Patients undergoing laparoscopic anti-reflux surgery (LARS) often experience improved quality of life and reduced gastroesophageal reflux disease (GERD) symptoms. This study aimed to assess the impact of LARS on epithelial remodeling and repair in the esophageal mucosa.

Upper gastrointestinal (GI) endoscopy was performed once on healthy controls (HC) and twice on GERD patients before and approximately 6 month after surgery, with esophageal biopsies collected. The expressions of E-cadherin (ECAD), Occludin (OCLN), Claudin 1 (CLDN1), Claudin 4 (CLDN4), Zonula Occludens -1 (ZO-1), and ZO-2 were analyzed in the biopsies, and dilated intercellular spaces (DIS) were examined under light microscopy.

The study included 22 GERD patients who were underwent for LARS, and 20 HCs. All patients had pathological reflux episodes. In the Post-LARS group, TEER increased significantly compared to Pre-LARS and HC (p < 0.05), while mucosal permeability decreased (p < 0.05). A significant negative correlation was found between TEER and permeability (p = 0.0002). DIS remained dilated in both Pre- and Post-LARS patients compared to HC (p < 0.05). Gene expression analysis revealed significant increases in ZO-1, OCLN, and ZO-2 Post-LARS (p < 0.05).

LARS improves mucosal integrity by enhancing TEER and reducing permeability in GERD patients, although DIS remains unchanged. The upregulation of tight junction genes such as ZO-1 and OCLN Post-LARS suggests that surgical intervention may support epithelial barrier restoration. DIS remains dilated after LARS; this might be reason that it is not an early marker in GERD pathogenesis. These findings enhance our understanding of GERD nature and may inform future target therapeutic strategies.

The concomitant hiatal hernia repair with endoscopic fundoplication (c-TIF) is a novel antireflux procedure that addresses the hiatus and the gastroesophageal flap valve for surgical candidates with GERD. We aim to compare the outcomes of a TIF vs surgical partial fundoplication (anterior and posterior) with regard to quality-of-life (QoL) scores at 12 months after surgery.

Following IRB approval, a prospectively maintained antireflux database was retrospectively reviewed to identify patients who underwent a c-TIF procedure or a surgical hiatal hernia repair with partial fundoplication. The primary endpoint was QoL scores at 2, 6, and 12 months from surgery, with attention to bloating and dysphagia scores. Secondary endpoints were proton pump inhibitor (PPI) use, 30-day outcomes, operating room time and costs, reoperation within 1 year. The 3 groups were compared using ANOVA for continuous variables and Pearson's chi-square test for categorical variables. A p value of <0.05 was considered indicative of statistical significance.

Demographics between groups were similar except for age, PPI use, and presenting symptoms. There was no difference between the 3 groups with regard to postoperative QoL scores, PPI use, dysphagia, or bloating. All 3 types of fundoplication are associated with significant improvement of all symptom types, and 65% to 80% of patients are no longer using a PPI at 12 months.

There are no differences in outcomes between the c-TIF and a surgical partial fundoplication. QoL scores significantly decrease with all partial fundoplications, and there are no differences in dysphagia or bloating between the 3 types of fundoplication. Long-term data are necessary to see whether either technique provides superior control of symptoms while minimizing dysphagia and bloating.

Proton pump inhibitors have become top-selling drugs worldwide. Serendipitously discovered as prodrugs that are activated by protonation in acidic environments, proton pump inhibitors inhibit stomach acid secretion by covalently modifying the gastric proton pump. Despite their widespread use, alternative activation mechanisms and potential target proteins in non-acidic environments remain poorly understood. Employing a chemoproteomic approach, we found that the proton pump inhibitor rabeprazole selectively forms covalent conjugates with zinc-binding proteins. Focusing on DENR, a protein with a C4 zinc cluster (that is, zinc coordinated by four cysteines), we show that rabeprazole is activated by the zinc ion and subsequently conjugated to zinc-coordinating cysteines. Our results suggest that drug binding, activation and conjugation take place rapidly within the zinc coordination sphere. Finally, we provide evidence that other proton pump inhibitors can be activated in the same way. We conclude that zinc acts as a Lewis acid, obviating the need for low pH, to promote the activation and conjugation of proton pump inhibitors in non-acidic environments.

Helicobacter pylori (H. pylori) infection has a protective effect on gastroesophageal reflux disease (GERD). Both of these diseases have a very high incidence and prevalence. As a result, GERD often recurs after anti-Helicobacter therapy. The problem of effective treatment of H. pylori infection and GERD is that the main groups of drugs [proton pump inhibitors (PPIs) and potassium-competitive acid blockers] have the possibility of side effects with use. Such supposed side effects have no evidence in randomized controlled trials that comply with the principles of evidence-based medicine. Morphological changes in the gastric mucosa after long-term use of antisecretory drugs should be considered as compensatory mechanisms of sanogenesis. The greatest concern for doctors who treat patients with antisecretory drugs is the risk of gastric carcinogenesis. This article presents an analysis of morphological and pathophysiological changes that occur after long-term use of antisecretory drugs (PPIs). Hypertrophy (hyperplasia) of G cells, enterochromaffin-like cells and possible fundic gland polyps (hyperplasia) are compensatory mechanisms of sanogenesis during long-term treatment with PPIs. These mechanisms are of primary importance for rehabilitation and prevention of complications in patients with GERD, non-steroidal anti-inflammatory drugs-gastropathy and other diseases during long-term treatment with PPIs. Understanding the pathophysiological and morphological mechanisms of compensation and adaptation, the mechanisms of sanogenesis and carcinogenesis will increase the number of indications for long-term use of PPIs with a high level of efficiency and safety of treatment. In addition, understanding the pathophysiological and morphological mechanisms of compensation and adaptation, the mechanisms of sanogenesis will allow us to forecast the side effects of long-term use of potassium-competitive acid blockers.

The aim of this study was to evaluate the prevalence of severe hypocalcemia in patients attending the emergency department. Symptoms, causes, treatment, and outcome of severe hypocalcemia as well as course of calcium concentrations were assessed. This retrospective case series included all adult patients with measurements of serum calcium concentrations presenting to the emergency department of the Bürgerspital Solothurn between January 01 in 2017 and December 31 in 2020. Medical record reviews were performed of all patients with severe hypocalcemia, defined by a serum calcium concentration < 1.9 mmol/L, to assess clinical presentation and management. 1265 (3.95%) patients had a serum calcium concentration of < 2.1 mmol/L of which 139 (11%) had severe hypocalcemia of < 1.9 mmol/L. 113 patients had at least one measurement of albumin. Of these, 43 (3.4%) had an albumin-corrected serum calcium < 1.9 mmol/L defining true, severe hypocalcemia. Hypocalcemia was identified and documented in 35% of all cases. The mean serum calcium concentration was 1.74 ± 0.14 mmol/L. Calcium concentrations in malignancy-related hypocalcemia were similar to non-malignancy-related hypocalcemia. The main symptoms attributed to hypocalcemia were cardiac and neurologic. 12% of patients with severe hypocalcemia received intravenous and 23% oral calcium replacement. Active malignancy was the main cause of severe hypocalcemia in 28%, while in most cases, the main cause remained unclear. 41.9% of severely hypocalcemic patients reattended the emergency department for another episode of hypocalcemia within 1 year. Hypocalcemia is common in patients attending the emergency department, however, appears to be neglected frequently. The disorder is often a manifestation of severe disease, triggered by multiple causes. Calcium replacement was administered in less than half of the patients with severe hypocalcemia in this study. Due to frequent readmissions to the emergency department and a high mortality, increased awareness of the disorder and careful follow-up are desirable.

Reports linking proton pump inhibitors (PPIs) with cognition and dementia show conflicting results, with limited evidence on underlying biological mechanisms. However, existing studies did not investigate brain microstructure, which could provide valuable insights into early structural changes indicative of cognitive decline. Analyses were based on cross-sectional baseline data from the Rhineland Study (n = 7,465; mean age 55.3 ± 13.7 years, range 30-95 years, 56.5% women). Using multivariate linear regression, we investigated associations between PPI use and cognition and brain macro- and microstructural measures (fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter integrity). Analyses were stratified by short-term (< 3 years) and long-term (≥ 3 years) PPI use, with additional age stratification (< 65 years; ≥65 years) for cognitive outcomes. PPI users, especially younger individuals, showed poorer global cognition and working memory. Notably, younger long-term users had worse total memory. PPI use was not associated with brain volume or FA, but both short-term and long-term users showed higher MD in cognitive-related brain regions. Our findings indicate that prolonged PPI use, particularly in younger long-term users, is associated with poorer cognitive performance. Moreover, PPI users showed higher MD, indicating potential white matter integrity disruptions. Further research is needed to ascertain causality and underlying mechanisms behind PPI-related cognitive decline.

Proton pump inhibitors (PPI) are widely used medications for gastrointestinal disorders. Recent research suggests a potential association between long-term PPI use and increased cardiovascular (CV) risk, creating a complex clinical dilemma. This review critically evaluates the current evidence for this association, considering the limitations of observational studies and the lack of definitive confirmation from randomized controlled trials.This review delves into the reported association between PPIs and adverse CV events, examining proposed mechanisms such as drug interactions, electrolyte imbalances induced by PPIs and their potential impact on cardiac and vascular function. Evidence suggests these mechanisms converge, with varying influence depending on patient populations.Clinicians require a risk-benefit analysis for each patient considering their CV risk profile. Alternative gastrointestinal therapies should be explored for high-bleeding risk patients. Medications with lower cytochrome-P450 interaction potential may be preferable among essential PPI users. Elucidating the specific mechanisms by which PPIs might influence CV health, assessing long-term vascular effects and investigating interactions with newer anticoagulant medications are crucial for future research.

(1) Background: Proton pump inhibitors (PPIs) are commonly prescribed for gastric disorders. In patients with liver cirrhosis, PPI use is associated with an increased risk of spontaneous bacterial peritonitis and increased mortality rates; therefore, they should be used with caution. This study aims to evaluate the appropriateness of PPI prescriptions in hospitalized cirrhotic patients against current clinical guidelines to identify patterns of misuse and guide better prescribing practices. (2) Methods: A retrospective study was conducted on liver cirrhosis inpatients in an internal medicine department from January 2022 to May 2023. The primary measure was the proportion of PPI prescriptions aligned with clinical guidelines. Medical files were entirely reviewed by researchers to assess the appropriateness of PPI prescriptions using the current guidelines. Outcomes included the identification of common reasons for PPI prescription and the rate of inappropriate PPI use among the study population. (3) Results: The study included 189 cirrhotic patients, with PPIs prescribed to 95 (50.2%) patients during hospitalization and 75 (39.7%) patients at discharge. Among those, 47.4% of the inpatients and 34.7% at discharge had no valid indication for PPI administration. The most common reason for PPI prescription during hospital stays was gastritis, followed by antiplatelet use in high-risk patients, ulcers, and upper gastrointestinal bleeding. The most common inappropriate indication was portal hypertensive gastropathy (PHG), followed by treatment with corticosteroids and anticoagulants alone. We did not find an association between PPI administration during hospital stays and infections. Only in 4% of cases patients should have received PPIs and did not. (4) Conclusions: There is a concerning overprescription of PPIs in cirrhotic patients, often deviating from established guidelines. It subjects patients to unnecessary risks. There is an urgent need for increased awareness and adherence to clinical guidelines regarding PPI prescriptions in cirrhotic patients.

Whether the long-term treatment of patients with proton pump inhibitors (PPIs) with different diseases [GERD, Zollinger-Ellison syndrome (ZES), etc.] can result in vitamin B12 (VB12) deficiency is controversial. In this study, in 175 patients undergoing long-term ZES treatment with anti-acid therapies, drug-induced control acid secretory rates were correlated with the presence/absence of VB12 deficiency, determined by assessing serum VB12 levels, measurements of VB12 body stores (blood methylmalonic acid (MMA) and total homocysteine[tHYC]), and other features of ZES. After a mean of 10.2 yrs. of any acid treatment (5.6 yrs. with PPIs), 21% had VB12 deficiency with significantly lower serum and body VB12 levels (p < 0.0001). The presence of VB12 deficiency did not correlate with any feature of ZES but was associated with a 12-fold lower acid control rate, a 2-fold higher acid control pH (6.4 vs. 3.7), and acid control secretory rates below those required for the activation of pepsin (pH > 3.5). Over a 5-yr period, the patients with VB12 deficiency had a higher rate of achlorhydria (73% vs. 24%) and a lower rate of normal acid secretion (0% vs. 49%). In conclusion, in ZES patients, chronic long-term PPI treatment results in marked acid hyposecretion, resulting in decreased serum VB12 levels and decreased VB12-body stores, which can result in VB12 deficiency.

Despite deprescribing initiatives to curb overutilization of proton pump inhibitors (PPIs), achieving meaningful reductions in PPI use is proving a challenge.

An international group of primary care doctors and gastroenterologists examined the literature surrounding PPI use and use-reduction to clarify: (i) what constitutes rational PPI prescribing; (ii) when and in whom PPI use-reduction should be attempted; and (iii) what strategies to use when attempting PPI use-reduction.

Before starting a PPI for reflux-like symptoms, patients should be educated on potential causes and alternative approaches including dietary and lifestyle modification, weight loss, and relaxation strategies. When commencing a PPI, patients should understand the reason for treatment, planned duration, and review date. PPI use at hospital discharge should not be continued without a recognized indication for long-term treatment. Long-term PPI therapy should be reviewed at least annually. PPI use-reduction should be based on the lack of a rational indication for long-term PPI use, not concern for PPI-associated adverse events. PPI use-reduction strategies involving switching to on-demand PPI or dose tapering, with rescue therapy for rebound symptoms, are more likely to succeed than abrupt cessation.

Globally, over 25% of the population suffers from acid-related disorders such as dyspepsia or gastroesophageal reflux disease (GERD), and around 7.6% of Indians report having GERD symptoms on a frequent enough basis to warrant a diagnosis. Over the past three decades, proton-pump inhibitors (PPIs) have been the mainstay of medical therapy for acid-peptic diseases like GERD, etc. Additionally, they are frequently prescribed for prophylactic purposes and in conjunction with non-steroidal anti-inflammatory drugs. PPIs are generally prescribed for four to eight weeks. However, it may be prescribed for patients with comorbidities and multiple medications for a longer period of time. While this remains true in terms of effectiveness, concerns have been raised about the safety of long-term PPI use and the serious adverse effects that may result. Some of the observational and population-based cohort studies have shown an association between long-term use of PPIs and an increased risk of pneumonia, major cardiovascular events, dementia, vitamin B12 deficiency, bone fractures, gastric cancer, and kidney injury, among others. This review analyzes the clinical data supporting the long-term use of PPIs and takes a deep dive into whether these several emerging long-term concerns apply to the currently available PPIs in India. We have summarized a vast array of studies, including randomized trials, cohort studies, and meta-analyses, that report low or high incidences of major health risks linked with PPIs and have assessed their appropriateness over a given period.

Proton pump inhibitors (PPIs) are one of the most commonly prescribed drug groups in developed countries. Their approved indications include gastroesophageal reflux disease, peptic ulcer disease, and prophylaxis against NSAID-induced gastroenteropathy in specific scenarios. Since their introduction into clinical practice, their usage has significantly increased, leading to concerns about possible inappropriate prescribing, which can result in a higher risk of side effects and increased economic costs. Consequently, in recent years, literature linking PPIs to various adverse effects has emerged, with some supported by robust evidence, while others are based on lower-quality evidence, requiring cautious interpretation. Among the adverse effects of PPIs, significant ones include an increased risk of fragility fractures, deficiencies in certain micronutrients such as vitamin B12 and magnesium, a higher incidence of enteric infections, especially Clostridioides difficile, complications in cirrhotic patients, and pharmacological interactions with other medications. In clinical practice, it is essential to periodically evaluate the rationale for prescribing these drugs and consider discontinuing them if there is no appropriate indication. Despite PPIs being generally safe medications, it is crucial to be aware of their potential adverse effects and appropriate indications to ensure their proper use.

Clostridioides difficile infection (CDI) is associated with high recurrence rates that have substantial effects on patients' quality of life. To investigate the risk factors and potential mechanisms contributing to recurrent CDI (rCDI), a total of 243 cases were enrolled in this study. The history of omeprazole (OME) medication and ST81 strain infection were considered the two independent risks with the highest odds ratios in rCDI. In the presence of OME, we detected concentration-dependent increases in the MIC values of fluoroquinolone antibiotics against ST81 strains. Mechanically, OME facilitated ST81 strain sporulation and spore germination by blocking the pathway of purine metabolism and also promoted an increase in cell motility and toxin production by turning the flagellar switch to the ON state. In conclusion, OME affects several biological processes during C difficile growth, which have fundamental impacts on the development of rCDI caused by ST81 strains. Programmed OME administration and stringent surveillance of the emerging ST81 genotype are matters of considerable urgency and significance in rCDI prevention.

Gastroesophageal reflux disease has a high incidence and prevalence in the general population. Clinical manifestations are heterogenous, and so is the response to medical treatment. Proton pump inhibitors are still the most common agents used to control reflux symptoms and for healing esophagitis, but they are not a one-size-fits-all solution for the disease. Patients with persistent troublesome symptoms despite medical therapy, those experiencing some adverse drug reaction, or those unwilling to take lifelong medications deserve valid alternatives. Anti-reflux Nissen fundoplication is an effective option, but the risk of adverse events has limited its spread. In recent years, advancements in therapeutic endoscopy have been made, and three major endoluminal alternatives are now available, including (1) the delivery of radiofrequency energy to the esophago-gastric junction, (2) transoral incisionless fundoplication (TIF), and (3) anti-reflux mucosal interventions (ARMI) based on mucosal resection (ARMS) and mucosal ablation (ARMA) techniques to remodel the cardia. Endoscopic techniques have shown interesting results, but their diffusion is still limited to expert endoscopists in tertiary centers. This review discusses the state of the art in the endoscopic approach to gastroesophageal reflux disease.

Proton pump inhibitors (PPI) may impact the absorption of vitamin B12. We performed a systematic review to ascertain if PPI use increases risk of vitamin B12 deficiency.

Electronic databases (PubMed, Embase, Scopus) were searched on first of September 2022. We selected studies that compared the frequency of vitamin B12 deficiency in PPI users and non-users. Pooled Odds Ratio (OR) was calculated for the occurrence of vitamin B12 deficiency in PPI users compared to non-users. The risk of bias was assessed using the Newcastle Ottawa scale.

Twenty-five studies were included. The pooled OR of vitamin B12 deficiency among PPI users (2852 participants) was higher than non-users (28070 participants) (OR 1.42, 95% CI: 1.16-1.73; I2 = 54%). Overall risk of PPI use among vitamin B12 deficient individuals was higher than those without deficiency (OR 1.49, 1.20-1.85; I2 = 68%). Most studies found no difference between serum vitamin B12 levels among PPI users compared to non-users.

Although the pooled OR of vitamin B12 deficiency was slightly increased in PPI users, but there was significant heterogeneity, and the pooled OR was too low to imply an association clearly. Better-designed prospective studies in long-term users may clarify the issue.

This study was not registered on PROSPERO.

Analysis of the efficacy/pharmacology of long-term/lifetime medical treatment of acid hypersecretion in a large cohort of ZES patients in a prospective study. This study includes the results from all 303 patients with established ZES who were prospectively followed and received acid antisecretory treatment with either H2Rs or PPIs, with antisecretory doses individually titrated by the results of regular gastric acid testing. The study includes patients treated for short-term periods (<5 yrs), patients treated long-term (>5 yrs), and patients with lifetime treatment (30%) followed for up to 48 years (mean 14 yrs). Long-term/lifelong acid antisecretory treatment with H2Rs/PPIs can be successfully carried out in all patients with both uncomplicated and complicated ZES (i.e., with MEN1/ZES, previous Billroth 2, severe GERD). This is only possible if drug doses are individually set by assessing acid secretory control to establish proven criteria, with regular reassessments and readjustments. Frequent dose changes both upward and downward are needed, as well as regulation of the dosing frequency, and there is a primary reliance on the use of PPIs. Prognostic factors predicting patients with PPI dose changes are identified, which need to be studied prospectively to develop a useful predictive algorithm that could be clinically useful for tailored long-term/lifetime therapy in these patients.