Introduction

In recent years, there has been increased focus on appropriate proton pump inhibitor (PPI) prescribing due to the growing awareness of the prevalence of long-term PPI use globally.1 Rebound acid hypersecretion (RAHS) has been described as potentially contributing to PPI overuse and treatment dependence1 . RAHS is a physiological phenomenon observed following PPI discontinuation after a minimum of 4 – 8-week use. However – despite being first described in 1996 – its clinical relevance, underlying mechanisms, prevalence, and impact on patient outcomes are still not completely understood.

Aims & Methods

The purpose of this rapid review is to assess the current evidence published on RAHS, the potential mechanisms behind the phenomenon, its prevalence and clinical significance in patients discontinuing PPI therapy.
A rapid review of peer-reviewed literature was conducted through Embase and PubMed. Systematic reviews and clinical studies were included if they examined RAHS, reported prevalence, or evaluated patient-reported symptoms post-PPI withdrawal. Key findings were extracted and summarised across three domains: physiological mechanisms, prevalence and severity, and patient impact.

Results

A total of 272 articles – published between 2005 and 2024 – were retrieved, with 7 articles meeting the inclusion criteria for final review. Five of these were clinical studies, whilst the remaining 2 were systematic literature reviews. All, except 1, of the studies included were conducted more than 10 years ago – 3 randomised controlled trials, 1 cross sectional study, and 1 study looked at pre-surgery patients without randomisation. The studies were heterogeneous in design, the study populations varied broadly between 7 and 150 participants, and the prevalence data appeared to be inconsistent. Studies show a physiological basis for RAHS, including upregulation of gastrin and enterochromaffin-like cell hyperplasia, during PPI therapy, leading to transient acid hypersecretion upon PPI withdrawal^2,3,4,5. Symptoms resembling dyspepsia or gastro-oesophageal reflux disease (GORD) recurrence were commonly reported in both healthy volunteers and patients^2,3,6,7. RAHS was transient in most cases^2,3,4 but may drive long-term PPI use due to misinterpretation of symptoms as disease recurrence. However, a small number of studies reviewed in the two systematic literature review papers challenged the existence of clinically meaningful RAHS, particularly after short-term or low-dose therapy^6,8.

Conclusion

There is growing evidence that RAHS is a physiologically plausible and clinically relevant phenomenon in long-term PPI users. It is suggested that RAHS may contribute to symptom recurrence and therapy dependence, resulting in the continuation of unnecessary PPI therapy. With the increasing efforts on PPI deprescribing due to growing concerns over long-term use when there’s a lack of appropriate indication, clinicians need to be aware of the potential for RAHS to act as a roadblock for patients. However, despite discussion about RAHS ongoing for almost 30 years, there is still limited understanding about its impact on patients and the potential contribution to the challenges of PPI deprescription. Most importantly, there’s limited understanding of appropriate management solutions to overcome these challenges. In order to improve education for both clinicians and patients, further research is required on appropriate management solutions for RAHS and to aid PPI deprescribing efforts.

References

1. Savarino E et al., Holistic management of symptomatic reflux: rising to the challenge of proton pump inhibitor overuse. Br J Gen Pract. 2022; 72(724):541-544.
2. Reimer C at el., Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology. 2009; 137(1):80-7, 87.e1.
3. Niklasson A et al., Dyspeptic symptom development after discontinuation of a proton pump inhibitor: a double-blind placebo-controlled trial. Am J Gastroenterol. 2010;105(7):1531-7.
4. Fossmark R et al., Rebound acid hypersecretion after long-term inhibition of gastric acid secretion. Aliment Pharmacol Ther. 2005; 21(2):149-54.
5. Helgadóttir H et al., The effects of long-term therapy with proton pump inhibitors on meal stimulated gastrin. Dig Liver Dis. 2014; 46(2):125-30.
6. Lødrup AB et al., Systematic review: symptoms of rebound acid hypersecretion following proton pump inhibitor treatment. Scand J Gastroenterol. 2013; 48(5):515-22.
7. Vales A et al., Randomised clinical trial: the use of alginates during preinvestigation proton pump inhibitor wash-out and their impact on compliance and symptom burden. BMJ Open Gastroenterol. 2023; 10(1):e001026.
8. Hunfeld NG et al., Systematic review: Rebound acid hypersecretion after therapy with proton pump inhibitors. Aliment Pharmacol Ther. 2007 Jan 1;25(1):39-46.

Disclosure

Introduction

Pre-cut sphincterotomy are most often used as a salvage procedure after failure of conventional methods of bile duct cannulation although its success is not guaranteed.　
When we performed initial pre-cut sphincterotomy, papilla is incited, with needle knife or sphincterotome, until the opening of bile duct is recognized to gain access to its lumen.
Our technique, in cases of not recognized the opening of bile duct, involves engaging the exposing underlying submucosal tissue layer of the papilla with the catheter and then seeking bile duct with the hydrophilic guide wire, completely dependent on fluoroscopic view.
The purpose of this study was to assess the efficacy and safety of our technique in cases of failed pre-cut.

Aims & Methods

We retrospectively analyzed the clinical records of consecutive patients undergoing ERCP between 1 January 2009 and 31 October 2024 at Mitsui Memorial Hospital, Tokyo, Japan.
Patients who underwent an ERCP plus pre-cut were included.
Patients were divided into two groups, in whom the common bile duct could be cannulated (Group A), and the common bile duct could not be cannulated and our technique was performed(Group B), after initial pre-cut.
The primary objective was a successful biliary cannulation, and the secondary objective was the complication in group B.
The complications and patient characteristics were compared between group A and B using Fisher’s exact test.

Results

Over a period of fourteen years ten months, 262 Pre-cut sphincterotomy (Needle knife sphincterotomy 108, Transpancreatic septotomy 126, Both 28) were performed. After initial pre-cut, we could achieve biliary access in 183 (Group A), and could not in 79. We performed our technique in 77 among these 79(group B).
In Group B, the therapeutic indications for ERCP were choledocholithiasis in 44 (57.1%) of cases, malignant and benign biliary obstruction in 29(37.7%) and 4(5.2%). The average age of the patients was 73 years (range 29-96) and 45 (58.4%) were male. Among 77 patients, a successful biliary cannulation was achieved in 72 (93.5 %). Complications were 15(19.5%). 2 patients presented bleeding (2.6 %) and required endoscopic treatment and transfusion of red blood cells. 9 (11.7 %) patients developed post-ERCP pancreatitis (1 severe, 8 mild pancreatitis). Guidewire related perforations that were resolved with conservative management occurred in 4(5.2%).
Alerted anatomy status was more frequently observed in group B than group A (p < 0.01). The other characteristics of both groups were similar. Total complications were more frequently observed in group B (p ＝ 0.03).

Conclusion

Our technique in cases of failed pre-cut sphincterotomy is found to be highly effective method to get biliary access, but carried a higher adverse event rate.

Introduction

Abdominal pain is a common symptom in clinical settings, but its prevalence and impact on individuals in the global population are poorly understood.

Aims & Methods

We aimed to use the population-based Rome Foundation Global Epidemiology Study (RFGES)¹ dataset to assess the prevalence and burden of abdominal pain in the global population. Data from all 54127 individuals in 26 countries covering 6 world regions (Asia, Middle East, Eastern Europe, Western Europe, North America, and Latin America) surveyed via the Internet (49.1% females; mean age 43.7 years, range 18-97) were included in the analyses. The survey included the Rome IV diagnostic questionnaire, the PROMIS Global-10 quality of life (QoL) questionnaire, the Patient Health Questionnaire PHQ-4 (anxiety and depression), and questions about medical history and healthcare utilization. Survey respondents who reported pain anywhere in the abdomen in the past 3 months were classified as abdominal pain cases, and all others as controls.

Results

Abdominal pain was reported by 51.9% (95% CI: 51.4, 52.3) of people in the global sample. The prevalence was higher among women than men [59.6% (59.0, 60.1) vs. 44.4% (43.8, 45.0)], and declined across age groups: 60.5% (59.8, 61.2) for ages 18 to 34, 54.6% (53.8, 55.4) for ages 35 to 49 years, 45.5% (44.6, 46.4) for 50-64 years, and 37.7% (36.7, 38.7) for 65+ years. Abdominal pain prevalence varied markedly between world regions, from a low of 41.2% (40.2, 42.2) in Asia to a high of 66.5% (65.3, 67.7) in Eastern Europe. Among the 26 individual countries, it ranged from 32.1% (30.2, 33.9) in Japan to 69.3% (67.2, 71.3) in Egypt.
Individuals with abdominal pain were twice as likely as controls to meet criteria for one or more of the 22 disorders of brain-gut interaction (DGBI) assessed [54.2% (53.6, 54.8) vs. 25.0% (24.5, 25.5)] and more than twice as likely to report a history of organic gastrointestinal disorders: [9.8% (9.4, 10.1) vs. 4.2% (3.9, 4.4)]; p<0.0001 for both. However, 38.9% of people with abdominal pain neither met DGBI criteria nor had organic GI disease history.
People with abdominal pain had significantly lower physical and mental quality of life scores than controls, showed more impairment in work productivity and life activities, were more likely to have ever visited a doctor because of a bowel problem, and more likely to visit doctors frequently (at least monthly) for any health reasons. They also more commonly reported being concerned about their bowel functioning. For details see Table 1.

Conclusion

Abdominal pain affects half the adult global population, including many people who have no GI disorders. It is more common in women, younger individuals, and people in non-Asian countries. Having abdominal pain is associated with poorer quality of life, impaired work and life functioning, increased psychological symptoms and greater healthcare utilization. These findings underscore that abdominal pain, as a symptom rather than only as a part of diagnosed disorders, warrants attention by healthcare services and researchers to better address unmet needs of sufferers.

References

1. Sperber et al. Worldwide Prevalence and Burden of Functional Gastrointestinal Disorders, Results of Rome Foundation Global Study. Gastroenterology. 2021 Jan;160(1):99-114.e3. doi: 10.1053/j.gastro.2020.04.014.

Disclosure

BBDF, CA and RL are currently employees of Opella, a Sanofi company and may hold shares or stock options in the company. OSP receives licensing fees from MetaMe Health. MS has received unrestricted research grants from BioGaia; served as consultant/advisory board member for Biocodex, Tillotts, BioGaia, Renapharma, and AlfaSigma; and served on speakers' bureau for Tillotts, Takeda, Biocodex, Sanofi, Abbvie, Janssen Immunology, Pfizer, BioGaia, Renapharma, Mayoly and Bromatech. JT has given scientific advice to Aclipse, Adare, AlfaSigma, Bio-Codex, Clasado, Danone, Falk, FitForMe, Ironwood, Kyowa Kirin, Menarini, Promed, Ricordati, Takeda, Tsumura and Truvion Pharmaceuticals; received research support from Biohit, Kiowa Kirin, ProMed, Sofar, Takeda and Tsumura; and served on the speaker bureau for Abbott, Bio-Codex, Mayoly, Menarini, ProMed, Reckitt-Benckiser, Schwabe, Takeda, Thai Meiji and Truvion Pharmaceuticals. JH, DAD, ADS and SIB have no conflicts of interest to declare.

Clinical Case Summary

Immune checkpoint inhibitors (ICI) revolutionized both treatment and outcome of multiple malignancies. However, they are frequently associated with immune-related adverse events (irAE), commonly affecting the gastrointestinal tract with an increased incidence and severity when combining agents.
A 41-year-old man presented with abdominal pain and bloody diarrhea after treatment with dual ICI therapy for lymphogenic progression after partial nephrectomy in the past. The initial work-up revealed positive stool samples for C.difficile – antibiotic treatment with negativization of stool samples was completed with no significant improvement. A colonoscopy was then performed, revealing severe ulcerative pancolitis with no ileal involvement. Based on the use of ICI 40 days prior to manifestation, the diagnosis of immune-related pancolitis was made. Local and systemic steroids at 1 mg/kg were initiated, achieving clinical remission. ICI therapy was permanently discontinued.
During steroid tapering a clinical relapse occurred – dosage was increased to 2 mg/kg with only partial improvement. A follow-up colonoscopy showed moderate pancolitis with a narrow fistula 30cm above the dentate line with an intraluminal free-moving foreign body (clips) from the nephrectomy, which was not detected on MRI. A second line therapy with three intravenous infusions of Vedolizumab was applied. A complete clinical response (resolvement of diarrhea and normalization of calprotectin levels) was achieved for three months, followed by a new relapse of symptoms with endoscopically confirmed moderate pancolitis. Considering the chronically recurrent course, the patient was put on an ongoing Vedolizumab treatment with no further relapses up to present date.
Immune-related colitis is a condition with an unpredictable natural course. Not all patients benefit from induction therapy only. Nevertheless, the duration of immunosuppressive treatment for long-term remission remains unclear at times.

References

1. Colonoscopy revealing severe ulcerative pancolitis
2. Follow up colonoscopy with a free moving foreign body
3. MRI and CT findings

Introduction

Endoscopic retrograde cholangiopancreatography (ERCP) is a widely utilized procedure for managing biliary and pancreatic disorders (1). ERCP is associated with complications, and potential factors influencing the ERCP outcomes is a critical area of research (2). Among these factors, obesity has emerged as a variable of interest due to its increasing prevalence globally and its known associations with a range of health conditions (3). Previous studies have yielded conflicting results on the influence of obesity on ERCP outcomes, with some reporting higher complication rates, while others found no significant associations (4, 5). The interplay between weight and procedural outcomes across a spectrum of BMI categories remains underexplored. This study aimed to assess the impact of body mass index (BMI) on clinical aspects and procedural outcomes of ERCP.

Aims & Methods

A total of 2143 patients who underwent ERCP at Hitit University Hospital between January 2020 and February 2024 were initially included. Of these, 1315 patients were excluded due to incomplete clinical information, previous ERCP history, altered anatomy and pregnancy, resulting in a final cohort of 828 patients for analysis.
The included patients were stratified into BMI categories: ≤30 kg/m² and >30 kg/m². Additionally, subgroup analyses were performed across finer BMI classifications: ≤20, 20 to ≤25, 25 to ≤30, 30 to ≤35, and >35 kg/m². Clinical and procedural parameters evaluated included admission diagnoses of acute pancreatitis and acute cholangitis (according to Tokyo cholangitis grade), American Society of Anesthesiologists (ASA) scores, gender, history of cholecystectomy, cannulation success, cannulation time, post-ERCP complications including post-ERCP pancreatitis and other complications according to modified Cotton criteria and 30-day readmission rates. The relationships between BMI and the clinical aspects as well as procedural outcomes of ERCP were investigated.

Results

The study cohort consisted of 828 patients, with 75.8% (n=628) having a BMI ≤30 kg/m² and 24.2% (n=200) having a BMI >30 kg/m². Within the finer BMI categories, 3.7% (n=31) of patients had a BMI ≤20 kg/m², 24.2% (n=200) were in the 20 to ≤25 kg/m² range, 47.9% (n=397) were in the 25 to ≤30 kg/m² range, 19.7% (n=163) were in the 30 to ≤35 kg/m² range, and 4.5% (n=37) had a BMI >35 kg/m². The majority of patients (47.9%) were within the BMI range of 25–30 kg/m², reflecting a significant proportion of overweight individuals in the cohort. Patients with a BMI >35 kg/m² constituted the smallest group, accounting for only 4.5% of the total population.
The study found no statistically significant differences between the groups concerning admission rates for acute pancreatitis and acute cholangitis, ASA scores, cannulation success, post-ERCP complications, and readmission within 30 days after the procedure (p>0.05). Notably, women were found to be significantly more obese (p<0.001), and a higher weight was associated with an increased history of cholecystectomy (p=0.013).
Additionally, there were no significant differences in average age, Charlson comorbidity index, cannulation time, length of hospital stay, or white blood cell count at admission between the BMI groups (p>0.05). However, CRP and total bilirubin levels were significantly higher in the non-obese group compared to the obese group (p=0.01 and p=0.011, respectively).

Conclusion

BMI did not influence the incidence of acute pancreatitis or acute cholangitis on admission, ASA scores, cannulation success or time, post-ERCP complications, length of hospital stays, or 30-day readmission rates. Interestingly, higher CRP and total bilirubin levels were observed in patients without obesity at admission, warranting further investigation into their clinical implications.

References

1. Tokmak S TS. History of ERCP. The Turkish Journal of Academic Gastroenterology 2021;20: 1-2.
2. Duzenli T, Koseoglu H. Endoscopic Retrograde Cholangiopancreatography During the COVID-19 Pandemic: Effects of Enhanced Personal Protective Equipment. Dig Dis Sci 2021;66: 1845-1851.
3. Alfaris N, Alqahtani AM, Alamuddin N, Rigas G. Global Impact of Obesity. Gastroenterol Clin North Am2023;52: 277-293.
4. Deenadayalu VP, Blaut U, Watkins JL, Barnett J, Freeman M, Geenen J, et al. Does obesity confer an increased risk and/or more severe course of post-ERCP pancreatitis?: a retrospective, multicenter study. J Clin Gastroenterol2008;42: 1103-1109.
5. Fujisawa T, Kagawa K, Hisatomi K, Kubota K, Sato H, Nakajima A, et al. Obesity with abundant subcutaneous adipose tissue increases the risk of post-ERCP pancreatitis. J Gastroenterol 2016;51: 931-938.

Introduction

Among immune-related adverse events (irAEs) caused by immune checkpoint inhibitors (ICIs), gastrointestinal irAEs (GI-irAEs) are relatively rare, and their risk factors and prognostic implications remain unclear.

Aims & Methods

We retrospectively analyzed 1,104 patients who initiated ICI therapy at our institution between January 2016 and December 2022 and for whom survival data were available. GI-irAEs were defined as colitis with an increase of ≥3 bowel movements/day from baseline in the absence of other causes, or symptomatic gastritis confirmed histologically. Risk factors and prognostic impact of GI-irAEs were evaluated.

Results

The median duration of ICI therapy was 107 days. The cohort included 754 males (68%) with a median age of 69 years. The primary tumor types were lung cancer (32%), gastrointestinal cancers (19%), urothelial carcinoma (13%), head and neck cancer (13%), and melanoma (11%). The overall response rate was 27.8%, and the disease control rate was 49.0%. irAEs of any grade occurred in 310 patients (28%), and GI-irAEs were observed in 30 patients (2.7%). In univariate logistic regression analysis, use of anti-CTLA-4 antibody, combination ICI therapy, a prognostic nutritional index (PNI) ≥ 40, and platelet-to-lymphocyte ratio (PLR) ≥ 1.8 were associated with an increased risk of GI-irAEs. In multivariate analysis, only anti-CTLA-4 antibody use remained a significant risk factor (odds ratio: 9.2; 95% CI: 1.9–45). Kaplan–Meier analysis revealed that patients with GI-irAEs had significantly longer overall survival (OS) compared to those without irAEs in the overall cohort (median OS: 22.9 vs. 12.6 months, P < 0.0001). However, this difference was not observed in landmark analyses at 4 and 8 weeks post-treatment. Subgroup analysis based on PNI showed that in patients with PNI ≥ 40, those with GI-irAEs had significantly longer OS than those without irAEs (median not reached vs. 19.3 months, P = 0.0003). In contrast, in patients with PNI < 40, GI-irAE cases tended to have shorter OS than non-irAE cases (8.2 vs. 9.3 months). This trend was consistent in landmark analyses at 4 and 8 weeks.

Conclusion

The impact of GI-irAEs on prognosis appears to differ depending on the patient’s nutritional status. Particular caution is warranted for patients in poor general condition receiving ICIs, especially those involving anti-CTLA-4 antibodies, as GI-irAEs may serve as a poor prognostic factor in this population.