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Transient lower esophageal sphincter relaxation ( TLESR) is the major mechanism of gastroesophageal reflux, but the regulation of TLESR by stimuli in the esophagus is incompletely understood. We have recently reported that acid infusion in the esophagus substantially (by 75%) increased the number of meal-induced TLESR in healthy subjects. We concluded that the TLESR reflex triggered by gastric distention with meal was enhanced by the stimulation of esophageal nerves by acid. However, the possibilities that the acid infused into the esophagus acts after passing though lower esophageal sphincter in stomach to enhance TLESR, or that the acid directly initiates TLESR from the esophagus were not addressed. Here, we evaluated the effect of acid infusion into the proximal stomach on meal-induced TLESR (study 1) and the ability of acid infusion into the esophagus to initiate TLESR without prior meal (study 2). We analyzed TLESRs by using high-resolution manometry in healthy subjects in paired randomized studies. In study 1, we found that acid infusion into the proximal stomach did not affect TLESRs induced by standard meal. The number of meal-induced TLESRs following the acid infusion into the proximal stomach was similar to the number of meal-induced TLESRs following the control infusion. In study 2, we found that acid infusion into the esophagus without prior meal did not initiate TLESRs. We conclude that the increase in the meal-induced TLESRs by acid in the esophagus demonstrated in our previous study is not attributable to the action of acid in the stomach or to direct initiation of TLESR from the esophagus by acid. Our studies are consistent with the concept that the stimuli in the esophagus can influence TLESRs. The enhancement of TLESR by acid in the esophagus may contribute to pathogenesis of gastroesophageal reflux in some patients. [ABSTRACT FROM AUTHOR]

Background and Aim: COVID-19 can be presented with various gastrointestinal symptoms. Shortly after the pandemic outbreak, several machine learning algorithms were implemented to assess new diagnostic and therapeutic methods for this disease. The aim of this study is to assess gastrointestinal and liver-related predictive factors for SARS-CoV-2 associated risk of hospitalization., Methods: Data collection was based on a questionnaire from the COVID-19 outpatient test center and from the emergency department at the University Hospital in combination with the data from internal hospital information system and from a mobile application used for telemedicine follow-up of patients. For statistical analysis SARS-CoV-2 negative patients were considered as controls in three different SARS-CoV-2 positive patient groups (divided based on severity of the disease). The data were visualized and analyzed in R version 4.0.5. The Chi-squared or Fisher test was applied to test the null hypothesis of independence between the factors followed, where appropriate, by the multiple comparisons with the Benjamini Hochberg adjustment. The null hypothesis of the equality of the population medians of a continuous variable was tested by the Kruskal Wallis test, followed by the Dunn multiple comparisons test. In order to assess predictive power of the gastrointestinal parameters and other measured variables for predicting an outcome of the patient group the Random Forest machine learning algorithm was trained on the data. The predictive ability was quantified by the ROC curve, constructed from the Out-of-Bag data. Matthews correlation coefficient was used as a one-number summary of the quality of binary classification. The importance of the predictors was measured using the Variable Importance. A 2D representation of the data was obtained by means of Principal Component Analysis for mixed type of data. Findings with the p -value below 0.05 were considered statistically significant., Results: A total of 710 patients were enrolled in the study. The presence of diarrhea and nausea was significantly higher in the emergency department group than in the COVID-19 outpatient test center. Among liver enzymes only aspartate transaminase (AST) has been significantly elevated in the hospitalized group compared to patients discharged home. Based on the Random Forest algorithm, AST has been identified as the most important predictor followed by age or diabetes mellitus. Diarrhea and bloating have also predictive importance, although much lower than AST., Conclusion: SARS-CoV-2 positivity is connected with isolated AST elevation and the level is linked with the severity of the disease. Furthermore, using the machine learning Random Forest algorithm, we have identified the elevated AST as the most important predictor for COVID-19 related hospitalizations., Competing Interests: The authors declare that they have no competing interests., (© 2022 Lipták et al.)

Introduction: Insulinomas are rare neuroendocrine tumors of pancreas. Clinical manifestations include various symptoms of hypoglycemia, which is the result of insulin overproduction. Symptoms of hypoglycemia are heterogenous what most probably contributes to diagnostic delay. In this study we retrospectively evaluated clinical features of hypoglycemia. We discovered that a substantial number of patients suffered from hypoglycemia unawareness., Materials and Methods: We performed retrospective analysis of prospectively collected patients with histologically confirmed insulinoma. We evaluated clinical features and signs of hypoglycemia and the duration of symptoms and performed thorough review of the patients' files in order to identify whether patients had been falsely diagnosed previously. Each patient underwent 72 hour fasting test during which levels of immunoreactive insulin (IRI), C-peptide and nadir blood glucose level were obtained. Based on the clinical findings and results of 72 hour fasting test we identified a subgroup of patients with hypoglycemia unawareness. These had an episode of clinically silent hypoglycemia. We compared IRI and C-peptide levels obtained at the time of the fasting test termination in the unawareness group and the group without hypoglycemia unawareness., Results: Twenty two patients with insulinoma that had been hospitalized in our tertiary center were included in the analysis. Mean age was 51±16.7 years. The most common symptom reported by 63.6% of patients was fatigue, followed by increased appetite with consequent weight gain and the loss of consciousness, both reported by 40.9% of patients. Based on the review of clinical features and the results of the fasting test we identified a group of patients with hypoglycemia unawareness. We labeled the patient accordingly in case of the loss of consciousness in personal history as well as asymptomatic hypoglycemia or severe neuroglycopenic symptoms during the fasting test without any accompanying or preceding clinical signs. There were 7 patients with hypoglycemia unawareness in our cohort (31.8%). Patients with this phenomenon had significantly lower levels of both IRI (2.35±1.25 vs. 5.88±3.92ng/ml, p=0.01) and C-peptide (9.14±7.36 vs. 50±42.8 µU/ml, p=0.01) than the rest of the patients. Nadir blood glucose level during the fasting test showed no significant difference (9.4±8.2 vs. 12.2±8.2 months, p=0.28) in the unawareness group and the rest of the patients, respectively., Conclusion: We described the phenomenon of unawareness to hypoglycemia in the patients with insulinoma. This has not been recognized in insulinoma patients yet since available evidence mostly relates to type I diabetic patients. It might lead to higher morbidity and diagnostic delay. Further studies with prospective evaluation should be performed to further confirm relatively high prevalence in patients with insulinoma.

Mixed connective tissue diseases (MCTD) is a very rare autoimmune disease connecting clinical signs of systemic lupus, systemic sclerosis, polymyositis and rheumatoid arthritis. Clinical manifestations are very diverse. In some patients, the digestive tract is affected in varying degrees. The esophagus is affected most often, and patients are complaining of dysphagia. Morphologically, this disorder is similar to the injure in systemic scleroderma. In this case, we describe a unique case of a severe damage of digestive tract manifested by esophageal motility disorders, cachectization, ascites, and repeated ileus conditions.

Background: Standard treatment for esophageal epiphrenic diverticula associated with achalasia includes surgical diverticulectomy, myotomy and anterior fundoplication. However, several case reports published recently suggest that endoscopic approach using per oral endoscopic myotomy is a safe and effective alternative. Methods: This is a retrospective review of a single center case series of patients with achalasia and epiphrenic diverticula. During the treatment, the POEM guided on the opposite site of the diverticular neck without diverticulotomy was performed. Symptomatic outcome was evaluated 3 months after procedure and afterwards with the median follow-up time of 24 months. High resolution manometry was performed 3 months after the procedure. Results: Seven patients with esophageal epiphrenic diverticula were included. POEM was successfully performed in all patients, with no complications in the periprocedural period. We observed a significant reduction of Eckardt score and the relaxation pressure of the lower esophageal sphincter (31.8 vs. 8.8 mmHg, p < .0001). Conclusions: POEM is a promising approach in the management of achalasia and esophageal epiphrenic diverticula. We demonstrated its safety, efficiency and ability to provide symptom reduction and decrease of the LES relaxation pressure even without diverticulotomy. Multicentric studies on larger cohorts of patients and with longer follow-up time are required to confirm these results.

Background: Several studies demonstrated that proton pump inhibitors (PPIs) co-administrated with dabigatran in patients with atrial fibrillation (AF) decreased dabigatran trough and peak plasma levels. However, it is still unknown whether this interaction is reversible or not, and whether the withdrawal of PPI would lead to normalization of dabigatran plasma levels., Aim of Study: The aim of this study was to determine the effect of PPI withdrawal on dabigatran plasma levels in patients with AF., Methods: This pilot prospective study enrolled 23 AF patients on long-term dabigatran and PPI therapy (omeprazole 20 mg twice daily or pantoprazole 40 mg once daily). Dabigatran trough and peak levels (ng/mL) were tested on PPI and after a 2-week period of PPI withdrawal with Hemoclot Thrombin Inhibitor Assay., Results: The analysis of dabigatran plasma levels demonstrated significant elevation in trough dabigatran levels after 2 weeks of PPI withdrawal (97.2 ± 79.7 vs. 163.8 ± 105.5 ng/mL; P < 0.05). Moreover, significantly higher peak dabigatran levels were observed after 2 weeks of PPI withdrawal (142.4 ± 102.8 vs. 255 ± 129.5 ng/mL; P ≤ 0.001)., Conclusions: This study showed that a 2-week period of PPI withdrawal lead to a significant increase in dabigatran trough and peak plasma levels in patients with AF.

Objectives: The usefulness of pharyngeal pH monitoring in patients with symptoms attributed to laryngopharyngeal reflux (LPR) has been questioned. One problem is the uncertainty whether the pharyngeal pH monitoring captures the aspects of LPR which are responsible for symptoms. We aimed to gain more insight into this problem by performing a comprehensive analysis of acidic pharyngeal reflux before and after the treatment with proton pump inhibitors (PPIs) in patients with suspected LPR., Methods: We used simultaneous pharyngeal and distal esophageal 24-hour pH/impedance monitoring to establish the gastroesophageal origin of pharyngeal reflux, and an unbiased approach to analysis by evaluating a whole range of pharyngeal reflux acidity (pH < 6, pH < 5.5, pH < 5.0, pH < 4.5 and pH < 4.0)., Results: PPI treatment substantially (by ~50%) improved the symptoms attributed to LPR. In contrast, PPI did not reduce the number of pharyngeal reflux episodes or duration of pharyngeal acid exposure at any pH level. This was also true in a subgroup of patients considered to be good responders to PPI (symptoms improvement by ~75%). Furthermore, good responders did not have more acidic pharyngeal reflux than the patients who were less responsive to PPI., Conclusions: PPI treatment did not reduce acidic pharyngeal reflux despite substantially improving the symptoms attributed to LPR. This may be because pharyngeal pH monitoring does not quantitatively capture the aspects of LPR responsible for symptoms or because acid causes the symptoms also by mechanisms other than LPR. Our results argue against the utility of pharyngeal pH monitoring in patients with suspected LPR.

Recent studies in animal models have reported that some afferent fibers innervating the esophagus express the cold receptor TRPM8. In the somatosensory system the stimulation of TRPM8 leads to cold sensations and in certain circumstances alleviates pain. It is therefore hypothesized in this paper that the esophageal infusion of the TRPM8 activator menthol evokes cold sensations from the esophagus and alleviates heartburn in humans. The esophageal infusion of menthol (3 mM, 20 min) evoked cold sensations in 11 of 12 healthy subjects. In striking contrast, the esophageal infusion of menthol evoked heartburn in 10 of 10 patients with gastroesophageal reflux disease (GERD). In healthy subjects the cold sensation evoked by menthol was perceived only as a minor discomfort as evaluated by the visual analog scale (VAS score 1.9 ± 0.3 on the scale 1-10). However, in patients with GERD the menthol-induced heartburn was perceived as painful (VAS score 5.6 ± 0.6, P < 0.01 compared to healthy subjects). It is concluded that the sensations evoked by esophageal infusion of menthol change from relatively nonpainful cold sensations in healthy subjects to painful heartburn sensations in patients with GERD. These qualitative and quantitative changes indicate substantial alterations in afferent signaling mediating sensations from the esophagus in patients with GERD., (© The Author(s) 2019. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Laryngopharyngeal reflux (LPR) is suspected when the symptoms are attributed to the penetration of acidic gastroesophageal reflux (GER) into the larynx. However, the relationships between the intensity of LPR and symptoms and laryngeal injury have not been elucidated. Several factors confound the study of LPR, namely pH is monitored in the pharynx (pharyngeal reflux) but the pharyngeal acidity (pH) required to induce laryngeal injury is unknown, the GER origin of pharyngeal acid is not always established, and a recent treatment with proton pump inhibitors (PPI) confounds the analysis., Aims: We aimed to limit these confounding factors to analyze the relationship between LPR and symptoms and laryngeal injury., Methods: We used dual pharyngeal and distal esophageal 24-h pH/impedance monitoring to establish GER origin of pharyngeal reflux, we used an unbiased approach to analysis by evaluating a whole range of acidity (pH < 6, pH < 5.5, pH < 5.0, pH < 4.5 and pH < 4.0) in patients with suspected LPR without PPI for  > 30 days., Results: Pharyngeal reflux was (median[IQR]) 14[8-20.5] and 4[1.5-6.5] pharyngeal reflux episodes with pH < 6.0 and pH < 5.5, respectively. Pharyngeal reflux with pH < 5.0 was rare. Comprehensive analysis did not reveal any correlation between symptoms (reflux symptom index) or laryngeal injury (reflux finding score) and the number of pharyngeal reflux episodes or duration of pharyngeal acid exposure at any pH level., Conclusion: Unbiased comprehensive approach did not reveal any relationship between acidic pharyngeal reflux and the symptoms or laryngeal injury attributed to LPR. Limited clinical usefulness of pharyngeal monitoring reported by others is unlikely due to confounding factors.

The sensitization of cough reflex observed in patients with gastroesophageal reflux disease (GERD) is attributed to activation of vagal C-fibers innervating the esophagus by acid, while the heartburn in GERD is mediated by esophageal acid sensitive C-fibers derived from (dorsal root ganglia) DRG. Here we explored the relationship between cough reflex sensitivity (CRS) and esophageal sensitivity to acid. We evaluated CRS to capsaicin inhalation and esophageal sensitivity to acid (intensity of heartburn evoked by esophageal infusions of acid pH = 3, 2 and 1) in patients with GERD and chronic heartburn before and 3 months after proton pump inhibitor (PPI) treatment. There was no correlation between CRS and esophageal sensitivity to acid at any pH tested. PPI treatment substantially reduced esophageal sensitivity to acid but did not affect CRS. We conclude that a simple direct relationship between CRS and esophageal sensitivity to acid is unlikely. The results indicate that spinal and vagal afferent pathways from the esophagus are probably influenced separately in subjects with GERD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

In daily clinical practice it's important to think of neuroendocrine tumors, since their prevalence for the past 5 years exceeded even the common occurrences of stomach, esophageal and pancreatic cancers. Patients diagnosed early and accurately with NET, have a greater chance for complete cure. The diagnostic tools over the past century were significantly inefficient in diagnosing NET i.e. (40% of tumors were not localized after USG, CT, MRI, AG investigations). Until the past 2 decades that major turnover in diagnostic methods has been achieved. In particular, the introduction of the somatostatine receptor scintigrafy (SRS) and endoscopic ultrasonography (EUS) have increased sensitivity of localization diagnostics up to 90%. Our work is to test the success of the localization diagnostics in 22 patients with surgically and histologically confirmed NET ofthe pancreas and duodenum. These patients fulfilled jointly SRS, CT and/or MRI, but also classic USG and EUS. From our comparison, clearly endoscopic USG is the most efficient tool with 90% sensitivity.

The aim of the one-year prospective study was to estimate the prevalence of non-steroidal anti-inflammatory drugs using in patients with symptomatic gastroduodenal ulcers, the upper gastrointestinal bleeding and perforation (PUB--perforation, ulcer, bleeding). Among of 326 patients with PUB, prevalence of non-steroidal anti-inflammatory drugs using was 60%. In the group of 194 patients with non-steroidal antiinflammatory drugs induced PUB, 49% patients took aspirin, 38% non-aspirin non-steroidal anti-inflammatory drugs and 13% their combination. Low dosing aspirin (daily dosis < or =200 mg) was associated with PUB in 21% of patients. Age higher than 60 years and women had statisticaly signiticant higher prevalence of non-steroidal anti-inflammatory drugs induced PUB.

Introduction: Liver biopsy is the most specific diagnostic modality in hepatology, but information about its application in Slovakia is rather obscure., Methods: The authors performed a correspondence study with the aim to find out how many biopsy examinations has been done in Slovakia in 2001, for which indications, what kind of techniques have been applied and which small or great complications were encountered., Results: It was established that in the year 2001, 400 biopsies for diffuse liver diseases were performed. There were 296 percutaneous biopsies, 82 laparoscopic biopsies and 22 trans-jugular biopsies forming the survey. Acute viral hepatitis was the most frequent indication, whereas non-alcohol steatohepatitis was a rare indication in spite of the high prevalence. The frequency of great complications was 0.00025%. No death associated with this procedure was reported., Conclusion: Liver biopsy has been done in Slovakia in indications, ways and with the frequency of complications, which were comparable with data from literature.

The authors describe the diagnostic algorithm of Zollinger-Ellison's syndrome which proved useful in the diagnosis of 73 patients with a confirmed diagnosis. They evaluate the diagnostic validity of anamnestic and clinical data, of different examination methods and compare them with experience assembled abroad. For the diagnosis of sporadic gastrinomas the onset of the disease after the age of 40 years is important, the development of serious peptic complications (haemorrhage F-70%, M-59%, perforation M-54%, F-47%) and the presence of watery diarrhoea (41%). As to laboratory parameters they rely on high BAO values (96% > 15 mmol H+/hour and 100% > 5 mmol H+ after gastric resection. Less important is the examination of basal serum gastrin (almost 30% patients have normal or liminal values of BSG--empirically set at 100-150 pg. ml-1). The authors draw attention to the fact that patients with ZES after gastric resections may have BSG values lower than 100 pg/ml (12%). A positive secretin test has a higher validity (rise of SG by 150-200 pg. ml-1 above basal values) positive in 82.2% patients, liminally positive in 11% and negative in 6.3% patients. An even higher diagnostic value was possessed by a BAO/MAO index higher than 0.6 which was positive in 93.4% patients. At present it is not used as pentagastrin is not available. Every year they diagnose 4-6 new cases of ZES which with regard to the number of inhabitants (5 million) places Slovakia along with Denmark and Sweden among the countries with the highest detection rate (0.8-1.2 ZES cases/1 million per year).

The aim of our study is to give a survey of the most efficient methods for treatment and prevention of non-steroidal anti-inflammatory drug (NSAID)-induced gastrointestinal adverse in cases when antiphlogistic treatment cannot be discontinued due to active and progressive joint disease. Analysis of published studies shows that, the proton pump inhibitors (omeprazole) are the most efficient agents in treatment of gastric and duodenal ulcers induced by NSAIDs. The analysis shows a reliable effect of prostaglandin analogues (misoprostol) as well. Prostaglandin analogues (misoprostol) proved the most effective in treatment of gastric erosions. Prophylaxis of adverse gastrointestinal mucosal abnormalities can be primary or secondary. Secondary prevention is intended for patients with gastrointestinal symptoms or those treated for mucosal defects (ulcer, erosions). The standard prevention using H2-antagonists or sucralphate does not provide sufficient protection against NSAID in these patients, but omeprazole reduces the chance of a peptic lesion relapse. Primary prevention is intended for patients with a higher risk of gastrointestinal complications (age above 60, history of peptic ulcer, a higher dose of NSAID, simultaneous treatment with glucocorticoids or anticoagulants). Diclofenac with misoprostol and nabumetone reduce the incidence of gastroduodenal ulcers and their complications in short-term as well long-term studies. Meloxicam reduces the incidence of gastroduodenal mucosal abnormalities is short-term studies. Nimesulide is associated with a lower incidence of adverse gastrointestinal events, but the fact is that, reliable data on gastroduodenal ulcer incidence reduction or their complications are not available.

Objective: Genetic susceptibility to systemic lupus erythematosus (SLE) is conferred not only by various genes within the major histocompatibility complex (MHC) region, but also by several other non-MHC linked genes. The negatively signalling molecule CTLA-4 is involved in establishing and maintaining of peripheral T cell tolerance, which controls T cell activation and reactivity. Its attenuating action helps to prevent an inappropriate initiation of T cell responses to self antigens and to terminate ongoing T cell responses. We tested if there was an association between CTLA-4 and SLE, a disease with B and T cell hyperreactivity and impaired peripheral T cell tolerance., Methods: Using the polymerase chain reaction--restriction fragment length polymorphism method with Bbv I digestion, we assessed an exon 1 transition dimorphism (49 A/G) of the CTLA-4 gene in 102 SLE patients and in 76 healthy controls., Results: The distribution of CTLA-4 exon 1 genotypes in the SLE group was significantly different from that in the controls (chi 2 = 6.178, p < 0.05). 17.6% of the SLE patients were G/G homozygotes compared to 5.3% of the controls; 36.3% were A/G heterozygotes vs 40.8% of controls; and 46.1% were A/A homozygotes vs 53.9% of the controls. The frequency of the G allele was significantly higher in SLE patients (35.8%) than in controls (25.7%; chi 2 = 4.142, p = 0.042)., Conclusion: Our results indicate that the non-MHC linked CTLA-4 gene could confer susceptibility in SLE, as it does in various other autoimmune diseases (Hashimoto thyroiditis, Graves' disease, IDDM).

Objective: ACE takes part in the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin-II and inactivating bradykinin. ACE gene insertion/deletion polymorphism is associated with the level of circulating enzymes--subjects with the DD genotype have higher levels of circulating ACE than subjects with the II genotype and show an increased tendency towards impaired vascular function and structure. Patients with systemic lupus erythematosus (SLE) suffer from differentially expressed vascular pathology. We attempted to determine whether the type of ACE polymorphism could contribute to this pathology., Methods: 101 SLE patients fulfilling the ACR criteria were investigated. The I/D polymorphism was ascertained by PCR, followed by electrophoresis of the amplified fragments and UV visualization., Results: The frequency of the D allele was higher in the SLE group (0.623) than in the controls (0.520) (chi 2 test, p < 0.025). The distribution of the ACE genotype in SLE group was different from that in the control group (p < 0.05). An association between the DD genotype and visceral damage (p < 0.006) was observed., Conclusion: Our results suggest that in the multifactorially determined vascular pathology of SLE, changes associated with I/D polymorphism could influence vessel wall inflammation (monocyte adhesion and activation with cytokine release, T-lymphocyte metabolism), a tendency towards vascular impairment (neointimal proliferation, vasospasm, platelet activation, myocyte proliferation) and lead to the subsequent ischemia. The ACE gene could serve as the visceral damage indicator in SLE.

Mucosa-associated lymphoid tissue (MALT) is an autonomous part of the immune system with a specific function, histological structure and circulation of cells. As a result of malignant transformation of this tissue maltomas develop, peripheral extranodal non-Hodgkin lymphomas of B-origin more than two-thirds of which are found in the digestive system. The authors investigated in a retrospective study the effectiveness of different types of treatment of maltomas of the digestive tract with a low and high grade of malignity in 16 patients. It appears that splenectomy is not necessary in these patients and that the effectiveness of primary chemotherapy with a view of inducing complete remission of the disease is comparable with surgical treatment and subsequent adjuvant treatment without deterioration of the patient s life by mutilating surgery. An integral part of treatment of gastric maltomas is eradication of infection caused by Helicobacter pylori.

In an open clinical endoscopically controlled study in 30 consecutive patients with rheumatic diseases complicated by the ulcerative and erosive form of gastroduodenopathy induced by non-steroidal antiinflammatory drugs and oesophagitis, after four weeks treatment with oral famotidine (one dose of 40 mg/day) confirmed a significant improvement of the mean oesophageal (0.67 +/- 1.06 vs. 0.03 +/- 0.18, p rrr 0.01) gastric 2.10 +/- 1.49 vs. 0.63 +/- 0.85, p rrr 0.001) and duodenal mucosal score (1.80 +/- 1.52 vs. 0.43 +/- 0.82, p rrr 0.001). After four weeks treatment 71% lesions (5/7) in the oesophagus were cured, 77% gastric lesions (10/13) and 75% duodenal lesions (9/12). Treatment with non-steroid antirheumatics proceeded.