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Background Atrophic gastritis (AG) and use of proton pump inhibitors (PPIs) result in gastric acid suppression that can impair the absorption of vitamin B-12 from foods. The crystalline vitamin B-12 form, found in fortified foods, does not require gastric acid for its absorption and could thus be beneficial for older adults with hypochlorhydria, but evidence is lacking. Objectives To investigate associations of AG and PPI use with vitamin B-12 status, and the potential protective role of fortified foods, in older adults. Methods Eligible participants (n = 3299) not using vitamin B-12 supplements were drawn from the Trinity-Ulster and Department of Agriculture cohort, a study of noninstitutionalized adults aged ≥60 y and recruited in 2008–2012. Vitamin B-12 status was measured using 4 biomarkers, and vitamin B-12 deficiency was defined as a combined indicator value

Objective Calcium is an essential mineral involved in the functioning of nearly every human cell. Calcium levels are regulated by dietary absorption, vitamin D status, and parathyroid hormone (PTH). This report describes a patient in whom childhood bowel resection and partial gastrectomy resulted in malabsorptive hypocalcemia in adulthood. Case Report A 21-year-old man presented with syncope and a fall resulting in a right femoral neck fracture. His medical history included small bowel obstructions at age 9 requiring bowel resection, and at age 12 with gastric perforation and partial gastrectomy. Laboratory values showed calcium level of 4.9 mg/dL (8.9-10.3 mg/dL). PTH level was 273 pg/mL (12.0-88.0 pg/mL), 25-hydroxy-vitamin D was 28 ng/dL (30-100 ng/mL), and 1,25-dihydroxy-vitamin D was 54 pg/dL (18-72 pg/mL). Furthermore, magnesium and phosphorus levels were 2.1 mg/dL (1.5-2.6 mg/dL) and 4.4 mg/dL (2.4-4.7 mg/dL), respectively. Calcium levels improved to 9.5 mg/dL on 10% calcium gluconate drip but could not be maintained above 7 mg/dL on oral calcium carbonate supplementation, despite doses as high as 3750 mg three times daily with calcitriol 0.75 mcg twice daily. After switching from calcium carbonate to calcium citrate 3500 mg three times daily, the calcium level improved and was maintained between 8.3 and 9.0 mg/dL. Discussion High calcium needs, other nutrient deficiencies, and response to calcium citrate versus calcium carbonate suggest malabsorption from achlorhydria and small bowel resection. Conclusion This case emphasizes the gastrointestinal physiology in calcium homeostasis and highlights the recognition of hypocalcemia as a complication of gastric and bowel resection.

Vitamin B12 is an essential nutrient which plays an important role in neurological function, hematopoiesis, and DNA synthesis. Low levels usually stem from either poor intake or a malabsorptive process. Presently, the most common cause of vitamin B12 deficiency is food-bound cobalamin malabsorption, which occurs when there is impaired release of vitamin B12 from ingested food due to an outstanding factor preventing the release of the nutrient from its transport protein. Such causes include achlorhydria, gastritis, gastrectomy, or the use of PPIs or antacids. A rarer cause is autoimmune chronic atrophic gastritis, resulting in pernicious anemia. In this disease process, there is destruction of parietal cells and thus a reduction in intrinsic factor, which is essential to the absorption of vitamin B12. Deficiency will result in a variety of abnormalities including but not limited to pancytopenia, paresthesias, and neuropsychiatric symptoms. A rare manifestation of vitamin B12 deficiency is hemolytic anemia, which occurs due to intramedullary and extramedullary dysfunction. This case describes a 46-year-old male with no past medical history who presented with chest pain, fatigue, and progressive weakness, found to have hemolytic anemia, ultimately attributed to vitamin B12 deficiency. Antiparietal cell antibodies and intrinsic factor antibodies (IFA) were both negative. Still, the patient underwent an endoscopy with biopsies of the stomach; pathology was consistent with chronic metaplastic atrophic gastritis. The patient improved with intramuscular vitamin B12 supplementation. This case highlights both a rare cause and presentation of vitamin B12 deficiency. Patients with autoimmune chronic atrophic gastritis should have antiparietal cell or intrinsic factor antibodies. Still, seronegative patients have been reported, like this patient. Additionally, hemolytic anemia secondary to vitamin B12 deficiency is uncommon. The presentation will usually mirror that of a thrombotic microangiopathy (TMA), including hemolytic anemia with schistocytes on peripheral blood smear and thrombocytopenia, as it did in this patient. This clinical entity is described as pseudothrombotic microangiopathy and is crucial to identify in order to prevent the initiation of invasive treatment strategies such as plasmapheresis.

Context.— Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumors (GNETs). Whether drugs that can elevate serum gastrin levels, such as proton pump inhibitors (PPIs), can produce the same tissue effect is not known, and there is no concrete evidence linking the use of PPIs to GNETs outside animal models and case reports. Objective.— To explore the clinicopathologic association for GNETs of presumed ECL cell origin that cannot be reliably placed into any of the 3 established categories currently recognized by the World Health Organization. Design.— This is a retrospective clinicopathologic study of GNETs in the body/fundus during a period of 15 years (2005–2019). Results.— Of a total of 87 cases, 57 (65.5%) were associated with atrophic gastritis, 2 (2.3%) were associated with Zollinger-Ellison syndrome, and 28 (32.2%) were unclassified. Of the latter, 11 were consistent with true sporadic/type 3 GNETs, while 17 had background mucosal changes of parietal cell and ECL cell hyperplasia but without underlying detectable gastrinoma, and 88.2% (15 of 17) of patients from this group had documented long-term PPI use. This subtype of GNETs was more commonly multifocal and of higher grade (P = .03) than “true” sporadic GNETs. Conclusions.— A subset of GNETs arises in the background of gastric mucosal changes suggestive of hypergastrinemia, but without underlying gastrinoma, and could be linked to long-term PPI use.

Caustic ingestion can lead to structural changes in the upper gastrointestinal tract. However, there are limited data on the effect of caustic ingestion on gastric secretion. This study was planned to determine the changes in gastric acid output in patients with caustic ingestion. It was a prospective study done at a tertiary care center in northern India. Twenty consecutive patients in chronic phase of caustic ingestion were evaluated for the study. The gastric secretory function was estimated in the basal state and following pentagastrin stimulation. These results were compared with normal values for our laboratory. The mean age of the included patients (n = 20) was 27.35 ± 2.96 years and 14 patients were male. Sixteen (80%) patients had a history of acid ingestion. Patients with caustic ingestion had significantly lower mean gastric acid secretion (0.8 ± 0.4 mEq/h vs. 4 ± 0.4 mEq/h; p

Chronic diarrhea is a common chief complaint in the pediatric population with a wide range of diagnostic differentials; as such, whilst suspecting common causes, less prevalent conditions tend to be overlooked, such as neuroendocrine tumor pathologies. VIPomas are characterized by hypersecretion of the vasoactive intestinal peptide (VIP), causing watery diarrhea, hypokalemia, and achlorhydria. Nonetheless, its low incidence rate in children makes it an easily unnoticed pathology. Herein, we report a case of a 14-year-old female patient and a review of relevant literature. The patient complained of 7-month history of watery diarrhea, multiple emetic episodes, and relevant past medical history of multiple hospitalizations. Chronic diarrheal disease work-up studies, including a high VIP scintigram, showed a lesion suggestive of a VIPoma-type neuroendocrine pancreatic tumor. A distal pancreatectomy was performed with a complete resolution of the symptoms. When faced with a pediatric patient presenting with chronic secretory diarrhea and whose work-up studies rule out the most common pathologies, the possible presence of a neuroendocrine tumor as VIPoma should be considered. J Med Cases. 2021;12(5):195-201 doi: https://doi.org/10.14740/jmc3535

pH-dependent drug-drug interactions (DDIs) with poorly soluble, weakly basic drugs may lead to clinical implications. Dasatinib is a tyrosine kinase inhibitor with reduced absorption in patients on acid-reducing agents (ARAs). The objective of this study is to investigate the influence of gastric pH on dasatinib supersaturation and determine if vitamin C (L-ascorbic acid) can improve dasatinib concentrations under simulated hypochlorhydric gastric conditions.A dynamic, in vitro, multi-compartment, simulated stomach duodenum (SSD) model mimicking fluid volumes and transfer rates was used to investigate the concentration of BCS class IIb drugs versus time curves. Dasatinib and lamotrigine were explored under normal, fasted, simulated gastric fluids (pH 2) (FaSGF), hypochlorhydric simulated gastric fluids (pH 4.5) (FaSGFSignificant supersaturation of dasatinib was observed in the duodenum compartment of the SSD model in FaSGF. A 90% reduction in dasatinib AUCThe SSD model serves as a good in vitro tool for assessing the effect of pH-dependent DDIs on bioavailability of weakly basic drugs with solubility/ dissolution limited absorption. Vitamin C provides a promising approach for improving bioavailability of poorly soluble, weakly basic drugs in hypochlorhydric patients.

A 69-year-old woman with multiple neuroendocrine neoplasms (NENs) was referred to our hospital. Although she had extreme hypergastrinemia (11,675 pg/mL), no findings that indicated types I to III gastric NENs were found. Although gastric corpus atrophy was suspected on conventional white-light imaging, findings on magnifying endoscopy with narrow-band imaging indicated no severe atrophy. A biopsy from the background fundic gland mucosa revealed no atrophic changes, parietal cells with vacuolated cytoplasm and negative findings for H

Heart failure (HF) is an increasing global health crisis, affecting 40 million people and causing 50% mortality within 5 years of diagnosis. A fuller understanding of the genetic and environmental factors underlying HF, and novel therapeutic approaches to address it, are urgently warranted. Here, we discovered that cardiac-specific germline deletion in mice of potassium channel β subunit-encoding Kcne2 (Kcne2(CS−/−)) causes dilated cardiomyopathy and terminal HF (median longevity, 28 weeks). Mice with global Kcne2 deletion (Kcne2(Glo−/−)) exhibit multiple HF risk factors, yet, paradoxically survived over twice as long as Kcne2(CS−/−) mice. Global Kcne2 deletion, which inhibits gastric acid secretion, reduced the relative abundance of species within Bacteroidales, a bacterial order that positively correlates with increased lifetime risk of human cardiovascular disease. Strikingly, the proton-pump inhibitor omeprazole similarly altered the microbiome and delayed terminal HF in Kcne2(CS−/−) mice, increasing survival 10-fold at 44 weeks. Thus, genetic or pharmacologic induction of hypochlorhydria and decreased gut Bacteroidales species are associated with lifespan extension in a novel HF model.

Small intestinal bacterial overgrowth (SIBO) is a common gastrointestinal (GI) problem, but its diagnosis is often missed in the clinical setting. Because its diagnosis mostly requires invasive testing, often its true prevalence is unknown. Commonly presenting complaints include abdominal distension, diarrhea, and malabsorption. Multiple predisposing factors have been recognized in peer-reviewed literature, including achlorhydria, motility disorders, anatomical abnormalities of the gastrointestinal tract, and immunodeficiency disorders, including cancer. Multiple culture-dependent and independent methods are used to confirm diagnosis. Symptomatic relief can be achieved through multiple antibiotics regimens, but correction of underlying etiology, if possible, is necessary for long-lasting cure. Increased awareness and clinical vigilance can transform the landscape of SIBO via better management of patients with GI and related disorders.

Among the physiological functions declining with aging, decreased secretion of gastric fluid, achlorhydria, is commonly observed. We evaluated the digestion of meat (chicken, beef, and pork) and soy proteins using in vitro conditions mimicking gastrointestinal (GI) digestion in adults (control, C) and elderly individuals with achlorhydria (EA). Changes in degrees of hydrolysis (DH), SDS-PAGE profiles, peptide concentrations, and proteomic profiles during digestion were investigated. Digestion under the EA conditions markedly decreased DH, especially for soy proteins. SDS-PAGE profiling and proteomics showed that myofibrillar/sarcoplasmic proteins from meat and glycinin/beta-conglycinin from soy were most affected by digestion conditions. Our results indicated that differences in the digestibility of meat protein between EA and control conditions gradually narrowed from the gastric to the intestinal phase for meat protein, while a pronounced difference persisted in the intestinal phase for soy protein. Our work provides new insight of value for future dietary recommendations for elderly individuals.

Autoimmune polyendocrine syndrome (APS) is assumed to involve an immune system malfunction and entails several autoimmune diseases co-occurring in different tissues of the same patient; however, they are orphans of its accurate diagnosis, as its genetic basis and pathogenic mechanism are not understood. Our previous studies uncovered alterations in the ATPase H+/K+ Transporting Subunit Alpha (ATP4A) proton pump that triggered an internal cell acid–base imbal-ance, offering an autoimmune scenario for atrophic gastritis and gastric neuroendocrine tumors with secondary autoimmune pathologies. Here, we propose the genetic exploration of APS involving gastric disease to understand the underlying pathogenic mechanism of the polyautoimmune scenario. The whole exome sequencing (WES) study of five autoimmune thyrogastric families uncovered different pathogenic variants in SLC4A2, SLC26A7 and SLC26A9, which cotransport to-gether with ATP4A. Exploratory in vitro studies suggested that the uncovered genes were involved in a pathogenic mechanism based on the alteration of the acid–base balance. Thus, we built a custom gene panel with 12 genes based on the suggested mechanism to evaluate a new series of 69 APS patients. In total, 64 filtered putatively damaging variants in the 12 genes of the panel were found in 54.17% of the studied patients and none of the healthy controls. Our studies reveal a constellation of solute carriers that co-express in the tissues affected with different autoimmune diseases, pro-posing a unique genetic origin for co-occurring pathologies. These results settle a new-fangled genetics-based mechanism for polyautoimmunity that explains not only gastric disease, but also thyrogastric pathology and disease co-occurrence in APS that are different from clinical incidental findings. This opens a new window leading to the prediction and diagnosis of co-occurring autoimmune diseases and clinical management of patients., This research was funded by the H2020 BRIDGES project, grant number 634935, and by the 2017 BBMRI-LPC Whole Exome Sequencing Call and Instituto de Salud Carlos III, co-funded by the European Regional Development Fund (ERDF), grant number (PI16/00440)

ObjectiveWe aimed to study the prevalence of achlorhydria (AC) in a large Asian population.DesignMedical records of patients who underwent oesophagogastroduodenoscopy (OGD) with Congo red staining method at the Vichaiyut Hospital from January 2010 to December 2019 were retrospectively reviewed.ResultsA total of 3597 patients was recruited; 223 were excluded due to concurrent use of proton pump inhibitors. Eighteen from 3374 patients (0.53%) had AC. Seven patients were presented with permanent AC (5F, 2M) (median age=69 years; range 58–92). Among 11 patients with temporary AC (5M, 6F: mean age 73.4 years; SD 13.2 years), all had gastrointestinal Helicobacter pylori bacterial infection and were over 45 years old. After successful treatment for H. pylori, AC was absent among patients with temporary AC. If counting only patients over 45 years of age, the prevalence of AC was 0.68% (18/2614). No adverse events arising from Congo red occurred.ConclusionAC is relatively rare. Permanent and temporary AC were found only when they were over 55 and 45 years old, respectively. Staining Congo red on gastric mucosa can be safely and routinely incorporated into the OGD procedure for early detection of AC. We recommended a low-cost screening test such as serum vitamin B levels for screening only in patients aged 50 and over.

The article defines chronic gastritis as a polyetiological and polypathogenetic stomach disease with a chronic, slowly progressing course, which is based on a specific inflammatory process with lymphoplasmocytic infiltration of its mucosa and neutrophilic component indicating its activity, and with development of disregenerative, dystrophic changes, leading to its secretory insufficiency, manifested hypo- and achlorhydria and gastric achilia. The history of studying chronic gastritis from the beginning of the 19th century till present days is briefly described. It is proposed to distinguish between causal (Helicobacter pylori, etc.) and predisposing (alcohol, smoking, coarse food, etc.) factors in the development of chronic gastritis. The analysis of various classifications of gastritis is carried out: based on etiology, pathogenesis, functional features, clinic, endoscopic and histological characteristics. The Sydney, Houston classifications, the OLGA system are described. Particular attention is paid to diagnosis, biopsy technique of the gastric mucosa, ratio of diagnoses of chronic gastritis and functional dyspepsia, as well as the role of gastric microflora in development of gastritis. It is revealed that gastric microflora in chronic gastritis is represented by numerous types of bacteria (more often in the form of bacterial associations), moreover, Helicobacter pylori is not the dominant microorganism colonizing the stomach, and the mucosal microflora found in the stomach has adhesiveness, invasiveness and pathogenic properties, including its urease activity.

Proton pump inhibitors (PPIs) are common medications within the practice of gastroenterology. These drugs, which act through the irreversible inhibition of the hydrogen/potassium pump (H+/K+-ATPase pump) in the gastric parietal cells, are used in the treatment of several acid-related disorders. PPIs are generally well tolerated but, through the long-term reduction of gastric acid secretion, can increase the risk of an imbalance in gut microbiota composition (i.e., dysbiosis). The gut microbiota is a complex ecosystem in which microbes coexist and interact with the human host. Indeed, the resident gut bacteria are needed for multiple vital functions, such as nutrient and drug metabolism, the production of energy, defense against pathogens, the modulation of the immune system and support of the integrity of the gut mucosal barrier. The bacteria are collected in communities that vary in density and composition within each segment of the gastrointestinal (GI) tract. Therefore, every change in the gut ecosystem has been connected to an increased susceptibility or exacerbation of various GI disorders. The aim of this review is to summarize the recently available data on PPI-related microbiota alterations in each segment of the GI tract and to analyze the possible involvement of PPIs in the pathogenesis of several specific GI diseases.

Vasoactive intestinal peptide-producing tumors (VIPoma) usually originate in the pancreas and are characterized by diarrhea, hypokalemia, and achlorhydria (WDHA syndrome). In adults, nonpancreatic VIPoma is very rare. Herein, we report an unusual case of VIP-producing pheochromocytoma marked by persistent shock, flushing, and watery diarrhea and high sensitivity to octreotide. A 53-year-old woman was hospitalized for sudden-onset hypertension with convulsions, which then rapidly evolved to persistent shock, flushing, and watery diarrhea. Abdominal computed tomography indicated a left adrenal mass, accompanied by bleeding; and marked elevations of both plasma catecholamine and VIP concentrations were documented via laboratory testing. Surprisingly, all clinical symptoms responded swiftly to octreotide treatment. Once surgically treated, hormonal levels normalized in this patient, and the clinical symptoms dissipated. Postoperative pathological and immunohistopathological studies confirmed a VIP-secreting pheochromocytoma with strong, diffuse positivity for somatostatin receptor type 2. During a 6-mo follow-up period, she seemed in good health and was symptom-free.

The aim: Of the study was to study the activity of superoxide dismutase and catalase in the gastric mucosa of rats under long-term administration of omeprazole and combined administration of omeprazole with Symbiter and Apibact multiprobiotics.Materials and methods: The study was carried out on 40 white non-linear male rats with an initial weight of 160-180 g. All animals were divided into 4 groups. Group I was the control. Group II was administered omeprazole once a day within the period of 28 days. Group III was administered a combination of omeprazole and Symbiter® multiprobiotic. Group IV was administered a combination of omeprazole and Apibact® multiprobiotic. The activity of superoxide dismutase in cells was determined by Chevars et al. . The catalase activity in cells was determined by Korolyuk et al. . Statistical processing of the results was performed using the "Statistica 7.0" software.Results: The activity of SOD and catalase in the gastric mucosa of rats after 28 days of omeprazole administration increased compared to the control. Probiotics reduced the activity of SOD compared to the group of rats where omeprazole only was administered. The catalase activity in the gastric mucosa of rats which were jointly administered omeprazole and multiprobiotics for 28 days did not statistically significantly differ from the similar index in the control group.Conclusions: Prolonged gastric juice hypochlorhydria led to depletion of antioxidant protection enzymes. Multiprobiotics reduced the manifestation of the inflammatory process in the gastric mucosa.

Hypochlorhydria and achlorhydria are conditions in which the production of hydrochloric acid (HCl) in the stomach is reduced or completely absent, mostly because of an underlying medical condition, such as gastric cancer. Subtotal or total gastrectomy is commonly performed in patients who suffer from gastric cancer. But, advances in the field of tissue engineering allowed the fabrication and regeneration of many tissues, therefore supporting the idea that hypochlorhydria and achlorhydria could be treated in that manner, especially by nano-scaffolding, the process of tissue regrowing using polymer fibres at a nanoscale. The main goal of this article is to present theoretical premises of tissue engineering and combine findings from multiple studies which, when formulated in a form composed of four steps (preparation of the polymeric biodegradable nano-scaffold, preparation and multiplication of gastric cells, integration of gastric cells into a nano-scaffold and transplantation of the nano-scaffolded tissue into the interior of the stomach), followed by the vascularisation process and biodegradation, gives a novel theoretical possibility when it comes to managing these patients. We gathered scientific articles, professional literature and electronic books by researching databases, such as PubMed and Google Scholar, which were used as main sources of information when creating this article. Additionally, we used Medical Subject Headings (MeSH) in order to make a more precise search. Further research is needed for this procedure to resuscitate and make treatment of hypochlorhydria and achlorhydria easier and more efficient.

A 10-year-old girl with genetically confirmed Jervell-Lange-Nielsen syndrome treated with beta-blocker and developed electrical storm after changing propranolol syrup to tablets. Jervell-Lange-Nielsen is characterised by long QT and congenital sensorineural deafness, with high risk of malignant arrhythmias at early ages. Gastric involvement and achlorhydria may be present, with subsequent alteration of medication bioavailability which can trigger severe arrhythmic complications.

Helicobacter pylori is a class one carcinogen which causes chronic atrophic gastritis, gastric intestinal metaplasia, dysplasia and adenocarcinoma. The mechanisms by which H. pylori interacts with other risk and protective factors, particularly vitamin C in gastric carcinogenesis are complex. Gastric carcinogenesis includes metabolic, environmental, epigenetic, genomic, infective, inflammatory and oncogenic pathways. The molecular classification of gastric cancer subtypes has revolutionized the understanding of gastric carcinogenesis. This includes the tumour microenvironment, germline mutations, and the role of Helicobacter pylori bacteria, Epstein Barr virus and epigenetics in somatic mutations. There is evidence that ascorbic acid, phytochemicals and endogenous antioxidant systems can modify the risk of gastric cancer. Gastric juice ascorbate levels depend on dietary intake of ascorbic acid but can also be decreased by H. pylori infection, H. pylori CagA secretion, tobacco smoking, achlorhydria and chronic atrophic gastritis. Ascorbic acid may be protective against gastric cancer by its antioxidant effect in gastric cytoprotection, regenerating active vitamin E and glutathione, inhibiting endogenous N-nitrosation, reducing toxic effects of ingested nitrosodimethylamines and heterocyclic amines, and preventing H. pylori infection. The effectiveness of such cytoprotection is related to H. pylori strain virulence, particularly CagA expression. The role of vitamin C in epigenetic reprogramming in gastric cancer is still evolving. Other factors in conjunction with vitamin C also play a role in gastric carcinogenesis. Eradication of H. pylori may lead to recovery of vitamin C secretion by gastric epithelium and enable regression of premalignant gastric lesions, thereby interrupting the Correa cascade of gastric carcinogenesis.

Caustic ingestion can lead to structural changes in the upper gastro-intestinal tract. However, there is limited data on the effect of caustic ingestion on gastric secretion. This study was planned to determine changes in gastric acid output after sham feeding in patients with caustic induced esophageal stricture and to compare it with healthy controls. It was a prospective study done at tertiary care center in North India. Consecutive patients with caustic induced esophageal stricture were evaluated for the study. Gastric secretory function was estimated in the basal state and after modified sham feeding. These results were compared with age-matched controls. The mean age of the included patients (n = 18) was 30.11 ± 9.19 years and 13 patients were male. 16 (88%) patients had history of acid ingestion. Patients with caustic sequelae had significantly lower basal and stimulated acid secretion compared to controls (n = 10) (5.84 ± 2.44 mmol/hr; p

Highlights • Gastrointestinal symptoms like diarrhea sometimes occur in COVID-19 disease • Fecal samples from COVID-19 patients sometimes test positive for COVID-19 markers • COVID-19 virus can survive pH 3-5 typical of gastric environment in hypochlorhydria • COVID-19 virus could escape the hypochlorhydric stomach and infect the intestine • COVID-19 Fecal-oral transmission in addition to airborne should be considered, COVD-19 disease is characteristically respiratory in nature; however, some patients have gastrointestinal symptoms. These include changes in taste, nausea/vomiting, abdominal pain, and diarrhea. A report has been published of a young patient who repeatedly tested positive in stool samples while nasopharyngeal tests remained negative. This raises doubts about our understanding of the dynamics of COVID-19 disease. The current report describes a need for selective stool testing to explore fecal shedding of viral RNA and presents a hypothesis for direct infection of enterocytes in cases of hypochlorhydria.

The long-term use of proton pump inhibitors (PPIs) can lead to increased gastric pH, hypochlorhydria and in some cases to achlorhydria when compared to other acid-suppressing agents like histamine-2 (H2) receptor blockers and antacids. These consequences by the use of long-term PPIs may lead to significant vitamin (B12 and C) and mineral (iron, calcium and magnesium) deficiencies which needs gastric acid for their absorption and bioavailability. Long-term use of PPIs by the pregnant patients may impose a potential risk of congenital malformations. Various studies have recommended the life style modifications and antacid use as first choice among pregnant womens by preserving PPIs (omeprazole as a safe choice of PPI) for severe conditions of gastroesophageal reflux disease. The long-term acid suppression by PPIs can also lead to enteric, respiratory and urinary tract infections. The hypochlorhydria by chronic PPIs use may induce hypergastrinemia, which ultimately mediates the gastric polyps, gastric carcinoids and gastric cancer. The concomitant use of PPIs with antiplatelet drugs like clopidogrel can impose the patients to major adverse cardiac events. This review has enlisted the comprehensive information regarding the adverse effects induced by long-term use of PPIs and their possible relations. Considerable studies like case-control, randomized trials, cohort studies and meta-analysis were reported in supporting these adverse effects. The clinicians and patients should be cautious about these effects so that they can avoid the serious outcomes. PPIs should be avoided for long-term use mainly in older adults unless there is a proper indication.

Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H+, K+-adenosine triphosphatase (ATPase), the enzyme primarily responsible for gastric lumen acidification. Here, we describe the characterization of mice deficient in the H+, K+-ATPase α subunit (Atp4a−/−) to determine the role of this protein in the biosynthesis of this membrane system and the biology of the gastric mucosa. Atp4a−/− mice were produced by gene targeting. Wild-type (WT) and Atp4a−/− mice, paired for age, were examined at 10, 12, 14 and 16 weeks for histopathology, and the expression of mucin 2 (MUC2), α-methylacyl-CoA racemase (AMACR), Ki-67 and p53 proteins was analyzed by immunohistochemistry. For further information, phosphoinositide 3-kinase (PI3K), phosphorylated-protein kinase B (p-AKT), mechanistic target of rapamycin (mTOR), hypoxia-inducible factor 1α (HIF-1α), lactate dehydrogenase A (LDHA) and sirtuin 6 (SIRT6) were detected by Western blotting. Compared with the WT mice, hypochlorhydric Atp4a−/− mice developed parietal cell atrophy and significant antral inflammation (lymphocyte infiltration) and intestinal metaplasia (IM) with elevated MUC2 expression. Areas of dysplasia in the Atp4a−/− mouse stomach showed increased AMACR and Ki-67 expression. Consistent with elevated antral proliferation, tissue isolated from Atp4a−/− mice showed elevated p53 expression. Next, we examined the mechanism by which the deficiency of the H+, K+-ATPase α subunit has an effect on the gastric mucosa. We found that the expression of phosphorylated-PI3K, p-AKT, phosphorylated-mTOR, HIF-1α, LDHA and SIRT6 was significantly higher in tissue from the Atp4a−/− mice compared with the WT mice (P

A 68-year-old woman with an 11-day history of sudden abdominal pain and severe watery diarrhea was transferred to our hospital due to an exacerbation of renal function despite hydration. After treatment for dehydration and acidemia was provided in our intensive care unit, patient's renal function improved. Contrast-enhanced abdominal computed tomography was finally performed, revealing a hypervascular pancreatic mass with multiple hepatic masses. This imaging finding along with her clinical symptoms indicated watery diarrhea hypokalemia achlorhydria (WDHA) syndrome caused by a pancreatic VIPoma. Somatostatin analog was administered immediately leading to the improvement of her diarrhea and her general condition. As a result, endoscopic ultrasonography-guided fine-needle aspiration could be performed. Consequently, she was diagnosed with a pancreatic neuroendocrine tumor. She then underwent surgical resection of the pancreatic tumor and liver metastasis. As revealed in the immunohistochemical analysis of the excised tumor tissue, VIP was highly expressed, resulting in the final diagnosis of pancreatic VIPoma. Therefore, the immediate use of a somatostatin analog is crucial for improving the patient's general condition and achieving a definitive diagnosis pathologically when a patient is suspected of having a pancreatic VIPoma.

Iron deficiency (ID) workup is a common challenge for gastrointestinal endoscopy. In premenopausal women current guidelines recommend serologic evaluation of coeliac disease only. Here we systematically tested serologic screening for autoimmune gastritis (AIG) in a large cohort of patients with ID. This is a retrospective analysis of patients who attended an out-patient clinic specialized for ID. Patients with ferritin50 µg/L or transferrin saturation15% were included. Laboratory workup included endomysial antibodies and parietal-cell antibodies (PCA). Upper gastrointestinal endoscopy with pH-measurement of gastric juice and histology was performed to confirm positive serologic results. Three hundred seventy-three patients with ID were included, about half of whom were anemic. Patients were predominately female with a median age of 40 (confidence interval 11). Positive endomysial antibodies were found in 4 (1%) patients, elevated levels of PCA (20 U/mL) were found in 69 (18.5%) patients, PCA100 U/mL in 23 (6.2%). Twenty-six were followed up by gastroscopy; in 12 of 26 patients the diagnosis of AIG was confirmed by histology with 2 additional patients diagnosed as early and/or questionable AIG. A sensitivity of 93% and a specificity of 98% were estimated for a PCA cut-off of 100 U/mL. In 20 patients gastric pH was measured. Achlorhydria was found in 7 patients all diagnosed with AIG. In this ID cohort AIG is by far more common than coeliac disease. PCA above 100 U/mL are a sensitive and specific cut-off for workup of patients with ID prior to endoscopy. Serologic suspicion of AIG helps preselection of patients for endoscopic workup for ID.

Introduction: Gastric hypohlorhydria is the result of inflammatory process in the intestine caused by dysbiosis. Multiprobiotics significantly improve the colon's motility. Not only probiotics, but also synbiotics are used to eliminate dysbiosis. The aim of the work was to study the effect of Opefera on spontaneous and stimulated contractile activity of the colon in rats.Materials and methods: The studies were carried out on 30 white rats, divided into 3 groups. The rats of group I served as controls; they daily received water for injections for 28 days. Group II rats received omeprazole daily for 28 days and rectally - water. Rats of group III were given omeprazole and Opefera simultaneously during 28 days. On the 29th day the colon motility was examined by the balonography method [13]. To do this, the "Jaguar" automated unit was used. For statistic data processing, Student's t-criterion for independent samples was applied.Results: In the group of rats, which received omeprazole and Opefera simultaneously during 28 days, the index of motor activity increased compared to the group of rats given omeprazole only. Thus, application of the Opefera drug enhances the spontaneous and stimulated motility of the colon, suppressed by prolonged hypochlorhydria of gastric juice.Conclusion: The Opefera drug stimulates spontaneous and stimulated motility of the colon, suppressed by prolonged hypochlorhydria of gastric juice. Opefera application is expedient in patients with prolonged hypochlorhydria of various genesis to normalize the colon contractile activity.

Gastric juice is a unique combination of hydrochloric acid (HCl), lipase, and pepsin. Acidic gastric juice is found in all vertebrates, and its main function is to inactivate microorganisms. The phylogenetic preservation of this energy-consuming and, at times, hazardous function (acid-related diseases) reflects its biological importance. Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world. Due to the reduced prevalence of Helicobacter pylori infection as well as the increased use of inhibitors of gastric acid secretion, the latter has become the most important cause of gastric hypoacidity. In the present manuscript, we review the microbiological consequences of removing gastric acidity. The resulting susceptibility to infections has not been studied extensively, and focus has mainly been restricted to bacterial and parasitic agents only. The strongest evidence concerning the relationship between hypochlorhydria and predisposition to infections relates to bacterial infections affecting the gastrointestinal tract. However, several other clinical settings with increased susceptibility to infections due to inhibited gastric acidity are discussed. We also discuss the impact of hypochlorhydria on the gut microbiome. This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Background Although autoimmune gastritis (AIG) is generally considered relatively rare, we frequently encounter AIG among patients at to our hospital who have experienced at least two episodes of Helicobacter pylori eradication failure. Aims We investigated the incidence of AIG in consecutive patients who consulted our department for H. pylori eradication with reference to eradication history. Methods A total of 404 consecutive patients who visited the H. pylori-specific out-patient unit of our hospital from June 2015 to June 2017 were enrolled. Of these, 137 were treatment-naive, 47 had failed treatment once (single failure), and 220 had failed treatment twice or more (multiple failures) by 13 C-UBT. Gastroscopy was performed in all patients. Culture tests of gastric mucosal samples were performed for H. pylori and other bacteria positive for urease activity. Anti-parietal cell antibody (APCA) was measured. Patients with severe atrophy in the gastric corpus and positivity for APCA were diagnosed as having AIG. Results A total of 43 patients were diagnosed as having AIG, of whom two were treatment-naive (1.5%, 2/137), 1 failed eradication once (2.1% 1/47), and 40 failed treatment at least twice (18.2%, 40/220). The incidence of AIG was significantly higher in the multiple failure group than in the single failure or treatment-naive groups. Urease-positive bacteria, such as Klebsiella pneumoniae and alpha-streptococcus, were identified in 33 of the 35 AIG patients who underwent culture testing. Conclusion AIG patients were often misdiagnosed as refractory to eradication therapy, probably because achlorhydria in AIG might allow urease-positive bacteria other than H. pylori to colonise the stomach, causing positive 13 C-UBT results.

Pernicious anemia (PA) develops from atrophic gastritis due to autoimmune destruction of parietal cells and results in achlorhydria, vitamin B12 and iron deficiencies, anemia, neurologic deficits, and premalignant and malignant stomach lesions. We report the presentation, diagnosis and gastric complications of PA in patients from an endocrinology practice.Thirty-four patients (31 female, 3 male) with PA who underwent esophagogastroduodenoscopy (EGD) or gastrectomy were identified. Pertinent clinical, laboratory, and pathology findings were reviewed and summarized.The mean age of patients was 58.6 ± 14.2 years; the onset of PA was age 50.2 ± 15.3 years. Anemia reflected vitamin B12 and/or iron deficiencies. Parietal cell antibodies (PCA) were detected in 97% of patients, and intrinsic factor blocking antibody (IFBA) was found in 52%. Fasting gastrin and chromogranin A levels were elevated (1,518.0 ± 1,588.3 pg/mL, and 504.9.1 ± 1,524.9 ng/mL respectively). Autoimmune or immunologic diseases (AIDs) were present in 32/34 patients. Stomach pathology showed premalignant or malignant lesions in 26 patients, including gastric neuroendocrine tumors (GNETs) in 6 and adenocarcinoma in 1. One patient presented with neurologic symptoms and subacute combined degeneration of the posterior column of the spinal cord.PA should be suspected in patients with unexplained anemia or neurologic symptoms. The diagnosis of PA relies on fasting gastrin and gastric auto-antibody testing, in addition to hematologic evaluation. EGD with measurement of gastric pH and biopsies of the fundus and antrum identifies patients with achlorhydria, atrophic gastritis, and premalignant and malignant stomach lesions. EGD surveillance of patients with high-risk stomach lesions is recommended.AID = autoimmune or immunologic disease; EGD = esophagogastroduodenoscopy; GNET = gastric neuroendocrine tumor; IFBA = intrinsic factor blocking antibody; PA = pernicious anemia; PCA = parietal cell antibody; T1D = type 1 diabetes.

Majority of bioequivalence studies are conducted in healthy volunteers. It has been argued that bioequivalence may not necessarily hold true in relevant patient populations due to a variety of reasons which affect one formulationmore than the other for instance in achlorhydric patients where elevated gastric pH may lead to differential effects on formulations which are pH-sensitive with respect to release or dissolution. We therefore examined achlorhydria-related disparity in bioequivalence of levothyroxine and nifedipine formulations using virtual bioequivalence within a physiologically-based pharmacokinetic (PBPK) modelling framework. The in vitro dissolution profiles at neutral pH were incorporated into PBPK models to mimic the achlorhydria with in vitro–in vivorelationship established using bio-relevant pH media. The PBPK models successfully reproduced the outcome of the bioequivalence studies in healthy volunteers under the normal conditions as well as under proton pump inhibitor-induced achlorhydria. The geometric mean test/reference ratios for Cmax and AUC between levothyroxine tablet and capsule in patients receiving proton pump inhibitor were 1.21 (90%CI, 1.13–1.29) and 1.09 (90%CI, 1.02–1.17), respectively. Extension of the virtual bioequivalence study to Japanese elderly, who show high incidence of achlorhydria, indicated bio-inequivalence which Cmax and AUC ratios between nifedipine control-released reference and test formulations were 3.08 (90%CI, 2.81–3.38) and 1.57 (90%CI, 1.43–1.74), respectively. Virtual bioequivalence studies through the PBPK models can highlight the need for conduct of specific studies in elderly Japanese populations where there are discrepancies in pH-sensitivity of dissolution between the test and reference formulations.

OBJECTIVES: To document the existence of primary pancreatic secretinoma in patients with watery diarrhea syndrome (WDS) and achlorhydria and establish secretin as a diarrheogenic hormone. BACKGROUND: Vasoactive intestinal peptide (VIP) has been widely accepted as the main mediator of WDS. However, in 1968, Zollinger et al reported 2 female patients with pancreatic neuroendocrine tumors, WDS, and achlorhydria. During surgery on the first, a 24-year-old patient, they noticed distended duodenum filled with fluid and a dilated gallbladder containing dilute bile with high bicarbonate concentration. After excision of the tumor, WDS ceased and gastric acid secretion returned. The second, a 47-year-old, patient’s metastatic tumor extract given intravenously in dogs, produced significantly increased pancreatic and biliary fluid rich in bicarbonate. They suggested a secretin-like hormone of islet cell origin explains WDS and achlorhydria. These observations, however, predated radioimmunoassay, immunohistochemical staining, and other molecular studies. METHODS: The first patient’s tumor tissue was investigated for secretin and VIP. Using both immunohistochemistry and laser microdissection and pressure catapulting technique for RNA isolation and subsequent reverse transcription polymerase chain reaction, the expression levels of secretin, and VIP were measured. RESULTS: Immunoreactive secretin and its mRNA were predominantly found in the tumor tissue whereas VIP and its mRNA were scarce. CONCLUSIONS: The findings strongly support that the WDS and achlorhydria in this patient may have been caused by secretin as originally proposed in 1968 and that secretin may act as a diarrheogenic hormone.

Summary Underproduction of hydrochloric acid into the stomach is frequently encountered in subjects from developing countries. We explore the hypothesis that hypochlorhydria compromises the gastric barrier and favours bacterial overgrowth in the proximal parts of the small intestine where nutrient absorption takes place. Food calories are thus deviated into bacterial metabolism. In addition to an adequate caloric supply, correcting hypochlorhydria might be needed to decrease childhood malnutrition.

Purpose To propose media for simulating the intragastric environment under reduced gastric acid secretion in the fasted state at three levels of simulation of the gastric environment and evaluate their usefulness in evaluating the intragastric dissolution of salts of weak bases. To evaluate the importance of bicarbonate buffer in biorelevant in vitro dissolution testing when using Level II biorelevant media simulating the environment in the fasted upper small intestine, regardless of gastric acid secretions. Methods Media for simulating the hypochlorhydric and achlorhydric conditions in stomach were proposed using phosphates, maleates and bicarbonates buffers. The impact of bicarbonates in Level II biorelevant media simulating the environment in upper small intestine was evaluated so that pH and bulk buffer capacity were maintained. Dissolution data were collected using two model compounds, pioglitazone hydrochloride and semifumarate cocrystal of Compound B, and the mini-paddle dissolution apparatus in biorelevant media and in human aspirates. Results Simulated gastric fluids proposed in this study were in line with pH, buffer capacity, pepsin content, total bile salt/lecithin content and osmolality of the fasted stomach under partial and under complete inhibition of gastric acid secretion. Fluids simulating the conditions under partial inhibition of acid secretion were useful in simulating concentrations of both model compounds in gastric aspirates. Bicarbonates in Level III biorelevant gastric media and in Level II biorelevant media simulating the composition in the upper intestinal lumen did not improve simulation of concentrations in human aspirates. Conclusions Level III biorelevant media for simulating the intragastric environment under hypochlorhydric conditions were proposed and their usefulness in the evaluation of concentrations of two model salts of weak bases in gastric aspirates was shown. Level II biorelevant media for simulating the environment in upper intestinal lumen led to underestimation of concentrations in aspirates, even when bicarbonate buffer was used.

Background: Studies have found an association between proton pump inhibitor (PPI) use and Clostridium difficile infection. The purpose of this study was to determine whether the mechanism by which PPIs induce an increased risk of C. difficile infection is supported by the same mechanism acting in another cause of achlorhydria, pernicious anaemia. Methods: Using a database of anonymised primary care records between 1990 and 2013, we selected exposed patients with a diagnosis of pernicious anaemia treated with vitamin B12 therapy. Each exposed patient was matched by age, gender and general practice to up to 10 controls. Cox regression analysis was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for C. difficile infection with pernicious anaemia, adjusted for potential confounders. Results: We identified 45,467 exposed patients matched to 449,635 controls. The crude incidence rate of C. difficile infection was 1.85/1000 person-years for the exposed cohort and 1.09/1000 person-years for controls. Patients with pernicious anaemia had a greater risk of C. difficile infection than the controls (adjusted HR 1.57, 95% CI 1.40–1.76). Conclusions: Pernicious anaemia patients have an increased risk of C. difficile infection. This supports the theory that severe achlorhydria is the mechanism that increases the risk of C. difficile infection in long-term PPI users.

The present study was aimed to evaluate the applicability of a self-micellizing solid dispersion (SMSD) system of itraconazole (ITZ) with the use of Soluplus® to achieve improved dissolution and stable oral absorption of ITZ under hypochlorhydric conditions. The SMSD of ITZ (SMSD/ITZ) was prepared by the freeze-drying method. Physicochemical properties of SMSD/ITZ were assessed in terms of morphology, crystallinity, particle size, thermal behavior, dissolution profile, and stability. The pharmacokinetic profile of SMSD/ITZ was evaluated in both normal rats and omeprazole-treated rats as a hypochlorhydric model. From the crystallinity assessment, ITZ in SMSD/ITZ might exist in an amorphous state. The dissolution behavior of SMSD/ITZ was markedly improved under both acidic and neutral conditions through the formation of nano-micelles with a diameter of 127nm. The degradation of ITZ in SMSD/ITZ was negligible after storage under accelerated conditions at 40°C or 40°C/75%RH for 4weeks. Under light exposure, ca. 33% of ITZ in SMSD/ITZ was degraded, suggesting the need for protection from light. Although the oral absorption of crystalline ITZ was negligible, SMSD/ITZ showed an improved pharmacokinetic profile in normal rats, with an absolute bioavailability (BA) of 2.9%, and even 6.3% in the hypochlorhydric model. From these findings, SMSD technology could be beneficial for improving the absorption profiles of weak basic drugs, even in hypochlorhydric patients.

Netazepide, a gastrin/CCK2 receptor antagonist, once daily for 12 weeks reduced the number of tumours and size of the largest one in 16 patients with autoimmune chronic atrophic gastritis (CAG), achlorhydria, hypergastrinaemia and multiple gastric neuroendocrine tumours (type 1 gastric NETs), and normalised circulating chromogranin A (CgA) produced by enterochromaffin-like cells, the source of the tumours. The aim was to assess whether longer-term netazepide treatment can eradicate type 1 gastric NETs.After a mean 14 months off netazepide, 13 of the 16 patients took it for another 52 weeks. Assessments were: gastroscopy; gene-transcript expression in corpus biopsies using qPCR; blood CgA and gastrin concentrations; and safety assessments.While off-treatment, the number of tumours, the size of the largest one, and CgA all increased again. Netazepide for 52 weeks: cleared all tumours in 5 patients; cleared all but one tumour in one patient; reduced the number of tumours and size of the largest one in the other patients; normalised CgA in all patients; and reduced mRNA abundances of CgA and histidine decarboxylase in biopsies. Gastrin did not increase further, confirming that the patients had achlorhydria. Netazepide was safe and well tolerated.A gastrin/CCK2 receptor antagonist is a potential medical and targeted treatment for type 1 gastric NETs, and an alternative to regular gastroscopy or surgery. Treatment should be continuous because the tumours will regrow if it is stopped. Progress can be monitored by CgA in blood or biomarkers in mucosal biopsies. This article is protected by copyright. All rights reserved.

A 45-year-old woman visited a local clinic with left-flank abdominal pain. Abdominal computed tomography (CT) revealed a tumor 20 cm in diameter in the left adrenal gland. She was referred to our hospital for further treatment. No endocrinological abnormality was detected on either serum or urine examination. CT and haematology findings led to a preoperative diagnosis of primary adrenal carcinoma, and we performed a left adrenalectomy. Histopathological examination revealed a paraganglioma with intact adrenal gland. Therefore we diagnosed this case as primary retroperitoneal paraganglioma. Six months after the surgery, she developed peritoneal dissemination including bilateral ovarian metastases. After cytoreductive metastasectomy, she received 131I-meta-iodobenzylguanidine (MIBG) radiotherapy. During the following five-year follow-up, MIBG radiotherapy in conjunction with cytoreductive metastasectomy (3 surgeries and 6 sessions of 131I-MIBG radiotherapy) was performed, aiming at disease control. Five years after the initial surgery, liver, lung, and intra-peritoneal dissemination progressed. Thereafter, she developed severe diarrhea, hypokalemia, and metabolic acidosis with an elevated level of vasoactive intestional peptide, which was consistent with water diarrhea, hypokalemia, achlorhydria (WDHA) syndrome. Despite intensive treatments such as with a somatostatin analogue, she died two months after the onset of this syndrome.

Type I gastric neuroendocrine tumors (gNETs) arise from hypergastrinemia in patients with autoimmune chronic atrophic gastritis. According to the classical model, the gastric H+/K+ ATPase was the causative autoantigen recognized by CD4+ T cells in chronic autoimmune scenario that secretes IL-17 and correlates with parietal cell (PC) atrophy, which drives to gastric achlorhydria and increases the risk for gastric neoplasms. However, the mechanism by which the inflammatory response correlates with PC atrophy is not clearly defined. Recently, we found that the ATP4Ap.R703C mutation impaired PC function and gastric acidification, which drove familial gNET. Our group constructed a knock-in mouse model for the ATP4A mutation, which has served us to better understand the relation between impaired capability to export protons across the plasma membrane of PCs and tumor progression. The ATP4Ap.R703C mutation drives gastric achlorhydria, but also deregulates the acid–base balance within PCs, affecting mitochondrial biogenesis. Mitochondrial malfunction activates ROS signaling, which triggers caspase-3-mediated apoptosis of parietal cells. In addition, when gastric euchlorhydria was restored, mitochondrial function is recovered. Infection by H. pylori promotes destabilization of the mitochondria of the PCs by a mechanism similar to that described for APT4Ap.R703C carriers. A genetic origin that drives mitochondria alteration would initiate the gastric chronic inflammation instead of the classical IL-17 secretion-mediated mechanism explanation. Gastric euchlorhydria restoration is suggested to be indicated for mitochondrial recover. Our results open a new window to understand gastric neoplasms formation but also the inflammatory mechanisms and autoimmune disorders conducted by genetic origin that composes a premalignant scenario.

The diagnosis of gastric neuroendocrine tumors (NETs) is being made with increased frequency likely as a result of more upper endoscopies being done for unrelated reasons. It is therefore vital that gastroenterologists become familiar with the basic work-up and management of patients found to have these tumors. This review describes the classification, pathophysiology, clinical characteristics, and treatment options of the different gastric NETs. In addition to the three traditional subtypes of gastric NETs, additional cases associated with achlorhydria and appropriate hypergastrinemia may exist. The management of gastric NETs between 1 and 2 cm in size remains controversial and needs to be individualized. Gastric NETs are uncommon but are now diagnosed more frequently. This review highlights the role of hypergastrinemia in their development and the controversies around their management.

Although the actual prevalence of chronic atrophic gastritis is unknown and it is probable that this entity goes largely underdiagnosed, patients in whom diagnosis is established usually present advanced stages of disease. Destruction of parietal cells, either autoimmune-driven or as a consequence of Helicobacter pylori infection, determines reduction or abolition of acid secretion. Hypo/achloridia causes an increase in serum gastrin levels, with an increased risk of the development of neuroendocrine tumors. Microcytic, hypochromic anemia frequently precedes the development of megaloblastic, vitamin B12-associated anemia. Moreover, vitamin B12 deficiency,may cause elevation of homocysteine, with an increase in the cardiovascular risk, and may be associated with neurological manifestations, mainly characterized by spinal cord demyelination and atrophy, with ensuing sensory-motor abnormalities. Gastrointestinal manifestations seem to be associated with non-acid reflux and tend to be non-specific. (www.actabiomedica.it)

Helicobacter pylori is the strongest risk factor for gastric adenocarcinoma, which develops within a hypochlorhydric environment. We sequentially isolated H. pylori (strain J99) from a patient who developed corpus-predominant gastritis and hypochlorhydia over a 6-year interval. Archival J99 survived significantly better under acidic conditions than recent J99 strains. H. pylori arsRS encodes a 2-component system critical for stress responses; recent J99 isolates harbored 2 nonsynonymous arsS mutations, and arsS inactivation abolished acid survival. In vivo, acid-resistant archival, but not recent J99, successfully colonized high-acid-secreting rodents. Thus, genetic evolution of arsS may influence progression to hypochlorhydia and gastric cancer.

Efficient calcium absorption is essential for skeletal health. Patients with impaired gastric acidification display low bone mass and increased fracture risk because calcium absorption is dependent on gastric pH. We investigated fracture healing and post‐traumatic bone turnover in mice deficient in Cckbr, encoding a gastrin receptor that affects acid secretion by parietal cells. Cckbr−/− mice display hypochlorhydria, calcium malabsorption, and osteopenia. Cckbr−/− and wildtype (WT) mice received a femur osteotomy and were fed either a standard or calcium‐enriched diet. Healed and intact bones were assessed by biomechanical testing, histomorphometry, micro‐computed tomography, and quantitative backscattering. Parathyroid hormone (PTH) serum levels were determined by enzyme‐linked immunosorbent assay. Fracture healing was unaffected in Cckbr−/− mice. However, Cckbr−/− mice displayed increased calcium mobilization from the intact skeleton during bone healing, confirmed by significantly elevated PTH levels and osteoclast numbers compared to WT mice. Calcium supplementation significantly reduced secondary hyperparathyroidism and bone resorption in the intact skeleton in both genotypes, but more efficiently in WT mice. Furthermore, calcium administration improved bone healing in WT mice, indicated by significantly increased mechanical properties and bone mineral density of the fracture callus, whereas it had no significant effect in Cckbr−/− mice. Therefore, under conditions of hypochlorhydria‐induced calcium malabsorption, calcium, which is essential for callus mineralization, appears to be increasingly mobilized from the intact skeleton in favor of fracture healing. Calcium supplementation during fracture healing prevented systemic calcium mobilization, thereby maintaining bone mass and improving fracture healing in healthy individuals whereas the effect was limited by gastric hypochlorhydria. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1914–1921, 2016.

Gastrin exerts trophic effects on all cells of the gastric oxyntic mucosa including enterochromaffin-like (ECL) cells. Hypergastrinemia may result from hypoor achlorhydria due to chronic atrophic gastritis, from longterm drug-induced acid suppression or from gastrinoma occurring as part of the multiple endocrine neoplasia (MEN) 1 syndrome [1]. We describe here a man who developed an atypical, benign gastric carcinoid or neuroendocrine tumor (NET), after being treated with a proton pump inhibitor (PPI) for 20 years.

Chronic atrophic gastritis is a generally asymptomatic condition of great importance because it develops into gastric cancer in a number of patients. It is described as an atrophy of the gastric mucosa. There are two types of atrophic gastritis: a gastric body predominant type in patients with infection of Helicobacter pylori, and an autoimmune type, limited to the gastric body and fundus. The autoimmune type is quite rare and affects people of all ethnicities. Globally, H. pylori infection is very common and is considered a class I carcinogen due to the large number of patients who subsequently develop gastric cancer. The pathogenesis of the autoimmune type involves an antibody-mediated loss of parietal cells resulting in achlorhydria and an antibody-mediated loss of intrinsic factor that causes pernicious anemia. The diagnosis of H. pylori infection is based on endoscopy and culture of the organisms. Patients with atrophic gastritis as well as H. pylori infection should be treated with antibiotics to eradicate the organism. Patients with the autoimmune type need to be evaluated for anemia, and if present, treated with vitamin B12.

Chronic autoimmune atrophic gastritis (CAAG) is an organ-specific autoimmune disease, which affects the corpus-fundus gastric mucosa. Although it has been described for several years, the real pathophysiological mechanisms, the natural history and the possible neoplastic complications are not completely known. Atrophy of the gastric mucosa is the endpoint of the chronic processes, with the loss of glandular cells and their replacement by intestinal-type epithelium, pyloric-type glands, and fibrous tissue. As a consequence, hydrochloric acid, pepsin and intrinsic-factor is impaired resulting in pernicious anemia. The exact causal agent is not yet known, but both genetic and environmental factors seem to play a decisive role. Moreover, the clinical onset may assume different characteristics; differently from what previously observed, recent evidence has reported the onset of CAAG at a younger age, frequently with iron deficiency anemia or upper gastro-intestinal symptoms. The diagnosis of CAAG might be challenging and usually requires the combination of clinical, serological and histopathologic data; moreover, CAAG patients are often misdiagnosed as refractory to HP eradication therapy, probably because achlorhydria might allow urease-positive bacteria other than H pylori to colonize the stomach, causing positive 13C-urea breath test results. However, biopsy is the most reliable method to evaluate the presence of metaplastic atrophic gastritis. In order to assess the severity of gastric atrophy and intestinal metaplasia, OLGA and OLGIM staging systems have been proposed and seem to correlate with the risk of developing gastric adenocarcinoma. Indeed, CAAG represents a pre-neoplastic condition, as patients with CAAG are very likely to develop either type-1 gastric neuroendocrine tumors and gastric adenocarcinomas, as well as several other neoplastic diseases. To date, the need, the intervals and cost-effectiveness of endoscopic/histological surveillance for patients with CAAG/pernicious anemia are yet to be established.

Background Autoimmune metaplastic atrophic gastritis is a chronic progressive inflammatory condition. The clinical spectrum includes pernicious anemia, atrophic gastritis, antibodies to parietal cell antigens and intrinsic factor, achlorhydria, hypergastrinemia and carcinoma. It is rare in paediatric cohorts. Case presentation We present the case of a boy with metaplastic atrophic gastritis in whom immune dysregulation, polyendocrinopathy, enteropathy, X-linked(IPEX) syndrome was confirmed by FOXP3 gene mutation. The patient was referred to the hospital at the age of 3 years with recurrent emesis, diarrhoea and malnutrition. His elder brother died at 9 years of age from acute respiratory distress syndrome and renal tubular acidosis. The patient was allergic to cow milk formula and noodles. Oesophagegastroduodenoscopy revealed redness, erosion and edema throughout the stomach; whitish granules in the duodenal bulb; and edema in the second part of the duodenum. Biopsies showed extensive villous atrophy and goblet cell depletion in the duodenum. He was diagnosed with type-1 diabetes mellitus (T1DM) during the treatment of methylprednisolone. Serum antibodies against glutamic acid decarboxylase and pancreatic islets were detected. The patient’s FOXP3 gene was sequenced; this identified that the patient was hemizygous for a pathogenic variant [NM_014009.3:c.748_750del (p.Lys250del)]. Conclusion Metaplastic atrophic gastritis is rarely reported in patients with IPEX. Clinical gastroenterologists should be aware of IPEX syndrome when facing the complex syndromes of metaplastic atrophic gastritis and endocrinopathy.

Vasoactive intestinal polypeptide-secreting tumors (VIPomas) are rare neuroendocrine tumors that often present as watery diarrhea, hypokalemia, and achlorhydria or hypochlorhydria. In this study, we present our institutional experience of diagnosis and treatment of VIPomas, along with a review of the Chinese literature since 1980. Patient #1, diagnosed in 1984 and with intact clinical records, shows the natural history of this disease. Patient #2, diagnosed in 2015, shows the results of evaluation by nuclear medicine techniques and the outcomes of standardized treatment. Comprehensive review of 41 cases allows evaluation of clinical characteristics, treatments and outcomes of pancreatic VIPoma patients. All patients presented with watery diarrhea. The average stool volume reached 3247 mL per day. Average serum VIP level was 839.3 ng/L. Twelve of the 41 cases were reported to have metastases at diagnosis. Somatostatin receptor scintigraphy and 18FDG PET-CT are efficient methods for detection of VIPoma. Surgical excision can promptly alleviate hormonal symptoms.