Clinical Case Summary

Background/History: A 28-year old male presented with symptoms of chest pain, excessive throat noises, bloating and reported inability to belch with specific triggers inclusive of carbonated drinks. Previous treatment included a trial of PPI therapy, cricopharyngeal dilatation and cricopharyngeal Botox therapy - none proved efficacious. High-resolution oesophageal impedance-manometry (OM) and ambulatory 24-hour oesophageal impedance and pH studies (24hr pHZ) were requested to further investigate his symptoms.
Initial findings - standard protocols: Initial OM demonstrated ostensibly normal findings aside from recurrent weak oesophageal motility. 24hr pHZ showed a normal incidence of acidic and non-acidic reflux, however, there was an unusual pattern of recurrent, prolonged periods of gastric belching with apparent re-swallowing of the air bolus [image 1 - pHZ]. In order to reproduce symptoms in clinic and identify whether the air bolus was able to traverse the upper oesophageal sphincter (UOS), this patient was re-referred for OM with addition of a tailored extended protocol.
Extended OM protocol: Addition of a 330mL carbonated drink with positional changes and prolonged monitoring. Symptoms were replicated in clinic with reported chest pain, throat noises and inability to belch. OM showed a repeating pattern of symptomatic gastro-oesophageal gaseous reflux with retrograde movement of air to the distal UOS, followed by increased oesophageal pressure, and failed UOS relaxation which prevented air being expelled as a belch [image 2]. Final diagnosis - RCPD or Abelchia.
Recommended therapeutic management: High dose (100U), multi-site botulinum toxin A (Botox) injection into the cricopharyngeal muscle. The patient is due to undergo repeat Botox therapy.
Points to be discussed: Why did this patient not respond to initial Botox therapy? Failure of the afferent neural pathway to respond to a sub-optimal dose? Recommendation - repeat Botox (higher dose, multi-site).

References

Karagama, Y. 2021. Abelchia: inability to belch/burp—a new disorder? Retrograde cricopharyngeal dysfunction (RCPD). In: European Archives of Oto-Rhino-Laryngology. 278:5087–5091.
Oude Nijhuis, R. A. B., Snelleman, J. A., . Oors, J. M. et al. 2022. The inability to belch syndrome: A study using concurrent high_resolution manometry and impedance monitoring. In: Neurogastroenterology and Motility. y. 34:e14250.

Clinical Case Summary

54-year-old male, with gastroesophageal reflux disease medicated with PPIs, was admitted due to acute exacerbation of watery chronic-diarrhea (>10 bowel movements/day). The patient was dehydrated, hypotensive and presented acute-kidney-injury AKIN-3. Abdominal CT-scan identified diffuse gastric wall-thickening and a 20 mm nodule at the gastroduodenal junction. Due to suspicion of Zollinger-Ellison Syndrome (ZES), the PPI-dose was optimized with symptomatic improvement. Subsequently, for hormonal assay, PPI was switched to an H2 blocker. Approximately 72h after the switch, melena with hemodynamic instability was identified, and upper-endoscopy revealed extensive duodenal peptic ulcer disease (Forrest-IIc and III ulcers). After 72h without PPI, gastrin 4390 ng/L and gastric-pH 2.9 were documented.
The hospitalization was marked by two episodes of upper gastrointestinal haemorrhage (UGIH), with hemodynamic instability and admission in the intensive care unit. Besides PPI and endoscopic-hemostatic-therapy (EHT), octreotide was initiated. PET-DOTATOC-Ga-68 scan revealed nodal metastasis. The patient underwent antrectomy with Y-Roux-reconstruction (neuroendocrine-tumor, mitotic-index < 1/2mm², ki67 <3%, pT2N1-R2). On the 2nd postoperative-day, UGIH recurrence with hemodynamic instability occurred, leading to re-laparotomy and intraoperative retrograde-enteroscopy with EHT (Over-the-scope-Clip) and gastroduodenal artery ligation. The patient remained stable, without UGIH, and gastrin 20 ng/L. After 2-months, he was discharged and referred to Oncology (N1R2).
ZES caused by gastrinomas, is a rare condition requiring high clinical suspicion and symptoms typically begin years before diagnosis. Metastatic disease determines prognosis, but complications are associated with considerable morbimortality. This case illustrates the diagnostic/treatment dilemmas of ZES and gastrinoma staging/treatment, as well as the therapeutic challenge of one of its most feared complications, UGIH.

References

Image 1 - Abdominopelvic CT scan showing gastric wall thickening and a nodule in the gastrinoma triangle.
Image 2 - Upper gastrointestinal endoscopy – upper gastrointestinal haemorrhage.
Image 3 - PET-DOTATOC-Ga-68 scan result – tumor and nodal metastasis
Image 4 - Histopathological study of the surgical specimen compatible with neuroendocrine tumor - H&E as well as neuroendocrine markers.

Disclosure

Nothing to declare

Introduction

The distinction between eosinophilic esophagitis (EoE) and other causes of dysphagia in clinical practice can be difficult without histology. In addition, failure to collect esophageal biopsies represents one of the reasons for a delayed diagnosis in patients with EoE. Current guidelines recommend multiple esophageal biopsies in all patients reporting dysphagia although this may not be cost-effective.

Aims & Methods

To optimize resources allocation in the diagnostic workup of EoE, we developed and thereafter validated on an independent cohort of patients two point-of-care machine learning (ML) tools to predict a diagnosis of EoE: 1) based on clinical history data alone and 2) based on clinical-endoscopic findings, prior to the results of esophageal biopsies. This was a two-step multi-center international study conducted in three European tertiary referral centers for EoE (London, Pisa, and Padua). We build predictive ML models based on retrospectively extracted clinical data alone (age at diagnosis, sex, presence or absence of heartburn, chest pain, postprandial nausea/dyspepsia, history of food impaction requiring endoscopic removal, allergic rhinitis, asthma, nasal polyposis) and on clinical and upper endoscopy (EGDS) (exudates, rings, edema, furrows, stricture) data collected from 273 EoE and 55 non-EoE dysphagia (NED) patients in London. We performed an external validation of the models on an independent cohort of 93 prospectively enrolled patients reporting dysphagia at Pisa and Padua University Hospitals. The performance of the models was described with area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). We then developed a freely downloadable software for use in clinical practice at the point-of-care.

Results

The machine learning model trained on clinical data alone showed AUC of 0.82, and sensitivity, specificity, PPV, and NPV of 0.75, 0.82, 0.82, 0.75, respectively, for the diagnosis of EoE in the external validation cohort. Among clinical data alone, the patients’ age at diagnosis and sex had the highest predictive ability. The machine learning model trained on a combination of clinical and endoscopic data showed AUC of 0.93, and sensitivity, specificity, PPV, and NPV of 0.88, 0.95, 0.95, 0.87, respectively, in the external validation cohort. Among clinical and endoscopic data, the patients’ age at diagnosis, esophageal rings at endoscopy, and sex had the highest predictive ability. The models’ performance in the development and external validation cohorts is reported in Table 1.

Conclusion

The international external validation of our ML tools, as well as the freely available software, allow generalizability of our findings to other settings. Our software can be easily used at the point-of-care to optimize resources allocation in the diagnostic workup of EoE and 1) Support the clinical suspicion of EoE even in the absence of endoscopic findings, 2) Support decision making in performing repeat EGDS in patients in whom biopsies had been omitted, 3) Support decision making in performing repeat EGDS in patients with persistent EoE symptoms who had non-diagnostic levels of eosinophils at a previous EGDS performed while on proton-pump inhibitors, 4) Avoid unnecessary biopsies in very low-risk patients.

Introduction

Clinical trials in coeliac disease require reliable histological metrics to quantify mucosal damage and demonstrate improvement with treatment. Regulatory agencies are recognizing this and expect some form of histological assessment in coeliac disease trials. Qualitative scoring systems are highly variable among readers. It has been suggested that quantitative scoring provides better consistency among different readers.

Aims & Methods

This study aimed to assess the variability that occurs when quantifying villus height (Vh), crypt depth (Cd) and the Vh:Cd ratio, and identified approaches to improve correlation among observers at different institutions. A set of 236 slides stained with haematoxylin and eosin from 28 patients with coeliac disease on a gluten-free diet (NCT03738475) were used. Quantitative scoring of Vh, Cd, Vh:Cd ratio and the sum of Vh and Cd were initially compared between different institutions that prioritized ocular microscopy or digital pathology. Additionally, the change from baseline with gluten ingestion for each of these measurements was compared between institutions. Improvements to inter-reader correlations were assessed by implementing a common digital pathology software and using agreed upon criteria for making quantitative measurements. Data sets were subjected to statistical analysis to understand correlation and significance. Regression slopes were calculated and the coefficient of determination, R², was derived as a measure of linearity. The concordance correlation coefficient was calculated as an index of agreement beyond linearity. Pairwise Pearson correlation coefficients between readers from different institutions were calculated to demonstrate the degree of association between readers.

Results

Initial inter-reader analysis found that Vh:Cd ratios had a similar, linear trend between readers, regardless of ocular or digital pathology usage, but that there was a consistent systematic difference partially due to differences in reader assessment of the location of the crypt–villus border. Use of a common digital pathology platform and clear scoring criteria greatly improved inter-reader correlations, even when scoring was done by a non-pathologist. Importantly, the assessment of change from baseline in the quantitative measurements after gluten exposure was also highly concordant (Table). The software also enabled visual comparison of readers’ individual measurements of the crypt and villous lengths allowing potential reasons for differences in these measurements to be identified.

Table 1. Changes from baseline in Vh and Cd metrics obtained via ocular microscopy and digital pathology after gluten challenge.

Conclusion

The results suggest that quantitative histology in coeliac disease is reliable and can be improved through digital pathology, software measurement aids and attention to selecting optimally oriented sections. Given the ease with which pathologists without training in the use of quantitative histology software can produce results similar to those from experienced central laboratories, quantitative histology may be feasible outside the clinical trial setting.

Disclosure

AV has nothing to disclose. DAL, DR, DC, GS, JM and QL are employees of Takeda Development Center Americas, Inc. and receive stock or stock options. JI is the founder and owner of Jilab, Inc.; is a Full Professor at Tampere University, Medical Faculty; and has a consulting agreement with Takeda. JAM has grants from Nexpep/ImmusanT, National Institutes of Health, Immunogenix, Takeda Pharmaceutical, Allakos, Oberkotter, Cour; and has received consultancy fees from Bionix, Lilly Research Laboratory, Johnson & Johnson, Dr. Schar USA, UCB Biopharma, Celimmune, Intrexon Corporation, Dren Bio, Reistone Pharma, Chugai Pharma, Kanyos, Boehringer Ingelheim, Equillium and Torax Medical. MR is a consultant for Takeda and Bristol Myers Squibb. MZC has nothing to disclose. TTW has nothing to disclose.
Funding statement: This study was sponsored by Takeda Development Center Americas, Inc. Medical writing support was provided by Oxford PharmaGenesis, Oxford, UK and was funded by Takeda Pharmaceuticals.

Clinical Case Summary

Fistulization between the gallbladder and the gastrointestinal tract is a rare clinical entity, which may result in the migration of a calculus along the path. It typically presents with nonspecific symptoms, making its diagnosis difficult.
Clinical case: A 65-year-old male went to the emergency department due to a 3 day history of vomiting and prolonged abdominal pain, postprandial fullness, anorexia and weight loss for 3 months. He presented with pain in the upper quadrants of the abdomen and right lower quadrant. There was a mild leukocytosis, anemia and a C-reactive protein of 3.99mg/dL. An abdominal ultrasound and CT scan showed several hypodense hepatic nodules, exuberant cholelithiasis without parietal gallbladder thickening, and heterogeneous intragastric content at the level of the antrum, conditioning upstream distension. Abdominal MRI was performed and characterized the liver lesions as hemangiomas. It also identified gastric, duodenal, and proximal jejunal distension, with parietal hyperenhancement of the duodenal bulb and fistulization between the gallbladder and duodenum. Due to food intolerance and persistent vomiting, an upper digestive endoscopy was performed, which identified a voluminous calculus (~5-7cm in diameter) in the gastric lumen, non-obstructive, and an apparent orifice at the bulbar level, possibly corresponding to the previously described fistula. No identification of gastroduodenal obstructive lesions justifying jejunal dilation were identified. He underwent exploratory laparotomy, and two stones were identified, one at the gastric level and the other at the ileal level close to the ileocecal valve. A gastrolithotomy and enterolithotomy were performed, which were complicated by anastomotic dehiscence and septic shock. The present case illustrates an intestinal and gastric obstruction conditioned by fistulization and subsequent migration of a calculus between the gallbladder and the gastrointestinal tract.

References

Brabender D, Sheikh MR, Zielsdorf S. Bouveret's Syndrome. J Gastrointest Surg. 2022 Jan;26(1):258-260. doi: 10.1007/s11605-021-05086-y. Epub 2021 Jul 29. PMID: 34327657
Le Mouel JP, Thiebault H, Hakim S. Bouveret's Syndrome. Clin Gastroenterol Hepatol. 2019 May;17(6):e55. doi: 10.1016/j.cgh.2018.02.006. Epub 2018 Feb 9. PMID: 29432920
Lai YT, Wu PH. Gallstone Ileus. N Engl J Med. 2022 Sep 8;387(10):924. doi: 10.1056/NEJMicm2204208. Epub 2022 Sep 3. PMID: 36053241
Bär F, Roblick U, Lehnert H. Gallstone ileus. Clin Gastroenterol Hepatol. 2011 Oct;9(10):A22. doi: 10.1016/j.cgh.2011.03.028. Epub 2011 Mar 31. PMID: 21458596

Disclosure

No

Introduction

Prucalopride, a 5-HT4 agonist approved for the treatment of refractory chronic constipation has been shown to reduce oesophageal acid exposure in healthy volunteers (Kessing BF, 2014) and improve oesophageal motility in gastroesophageal reflux (GER) patients with ineffective oesophageal motility (Lei W-Y, 2018). To date, no studies have evaluated its effect in patients with dysphagia and oesophageal dysmotility.

Aims & Methods

Our aim was therefore to evaluate the effect of prucalopride on dysphagia symptoms and to assess which, if any, motility or GERD diagnosis influenced outcome in patients with gastroscopy negative dysphagia. Clinical records, together with oesophageal high-resolution manometry (HRM) and available 24hr pH-monitoring (pH-MII) reports of patients referred for dysphagia to a single Neurogastroenterology Clinic between April 2017 and March 2024 were retrospectively reviewed. All patients had a previous negative gastroscopy with oesophageal biopsies, were not responsive to PPIs and were prescribed prucalopride as an add-on treatment at the initial dosage of 1 mg/daily with the possibility to increase to 2 mg/daily after one week in case of no response. A standardized template was used to collect clinical data and patient-reported response to treatment. Clinical response was defined as a self-reported improvement in dysphagia symptoms associated with a reduction in Eckardt score of at least one point. Data are expressed as median (QR).

Results

Thirty-five patients [median age 62 (28) years; 19 (54%) female] were included. Mean duration of follow-up was 12 (19) months. Twenty-two (63%) patients responded to Prucalopride with a significant improvement in the Eckardt score before to after treatment [3.5 (2.3) vs 1 (1.8); p<0.001)]. Six patients (27.3% of responders) responded to 1 mg, with the rest increasing to 2mg/daily. Response was maintained for a median of 14.5 (16) months.Thirteen (37.1%) patients did not respond, of which four (11.4%) experienced adverse events (diarrhoea, headache, abdominal pain) leading to an early treatment discontinuation. In these patients the Eckardt score did not change before to after the treatment [3 (3) vs 3.5 (2.3), respectively; p=0.85)]. None of the clinical (data not shown) or key manometric parameters were associated with treatment response [median basal distal contractile integral 283 (425) vs 340 (470)mmHg/s/cm; p=0.71 and median integrated relaxation pressure 6.2 (8) vs 8.4 (9.4)mmHg; p=0.13 in responders and non-responders, respectively]. However, there were trends for more patients with absent contractility to be non-responders, and more patients with EGJOO to be responders to prucalopride. Normal acid exposure time and number of reflux events were associated with a positive response to treatment (Table 1).

Table 1 – HRM and pH-monitoring characteristics of responder and non-responder patients at baseline.

Conclusion

Our study suggests Prucalopride might be a well-tolerated and useful treatment for dysphagia in patients with dysmotility disorders, mainly in the absence of pathological reflux. However, prospective randomized controlled studies are needed to confirm these data.