerns about consultation time.

Aims & Methods

Between February-April 2024, patients with IBD attending infusion units and outpatient clinics at a tertiary hospital in the United Kingdom were asked to complete the validated ICIQ-IBD (International Consultation on Incontinence Questionnaire for IBD patients), and the ICIQ-MLUTS / ICIQ-FLUTS (Male / Female Lower Urinary Tract Symptoms) questionnaire, which assesses bowel, bladder and sexual dysfunction symptom frequency and impact on quality of life (QoL) using a 5 point scale of never-always. Presence of symptoms was defined as those rated more than ‘never’. Regular symptoms were those occurring ‘most of the time’ or ‘always’. Patients were asked to rate QoL, bowel and sexual symptoms during both remission and relapse. Patients with unclassified IBD, microscopic colitis, stomas and J-pouches were excluded.

Results

One hundred and sixteen patients received the questionnaire. Sixteen were excluded on clinical grounds and 30 due to incomplete questionnaire data leaving 70 for analysis. Thirty-three (47%) were female, 38 (54%) had Crohn’s disease (CD) and 32 (46%) ulcerative colitis (UC). All patients were on biologics (96%) and/or JAK inhibitors (7%). Median age was 36 (range 20-77). Faecal urgency was the most commonly reported symptom, with 55 (79%) reporting symptoms during relapse and 45 (64%) during remission. Regular symptoms during remission were present in 9 (13%). Faecal incontinence (FI) was reported in 51 (73%) during relapse and 30 (43%) during remission. Regular FI symptoms were present in 6 (9%) during remission. Of those patients reporting to be sexually active (n=57), sexual dysfunction was common, reported in 41 (72%) during relapse and 25 (44%) during remission. Urinary incontinence (UI) was reported in 12 (17%) patients, with 10 (14%) patients reporting the presence of both UI and FI. Even during remission, patients commonly reported a bowel-control related QoL impact, with 31/70 (44%) reporting disruption to family, 36/70 (51%) to social and 38/67 (57%) to working life. Fourty-three out of 70 (61%) patients worried about getting to a toilet in time and 24/54 (44%) reported feeling less attractive to their partner.

Table 1: Bowel, sexual and bladder symptom frequency

N = 70

^A Symptoms reported more than ‘never’

^B Symptoms reported ‘most of the time’ or ‘always’

^C&D assessed using the ICIQ-IBD

^E patients reporting 'not applicable' excluded (n = 57)

Conclusion

Bowel, bladder and sexual dysfunction symptoms are common in IBD patients and negatively impact QoL. Even during remission, symptoms are more common than in the background population and interfere with QoL. An appreciation of the prevalence of these symptoms with proactive screening may facilitate triage to pelvic floor services for targeted care.

Introduction

Functional and organic bowel diseases in children often present with gastrointestinal (GI) symptoms, yet systematic data on symptom profiles at first presentation limited. Functional bowel disorders (FBD) are common and often require costly and invasive diagnostic procedures. The Pediatric Structured Assessment of Gastrointestinal Symptoms (pSAGIS) is a validated tool that facilitates structured and standardized symptom assessment in pediatric outpatient settings (1).

Aims & Methods

We aimed to compare GI symptoms at first presentation in children with subsequently diagnosed functional (FD), any organic bowel disease (aOD), and specifically inflammatory bowel disease (IBD) using the pSAGIS. The diagnosis of FD was based on the Rome IV criteria (2). From 2016 and 2023, 1550 children completed the pSAGIS questionnaire at their first outpatient visit at St. Anna Children’s Hospital, Vienna. The tool assesses 21 GI symptoms (five grades, from no problem (0) to very severe (4)), grouped into five domains: abdominal pain, dyspepsia, diarrhea, constipation, and dysphagia/nausea. Symptom severity scores (0–12 to 20, depending on the number of items in each domain) were analyzed using median ± SD; p < 0.05 was considered significant.

Results

Of all patients (n=1550), 17.7% (n=274) were excluded due to non-gastroenterological diagnoses. 28.7% (n=445) were diagnosed with FD and 53.6% (n=831) with aOD, including 7.2% (n=111) with IBD. The number of symptoms rated as present (mild to very severe) was 6.4±3.0 SD (FD) vs. 4.8±2.9 SD (aOD) vs. 4.3±2.5 SD (IBD) (FD vs. aOD and vs. IBD: p<0.001). The number of symptoms rated as moderate to very severe was 4.3±3.7 SD (FD) vs. 2.2±3.2 SD (aOD) vs. 2.0±3.1 SD (IBD) FD vs. aOD and vs. IBD: p<0.001).

Symptom scores in all five domains were significantly higher in the functional group:

Conclusion

Children with functional bowel disorders report significantly higher symptom burden at first presentation compared to those with organic disease, including IBD. In addition to its role in long-term monitoring of treatment outcomes, pSAGIS may support early symptom-based differentiation. This could support more targeted diagnostic pathways and inform timely therapeutic decisions in pediatric gastroenterology.

References

(1) Hammer J et al, JPGN 2023; (2) Hyams JS et al, Gastroenterology 2016.

Introduction

Bowel, bladder and sexual dysfunction symptoms are common in patients with Inflammatory Bowel Disease (IBD). Despite significantly impacting on quality of life, few patients proactively seek help for these symptoms. For this reason clinician awareness of these functional symptoms in IBD patients is vital to identifying patients who may benefit from targeted treatment.

Aims & Methods

This study aimed to describe how well clinicians identified bowel, bladder and sexual dysfunction symptoms in IBD patients in the outpatient setting. Clinic letters from consecutive patients attending specialist IBD clinics at a tertiary hospital in the United Kingdom, from 1 January 2024, were reviewed retrospectively for documentation of bowel, bladder and sexual dysfunction symptoms. Patients with unclassified IBD, microscopic colitis, stomas and J-pouches were excluded. Data on patient demographics, IBD disease phenotype and activity were also collected.

Results

One hundred and twenty patients were included, of which 60/120 (50%) were male, 76/120 (63%) had ulcerative colitis (UC), and 44/120 (37%) had Crohn’s disease (CD), with median age 45 (range 18-88). Faecal urgency (FU) was the most commonly documented bowel symptom, documented in 26/120 (22%) patients, with 14/120 (12%) documenting the presence of FU and 12/120 (10%) documenting no FU. Faecal incontinence and constipation were each documented in 5/120 (4%) patients, and anorectal pain was documented in 3/120 (2.5%) patients. Urinary symptoms were only documented in one instance: urinary urgency in 1/120 (0.8%) patients. There was no documentation of urinary frequency or voiding dysfunction. Sexual dysfunction symptoms were not documented in any of the 120 letters, nor was impact of bowel symptoms on quality of life. FU was more frequently documented in patients with UC (11/76[14%]) compared to CD (3/44[7%]), whilst all cases of anorectal pain were documented in CD patients 3/44(7%), with no documentation of anorectal pain in any patients with UC. In patients with CD, documentation of FU was similar in remission (Harvey Bradshaw-Index (HBI) <4) and active disease (HBI≥ 4) groups (2/44 vs. 1/44, p=n.s.).

Conclusion

Bowel, bladder and sexual dysfunction symptoms are infrequently documented in patients with IBD. Failure to recognise these symptoms is likely to impair access to appropriate treatment. Introduction of a standardised reporting tool and improving IBD clinician awareness may facilitate best care for this patient group.