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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 < -0.5. A pepsinogen I:II ratio <3 was considered indicative of AG., Results: AG was identified in 15% of participants and associated with significantly lower serum total vitamin B-12 (P < 0.001) and plasma holotranscobalamin (holoTC; P < 0.001), and higher prevalence of vitamin B-12 deficiency (38%), compared with PPI users (21%) and controls (without AG and nonusers of PPIs; 15%; P < 0.001). PPI drugs were used (≥6 mo) by 37% of participants and were associated with lower holoTC concentrations, but only in participants taking higher doses (≥30 mg/d). Regular, compared with nonregular, consumption of fortified foods (i.e., ≥5 and 0-4 portions/wk, respectively) was associated with higher vitamin B-12 biomarkers in all participants, but inadequate to restore normal vitamin B-12 status in those with AG., Conclusions: Older adults who have AG and/or use higher doses of PPIs are more likely to have indicators of vitamin B-12 deficiency. Fortified foods, if consumed regularly, were associated with enhanced vitamin B-12 status, but higher levels of added vitamin B-12 than currently provided could be warranted to optimize status in people with AG., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

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., Competing Interests: The authors declare no conflict of interest.

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.

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., (© 2016 The British Pharmacological Society.)

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., (© 2016 The Authors. Journal of Orthopaedic Research Published by by Wiley Periodicals, Inc.)

Background: Gastrointestinal (GI) inflammation in mice and men are frequently accompanied by distinct changes of the GI microbiota composition at sites of inflammation. Helicobacter (H.) pylori infection results in gastric immunopathology accompanied by colonization of stomachs with bacterial species, which are usually restricted to the lower intestine. Potential microbiota shifts distal to the inflammatory process following long-term H. pylori infection, however, have not been studied so far., Methodology/principal Findings: For the first time, we investigated microbiota changes along the entire GI tract of Mongolian gerbils after 14 months of infection with H. pylori B8 wildtype (WT) or its isogenic ΔcagY mutant (MUT) strain which is defective in the type IV secretion system and thus unable to modulate specific host pathways. Comprehensive cultural analyses revealed that severe gastric diseases such as atrophic pangastritis and precancerous transformations were accompanied by elevated luminal loads of E. coli and enterococci in the caecum and together with Bacteroides/Prevotella spp. in the colon of H. pylori WT, but not MUT infected gerbils as compared to naïve animals. Strikingly, molecular analyses revealed that Akkermansia, an uncultivable species involved in mucus degradation, was exclusively abundant in large intestines of H. pylori WT, but not MUT infected nor naïve gerbils., Conclusion/significance: Taken together, long-term infection of Mongolian gerbils with a H. pylori WT strain displaying an intact type IV secretion system leads to distinct shifts of the microbiota composition in the distal uninflamed, but not proximal inflamed GI tract. Hence, H. pylori induced immunopathogenesis of the stomach, including hypochlorhydria and hypergastrinemia, might trigger large intestinal microbiota changes whereas the exact underlying mechanisms need to be further unraveled.

Objectives: Secretin stimulation testing (SST) is used to evaluate patients with hypergastrinemia in the diagnosis of Zollinger-Ellison syndrome. Case series have documented false-positive SST in patients with achlorhydria. This study reviews our experience with SST in hypochlorhydric and achlorhydric patients., Methods: We examined 27 patients with hypochlorhydria or achlorhydria based on a predefined basal acid output (BAO) measurement of less than 5.0 mEq/h who also underwent SST for diagnosis of Zollinger-Ellison syndrome. We report the frequency of false-positive SST results in this setting., Results: Three hundred thirty patients underwent gastric analysis of which 27 had BAO of less than 5.0 mEq/h and SST conducted. The mean (SD) fasting gastrin level was 247 (304) pg/mL, and the mean (SD) BAO measurement was 1.6 (1.8) mEq/h. Twenty patients were off, and 7 were on antisecretory therapy at time of testing. Four patients had false-positive SST results: 3 with gastric atrophy (BAO = 0 mEq/h) and 1 with drug-induced hypochlorhydria (BAO = 0.5 mEq/hr). These false-positive test results were confirmed by structural and functional imaging studies., Conclusions: We have identified a 14.8% false-positive rate in SST in patients with hypochlorhydria or achlorhydria. Growing literature has identified severe consequences associated with discontinuing antisecretory treatment for testing; therefore, SST will require interpretation in the setting of gastric acid suppression and needs to be interpreted in this context.

Background: Gender and gastric acid have been suggested to be independently involved in the pathophysiology of functional dyspepsia, but the interrelationship among gender, dyspeptic symptoms, and gastric acid secretion remains to be evaluated. We sought to explore this issue in dyspeptic patients., Methods: A total of 89 outpatients (male, 36; mean age, 55.6 years) with dyspeptic symptoms were analyzed. The degree of dyspeptic symptoms was evaluated and scored using a symptom questionnaire consisting of 3 subcategories: dysmotility-related symptoms, reflux-related symptoms, and epigastric pain-related symptoms. Stimulated gastric acid secretion was directly measured using an endoscopic gastrin test., Results: The total symptom scores and the epigastric pain-related symptom scores were significantly higher in female patients than in male patients. The dysmotility-related and reflux-related symptom scores were also higher, but not significantly, in the female patients. Multiple regression analysis of age, gender, habitual drinking, smoking, Helicobacter pylori infection, and gastric acid secretion revealed that gender and gastric hypochlorhydria, defined as less than 2.1 mEq/10 min in the endoscopic gastrin test, were significantly associated with higher dyspeptic symptom scores. The total scores and the dysmotility-related scores were significantly higher in the patients with gastric hypochlorhydria than in those with gastric non-hypochlorhydria, and this difference was found to be present only in females., Conclusions: Gastric hypochlorhydria in female dyspeptic patients may be involved in the exacerbation of dyspeptic symptoms. Differences in the responsiveness to gastric hypochlorhydria between males and females may be partly responsible for the gender differences in the prevalence and severity of dyspeptic symptoms.

Background and Aims: Atrophic gastritis (AG) results most often from Helicobacter pylori (H. pylori) infection. AG is the most important single risk condition for gastric cancer that often leads to an acid-free or hypochlorhydric stomach. In the present paper, we suggest a rationale for noninvasive screening of AG with stomach-specific biomarkers., Methods: The paper summarizes a set of data on application of the biomarkers and describes how the test results could be interpreted in practice., Results: In AG of the gastric corpus and fundus, the plasma levels of pepsinogen I and/or the pepsinogen I/pepsinogen II ratio are always low. The fasting level of gastrin-17 is high in AG limited to the corpus and fundus, but low or non-elevated if the AG occurs in both antrum and corpus. A low fasting level of G-17 is a sign of antral AG or indicates high intragastric acidity. Differentiation between antral AG and high intragastric acidity can be done by assaying the plasma G-17 before and after protein stimulation, or before and after administration of the proton pump inhibitors (PPI). Amidated G-17 will rise if the antral mucosa is normal in structure. H. pylori antibodies are a reliable indicator of helicobacter infection, even in patients with AG and hypochlorhydria., Conclusions: Stomach-specific biomarkers provide information about the stomach health and about the function of stomach mucosa and are a noninvasive tool for diagnosis and screening of AG and acid-free stomach.

Unlabelled: Gastric juice is a unique combination of hydrochloric acid and the proteolytic enzyme pepsin. Its main function is to inactivate ingested microorganisms. Prions cause fatal transmissible degenerative encephalopathies in animals and man. These diseases have attracted attention due to the proposed link between bovine spongiform encephalopathy in cattle and the occurrence of a new variant Creutzfeldt-Jakob disease in humans where the most probable route of transmission is via contaminated food. The role of gastric juice in the protection against these agents is not settled., Objective: The aim of this study was to examine if drug-induced gastric hypoacidity increases the susceptibility of prion infection transmitted by the oral route., Material and Methods: Forty-six mice (tg338) were given brain homogenates contaminated with scrapie by gastric intubation. Twenty-two of these animals were concomitantly dosed with omeprazole increasing the median gastric pH from 1.2 to 5.3. After 381 days, the animals were sacrificed and all the brains were examined for detection of pathogenic prion proteins by enzyme-linked immunosorbent assay and western blot., Results: Drug-induced decrease in gastric acidity more than doubled the rate (59% vs. 25%, p < 0.035) of brain infection compared to controls with normal gastric acidity at the time of inoculation., Conclusions: Our results demonstrate that the normal gastric juice constitutes a significant defense against prion disease in mice. Thus, gastric hypochlorhydria would be expected to enhance the susceptibility to prion infection by the oral route. This finding may have relevance to the pathogenesis of the new variant Creutzfeldt-Jakob disease and prion diseases in general.

Pernicious anemia is a macrocytic anemia due to cobalamin deficiency, which is the result of intrinsic factor deficiency. Pernicious anemia is associated with atrophic body gastritis, whose diagnostic criteria are based on the histologic evidence of gastric body atrophy associated with hypochlorhydria. Serological markers suggesting the presence of oxyntic mucosa damage are increased levels of fasting gastrin and decreased levels of Pepsinogen I. Without the now obsolete Schilling's test, intrinsic factor deficiency may not be proven, and gastric intrinsic factor output after pentagastric stimulation has been proposed. Intrinsic factor autoantibodies are useful surrogate markers of pernicious anemia. The management of patients with pernicious anemia should focus on the life-long replacement treatment with cobalamin and the monitoring to early diagnose an eventual onset of iron deficiency. Moreover, these patients should be advised about possible gastrointestinal long-term consequences, such as gastric cancer and carcinoids.

Background/aims: Previous studies have suggested that hypochlorhydria has the potential to produce adverse effects such as the development of infections of the intestinal or respiratory tract and impaired drug absorption. This indicates the importance of obtaining a noninvasive method by which this condition may be diagnosed. The purpose of this study was to determine whether fasting gastric pH could be predicted noninvasively using serum biological markers., Methodology: One hundred thirty-two patients undergoing diagnostic upper gastrointestinal endoscopy were recruited. Serum levels of pepsinogen-I, pepsinogen-II and Helicobacter pylori antibody were analyzed and the pH of fasting gastric juice determined. Multiple linear regression analysis was used to determine the best predictors of fasting gastric pH., Results: Pepsinogen-I and the presence of Helicobacter pylori were independent predictors of fasting gastric pH, and a high coefficient of determination was obtained (R2 = 0.503, root mean square error = 1.45). The equation for this model was as follows: fasting gastric pH = 2.97-0.026 (pepsinogen-I)+2.76 (presence of Helicobacter pylori: 0=absent, 1=present)., Conclusions: The model equation offers a noninvasive method by which to identify patients at high-risk of developing complications induced by hypochlorhydria.

Objective: Hypergastrinemia is known to induce enterochromaffin-like (ECL) cell derived tumors in rodents and man. In this study, we have examined the effect of life-long gastric anacidity and secondary hypergastrinemia in H(+)/K(+)-ATPase beta subunit knockout (KO) mice., Material and Methods: Female H(+)/K(+)-ATPase beta subunit KO mice and controls were followed up to 20 months before being sacrificed. At termination, intragastric acidity was measured and internal organs were examined for macroscopic and histological changes. Plasma gastrin and serum albumin were measured., Results: KO mice were anacidic and hypergastrinemic. The oxyntic mucosa was markedly, and with increase in age, hyperplastic with cystic dilatations resembling the changes seen in patients with Menetrier's disease. Serum albumin in KO mice did not differ from controls. KO mice had a marked ECL cell hyperplasia, but only one gastric carcinoma was found., Conclusion: H(+)/K(+)-ATPase beta subunit KO mice develop Menetrier-like changes in the stomach, and may be useful in studying the pathogenesis and treatment of Menetrier's disease. The reason why only one KO mice developed gastric neoplasia whereas the histamine-2 blocker loxtidine has previously been found to regularly induce ECL cell carcinoids in mice is not known.

Background & Aims: Pernicious anemia (PA) is characterized by vitamin B-12 deficiency and achlorhydria, both of which have a detrimental effect on bone strength. The principle aim of this study was to determine the risk of hip fracture in patients with PA., Methods: This is a retrospective cohort study using the General Practice Research Database (GPRD) from the United Kingdom. GPRD data from May 1987 until April 2002 were utilized to identify patients between 40 and 90 years of age at the time of GPRD enrollment. The exposed group contained patients with a diagnosis of PA being treated with vitamin B-12 therapy. We matched each patient having a diagnosis of PA with 4 randomly selected non-PA patients with respect to age (+/-1 year) and sex. Cox regression analysis was used to determine the hazard ratio (HR) for hip fracture associated with PA., Results: Nine thousand five hundred six patients with a diagnosis of PA receiving vitamin B-12 injection therapy were identified and compared to 38,024 controls. Patients with PA had a greater risk of hip fracture than the controls (HR = 1.74; 95% CI: 1.45-2.08). The increase in hip fracture risk was even more pronounced among those patients newly diagnosed with PA during GPRD follow-up (HR = 2.63; 95% CI: 2.03-3.41)., Conclusions: Patients with a diagnosis of PA have an elevated risk of hip fracture. The increased hip fracture risk was persistent even years after vitamin B-12 therapy. Chronic achlorhydria could be the mechanism contributing to the persistently elevated hip fracture risk., (2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Malabsorption of dietary calcium is a cause of osteoporosis. Dissolution of calcium salts (e.g. calcium carbonate) in the stomach is one step in the proper active and passive absorption of calcium as a calcium ion (Ca(2+)) in the proximal small intestine. Stomach acid markedly increases dissolution and ionization of poorly soluble calcium salts. If acid is not properly secreted, calcium salts are minimally dissolved (ionized) and, subsequently, may not be properly and effectively absorbed. Atrophic gastritis, gastric surgery, and high-dose, long-term use of antisecretory drugs markedly reduce acid secretion and may, therefore, be risk conditions for malabsorption of dietary and supplementary calcium, and may thereby increase the risk of osteoporosis in the long term.

Objective: There is an increased risk of gastrointestinal carcinoma and smoking-related diseases after partial gastrectomy for peptic ulcer disease. The purpose of this study was to evaluate long-term cancer incidence and mortality after parietal cell vagotomy (PCV), a surgical method with a low rate of side effects, but creating hypochlorhydria in the stomach mimicking long-term treatment with antisecretory drugs., Material and Methods: Data on 383 ulcer patients operated on with PCV during 1971-80 at Lund University Hospital were compared with the national registers for cause of death and cancer incidence for selected diagnoses. Median follow-up was 28 years and 31 years, respectively. Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) were calculated., Results: An increased incidence of cancer in the respiratory organs (SIR 1.97, 95% CI: 1.08-3.31) and prostate carcinoma (SIR 1.85, 95% CI: 1.22-2.69) was found, and among men also an increased mortality in prostate carcinoma (SMR 3.85, 95% CI: 1.41-8.38) and chronic respiratory disease (SMR 2.76, 95% CI: 1.01-6.02). Overall mortality was similar to that of the background population and no increased risk of gastrointestinal malignancies was observed., Conclusions: Patients with peptic ulcer operated on with PCV have a long-term increased risk of smoking-related diseases, but PCV does not seem to increase the risk of gastrointestinal carcinoma. An increased risk of, and mortality in prostate carcinoma was found, a cancer previously not found to be related to smoking. This might be the result of surgery-induced hypochlorhydria, which warrants further investigation in patients on long-term proton-pump inhibitors.

Postoperative ileus, a delay of gastrointestinal (GI) motility beyond 3 days, is common in patients after GI surgery. This disorder increases length of hospital stay and costs millions of dollars annually. This study was done to determine clinical factors associated with paralytic ileus. An interdisciplinary team developed a data collection tool based on eight hypotheses derived from a review of literature on factors that contribute to ileus. In a retrospective medical record review of 101 patients who had abdominal surgery, 44 developed postoperative ileus and 57 did not. Data analysis found that three factors were statistically significant in reducing ileus: (1) early postoperative introduction of fluids and food, (2) avoidance of positive fluid balance exceeding 1,000 ml, and (3) avoiding potassium elevations over a 3-day period. A trend identified that the use of nonsteroidal anti-inflammatory drugs could reduce the incidence of ileus. Clinical implications include the importance of encouraging early oral intake, monitoring fluid intake and output in postoperative patients, and identifying positive fluid balance early to prevent it from continuing.

Purpose: To evaluate a 15-year-old boy with MLIV (mucolipidosis type IV) and clinical abnormalities restricted to the eye who also had achlorhydria with elevated blood gastrin levels., Methods: In addition to a detailed neuro-ophthalmic and electrophysiological assessment, his mutant mucolipin-1 was experimentally expressed in liposomes and its channel properties studied in vitro., Results: The patient was a compound heterzygote for c.920delT and c.1615delG. Detailed neuro-ophthalmic examination including electroretinography showed him to have a typical retinal dystrophy predominantly affecting rod and bipolar cell function. In vitro expression of MCOLN1 in liposomes showed that the c.1615delG mutated channel had significantly reduced conductance compared with wild-type mucolipin-1, whereas the inhibitory effect of low pH and amiloride remained intact., Conclusions: These findings suggest that reduced channel conductance is relatively well tolerated by the brain during development, whereas retinal cells and stomach parietal cells require normal protein function. MLIV should be considered in patients with retinal dystrophy of unknown cause and screened for using blood gastrin levels.

Gastric hypoacidity and hypergastrinaemia are seen in several conditions associated with an increased risk of gastric malignancy. Hypoacidity and hypergastrinaemia are closely related and their long-term effects are difficult to study separately in patients. Studies using animal models can provide valuable information about risk factors and mechanisms in gastric cancer development as the models allow a high degree of intervention when introducing or eliminating factors possibly affecting carcinogenesis. In this report, we briefly review findings from relevant animal studies on this topic. Animal models of gastric hypoacidity and hypergastrinaemia provide evidence hypergastrinaemia is a common causative factor in many otherwise diverse settings. In all species where sufficient hypoacidity and hypergastrinaemia have been induced, a proportion of the animals develop malignant lesions in the gastric oxyntic mucosa.

Background: Patients infected by Helicobacter pylori who have first-degree relatives with gastric cancer have an 8-fold increased risk of developing gastric cancer themselves. Mucins are high-molecular-weight glycoproteins that play a cardinal role in the protective mechanism of the gastric epithelium., Aim: To study gastric acid and mucin secretion in dyspeptic patients with and without a family history of gastric cancer and H. pylori infection., Materials and Methods: Twenty-six dyspeptic patients underwent esophago-gastro-duodenoscopy, gastric biopsies, and acid and mucin secretory tests. The sample was divided by family history of gastric cancer and H. pylori status., Results: Patients who were infected by H. pylori had a significantly higher degree of inflammation than those who were not. H. pylori-positive patients with a positive family history had a lower basal and maximal gastric acid output than infected patients with no family history and noninfected controls, and a higher basal and maximal mucin output than infected patients with no family history. MUC5AC was the major mucin species expressed in gastric juice., Conclusions: In patients with relatives with gastric cancer, H. pylori infection is associated with a more severe inflammatory reaction consisting of decreased gastric acid secretion and increased mucin secretion.

The authors review the complex biological reality of gastric adenocarcinoma from several viewpoints. It is a neoplasm histologically expressed as a dual process (intestinal and diffuse types) with a broad cytological diversity. From an epidemiological point of view, it behaves as an entity with a deep geographical asymmetry and a changing incidence, currently decreasing. There is a multifactorial etiology with a combination of genetic, infectious (H. pylori), nutritional and environmental factors. It might have a multiphasic gestation from precancerous lesions, though not always following a lineal sequence. We only know fragmentary portions of its pathogenesis whose common denominator is a potentially mutagenic mitogenic activation of the epithelial cells implicated. A good knowledge of this complex biological reality will allow the identification of better markers for an early diagnosis as well as vulnerable etiopathogenetic points for a useful prevention and therapy.

Proton pump inhibitors are potent drugs producing profound suppression of gastric acid secretion. Consequently, they are highly effective at treating acid-related disorders. There have been concerns that the suppression of gastric acid will alter the bacterial flora of the upper gastrointestinal tract and lead to complications such as cancer, enteric or other infections and malabsorption. Studies have confirmed that proton pump inhibitors do alter the bacterial population but present evidence indicates that this only rarely leads to clinical disease. As with all drugs, proton pump inhibitors should only be used for disorders shown clearly to benefit from the therapy and where the benefits will outweigh the small risks associated with them. Further research to more fully quantify the risk associated with PPI therapy is required.

Gastrin and gastrin receptor-deficient mice have been used for genetic dissection of the role of gastrins in maintaining gastric homeostasis and control of acid secretion. The gastrin knockout mice are achlorhydric due to inactivation of the ECL and parietal cells. Moreover, this achlorhydria is associated with intestinal metaplasia and bacterial overgrowth, which ultimately leads to the development of gastric tumours. The association between progastrin, progastrin-derived processing intermediates and colorectal carcinogenesis has also been examined through genetic or chemical cancer induction in several mouse models, although the clinical relevance of these studies remains unproven. While others have focused on models of increased gastrin production, the present review describes the lessons learned from gastrin-deficient mice. Study of these mice helps our understanding of how dysregulation of gastrin secretion may be implicated in human disease.

We describe a 54-year-old woman who had multiple gastric carcinoid tumors arising in the setting of marked hypergastrinemia associated with a lack of acid production by hypertrophic parietal cells. The serum gastrin level was 1,400 pg/mL, and investigation revealed no evidence for either of the recognized causes for hypergastrinemia-associated carcinoids, autoimmune gastritis, and Zollinger-Ellision syndrome. Partial gastrectomy was performed. Pathologic examination showed multiple intramucosal and invasive carcinoid tumors of the body and fundus in a background of marked ECL cell hyperplasia. There were no gastric or duodenal ulcerations. One perigastric lymph node was metastatically involved. The oxyntic mucosa showed marked hyperplasia and hypertrophy of the parietal cells. Some of these cells were vacuolated, and many displayed protrusions of apical cytoplasm into dilated oxyntic glands filled with inspissated eosinophilic material. Similar findings have occurred in 1 other patient, strongly indicating that the clinicopathologic alterations in the 2 cases are not random but, on the contrary, represent a very rare disorder of gastric carcinoids associated with an intrinsic acid secretion abnormality of the parietal cells.

Background & Aims: Apart from its importance as an acid secretogogue, the role of histamine as a downstream target of gastrin has not been fully explored. Previous studies have shown that the combination of hypergastrinemia and Helicobacter infection resulted in accelerated gastric cancer in mice. We used this model to examine the role of cholecystokinin 2 (CCK2)/gastrin receptor and histamine H2-receptor signaling in the development of gastric atrophy and cancer., Methods: Male hypergastrinemic mice (INS-GAS mice) were infected with Helicobacter felis and given the CCK2/gastrin receptor antagonist YF476 and/or the histamine H2-receptor antagonist loxtidine for 3 or 6 months. In addition, mice were treated with omeprazole alone or in combination with either YF476 or loxtidine for 3 months., Results: Mice treated with YF476 or loxtidine alone showed partial suppression of both gastric acid secretion and progression to neoplasia. The combination of YF476 plus loxtidine treatment resulted in nearly complete inhibition of both parameters. YF476 and/or loxtidine treatment did not alter the overall level of H. felis colonization but did result in significant down-regulation of the growth factors regenerating gene I and amphiregulin. Loxtidine treatment, with or without YF476, induced a mild shift in T-helper cell polarization. In contrast, omeprazole treatment resulted in mild progression of gastric hyperplasia/dysplasia, which was ameliorated by the addition of YF476 or loxtidine., Conclusions: The combination of CCK2/gastrin- and histamine H2-receptor antagonists has synergistic inhibitory effects on development of gastric atrophy and cancer in H. felis/INS-GAS mice, while the proton pump inhibitor showed no such effects. These results support an important role for the gastrin-histamine axis in Helicobacter-induced gastric carcinogenesis.

Background/aim: Chronic atrophic gastritis of the body-fundus with hypo-achlorhydria has been long since considered the precursor of gastric cancer (GC). A study has been made about the histological pattern of the body-fundic mucosa (oxyntic area) in course of preneoplastic lesions (epithelial dysplasia), associated or progressed to gastric cancer, in order to evaluate the real association with chronic atrophic gastritis and, therefore, with a reduced acid secretion., Methodology: The study of the histological condition of the body-fundic mucosa and of the acid secretion has been effected in 120 cases of epithelial dysplasia (ED) from January 1990 to November 1997. The casuistry is composed of 70 cases of low grade dysplasia (LGD) and 50 cases of high grade dysplasia (HGD). Gastric biopsy specimens were studied for dyspepsia: for each patient, at least 8 specimens were obtained from the lesion area and in surrounding areas. Besides, at least 4 biopsies have been performed in the opposite gastric region. ED diagnosis was effected according to well defined criteria. The histological study of gastric mucosa in gastritis was effected or revised in accordance with the updated Sydney system (Houston). Stimulated acid secretion was expressed as Maximal Acid Output (MAO), which is the amount of HCl produced in one hour, following stimulation with pentagastrin (6 micro-g/kg). The clinical outcome subdivision of ED was made using the criteria of Rugge et al. (12)., Results: HGD significantly associates with GC in comparison with LGD. The histological evaluation of the oxyntic area shows severe chronic atrophic gastritis (SCAG) in a low percentage of cases (15/120: 12.5%): LGD 9/70: 12.85% ; HGD 6/50: 12%. Complete achlorhydria has been noted in 5 cases of LGD and in 1 case of HGD only. In case of GC (43 subjects) SCAG has been evidenced in 10 cases and complete achlorhydria in 5 cases., Conclusions: From the data of the present experience emerges that the presence of SCAG of the oxyntic area in course of ED or early GC is limited to a low percentage of cases. Such concepts induce to modify some indications related to the endoscopic surveillance and, in accordance with the American Society of Gastrointestinal Endoscopy we are stating that there are no sufficient data to support subsequent endoscopic surveillance for the subjects with atrophic gastritis.

Background/aims: Data from previous studies on gastric acid secretion and the prevalence of H. pylori in liver cirrhosis patients remain poorly defined. H. pylori is a potential source of NH3, but the possible role of H. pylori in hepatic encephalopathy is not clear. The purpose of this study was to compare gastric acid secretion, the impact of H. pylori infection, and the production of NH3 between cirrhotic patients and healthy, matched controls., Methods: Twenty-nine patients with liver cirrhosis (HBV, n=12; Alcohol, n=12; HCV, n=5) were matched with 33 healthy persons for age and sex. None of the patients or controls were being treated with antacids, H2-receptor blockers or proton pump inhibitors. The pH and NH3 concentration was measured in gastric juice obtained by endoscopy. H. pylori infection was diagnosed using the rapid urease test. The level of NH3 in venous blood was also measured., Results: The average gastric pH was significantly higher in cirrhosis patients compared to controls (3.91 vs. 2.99, P<0.05). In addition, the prevalence of hypochlorhydria (defined as pH>4) was significantly greater in cirrhosis patients (45 vs. 21%, P<0.05). In contrast, the prevalence of H. pylori infection (62% vs. 58%) and gastric NH3 concentrations (3.4 vs. 3.3 mM/L) were similar between both groups. However, venous NH3 levels were significantly higher in cirrhotics than in controls (63.1 vs. 25.2 microM/L, P<0.05). The patients with H. pylori infection had significantly higher gastric NH3 concentration (3.8 vs. 1.6 mM/L) and gastric pH (3.87 vs. 2.76, P<0.05) than those without infection, but no significant difference in venous NH3 levels were detected (39.6 vs. 48.1 microM/L). In patients with cirrhosis, the presence of H. pylori infection was not correlated with either gastric or blood NH3 levels., Conclusions: The gastric pH of liver cirrhosis patients is higher than that of controls and a larger proportion of cirrhotic patients have hypochlorhydria. The prevalence of H. pylori in liver cirrhosis patients was similar to that in controls and no correlation was found between gastric and blood NH3 levels. Thus, H. pylori infection does not seem to play a major role in generation of elevated NH3 associated with hepatic encephalopathy.

Background: Although profound hypochlorhydria is considered to be an important risk factor for development of gastric cancer, long-term effect of Helicobacter pylori eradication on its reversibility remains uncertain., Aim: To clarify the change in acid secretion after eradication in a long-term follow-up over 5 years in patients with profound hypochlorhydria., Methods: Twenty-three H. pylori-positive patients with hypochlorhydria (<0.6 mmol/10 min) were enrolled prospectively. Assessment of gastrin-stimulated acid output and histologic evaluation of biopsy specimens were performed prior to, and 1, 7 months after eradication. Subsequently, gastric acid secretion was assessed for long-term period over 5 years after eradication in 12 patients., Results: Gastric acid secretion was reversed to normal range in nine of 23 patients (39%) at 7 months after eradication. In the long-term follow-up, gradual and significant recovery in gastric acid secretion was observed up to 2 years post-therapy. However, there was no additional increase during the last 3 years of 5-year follow-up period, leaving the acid secretory levels subnormal in the majority of the patients., Conclusions: This long-term follow-up study suggests that the pathologic process has already progressed to an irreversible stage in the majority of H. pylori-positive patients with marked body atrophy and profound hypochlorhydria.

Gastric cancer is a worldwide cancer especially frequent in Japan and South America. This cancer affects 10 to 70 people per 100,000 according to the countries. Since the end of the Second World War, the incidence of gastric cancer has been decreasing in France and accounts for less than 10 % of mortality. Helicobacter pylori infection, host genetic background, food regimen are known to be involved in this cancer. Helicobacter pylori should be eradicated in selected patients, such as patients' relatives with documented gastric cancer as well as patients having another gastrointestinal cancer.

A 49-year-old man presented with a 3-week history of vomiting and diarrhea. He reported foamy stools but no blood or melena and had crampy epigastric pain. He denied usage of antibiotics. He had been taking ranitidine for intermittent epigastric pain for the last few months and noted an 11-pound weight loss during the 3 weeks before admission. Stool was positive for Clostridium difficile toxin and Giardia lamblia antigen. Cultures and occult blood tests were negative. Oral metronidazole, 500 mg 3 times a day, was administered, and the patient was hydrated. The diarrhea resolved, and patient was discharged on the fourth hospital day. Prior antibiotic therapy is the most common risk factor for C difficile colitis. This patient developed concomitant infection with C difficile and G lamblia while he used ranitidine. He had no other risk factors for these infections. Hence, we propose that ranitidine-induced hypochlorhydria predisposed this patient to the enteric infections.

Gastric bacteria can either be ingested or ascend from the distal bowel; however, their survival is usually limited by gastric acidity and motility. A reduction in gastric acid can result in bacterial overgrowth in the stomach and proximal small bowel, and the number of organisms rises as the intragastric pH rises. The increased risk of noncardia gastric cancer seen in patients with hypochlorhydria may be explained by an excess of nitrites and N-nitroso compounds (NOCs). These compounds are found in the diet of populations with a high gastric cancer risk, but can also be produced by the organisms that exist in the hypochlorhydria stomach. It has long been hypothesized that nitrites and NOCs act as one of the triggers in the atrophy-metaplasia-dysplasia-carcinoma path. However, although indirect data have linked the premalignant changes of metaplasia and dysplasia to NOCs, direct measurement of gastric nitrites and NOCs has not confirmed such a link. The role of Helicobacter pylori in bacterial overgrowth is mainly as a cause of hypochlorhydria resulting from atrophic gastritis, leading to a reduction in the parietal cell mass. Acid-suppressing drugs can result in bacterial overgrowth and increased nitrites and NOCs, although there is no current evidence for an increased risk of gastric cancer in patients taking them. One explanation is that the stomach appears to be colonized by different organisms than those in patients with hypochlorhydria for other reasons. There is some evidence that bacterial overgrowth per se can cause gastric inflammation in mice; however, although in humans the degree of gastric inflammation is greater when overgrowth is more prominent this may simply reflect the greater degree of hypochlorhydria in patients with a more severe H pylori-induced inflammation.

Unlabelled: Iron deficiency may be the only presenting sign of malabsorption due to the presence of intestinal villous atrophy. Once gastrointestinal blood losses have been excluded, intestinal malabsorption should be investigated., Objectives: To determine the utility of jejunal biopsy in the evaluation of iron deficiency due to a defective absorption and the different diseases that may cause malabsortive iron deficiency., Methods: Seventy patients with iron deficiency (ferritin<25 ng/ml), referred to the Unitat de Proves Funcionals Digestives to perform a jejunal biopsy were included. Jejunal biopsy was obtained distal to Treitz with a Watson capsule. Histological changes were classified according to the criteria proposed by Marsh., Results: Jejunal biopsy was performed in 66 patients. Histology was normal in 25, unespecific in 1, showed inflammatory infiltrate in 12, hyperplastic changes in 2 and atrophy in 25. In one patient showed intestinal giardiasis. The clinical diagnosis was celiac sprue in 21 patients (32%), aclorhydria in 7 (10.5%), bacterial overgrowth in 1 (1.5%), intestinal giardiasis in 1 (1.5%), menstrual blood loss in 1 (1.5%) and 35(53%) patients remained without a definitive diagnosis., Conclusions: Jejunal biopsy is useful in the evaluation of iron deficiency due to intestinal malabsorption and reveals intestinal abnormalities in a significant number of cases.

Gastric cancer is the second commonest cause of death from malignancy in the world. Its pathogenesis is comparatively well understood and its aetiology multifactorial. Non-cardia gastric cancer usually arises in a stomach that has been inflamed over a long period and where atrophy and intestinal metaplasia have supervened. The commonest cause of gastric inflammation is infection with Helicobacter pylori. Colonization with this organism increases the relative risk of developing this cancer by about six [Helicobacter and Cancer Collaborative Group. Gut 2001; 49: 347-53]. Its likelihood increases with the severity and extent of the gastritis. Severity is influenced by the virulence of the infecting organism, the genetics of the host, bile reflux, dietary factors and the presence of hypochlorhydria which influences the extent, as well as the severity, of the inflammation. The only predisposing factor which can easily be manipulated is H. pylori infection, which can be successfully treated in 80-90% of cases using a 1-week therapeutic regimen.

In the present study we evaluated the relation among histology, H. pylori, IgG to H. pylori, gastric emptying, and acid secretion in 43 patients with fundic atrophic gastritis. On the basis of gastric acid secretion, patients were divided into three subgroups: patients with preserved acid secretion (Group 1), patients with hypochlorhydria (Group 2), and patients with achlorhydria (Group 3). Fundic glandular atrophy was more severe in hypoachlorhydric patients than in those with preserved acid secretion (P < 0.05 vs Group 2, P < 0.005 vs Group 3). H. pylori colonization was found in 94% of patients in Group 1, in 61% of patients in Group 2, and in only 8% of patients in Group 3 (P < 0.001 vs Group 1, P < 0.05 vs Group 2). Conversely, serological positivity to H. pylori was high in all three subgroups of patients (100% in Group 1, 77% in Group 2, 92% in Group 3). Gastric emptying was delayed in atrophic patients, particularly in those with hypoachlorhydria. Our data suggest that fundic atrophic gastritis represents a possible end stage of H. pylori infection, characterized by a progressive disappearance of the bacterium and a progressive deterioration of gastric functions.

Background: The common but incompletely understood entity of malabsorption of food bound cobalamin is generally presumed to arise from gastritis and/or achlorhydria., Aim: To conduct a systematic comparative examination of gastric histology and function., Subjects: Nineteen volunteers, either healthy or with low cobalamin levels, were prospectively studied without prior knowledge of their absorption or gastric status., Methods: All subjects underwent prospective assessment of food cobalamin absorption by the egg yolk cobalamin absorption test, endoscopy, histological grading of biopsies from six gastric sites, measurement of gastric secretory function, assay for serum gastrin and antiparietal cell antibodies, and direct tests for Helicobacter pylori infection., Results: The six subjects with severe malabsorption (group I) had worse histological scores overall and lower acid and pepsin secretion than the eight subjects with normal absorption (group III) or the five subjects with mild malabsorption (group II). However, histological findings, and acid and pepsin secretion overlapped considerably between individual subjects in group I and group III. Two distinct subgroups of three subjects each emerged within group I. One subgroup (IA) had severe gastric atrophy and achlorhydria. The other subgroup (IB) had little atrophy and only mild hypochlorhydria; the gastric findings were indistinguishable from those in many subjects with normal absorption. Absorption improved in the two subjects in subgroup IB and in one subject in group II who received antibiotics, along with evidence of clearing of H pylori. None of the subjects in group IA responded to antibiotics., Conclusions: Food cobalamin malabsorption arises in at least two different gastric settings, one of which involves neither gastric atrophy nor achlorhydria. Malabsorption can respond to antibiotics, but only in some patients. Food cobalamin malabsorption is not always synonymous with atrophic gastritis and achlorhydria, and hypochlorhydria does not always guarantee food cobalamin malabsorption.

It is well established that atrophic gastritis, pernicious anaemia and partial gastrectomy are associated with an increased risk of gastric carcinoma. These conditions all result in a low acid output state. Although the mechanism of gastric carcinogenesis is not known, the model proposed by Correa has provided the most attractive explanation to date. The suggestion is that prolonged hypochlorhydria predisposes to gastric carcinoma by an increase in the production of carcinogenic N-nitroso compounds. This hypothesis has led to concerns about the safety of long-term acid suppression in the management of a variety of acid-related gastrointestinal conditions.

Gastric acid stimulates the absorption of nutrients and is the most important non-immunological defence system against the constant bacterial invasion of our digestive tract. Patients with achlorhydria and resected stomachs have excessive growth of bacteria in the digestive tract and a much higher incidence of gastrointestinal infections. Modern treatment of reflux oesophagitis with acid secretion inhibitors creates a similar low acid state. Suppression of gastric acid secretion causes a dose dependent increased risk of a wide variety of intestinal infections especially for people over 65, immune compromised persons, sick patients with a reduced resistance and travellers to tropical areas. The potentially dangerous infections can be reduced by adequate counselling about the importance of gastric acid, the precaution of improved hygiene, on demand use of especially proton pump inhibitors and prescription of antacids and less potent acid inhibitors.

The impact on human health of Salmonella spp. on pork in The Netherlands is described. Subsequently, the effects of some currently proposed control strategies in the Dutch pork production chain are evaluated and quantified with the aid of a simple mathematical model. The estimated average incidence of cases of salmonellosis in the Netherlands is about 450 cases per 100,000 person years at risk (pyar). Some special risk groups for which the risks could be quantified are (1) persons with underlying diseases, such as neoplasms or diabetes mellitus (1200 cases/100,000 pyar); (2) persons with achlorhydria or who excessively use antacids (1100 cases/100,000 pyar); (3) persons who have recently been treated with antibiotics that disturb the normal gut flora (1700 cases/100,000 pyar); (4) nurses (900 cases/100,000 pyar); (5) caterers (900 cases/100,000 pyar); (6) slaughterline personnel (1800 cases/100,000 pyar). Furthermore, it is estimated that 15% (5-25%) of all cases of salmonellosis in The Netherlands are associated with the consumption of pork. Currently, proposed control measures regarding Salmonella in pigs and on pork in The Netherlands are codes of good manufacturing practices (GMP) that, in fact, formalize recommendations that can be found in many handbooks about pig breeding and pig slaughtering. When evaluated by a mathematical model constructed for this purpose, the proposed GMP codes from farm to cutting/retail could, at best, reduce the current levels of Salmonella-positive pigs and pork by 50-60%. If pigs were bred according to the rather costly specific pathogen-free concept (SPF), the prevalence of contaminated carcasses and pork could in total be reduced by 95% or more. However, implementing GMP codes from the transport phase up to the cutting/retail phase coupled with a decontamination step at the end of the slaughterline would be just as effective as GMP in combination with breeding using the SPF-concept. It is therefore concluded that the most efficient and cost-effective way of reducing the 'Salmonella problem' entailed by the consumption of pork would be to decontaminate carcasses under the precondition that the entire production chain strictly adheres to GMP principles. Therefore, the EU should also allow for more possibilities regarding the decontamination of carcasses than is currently the case. It is also concluded that current EU regulations relying on hazard analysis of critical control points (HACCP)-inspired production in cutting plants will not be effective in reducing the prevalence of Salmonella spp. on pork. This is mainly because (1) there is currently an almost steady stream of Salmonella-positive carcasses that enter the cutting process; (2) when contaminated carcasses are being processed, further cross-contamination during working hours is unavoidable; (3) no steps in the cutting process are intentionally designed to effectively reduce the risks or consequences of cross contamination of cuts and retail-ready products.

The effect of intraluminal acid and cholecystokinin (CCK) receptor blockade on the pancreatic secretory response was examined in rats. Blockade of gastric acid secretion by YM022 (CCK-B receptor antagonist) or famotidine (histamine-2 receptor antagonist) resulted in a significant suppression of casein-stimulated pancreatic exocrine secretion as determined by juice volume and amylase secretion. Ligation of the gastric pylorus, which leads to complete prevention of gastric acid from entering the duodenum, also suppressed pancreatic exocrine secretion. FK480 (CCK-A receptor antagonist) inhibited pancreatic exocrine secretion dose dependently at doses of 0.01-1.0 mg/kg. When submaximal doses of FK480 and YM022 were treated concomitantly, pancreatic exocrine secretion was inhibited more profoundly than when treated solely. Hydrochloric acid (HCl; 0.05 N), injected into the duodenum, stimulated pancreatic exocrine secretion to a level comparable to that exhibited by intraduodenal casein. This effect of HCl was inhibited by FK480 (1.0 mg/kg) but not by YM022 (1.0 mg/kg). These findings suggest that inhibition of gastric acid secretion leads to the suppression of pancreatic exocrine secretion through mechanisms mediated by CCK-A receptors.

Mucolipidosis type IV is an autosomal recessive lysosomal storage disease of unknown etiology that causes severe neurological and ophthalmological abnormalities. In an attempt to obtain insight into the nature of the metabolic abnormality in this disorder, we prospectively evaluated 15 consecutive patients, aged 2 to 23 years, over a period of 22 months. The finding of iron deficiency in some of the patients led us to the discovery that all patients but one had markedly elevated blood gastrin levels. None had vitamin B12 deficiency. Gastroscopy in three patients showed normal gross appearance of the mucosa in two patients, 4 and 7 years old, and mucosal atrophy in a 22-year-old. Parietal cells were present in normal numbers and contained large cytoplasmic inclusions that were confirmed immunohistochemically to be lysosomal in nature. Other gastric epithelial cells appeared normal. Parietal cells contained very few tubulovesicular membranes, suggesting cellular activation, whereas apical canaliculi appeared relatively nonactivated. Both subunits of the parietal cell H+/K+-ATPase were present, and both partially colocalized with f-actin at the apical membrane. We conclude that patients with mucolipidosis type IV are constitutively achlorhydric and have partially activated parietal cells. We hypothesize that the defective protein in this disease is closely associated with the final stages of parietal cell activation and is critical for a specific type of cellular vacuolar trafficking between the cytoplasm and the apical membrane domain.