Autoimmune Gastritis and Hypochlorhydria: Known Concepts from a New Perspective.

Autoimmune atrophic gastritis is an immune-mediated disease resulting in autoimmune destruction of the specialized acid-producing gastric parietal cells. As a consequence, in autoimmune atrophic gastritis, gastric acid secretion is irreversibly impaired, and the resulting hypochlorhydria leads to the main clinical manifestations and is linked, directly or indirectly, to the long-term neoplastic complications of this disease. In the last few years, autoimmune atrophic gastritis has gained growing interest leading to the acquisition of new knowledge on different aspects of this disorder. Although reliable serological biomarkers are available and gastrointestinal endoscopy techniques have substantially evolved, the diagnosis of autoimmune atrophic gastritis is still affected by a considerable delay and relies on histopathological assessment of gastric biopsies. One of the reasons for the diagnostic delay is that the clinical presentations of autoimmune atrophic gastritis giving rise to clinical suspicion are very different, ranging from hematological to neurological-psychiatric up to gastrointestinal and less commonly to gynecological-obstetric symptoms or signs. Therefore, patients with autoimmune atrophic gastritis often seek advice from physicians of other medical specialties than gastroenterologists, thus underlining the need for increased awareness of this disease in a broad medical and scientific community.

Deterioration of apatite orientation in the cholecystokinin B receptor gene (Cckbr)-deficient mouse femurs.

INTRODUCTION: The discrepancy between bone mineral density (BMD), the gold standard for bone assessment, and bone strength is a constraint in diagnosing bone function and determining treatment strategies for several bone diseases. Gastric hypochlorhydria induced by clinically used proton pump inhibitor (PPI) therapy indicates a discordance between changes in BMD and bone strength. Here, we used Cckbr-deficient mice with gastric hypochlorhydria to examine the effect of gastric hypochlorhydria on bone mass, BMD, and preferential orientation of the apatite crystallites, which is a strong indicator of bone strength. MATERIALS AND METHODS: Cckbr-deficient mice were created, and their femurs were analyzed for BMD and preferential orientation of the apatite c-axis along the femoral long axis. RESULTS: Cckbr-deficient mouse femurs displayed a slight osteoporotic bone loss at 18 weeks of age; however, BMD was comparable to that of wild-type mice. In contrast, apatite orientation in the femur mid-shaft significantly decreased from 9 to 18 weeks. To the best of our knowledge, this is the first report demonstrating the deterioration of apatite orientation in the bones of Cckbr-deficient mice. CONCLUSION: Lesions in Cckbr-deficient mice occurred earlier in apatite orientation than in bone mass. Hence, bone apatite orientation may be a promising method for detecting hypochlorhydria-induced osteoporosis caused by PPI treatment and warrants urgent clinical applications.

The occurrence, progression and development of four types of gastric mucosal atrophic lesions and their histopathological characteristics.

OBJECTIVE: To investigate the occurrence and development of gastric mucosal atrophic lesions and their histopathological characteristics. METHODS: Histopathological diagnosis and immunohistochemical staining using the EnVision two-step method were conducted on 1969 gastric mucosal atrophic lesions obtained from gastroscopic biopsy specimens. A total of 48-month three-stage endoscopic biopsy follow-ups were performed. RESULTS: When the gastric mucosal epithelium was affected by infection, chemical irritation, or immune or genetic factors, the gastric mucosal epithelium glands atrophied, the mucosa became thinner, the number of glands decreased, the intestinal epithelium progressed to metaplasia and smooth muscle fibre became hyperplasia. Such changes may lead to the proliferation and dysplasia of epithelial cells of the gastric mucosa and neoplastic hyperplasia in nature; this is referred to as gastric mucosal atrophic lesions in this study. According to this definition, the present study divided gastric mucosal atrophy into four types: (1) glandular atrophy of the lamina propria; (2) compensatory proliferative atrophy; (3) intestinal metaplasia atrophy; and (4) smooth muscle proliferative atrophy. The incidence rates of the above were 40.1% (789/1969), 14.3% (281/1969), 27.8% (547/1969) and 17.9% (352/1969), respectively. One- to 4-year follow-ups found that the changes were not significant and that the percentages of patients with disease exacerbation were 85.7% (1688/1969) and 9.8% (192/1969). The percentages of patients who developed low-grade intraepithelial neoplasia and high-grade intraepithelial neoplasia were 2.8% (55/1969) and 1.1% (21/1969), respectively; 0.7% (13/1969) of patients developed intramucosal cancer. CONCLUSION: Gastric mucosal atrophic lesions and histopathological staging are based on the morphological characteristics of gastric mucosal atrophy and the hypothesis of malignant transformation of cells during the occurrence and development of mucosal atrophy. Mastering pathological staging is beneficial to clinicians for enacting precise treatment and is important for reducing the incidence of gastric cancer.

Vitamin C Improves Dasatinib Concentrations Under Hypochlorhydric Conditions of the Simulated Stomach Duodenum Model.

PURPOSE: 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. METHODS: 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) (FaSGFhypo) and FaSGFhypo with 1000 mg of vitamin C. RESULTS: Significant supersaturation of dasatinib was observed in the duodenum compartment of the SSD model in FaSGF. A 90% reduction in dasatinib AUC∞ was observed in FaSGFhypo. Upon addition of vitamin C to FaSGFhypo, drug concentrations were restored to those observed in FaSGF. Lamotrigine AUC∞ in the duodenal compartment were similar in both FaSGF and FaSGFhypo. The in vitro trends observed for dasatinib and lamotrigine are reflective of the trends observed in vivo in subjects receiving treatment with ARAs. CONCLUSIONS: The 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.

Hypochlorhydria reduces mortality in heart failure caused by Kcne2 gene deletion.

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 ß subunit-encoding Kcne2 (Kcne2CS-/- ) causes dilated cardiomyopathy and terminal HF (median longevity, 28 weeks). Mice with global Kcne2 deletion (Kcne2Glo-/- ) exhibit multiple HF risk factors, yet, paradoxically survived over twice as long as Kcne2CS-/- 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 Kcne2CS-/- 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.

ACTIVITY OF SUPEROXIDE DISMUTASE AND CATALASE IN THE GASTRIC MUCOSA OF RATS UNDER THE PROLONGED ADMINISTRATION OF OMEPRAZOL AND COMBINATION OF OMEPRAZOLE AND MULTIPROBIOTICS.

OBJECTIVE: 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. PATIENTS AND METHODS: 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: 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. CONCLUSION: Conclusions: Prolonged gastric juice hypochlorhydria led to depletion of antioxidant protection enzymes. Multiprobiotics reduced the manifestation of the inflammatory process in the gastric mucosa.

A genetic origin for acid-base imbalance triggers the mitochondrial damage that explains the autoimmune response and drives to gastric neuroendocrine tumours.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

[Use of a somatostatin analog to improve a patient's condition and the subsequent diagnosis of pancreatic VIPoma:a case report].

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.

Comparison of the human gastric microbiota in hypochlorhydric states arising as a result of Helicobacter pylori-induced atrophic gastritis, autoimmune atrophic gastritis and proton pump inhibitor use.

Several conditions associated with reduced gastric acid secretion confer an altered risk of developing a gastric malignancy. Helicobacter pylori-induced atrophic gastritis predisposes to gastric adenocarcinoma, autoimmune atrophic gastritis is a precursor of type I gastric neuroendocrine tumours, whereas proton pump inhibitor (PPI) use does not affect stomach cancer risk. We hypothesised that each of these conditions was associated with specific alterations in the gastric microbiota and that this influenced subsequent tumour risk. 95 patients (in groups representing normal stomach, PPI treated, H. pylori gastritis, H. pylori-induced atrophic gastritis and autoimmune atrophic gastritis) were selected from a cohort of 1400. RNA extracted from gastric corpus biopsies was analysed using 16S rRNA sequencing (MiSeq). Samples from normal stomachs and patients treated with PPIs demonstrated similarly high microbial diversity. Patients with autoimmune atrophic gastritis also exhibited relatively high microbial diversity, but with samples dominated by Streptococcus. H. pylori colonisation was associated with decreased microbial diversity and reduced complexity of co-occurrence networks. H. pylori-induced atrophic gastritis resulted in lower bacterial abundances and diversity, whereas autoimmune atrophic gastritis resulted in greater bacterial abundance and equally high diversity compared to normal stomachs. Pathway analysis suggested that glucose-6-phospahte1-dehydrogenase and D-lactate dehydrogenase were over represented in H. pylori-induced atrophic gastritis versus autoimmune atrophic gastritis, and that both these groups showed increases in fumarate reductase. Autoimmune and H. pylori-induced atrophic gastritis were associated with different gastric microbial profiles. PPI treated patients showed relatively few alterations in the gastric microbiota compared to healthy subjects.

The Phylogeny and Biological Function of Gastric Juice-Microbiological Consequences of Removing Gastric Acid.

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.

[A Case of WDHA Water Diarrhea Hypokalemia Achlorhydria Syndrome that Developed after Multimodal Therapy for Retroperitoneal Paraganglioma].

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.

Influence of opefera on the colon motility of rats in the conditions of prolonged gastric juice hypoacidity.

OBJECTIVE: 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. PATIENTS AND METHODS: 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: 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: 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.

Amorphous solid dispersions of carvedilol along with pH-modifiers improved pharmacokinetic properties under hypochlorhydoria.

Carvedilol (CAR) belongs to biopharmaceutics classification system class-II drugs, with poor aqueous solubility and pH-dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR-ASD was prepared by freeze-drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized. Pharmacokinetic studies were carried out after oral administration of CAR samples in both normal and omeprazole-treated (30 mg/kg, p.o.) rats as a hypochlorhydria model. Among the tested six counter ions, citric acid (CA) was found to be a preferable pH-modifier of CAR with respect to the dissolution profile and photostability (both potency and colorimetric evaluation). In CAR-ASD formulation with 50% loading of CA (CAR-ASD/CA50), amorphization of CAR was observed during the preparation process. After the oral administration of crystalline CAR in rats under hypochlorhydric condition, there was a 34.4% reduction in the systemic exposure of CAR compared with that in normal rats. However, orally-dosed CAR-ASD/CA50 resulted in limited alterations of pharmacokinetic behavior between normal and omeprazole-treated rats. From these findings, addition of CA as pH-modifier in CAR-ASD might provide consistent pharmacokinetic behavior of CAR even under hypochlorhydric conditions.

Biorelevant Dissolution Models for a Weak Base To Facilitate Formulation Development and Overcome Reduced Bioavailability Caused by Hypochlordyria or Achlorhydria.

In this study, two dissolution models were developed to achieve in vitro-in vivo relationship for immediate release formulations of Compound-A, a poorly soluble weak base with pH-dependent solubility and low bioavailability in hypochlorhydric and achlorhydric patients. The dissolution models were designed to approximate the hypo-/achlorhydric and normal fasted stomach conditions after a glass of water was ingested with the drug. The dissolution data from the two models were predictive of the relative in vivo bioavailability of various formulations under the same gastric condition, hypo-/achlorhydric or normal. Furthermore, the dissolution data were able to estimate the relative performance under hypo-/achlorhydric and normal fasted conditions for the same formulation. Together, these biorelevant dissolution models facilitated formulation development for Compound-A by identifying the right type and amount of key excipient to enhance bioavailability and mitigate the negative effect of hypo-/achlorhydria due to drug-drug interaction with acid-reducing agents. The dissolution models use readily available USP apparatus 2, and their broader utility can be evaluated on other BCS 2B compounds with reduced bioavailability caused by hypo-/achlorhydria.

Netazepide, a gastrin/cholecystokinin-2 receptor antagonist, can eradicate gastric neuroendocrine tumours in patients with autoimmune chronic atrophic gastritis.

AIMS: Netazepide, a gastrin/cholecystokinin 2 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 normalized 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. METHODS: 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 quantitative polymerase chain reaction; blood CgA and gastrin concentrations; and safety assessments. RESULTS: 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; normalized 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. CONCLUSIONS: A gastrin/cholecystokinin 2 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.

Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption.

PURPOSE: Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria. METHODS: In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100 mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20 mg twice daily), and with 1500 mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. RESULTS: Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. CONCLUSIONS: The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.

Genetic Evolution of a Helicobacter pylori Acid-Sensing Histidine Kinase and Gastric Disease.

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.

Characteristics of the Human Upper Gastrointestinal Contents in the Fasted State Under Hypo- and A-chlorhydric Gastric Conditions Under Conditions of Typical Drug - Drug Interaction Studies.

OBJECTIVE: Evaluate the impact of reduced gastric acid secretion after administration of two acid-reducing agents on the physicochemical characteristics of contents of upper gastrointestinal lumen of fasted adults. MATERIALS AND METHODS: Eight healthy male adults, fasted from food for 12 h, participated in a three-phase crossover study. Phase 1: No drug treatment prior to aspirations. Phase 2: Oral administration of 40 mg pantoprazole at ~9 am the last 3 days prior to aspirations and at ~7 am on aspiration day. Phase 3: Oral administration of 20 mg famotidine at ~7 pm prior to aspirations and at ~7 am on aspiration day. Samples from the contents of upper gastrointestinal lumen were aspirated for 50 min, after administration of 240 ml table water at ~9 am. RESULTS: Reduction of gastric acid secretion was accompanied by reduced buffer capacity, chloride ion concentration, osmolality and surface tension in stomach and by increased pH (up to ~0.7 units) in upper small intestine during the first 50 min post-water administration. The mechanism of reduction of acid secretion seems to be important for the buffer capacity in stomach and for the surface tension in upper gastrointestinal lumen. CONCLUSIONS: Apart from gastric pH, reduced acid secretion affects physicochemical characteristics of contents of upper gastrointestinal lumen which may be important for the performance of certain drugs/products in the fasted state.

Iron Deficiency and IL1ß Polymorphisms in Helicobacter pylori-infected Children.

BACKGROUND: Helicobacter pylori infection has been associated with an imbalance of iron homeostasis. IL-1ß has been related with iron absorption disturbances through a variety of mechanisms. The aim of this study was to evaluate the presence of polymorphic variants for IL-1ß cluster and gastric IL1ß mRNA expression in H. pylori-infected children and their relationship with hypochlorhydria and iron deficiency (ID). PATIENTS AND METHODS: Prospective study of 123 symptomatic children. At endoscopy, antral biopsies were taken for urease test, pathology and culture and blood for analysis of ferritin, transferrin, serum iron, and total iron-binding capacity. Polymorphisms in the IL-1ß cluster (positions -511, -31, +3954, ILRN) were determined by PCR-RFLP. Gastric mucosal expression of IL-1ß mRNA was determined by RT-PCR. RESULTS: After exclusions, of 105 patients, 33 (31.4%) were H. pylori positive. Nine (8.6%) children were classified as iron deficient (ID). Helicobacter pylori positivity was associated with ID (OR: 5.1; 95% CI: 1.2-21.9) (p = .04). No significant differences were found in allele frequency for IL1ß gene cluster polymorphisms between infected and uninfected children. Helicobacter pylori-infected children with ID had significantly increased gastric IL1ß mRNA in comparison with infected children without ID. In addition, a significant positive correlation was observed between mucosal IL-1ß mRNA and fasting gastric juice pH. Gastric pH values were significantly increased in H. pylori-infected patients with ID compared to uninfected children. CONCLUSIONS: The established association between H. pylori infection and ID in children may be mediated by increased gastric mucosal IL-1ß.