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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.

Coronavirus disease 2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) which emerged in Wuhan, China in 2019 (1). Respiratory symptoms remain the most common clinical manifestations of COVID‐19. However, non‐respiratory symptoms are increasingly being recognized. Gastrointestinal (GI) symptoms such as anorexia, nausea, vomiting, diarrhea, and abdominal pain are noted in COVID‐19 patients either alone or in association with respiratory manifestations (2). Stool viral RNA can be detected by up to 50% in patients with diarrhea (3). This article is protected by copyright. All rights reserved.

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.

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.

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.

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.

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.

Background: Helicobacter pylori-infection has been associated with an imbalance of iron homeostasis. IL-1 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-1 cluster and gastric IL1β mRNA expression in H. pylori-infected children and their relationship with hypoclorhydria 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-1 cluster (positions -511, -31, +3954, ILRN) were determined by PCR-RFLP. Gastric mucosal expression of IL-1 mRNA was determined by RT-PCR. Results: After exclusions, out of 105 patients, 33 (31.4%) were H. pylori positive. Nine (8.6%) children were classified as iron deficient (ID). H. pylori positivity was associated with ID (OR: 5.1; 95% CI: 1.2-21.9) (p = 0.04). No significant differences were found in allele frequency for IL1β gene cluster polymorphisms between infected and uninfected children. H. pylori-infected children with ID had significantly increased gastric IL1β mRNA in comparison to infected children without ID. In addition a significant positive correlation was observed between mucosal IL-1β 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-1.

Background and Aim Autoimmune gastritis (AIG), an organ-specific autoimmune disease, is accompanied by achlorhydria, pernicious anemia, gastric carcinoid tumors, and gastric cancer. Patients with AIG initially respond to corticosteroids but have a great potential to relapse after treatment is withdrawn. This study examines the roles of cytokines in order to identify potential therapeutic options for AIG patients. Methods Using a mouse model of AIG, we monitored disease progression and administered antibodies in vivo to block cytokines. Results We developed a mouse model of AIG with early onset and rapid progression in which neonatal thymectomy (NTx) was performed on programmed cell death 1-deficient (PD-1−/−) mice on the BALB/c background. Using NTx–PD-1−/− mice, we found that in AIG lesions, interferon-γ, and tumor necrosis factor (TNF)-α together with interleukin-21 (IL-21) were highly expressed in the inflamed gastric mucosa. In addition, as with the injection of dexamethasone, in vivo administration of either anti-TNF-α or anti-IL-21 suppressed the development of AIG in NTx–PD-1−/− mice. Conclusions These data reveal the essential role of IL-21 in the development of AIG and suggest that in addition to corticosteroids, anti-TNF-α as well as anti-IL-21 have the potential to induce the remission of AIG, offering additional therapeutic options for AIG patients.

Background: Acetaldehyde, associated with alcohol consumption, has recently been classified as a group 1 carcinogen in humans. Achlorhydric atrophic gastritis is a well-known risk factor for gastric cancer. Achlorhydria leads to microbial colonization of the stomach. Several of these microbes are able to produce significant amounts of acetaldehyde by oxidation from alcohol. Acetaldehyde can be eliminated from saliva after alcohol intake and during smoking with a semi-essential amino acid, l-cysteine. The aim of this study was to determine whether cysteine can be used to bind acetaldehyde in the achlorhydric stomach after ethanol ingestion. Methods: Seven volunteers with achlorhydric atrophic gastritis were given either slow-release l-cysteine or placebo capsules in a double-blinded randomized trial. Volunteers served as their own controls. A naso-gastric tube was inserted to each volunteer. The volunteers ingested placebo or 200 mg of l-cysteine capsules, and ethanol 0.3 g/kg body weight (15 vol%) was infused intragastrically through a naso-gastric tube. Five-milliliter samples of gastric contents were aspirated at 5-minute intervals. Results: During the follow-up period, the mean acetaldehyde level of gastric juice was 2.6 times higher with placebo than with l-cysteine (13 vs. 4.7 μM, p

Serum vitamin B12 concentrations were determined in 129 patients and a pentagastrin test performed in 116 patients with dermatitis herpetiformis (DH). Low serum vitamin B12 levels were found in 27 patients (21%) and achlorhydria in 30. Forty-two patients with achlorhydria and/or vitamin B12 deficiency were subjected to further haematological and gastrointestinal investigations. Functional or morphological involvement of the small intestine was seen in almost all patients with vitamin B12 deficiency but, in addition, atrophic gastritis resulting in defective secretion of intrinsic factor (pernicious anaemia) was found in 8 cases (7% of all DH patients). Thus, a low vitamin B12 level in DH patients should result in a careful gastrointestinal examination as both an atrophic gastritis and a coeliac-like enteropathy have further clinical implications.

The influence of a liquid antacid on the absorption of iron from iron tablets was studied in healthy volunteers using a serum iron technique. Tablets containing ferrous salts (carbonate, fumarate, sulphate) with different in-vitro dissolution properties were studied. Co-administration of the antacid and the iron tablets resulted in a marked reduction of the absorption of iron from all preparations studied. The lowest absorption was found when ferrous carbonate was given with the antacid. This was ascribed to the fact that ferrous carbonate is almost completely insoluble at pH-levels near neutral. This was confirmed in a series of patients with achlorhydria in which the absorption from ferrous carbonate was virtually nil. It was concluded that iron tablets and antacid preparations should not be administered at the same time and that ferrous carbonate tablets should not be used in patients with achlorhydria.

Morbid obesity is a health problem that has been shown to be refractory to diet, exercise, and medical treatment. Surgeries designed to promote weight loss, termed bariatric surgery and typically involving a gastric bypass procedure, have recently been implemented to treat obesity with high success rates. However, long-term sequelae can result in micronutrient deficiencies. This review will focus on iron deficiency and its association with obesity and bariatric surgery. Iron deficiency develops after gastric bypass for several reasons including intolerance for red meat, diminished gastric acid secretion, and exclusion of the duodenum from the alimentary tract. Menstruating women, pregnant women, and adolescents may be particularly predisposed toward developing iron deficiency and microcytic anemias after bypass surgery. Preoperative assessment of patients should include a complete hematological work-up, including measurement of iron stores. Postoperatively, oral iron prophylaxis and vitamin C in addition to a multivitamin should be prescribed for bypass patients, especially for vulnerable populations. Once iron deficiency has developed, it may prove refractory to oral treatment, and require parenteral iron, blood transfusions, or surgical interventions. Bariatric surgery patients require lifelong follow-up of hematological and iron parameters since iron deficiency and anemia may develop years after surgery.

Most Americans do not meet the adequate intake (AI) for calcium; calcium supplements can help meet requirements. Calcium supplementation has been found to be beneficial for bone health in children, young adults, and menopausal women. In addition to calcium, vitamin D is necessary for bone health and is generally deficient in the industrialized world. Calcium from carbonate and citrate are the most common forms of calcium supplements. Calcium carbonate, the most cost-effective form, should be taken with a meal to ensure optimal absorption. Calcium citrate can be taken without food and is the supplement of choice for individuals with achlorhydria or who are taking histamine-2 blockers or protein-pump inhibitors. Calcium lactate and calcium gluconate are less concentrated forms of calcium and are not practical oral supplements. Research on hydroxyapatite as a source of calcium is limited, so this form of calcium is not recommended. The maximum dose of elemental calcium that should be taken at a time is 500 mg. U.S. Pharmacopeia-verified calcium supplements meet vigorous manufacturing and quality requirements. Absorption from calcium-fortified beverages varies and in general is not equal to that of milk. Potential adverse effects of calcium supplementation include gastrointestinal complaints. Renal calculi in most studies have not been associated with calcium supplementation. The risk of advanced and fatal prostate cancer has been associated with calcium intakes from food or supplements in amounts >1500 mg/d.

SUMMARY Although enterochromaffin-like (ECL) cells form the major endocrine cell population of the non-antral stomach, they have been largely overlooked in the study of gastric disease. In the human, their product and functions are unknown, but they are associated with histamine secretion in rodents. The cells are controlled by neural and hormonal factors, the most significant of the latter being gastrin. Interest in ECL cells has been stimulated by the observation that hyperplasia of these cells, sometimes leading to formation of gastric carcinoid tumours, occurs in conditions of persistent hypergastrinaemia — for example, in response to the achlorhydria of individuals with pernicious anaemia. The advent of new highly potent inhibitors of gastric acid secretion is allowing more information to be obtained on the physiology and functions of the ECL cell. However, there is clearly a great deal more to be discovered about this enigmatic endocrine cell type.

Expression of sonic hedgehog (Shh), a morphogen for the gastric fundic glands, is reduced in the atrophic mucosa that develops in association with Helicobacter pylori infection, resulting in impaired differentiation of the fundic gland cells, increased expression of trefoil factor family 2 (TFF2) and the formation of spasmolytic polypeptide (SP)-expressing metaplasia (SPEM), a preneoplastic lesion. However, it is still unresolved whether H. pylori-induced inflammation and the resultant reduction in parietal cell number or reduced parietal cell function per se reduces Shh expression. The present study was designed to clarify the expression of Shh and TFF2 in the context of parietal cell dysfunction in the absence of inflammation, using histamine H2 receptor-knockout (H2R-null) mice and an acid exposure model. Age-matched H2R-null mice and wild-type (WT) mice were used. The expression of Shh and TFF2 mRNA was quantified by quantitative RT-PCR. Immunohistochemistry was also performed to detect the expression of Shh, TFF2 and cell markers. To study the effects of acid exposure, HCl solution was administered to the animals. The H2R-null mice exhibited higher gastric pH, increased TFF2 expression and reduced Shh expression. Impaired mucous neck-to-zymogenic cell differentiation was observed in the H2R-null mice. Furthermore, Shh expression increased in the presence of gastric acid and showed a significant correlation with gastric surface pH. In conclusion, our results suggest that persistent parietal cell dysfunction alone (suppressed gastric acid secretion), in the absence of inflammation or parietal cell loss caused by H. pylori infection, may be sufficient to down-regulate Shh expression in TFF2-overexpressing preneoplastic lesions of the gastric fundus. Since exposure to acid restored fundic Shh expression, appropriate gastric acid secretion may play an important role in the morphogen dynamics involved in the maintenance of gastric fundic gland homeostasis. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Summary Background Gastric carcinoid tumours are rare, but are increasing in incidence. Aim To discuss tumour pathogenesis and outline current approaches to patient management. Methods Review of published articles following a Pubmed search. Results Although interest in gastric carcinoids has increased since it was recognized that they are associated with achlorhydria, to date there is no definite evidence that humans taking long-term acid suppressing medication are at increased risk. Type I tumours are associated with autoimmune atrophic gastritis and hypergastrinaemia, type II are associated with Zollinger–Ellison syndrome, multiple endocrine neoplasia-1 and hypergastrinaemia and sporadic type III carcinoids are gastrin-independent and carry the worst prognosis. Careful investigation of these patients is required, particularly to identify the tumour type, the source of hypergastrinaemia and the presence of metastases. Treatment can be directed at the source of hypergastrinaemia if type I or II tumours are still gastrin responsive and not growing autonomously. Type III tumours should be treated surgically. Conclusions Advances in our understanding of the pathogenesis of gastric carcinoids have led to recent improvements in investigation and management. Challenges remain in identifying the genetic and environmental factors, in addition to hypergastrinaemia, that are responsible for tumour development in susceptible patients.

Background: Gastric neoplasia is common in humans, yet controversy remains over contributions of chronic achlorhydria, gastrinemia and hyperplasia, to cancer risk. To study this, mice lacking the gastric H/K-ATPase (Atp4a(–/–) mice) were used to determine whether chronic loss of acid secretion, with attendant hypergastrinemia, predisposes to cancer phenotype. Methods: Atp4a(–/–) and Atp4a(+/+) mice, paired for age and gender, were examined at 3, 8, 12 and 20 months for histopathology, and for expression of the trefoil factor family (TFF)1–3, Reg IIIβ, γ and δ, osteopontin, CD44, chromogranin A, Crp-ductin, and galectin, all of which are important in cell growth. Results: By 8 months, the glandular stomach of the Atp4a(–/–) mice doubled in weight and thickness, and several modulators of growth were increased. Female Atp4a(–/–) mice were more hyperplastic than Atp4a(–/–) males at 12 and 20 months. By 1 year, severe mucocystic hyperplasia, incomplete intestinal metaplasia, ciliated metaplasia, a shift in mucins from neutral to acidic, and inflammation were widespread. Cells in the mucus pit zone developed a pyloric-type appearance, containing large hyaline-like, periodic acid–Schiff (PAS)-negative/alcian blue-negative inclusions. But critical characteristics of gastric neoplasia, such as nuclear atypia, invasion into the muscularis mucosa, and metastases were absent. In Atp4a(–/–) mice, chromogranin A and histidine decarboxylase, RegIIIγ and δ, TFF3, osteopontin and CD44 were upregulated while Reg IIIβ, and TFF1 were reduced. Conclusions: Chronic achlorhydria and hypergastrinemia in aged Atp4a(–/–) mice produced progressive hyperplasia, mucocystic and incomplete intestinal metaplasia, and the upregulation of growth factors without histological evidence of neoplasia. © 2005 Blackwell Publishing Asia Pty Ltd

The gastric hormone gastrin was the 2nd hormone to be identified and was initially recognized for its ability to induce acid secretion. Following the purification and subsequent development of specific radioimmunoassays for gastrin, it was also shown to be a regulator of oxyntic mucosal growth. To explore the importance of gastrin or its receptors for gastric development and gastric physiology both have been knocked out. The knock-out mice are viable, develop with any gross abnormalities, and are fertile. Even though gastrin acts as a growth factor during hypergastrinaemia there was no general atrophy of the gastrin mucosa in the knock-out mice. But the maturation of both parietal and ECL cells were disturbed and the number of parietal cells reduced. Furthermore, lack of gastrin impaired basal acid secretion and rendered the parietal cells unresponsive to histamine and acetylcholine, the other two major stimulators of gastric acid secretion. Despite the major changes in gastric physiology, the number of genes down-regulated in the gastrin knock-out mice is modest. The achlorhydria due to lack of gastrin also leads to bacterial overgrowth of the stomachs of the gastrin knockout mice, which could facilitate the development of gastric ulcer disease and cancer.

Background: Acetaldehyde is a known local carcinogen in the digestive tract in humans. Bacterial overgrowth in the hypochlorhydric stomach enhances production of acetaldehyde from ethanol in vivo after alcohol ingestion. Therefore, microbially produced acetaldehyde may be a potential risk factor for alcohol-related gastric and cardiac cancers. This study was aimed to investigate which bacterial species and/or groups are responsible for acetaldehyde formation in the hypochlorhydric human stomach and to characterize their alcohol dehydrogenase (ADH) enzymes. Methods: After 7 days of treatment with 30 mg of lansoprazole twice a day, a gastroscopy was performed on eight volunteers to obtain hypochlorhydric gastric juice. Samples were cultured and bacteria were isolated and identified; thereafter, their acetaldehyde production capacity was measured gas chromatographically by incubating intact bacterial suspensions with ethanol at 37°C. Cytosolic ADH activities, Km values, and protein concentration were determined spectrophotometrically. Results: Acetaldehyde production of the isolated bacterial strains (n= 51) varied from less than 1 to 13,690 nmol of acetaldehyde/109 colony-forming units/hr. ADH activity of the strains that produced more than 100 nmol of acetaldehyde/109 colony-forming units/hr (n= 23) varied from 3.9 to 1253 nmol of nicotinamide adenine dinucleotide per minute per milligram of protein, and Km values for ethanol ranged from 0.65 to 116 mM and from 0.5 to 3.1 M (high Km). There was a statistically significant correlation (r= 0.64, p < 0.001) between ADH activity and acetaldehyde production from ethanol in the tested strains. The most potent acetaldehyde producers were Neisseria and Rothia species and Streptococcus salivarius, whereas nearly all Stomatococcus, Staphylococcus, and other Streptococcus species had a very low capacity to produce acetaldehyde. Conclusions: This study demonstrated that certain bacterial species or groups that originate from the oral cavity are responsible for the bulk of acetaldehyde production in the hypochlorhydric stomach. These findings provide new information with the respect to the local production of carcinogenic acetaldehyde in the upper digestive tract of achlorhydric human subjects.

The role of gastrin in the pathophysiology of two diseases affecting the human stomach, the Zollinger Ellison syndrome (ZES) and the pernicious anemia (PA), is reviewed. Both diseases present chronic hypergastrinemia but from different origins. The ZES is characterized by the occurrence of ectopic endocrine gastrin-secreting tumors and PA by a fundic atrophic gastritis leading to complete atrophy of fundus and resulting in achlorhydria. In PA, the lack of acid induces continuous gastrin cell activation and is responsible for the subsequent gastrin hypersynthesis and secretion. In ZES, hypergastrinemia causes hypertrophy of the oxyntic mucosa, which, in addition, displays hyperplasia of parietal and mucus cells. In both diseases, hypergastrinemia also induces the hyperproliferation of enterochromaffin-like endocrine cells in the fundic mucosa, which can offer all aspects from hyperplasia, then dysplasia, until true carcinoid tumor. The influence of antisecretory treatments and MEN 1 in the ZES as well as that of several other factors and antrectomy in PA on the behavior of the different gastric cells is evoked. Finally, the role that gastrin and its receptor play in the maintenance of the normal development of gastric mucosa and gastric acid secretion is emphasized by results observed in gene knockout models.

Inhibitors of gastric acid secretion, particular proton pump inhibitors, are effective drugs in the treatment and prophylaxis of acid-related diseases. Proton pump inhibitors are therefore prescribed widely, often for minor complaints. Gastric acidity kills swallowed microorganisms, and acid secretion must be of biological importance because it is maintained in phylogenesis. Acid secretion is controlled by feedback mechanisms, mainly via gastrin. A decrease in acidity always causes an increase in plasma gastrin. The trophic effect of gastrin leads to hyperplasia and neoplasia of the enterochromaffin-like (ECL) cell. ECL cell derived tumours in man were previously regarded as rare, and also as rather benign. It is now clear that the ECL cell gives rise to a significant proportion of gastric carcinomas. Moreover, ECL cell carcinoids secondary to hypergastrinaemia may develop into highly malignant tumours. Treatment with a proton pump inhibitor is followed by rebound acid hypersecretion and decreased efficiency of H2-blockers, thus such treatment may induce a type of physical dependence. It is therefore reasonable to be cautious and not to treat younger (< 50 years) patients for long periods of time with profound inhibitors of gastric acid secretion. Chromogranin A in the blood is a sensitive marker of the ECL cell mass, and it could be used to survey patients on long-term proton pump inhibitors.

Background: Small bowel bacterial overgrowth secondary to drug-induced hypochlorhydria may be of particular importance in the elderly, in whom anti-ulcer drugs are commonly prescribed and the consequences of malabsorption may be severe. Methods: Duodenal aspirates were obtained from elderly individuals before (n=24) and during a 2-month treatment course with either omeprazole (20 mg daily; n=8) or ranitidine (300 mg b.d.; n=6), and from six patients with small bowel bacterial overgrowth who had diarrhoea and malabsorption. Results: Before treatment, duodenal bacterial counts were normal ( 105 cfu/mL. All remained asymptomatic and had normal lactulose breath H2 profiles during treatment. Conclusion: Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly but, in the short term, this bacterial overgrowth is not associated with malabsorption.

Hypochlorhydria is considered to be a risk factor for gastric cancer, both clinically and experimentally. In humans, the hypo‐acidic condition appears to be closely associated with the development of differentiated‐tyne gastric carcinomas. We investigated relationships between antral pH and histological types of gastric cancer using an animal model. A total of 7.65 g of N‐ethyl‐N′‐nitro‐N‐nitrosoguanidine (ENNG) was orally administered to male beagle dogs. Subsequently, the dogs were divided into four groups and underwent four surgical interventions designed to create various conditions in the antrum. Antral pM was recorded at the time of killing after an observation period ranging from 16 to 33 months. The number of gastrin‐secreting cells (G‐cells) was counted after immunohistochemical staining. Carcinomas were found in the antrum of 12 of the 21 dogs that had survived. Although limited doses of ENNG, such as those used in this study, have been reported to produce only undifferentiated adenocarcinomas, differentiated adenocarcinomas were found in seven of these 12 dogs. Antral pH and the number of G‐cells were significantly higher in these seven dogs than in the other five dogs, which had developed only undifferentiated adenocarcinomas. Bile inflow showed no significant effect on the development of differentiated adenocarcinomas. Neither atrophic gastritis nor intestinal metaplasia was seen in any of the dogs. These results suggest that the hypo‐acidic condition itself may play a role in the development of differentiated adenocarcinomas.

Background. It has been reported that vasoactive intestinal peptide (VIP)–producing tumors accompanied by watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome often produce multiple hormones biochemically and immunohistochemically. Methods. The authors examined the distribution of several peptides—VIP, peptide histidine methionine (PHM), neuropeptide Y (NPY), methionine–enkephalin (M-EK), somatostatin (SS), substance-P (Sub-P), corticotropin-releasing hormone, and tyrosine hydroxylase—with immunohistochemical studies and an in situ hybridization method in three ganglioneuroblastomas with WDHA syndrome. All patients had an extremely elevated plasma level of VIP. Results. Peptides examined immunohistochemically in the tumor were all detectable in ganglionic cells and some neurites. The coexistence of those peptides was observed with serial section staining. The presence of messenger RNA of VIP/PHM-27, NPY, and SS was detectable in the cytoplasm of the tumor cells with the in situ hybridization. Conclusions. It was shown that multiple genes of peptides are expressed simultaneously and translated to proteins in those tumors.

The main form of gastrin in antral mucosa, the amidated heptadecapeptide G17, is generated from an inactive precursor, progastrin, by steps involving endopeptidase cleavage and amidation. Gastrin cells are normally inhibited by gastric acid and in this study we have examined how suppression of acid by treatment with omeprazole for 6–8 weeks influences gastrin production in patients with oesophagitis. Plasma concentrations of total amidated gastrins in the fasting state increased from 18 to 43 pmol 1-1; assays specific for G17-immunoreactivity indicated that the plasma concentrations of this form increased from 6 to 12 pmol 1-1. In endoscopic biopsies of antral mucosa there was no change with omeprazole treatment in the concentrations of total amidated gastrins, or their immediate precursors, the Gly-extended gastrins. However, assays using an antibody that reacts with progastrin, together with size exclusion chromatography, indicated that tissue progastrin concentration increased 6-fold. The data suggest a modest net increase in gastrin production with omeprazole-treatment; because the ratio of tissue concentrations of total amidated gastrins to Gly-extended gastrins did not change, it would seem that the amidating capacity of the gastrin cell was maintained. However, the increase in progastrin concentrations suggests a relative failure of the initial steps of post-translational processing, and consequently that in certain circumstances endopeptidase cleavage of progastrin may be rate limiting.

Using stored serum samples collected during from 1970 to 1972 and/or 1977 to 1979 from a fixed population in Hiroshima and Nagasaki, Japan, serum ferritin, transferrin, and ceruloplasmin levels were determined immunologically for persons in whom stomach (233 cases) or lung cancer (84 cases) subsequently developed as well as for their controls. An elevated stomach cancer risk was associated with low antecedent serum ferritin levels, with more than a threefold excess among those in the lowest compared with the highest ferritin quintile. The risk did not vary with the time between blood collection and stomach cancer onset, remaining high among those with low ferritin levels 5 or more years before cancer diagnosis. Achlorhydria, diagnosed in a sample of the population about 10 years before the 1970-to-1972 blood collection and up to 25 years before cancer, was an independent marker of stomach cancer risk. In combination, low serum ferritin and achlorhydria were associated with a tenfold increase in the subsequent risk. No effect of transferrin or ceruloplasmin, independent of ferritin, was observed in the gastric cancer risk, and the risk of lung cancer was not related to these three serum proteins. These prospective findings indicate that biologic markers of an increased risk of stomach cancer can be detected long before cancer onset.

The islets of Langerhans, initially thought to be devoid of function, can be the site of tumour formation with serious and often lethal complications. One of the associated syndromes may be diarrhœal, due to secretion of a polypeptide of which the exact nature still awaits complete elucidation. This must ultimately be achieved by radioimmunoassay. The diarrhœogenic pancreatic tumours are discussed, three cases being reported in detail

An unselected series of 42 gastric carcinoids has been reviewed. Clinically the tumours simulated common gastric lesions including ulcer, polyp and carcinoma. No endocrine symptoms were identified. The tumours were most frequent in the body of the stomach and in 25% in that site were multiple. Morphologically most tumours when classified according to Soga (1974) demonstrated a mixed growth pattern. Six tumours displayed an atypical morphology (type D): they were larger and metastasized more frequently than the rest of the tumours. Six tumours contained a few scattered argentaffinic cells but the others were negative indicating negligible serotonin secretion in only a few cases. The Grimelius argyrophilic reaction was positive in most cells in all tested tumours except in three, two of which showed atypical morphology (type D). It is suggested that gastric carcinoids with a type D morphology or a minority cell population of argyrophil cells are dedifferentiated carcinoids which are biologically nearer to gastric carcinomas. The most frequent clinicopathological correlation was achlorhydria linking pernicious anaemia and gastric carcinoids. This indicates pathogenetic similarities between gastric carcinoids and gastric carcinomas.

Circulating parietal cell antibodies (PCA) were fund in 8 (5.4%) out of 147 diabetic children screened. Both sexes were equally represented, but the titres were higher in the girls. No clear relationship between the presence of these antibodies and age or the duration of diabetes was observed. Gastric studies were performed on 8 children with PCA (group A) and 41 without PCA (group B). Both basal (BAO) and maximal acid output (MAO) were significantly (p < 0.05) lower and fasting serum gastrin elevated (p < 0.01) in group A as compared with the control group. Two patients were achlorhydric. In group B, 17 patients out of the 41 studied had hyposecretion and one achlorhydria. The result became most obvious in the group with a duration and diabetes over 10 years, where MAO was significantly diminished (p < 0.05). Gastric morphology revealed atrophic gastritis in 3 patients from seven biopsies in group A and one out five biopsies for severe hyposecretion in group B. Two other children in group A had superficial gastritis. Serum ferritin levels decreased along with the duration of diabetes. Those with gastric mucosa had the lowest values.

Twenty-six of 100 cases of gastric adenocarcinoma contained argyrophil cells. All these tumours were carcino-embryonic antigen positive and 13 contained variable amounts of gastro-enteropancreatic peptides and amines. There was no significant difference in mucin type, extent or incidence of intestinal metaplasia between tumours with and those without endocrine cells. The prognosis for both groups was similarly poor, contrasting with that for carcinoid and atypical carcinoid. Endocrine cell hyperplasia was evident in the adjacent mucosa in some of the cases of endocrine positive tumours. There was no association between achlorhydria and the presence of endocrine cells in the tumours. The origin of the neoplastic endocrine cells remains speculative, occurring either as a mutation of a single stem cell or as a synchronous malignant transformation of two epithelial cell types exposed to a particular carcinogenic factor(s). Adenocarcinomas containing endocrine cells appear to be as biologically aggressive as the usual adenocarcinomas of the stomach and therefore should be treated in a like manner.

Different phosphates commonly used in food processing have been evaluated for their effects on iron and calcium absorption. In growing rats, addition of phosphates to diets caused decreased iron absorption, decreased hemoglobin concentrations and depressed liver iron values in both the control and achlorhydric animals. Liver iron values were somewhat depressed in the mature rats which was slightly more severe in the achlorhydric animals. Sodium pyrophosphate and sodium tripolyphosphate impaired iron metabolism more severely than dibasic sodium phosphate and sodium metaphosphate in both age groups; this effect tended to be greater in the achlorhydric animals. In the growing rats, addition of phosphates to the diets decreased calcium absorption and femur calcium content, the severity of which was greater in the achlorhydric animals. Sodium tripolyphosphate caused consistent decreases in bone calcium content. The phosphate effects were definitely more severe in the achlorhydric growing rats and tended to be more severe in the achlorhydric mature rats. The data presented indicate that the various phosphates have different effects on calcium and iron metabolism and that these effects are magnified by achlorhydria.

A women had hypergastrinaemia associated with the variety of gastritis (Type A) that is associated usually with pernicious anaemia, together with recurring bouts of severe abdominal pain. Fasting serum gastrin levels ranged between 600 and 2750 pg/ml. There was a rise in serum gastrin levels after a standard protein meal, indicative of a large G cell mass, and a fall after intragastric HCI, which led to a trial of treatment with HCI; this gave some symptomatic relief. After surgical antrectomy there was a profound fall of serum gastrin from a pre-operative level of 2500 pg/ml to constant values of 16--25 pg/ml, and complete and lasting relief from the bouts of abdominal pain.

This report presents a case of multicentric gastric carcinoid (gastrin containing) tumors of the fundus associated with achlorhydria and pernicious anemia. It is suggested that stimulation of the antral G cells and possibly fundic argyrophilic cells by achlorhydria associated with atrophic gastritis may lead to hyperplasia, and eventually to neoplasia in the latter, in the form of gastric carcinoid with gastrin production.

In 63 consecutive patients with primary hyperparathyroidism (HPT) a prospective screening study was undertaken for coexistent multiple endocrine neoplasma-(MEN)-syndrome type 1. The screening consisted of a clinical examination, a radiological examination of the sella turcica with skeletal tomography (and in equivocal cases computed tomography), visual field examination by perimetry and a hormonal evaluation including measurements of the serum levels of prolactin, gastrin, pancreatic polypeptide (PP) and subunits of human chorionic gonadotrophin (HCG-alpha and -beta). Clinical examination did not reveal any signs of endocrine disease suggestive of a MEN-1 syndrome. In only one case there was a radiological abnormality of the sella turcica; this patient had an empty sella syndrome and a raised serum prolactin value. All other prolactin values were within the normal range. In 41% of the patients raised serum gastrin levels were found; these tended to normalize after parathyroidectomy. As a group, patients with raised gastrin values were older than the others and generally they had hypo- or achlorhydria. The serum PP levels were raised in 28% of the patients but there was no clinical evidence of a pancreatic tumour in any of these cases, and the serum HCG-alpha and -beta levels were within the normal range in all patients but two. We conclude that the incidence of MEN-1 syndrome in unselected patients with primary HPT must be low, and that investigations for this syndrome are justified only in HPT patients with specific symptoms or with a positive family history.

SUMMARY High gastrin levels were found in twenty-one out of fifty-six consecutive patients (38%) with thyrotoxicosis. Following return to euthyroidism gastrin levels generally fell, but twelve patients (21%) remained hypergastrinaemic. Six of these patients (11%) had achlorhydria indicating atrophic gastritis of the antrum sparing type. No correlation between gastrin and triiodothyronine values was found. It is suggested that gastrin levels should be measured in thyrotoxic patients after treatment, and further control instituted in patients with raised gastrin levels. The relationship between gastric function, gastrin release and thyroid function seems complex. The interactions may involve both a direct effect of thyroid hormone on gastric acid production, adrenergic influences on gastrin release and linked phenomena with development of thyroid and gastric auto-immune diseases.

This report presents an adrenal ganglioneuroblastoma containing several kinds of neuronal peptides. The tumour was found in an autopsy case of a 3-year-old girl with clinical manifestation of intractable diarrhea, hypokalemia, achlorhydria, and with elevated levels of plasma vasoactive intestinal peptide (VIP). Immunoperoxidase staining showed many immuno-reactive VIP- containing cells, some somatostatin-and substance P-contalning cells on the tumour sections. Ultrastructurally, the tumour cells contained numerous secretory granules that could be divided mainly into two types; one is a small cored vesicle (50-150 nm in diameter) and the other large electron dense secretory granule (200-500 nm in diameter). It was suggested that the cells in ganglioneuroblastoma derived from neural crest are closely related to the cells that could differentiate into gut-hormone-producing cells.

The effect of acute stimulation of gastrin release on the number of antral gastrin-producing G-cells stained by conventional immunohistology was investigated in two experimental models. The substituted benzimidazole derivate BY 308 was administered at a dosage that induces complete achlorhydria and thereby led to marked hypergastrinaemia. Two hours after drug administration, antral G-cell density was increased by 14% and 35% in 12-h and 48-h fasted rats, respectively. Both serum gastrin levels and G-cell density further increased after 3 and 8 days' treatment with BY 308 whereas the somatostatin (D)-cell count did not change prior to 8 days' administration. In the isolated, vascularly perfused rat stomach, acetylcholine was perfused for 36 min; this regimen increased gastrin release four-fold and enhanced the G-cell count by 24% whereas 8 min acetylcholine perfusion did not alter G-cell density significantly but stimulated gastrin output. The results of this study suggest that acute changes in the secretory activity of the gastrin cell are accompanied by an alteration of the staining characteristics thus indicating that an increase in the antral G-cell count does not solely depend upon formation of new cells.

The very late occurrence of gastric carcinoids in a life-span carcinogenicity study with loxtidine in the rat might have resulted from continuous achlorhydria induced by this long-acting unsurmountable histamine H2-antagonist. The nature of the anti-secretory activity of loxtidine was compared with that of ranitidine on histamine-induced acid secretion in the perfused stomach preparation of the rat and in the rat isolated gastric mucosa preparation. Ranitidine and loxtidine had qualitatively different inhibitory effects on acid secretion, ranitidine being a competitive antagonist of histamine even at high concentrations, whereas the effect of loxtidine on both preparations was unsurmountable at relatively low concentrations. These results support the hypothesis that the late formation of gastric carcinoids in rats receiving loxtidine is a consequence of persistent achlorhydria caused by unsurmountable blockade of parietal cell H2-receptors.

Summary The major part of nitrate ingested by normal individuals from vegetables, water supplies, etc., is excreted unchanged. Where the stomach is colonised by bacteria however, as in achlorhydria, reduction to nitrite can occur with consequent methaemoglobinaemia. This problem is particularly marked in infants during the first few months of life if water supplies are rich in nitrate. Of greater potential importance to the majority of adults, however, is the formation within the body of N-nitroso compounds, the great majority of which are carcinogenic in experimental animals. A proportion of ingested nitrate is reduced microbiologically within the mouth to nitrite which then enters the acidic milieu of the normal stomach. Bacterial colonisation of the stomach occurs increasingly in old age, and is accompanied by the formation of increased levels of nitrite and N-nitroso compounds. Ascorbic acid is also ingested from many vegetables and is an inhibitor of the nitrosation process. Nevertheless, it is suggested that individuals with hypochlorhydria who may be particularly at risk from the formation of N-nitroso compounds in vivo should supplement their intake of this potentially protective agent.