Hypochlorhydria Abstracts 5

© 2012

Reassessment of the relative prevalences of antibodies to gastric parietal cell and to intrinsic factor in patients with pernicious anaemia: influence of patient age and race

            (Carmel 1992) Download

Anti-parietal cell antibody has been reported in nearly all patients with pernicious anaemia in past studies, in contrast with anti-intrinsic factor (IF) antibody which occurs in only 50-70% of such patients. However, observations in the more diverse patient population at our hospital suggest that these prevalences, originally described in predominantly elderly, white patients of European origin, no longer apply. Anti-IF antibody was found in 70% of the 324 patients, with blacks (84%) and Latin Americans (69%) having a significantly higher prevalence than whites (55%). In contrast, only 55% of the 266 patients tested had anti-parietal cell antibody. It was noteworthy that this low rate was similar in all racial groups. However, patients lacking anti-parietal cell antibody were significantly younger than those who had the antibody (54.8 +/- 17.8 vs 59.6 +/- 16.2 years, P = 0.022). Overall, a striking 30% of all patients had anti-IF antibody but not anti-parietal cell antibody, while only 13% had the latter antibody without having anti-IF antibody. This pattern was particularly striking among black patients. An interesting incidental observation was that gastrin levels were not associated with antibody status, but were significantly higher not only among women than among men but also among white and black patients than among Latin-American patients. The findings show that anti-parietal cell antibody is not found nearly as often in pernicious anaemia as has been reported in the past, and thus has no value as a diagnostic tool in pernicious anaemia. They also suggest clues to different expressions of pernicious anaemia or of its immunologic response, particularly among younger patients with the disease.

Update on cobalamin, folate, and homocysteine

            (Carmel, Green et al. 2003) Download

Three topics affecting cobalamin, folate, and homocysteine that have generated interest, activity, and advances in recent years are discussed. These are: (I). the application of an expanded variety of tools to the diagnosis of cobalamin deficiency, and how these affect and are affected by our current understanding of deficiency; (II). the nature of the interaction between homocysteine and vascular disease, and how the relationship is affected by vitamins; and (III). the improved understanding of relevant genetic disorders and common genetic polymorphisms, and how these interact with environmental influences. The diagnostic approach to cobalamin deficiency now allows better diagnosis of difficult and atypical cases and more confident rejection of the diagnosis when deficiency does not exist. However, the process has also become a complex and sometimes vexing undertaking. Part of the difficulty derives from the lack of a diagnostic gold standard among the many available tests, part from the overwhelming numerical preponderance of patients with subclinical deficiency (in which isolated biochemical findings exist without clinical signs or symptoms) among the cobalamin deficiency states, and part from the decreased availability of reliable tests to identify the causes of a patient's cobalamin deficiency and thus a growing deemphasis of that important part of the diagnostic process. In Section I, Dr. Carmel discusses the tests, the diagnostic issues, and possible approaches to the clinical evaluation. It is suggested no single algorithm fits all cases, some of which require more biochemical proof than others, and that differentiating between subclinical and clinical deficiency, despite their overlap, may be a helpful and practical point of departure in the evaluation of patients encountered in clinical practice. The arguments for and against a suggested expansion of the cobalamin reference range are also weighed. The epidemiologic data suggest that homocysteine elevation is a risk factor for vascular and thrombotic disease. In Section II, Dr. Green notes that the interactions of metabolism and clinical risk are not well understood and a causative relationship remains unproven despite new reports that lowering homocysteine levels may reduce vascular complications. Genetic and acquired influences may interact in important ways that are still being sorted out. The use of vitamins, especially folate, often reduces homocysteine levels but also carries potential disadvantages and even risks. Folate fortification of the diet and supplement use have also markedly reduced the frequency of folate deficiency, and cobalamin deficiency is now the more common deficiency state, especially among the elderly. Although genetic disorders are rare, they illuminate important metabolic mechanisms and pose diagnostic challenges, especially when clinical presentation occurs later in life. In Section III, Drs. Rosenblatt and Watkins use selected disorders to illustrate the subject. Imerslund-Grasbeck syndrome, a hereditary disorder of cobalamin absorption at the ileal level, demonstrates genetic heterogeneity. Finnish patients show mutation of the gene for cubilin, the multiligand receptor for intrinsic factor. Surprisingly, Norwegian and other patients have been found recently to have mutations of the AMN (amnionless) gene, mutations that are lethal in mice at the embryonic stage. Two disorders of cobalamin metabolism, cblG and cblE, are now known to arise from mutations of the methionine synthase and methionine synthase reductase genes, respectively. These disorders feature megaloblastic anemia and neurologic manifestations. The folate disorder selected for illustration, methylenetetrahydrofolate reductase (MTHFR) deficiency, paradoxically causes neurological problems but no megaloblastic anemia. This rare deficiency is the most common inborn error of folate metabolism. It is distinct from the very common MTHFR gene polymorphisms, mutations that cause mild to moderate reductions in MTHFR activity but no direct clinical manifestations. The MTHFR polymTHFR polymorphisms, especially the 677C-->T mutation, may contribute to vascular and birth defect risks, while reducing the risk of certain malignancies, such as colon cancer. These polymorphisms and those of genes for other enzymes and proteins related to cobalamin, folate, and homocysteine metabolism may be important role players in frequent interactions between genes and the environment.

Pernicious anemia: what are the actual diagnosis criteria?

            (Cattan 2011) Download

A gastric intrinsic factor output under 200 U/h after pentagastrin stimulation (N > 2000 U/h) is specific for pernicious anemia. The other findings are either variable or non specific. Serum intrinsic factor antibodies, considered as specific in general practice, are present only in half of the patients with pernicious anemia. In their absence, since the disappearance of the Schilling tests, the gastric tubage currently used for the study of gastric acid secretion, is obligatory for the simultaneous study of intrinsic factor output. This study is important to eliminate another disease much more frequent than pernicious anemia, the protein bound to cobalamin malabsorption was observed in achlorhydric simple atrophic gastritis in the presence of intrinsic factor secretion.

Serum ghrelin as a marker of atrophic body gastritis in patients with parietal cell antibodies

         (Checchi, Montanaro et al. 2007) Download

AIM: Autoimmune gastritis is frequently associated with autoimmune thyroiditis and other organ-specific autoimmune diseases, and may lead to atrophic body gastritis (ABG). We studied the diagnostic use of the measurement of serum ghrelin compared with other markers of gastric damage in predicting the presence of ABG in patients with autoimmune gastritis. METHODS: We studied 233 patients with autoimmune gastritis and 211 control subjects. All patients and control subjects were screened for circulating parietal cell antibodies (PCAs) and were tested for serum ghrelin, gastrin, pepsinogen I and II, and anti-Helicobacter pylori antibody levels. A total of 52 patients and 28 control subjects underwent a gastric endoscopy. RESULTS: In PCA/positive patients, mean (+/-sd) serum ghrelin levels were significantly lower (238 +/- 107 pmol/liter), and mean (+/-sd) serum gastrin levels were significantly higher (81.2 +/- 128.3 ng/ml), with respect to PCA/negative patients (282 +/- 104 pmol/liter and 20.7 +/- 13.3 ng/ml, respectively; P < 0.0001). Serum ghrelin and gastrin levels were inversely correlated (P = 0.004). A total of 40 patients had ABG documented by the gastric biopsy (90% in PCA/positive patients and 10% in PCA/negative patients). The receiver operating characteristic curve analysis revealed that a cutoff value for serum ghrelin of 188 pmol/liter was associated with the highest sensitivity and specificity (97.3 and 100%, respectively) in detecting gastric atrophy and was superior to gastrin (P = 0.012), PCA (P = 0.002), and the pepsinogen I/II ratio (P = 0.016) measurements. CONCLUSIONS: Our study demonstrates that ghrelin secretion is negatively affected by autoimmune gastritis, and its serum level represents the most sensitive and specific noninvasive marker for selecting patients at high risk for ABG.

Complexity of gastric acid secretion revealed by targeted gene disruption in mice

            (Chen and Zhao 2010) Download

Physiology of gastric acid secretion is one of the earliest subjects in medical research and education. Gastric acid secretion has been sometimes inadequately expressed as pH value rather than amount of gastric H(+) secreted per unit time. Gastric acid secretion is regulated by endocrine, paracrine and neurocrine signals via at least three messenger pathways: gastrin-histamine, CCK-somatostatin, and neural network. These pathways have been largely validated and further characterized by phenotyping a series of knockout mouse models. The complexity of gastric acid secretion is illustrated by both expected and unexpected phenotypes of altered acid secretion. For examples, in comparison with wild-type mice, gastrin and CCK double knockout and SSTR(2) knockout mice displayed a shift in the regulation of ECL cells from somatostatin-SSTR(2) pathway to galanin-Gal1 receptor pathway; a shift in the regulation of parietal cells from gastrin-histamine pathway to vagal pathway; and a shift in the CCK(2) receptors on parietal cells from functional silence to activation. The biological function of glycine-extended gastrin in synergizing gastrin-17 has been revealed in gastrin knockout mice. The roles of gastric acid secretion in tumorigenesis and ulceration have not been fully understood. Transgenic hypergastrinemic INS-GAS mice developed a spontaneous gastric cancer, which was associated with an impaired acid secretion. Gastrin knockout mice were still able to produce acid in response to vagal stimulation, especially after H. pylori infection. Taken together, phenotyping of a series of genetically engineered mouse models reveals a high degree of complexity of gastric acid secretion in both physiological and pathophysiological conditions.


Zinc deficiency: its role in gastric secretion and stress-induced gastric ulceration in rats

            (Cho, Fong et al. 1987) Download

The effects of zinc deficiency on gastric secretion and on cold-restraint stress-induced ulceration in rat stomachs have been studied. Administration of graded zinc deficient diets for 5 weeks significantly depressed the serum zinc concentration and decreased body weight gain in the rats. These diets significantly increased the gastric secretory volume, acid and pepsin. Zinc deficiency produced or aggravated the formation of glandular ulceration in the absence or presence of stress, respectively; it also decreased the mast cell count in the gastric glandular mucosa. It is concluded that zinc deficiency adversely affects the rats by reducing the body weight gain and producing ulceration which is probably mast cell-mediated. On the other hand, it increases gastric secretory functions.

Salmonellosis and the gastrointestinal tract: more than just peanut butter

            (Crum-Cianflone 2008) Download

Nontyphoidal salmonellosis is the leading cause of foodborne illness in the United States, causing about 1.4 million infections annually. Most cases of salmonellosis are due to ingestion of contaminated food items such as eggs, dairy products, and meats, but almost any foodstuff can be implicated, including peanut butter, as seen during a recent outbreak of more than 600 Salmonella infections. Although outbreaks often gain national media attention, the majority of nontyphoidal Salmonella infections in the United States occur sporadically. Risk factors for salmonellosis include gastric hypoacidity, recent use of antibiotics, extremes of age, and immunosuppressive conditions. Clinical manifestations of the infection most commonly involve self-limited gastroenteritis, but bacteremia and endovascular and localized infections may occur. Most cases of gastrointestinal involvement are self-limited, and antibiotic therapy is reserved for persons at risk for complicated disease. Preventive strategies by both industry and consumers are advocated to further reduce the occurrence of nontyphoidal salmonellosis.

Histidine-stimulated acid secretion in the conscious rat is mediated by amino acid uptake system N

            (Dimaline, Wilkinson et al. 1990) Download

The characteristics of sodium-dependent, histidine-stimulated gastric acid secretion were studied in the conscious gastric-fistulated rat. Intragastric L-histidine, but not glutamine, asparagine, glutamic acid or glycine, stimulated acid secretion. The histidine-stimulated acid secretion was inhibited by the presence of glutamine or asparagine, but not by glutamic acid or glycine. The substitution of lithium for sodium in the gastric perfusate was tolerated. Together with previous data, the results indicate that an N-like amino acid uptake system mediates histidine-stimulated acid secretion in the conscious rat.

Gastric Acid Production, Pancreatic Secretions and Blood Levels of Higher Alcohols in Patients with Fungal-type Dysbiosis of the Gut

         (Eaton 2004) Download

Purpose: Patients with gut dysbioses are clinically difficult to distinguish from those with food intolerance. The variety known as fungal-type is associated with the generation of small amounts of ethanol in the blood. A recent study has shown abnormalities of histidine metabolism. In view of this, gastric function was studied. This also provided data on pancreatic function.

Design: Two groups of newly referred patients, with similar symptom profiles, attending two clinicians were studied. Group A (42 patients) had positive ethanol fermentation tests: group B (37 patients) did not. There were 20 healthy control subjects. Levels of higher alcohols, short-chain fatty acids, gastric acid production and pancreatic exocrine secretions were measured and compared statistically.

Materials and Methods: Ethanol, higher alcohols and short-chain fatty acids were measured by gas-liquid chromatography. Gastric acid production, emptying time and pancreatic function were measured using a swallowed transducer.

Results: A significant number of group A patients had elevated levels of higher alcohols; all of these also showed excess short-chain fatty acids. Group B patients showed similar findings for both; these figures were not statistically significant. However, as compared with group B, group A patients were less likely to show lower levels of gastric acid and/or pancreatic enzyme production and these results were statistically highly significant.

Conclusions: As these findings show minimal effects on stomach and duodenum, it is suggested that fungal-type dysbiosis is largely an ileal condition. For these patients, the presence of elevated levels of higher alcohols with a positive ethanol test is a better indicator of disease severity


Gastric inhibitory polypeptide and insulin responses to orally administered amino acids in genetically obese hyperglycemic (ob/ob) mice

            (Flatt, Kwasowski et al. 1991) Download

The effects of oral administration of eight L-amino acids (alanine, arginine, cysteine, glycine, histidine, hydroxyproline, lysine and threonine) individually or as an amino acid mixture on plasma gastric inhibitory polypeptide (GIP), insulin and glucose concentrations were examined in 18-h fasted obese hyperglycemic (ob/ob) mice. At a dose of 5.4 mmol/kg body weight, arginine, cysteine, histidine and the amino acid mixture were equipotent in terms of increasing plasma GIP and insulin concentrations. Alanine, hydroxyproline and lysine also increased plasma GIP, but insulin concentrations were unchanged. In contrast, threonine failed to affect either GIP or insulin concentrations. There was no correlation between either the incremental or integrated GIP and insulin responses, and none of the amino acids administered affected circulating glucose concentrations. The results indicate that a range of essential and nonessential neutral and basic amino acids stimulate the release of GIP in ob/ob mice. However, GIP made only a modest contribution to the stimulation of insulin secretion following administration of amino acids in the presence of basal glycemia.

Acute gastritis with hypochlorhydria: report of 35 cases with long term follow up

            (Harford, Barnett et al. 2000) Download

BACKGROUND: Between 1976 and 1987, 35 cases of acute gastritis with hypochlorhydria (AGH) were seen in our research laboratory. The aims of this study were to determine the natural history of AGH and the role of Helicobacter pylori in its pathogenesis. METHODS: Archived serum and gastric biopsy samples obtained from AGH subjects were examined for evidence of H pylori colonisation. Twenty eight of 33 (85%) surviving AGH subjects returned a mean of 12 years after AGH for follow up studies, including determination of H pylori antibodies, basal and peak acid output, endoscopy, and gastric biopsies. A matched control group underwent the same studies. RESULTS: Archived material provided strong evidence of new H pylori acquisition in a total of 14 subjects within two months, in 18 within four months, and in 22 within 12 months of recognition of AGH. Prevalence of H pylori colonisation at follow up was 82% (23 of 28) in AGH subjects, significantly (p<0.05) higher than in matched controls (29%). Basal and peak acid output returned to pre-AGH levels in all but two subjects. CONCLUSIONS: One of several possible initial manifestations of H pylori acquisition in adults may be AGH. While H pylori colonisation usually persists, hypochlorhydria resolves in most subjects.


Magnesium hydrogen breath test using end expiratory sampling to assess achlorhydria in pernicious anaemia patients

            (Humbert, Lopez de Soria et al. 1994) Download

A modified magnesium hydrogen breath test, using end expiratory breath sampling, is described to investigate achlorhydria. The efficacy of this test in the diagnostic investigation of pernicious anaemia was compared with that of serum pepsinogen I. Twenty one patients with pernicious anaemia--that is, patients with achlorhydria--and 22 with healed duodenal ulcer and normal chlorhydria were studied. Magnesium hydrogen breath test, serum pepsinogen I, serum gastrin, and standard gastric acid secretory tests were performed in all subjects. The mean (SEM) hydrogen peak value was lower in patients with pernicious anaemia than in the duodenal ulcer group (21.7 (1.9) v 71.3 (5.2) ppm; p = 0.00005). The hydrogen peak value had a 95.2% sensitivity and a 100% specificity to detect pentagastrin resistant achlorhydria. Mean serum pepsinogen I concentrations were also significantly lower in patients with pernicious anaemia than in the duodenal ulcer group (10.7 (2.7) v 123.6 (11.8) micrograms/l p = 0.00005). Sensitivity and specificity to detect pernicious anaemia were both 100% for pepsinogen I. It is concluded that this modified magnesium hydrogen breath test is a simple, noninvasive, cost effective, and accurate method to assess achlorhydria and may be useful in the diagnostic investigation of patients with suspected pernicious anaemia.

Major parietal cell antigen in autoimmune gastritis with pernicious anemia is the acid-producing H+,K+-adenosine triphosphatase of the stomach

            (Karlsson, Burman et al. 1988) Download

In autoimmune gastritis antibodies against a membrane-bound parietal cell antigen of previously unknown function are present in the sera of patients. In this study, a vesicular membrane preparation of porcine gastric mucosa cells was found to be a potent antigenic source. This preparation blocked greater than 90% of antibody binding to a lysate of gastric mucosa cells. The membrane fraction contained H+,K+-ATPase (EC 3.6.1.36) as the major protein, which in sodium dodecyl sulfate-polyacrylamide gel electrophoresis migrated with a weight of 92 kD. After reduction and alkylation, this component was resolved into two bands of similar staining intensity (92 and 88 kD). Immunoblotting analysis showed that sera of patients recognized antigen with pattern identical to the major protein of the vesicular membranes. Protein A-Sepharose beads preincubated with immunoglobulins of five individual patient (but not control) sera were all found to reduce both the H+,K+-ATPase activity and the amount of parietal cell antigen of a preparation of vesicular membranes solubilized in n-octylglucoside. Taken together, the results of this study indicate that the major parietal cell antigen is identical to the acid-producing enzyme, H+,K+-ATPase, of the parietal cell.


Revisiting the parietal cell

         (Kopic, Murek et al. 2010) Download

The parietal cell is responsible for secreting concentrated hydrochloric acid into the gastric lumen. To fulfill this task, it is equipped with a broad variety of functionally coupled apical and basolateral ion transport proteins. The concerted scientific effort over the last years by a variety of researchers has provided us with the molecular identity of many of these transport mechanisms, thereby contributing to the clarification of persistent controversies in the field. This article will briefly review the current model of parietal cell physiology and ion transport in particular and will update the existing models of apical and basolateral transport in the parietal cell.

Pernicious anemia: new insights from a gastroenterological point of view

            (Lahner and Annibale 2009) Download

Pernicious anemia (PA) is a macrocytic anemia that is caused by vitamin B(12) deficiency, as a result of intrinsic factor deficiency. PA is associated with atrophic body gastritis (ABG), whose diagnosis is based on histological confirmation of gastric body atrophy. Serological markers that suggest oxyntic mucosa damage are increased fasting gastrin and decreased pepsinogen I. Without performing Schilling's test, intrinsic factor deficiency may not be proven, and intrinsic factor and parietal cell antibodies are useful surrogate markers of PA, with 73% sensitivity and 100% specificity. PA is mainly considered a disease of the elderly, but younger patients represent about 15% of patients. PA patients may seek medical advice due to symptoms related to anemia, such as weakness and asthenia. Less commonly, the disease is suspected to be caused by dyspepsia. PA is frequently associated with autoimmune thyroid disease (40%) and other autoimmune disorders, such as diabetes mellitus (10%), as part of the autoimmune polyendocrine syndrome. PA is the end-stage of ABG. Long-standing Helicobacter pylori infection probably plays a role in many patients with PA, in whom the active infectious process has been gradually replaced by an autoimmune disease that terminates in a burned-out infection and the irreversible destruction of the gastric body mucosa. Human leucocyte antigen-DR genotypes suggest a role for genetic susceptibility in PA. PA patients should be managed by cobalamin replacement treatment and monitoring for onset of iron deficiency. Moreover, they should be advised about possible gastrointestinal long-term consequences, such as gastric cancer and carcinoids.


Reassessment of intrinsic factor and parietal cell autoantibodies in atrophic gastritis with respect to cobalamin deficiency

            (Lahner, Norman et al. 2009) Download

OBJECTIVES: Atrophic body gastritis (ABG) is an autoimmune condition eventually manifesting itself as pernicious anemia (PA). Parietal cell autoantibodies (PCAs) and intrinsic factor autoantibodies (IFAs) are considered characteristics of these conditions. Recent studies on IFA and PCA frequency with respect to cobalamin deficiency in biopsy-proven ABG patients are lacking. We addressed this issue using new enzyme-linked immunosorbent assay (ELISA)-based assays. METHODS: Sera from 165 patients with histologically diagnosed ABG and 113 controls were tested for IFA and PCA using ELISA. A total of 81 ABG patients had cobalamin deficiency and macrocytic anemia (Group 1-PA), 36 had cobalamin deficiency without macrocytic anemia (Group 2), and 48 had normal cobalamin levels (Group 3). RESULTS: IFAs were detected in 44/165 ABG patients (27% sensitivity) and in 0/113 controls (100% specificity). PCAs were detected in 134 ABG patients (81% sensitivity) and in 11 controls (90% specificity). In Group 1, IFAs showed 37% sensitivity and 100% specificity, whereas PCAs showed 81% sensitivity and 90% specificity. Combining IFA and PCA testing increased the sensitivity to 61% in all ABG patients and to 73% in Group 1, while maintaining 100% specificity. CONCLUSIONS: IFAs are 100% specific for biopsy-proven ABG and occurred in 27% of patients. PCAs occurred in 81% of ABG patients and in 10% of controls. Combining IFA and PCA testing significantly increases their diagnostic performance for ABG and PA, yielding a 73% sensitivity for PA. The non-invasive combined PCA and IFA assessment may be useful in selecting patients at risk for autoimmune gastritis to be confirmed by gastroscopic-histologic examination.

Risk factors for Salmonella infection. Loss of gastric acid linked to candidiasis

            (Larner 1994) Download


Demand for Zn2+ in acid-secreting gastric mucosa and its requirement for intracellular Ca2+

            (Liu, Kohler et al. 2011) Download

BACKGROUND AND AIMS: Recent work has suggested that Zn(2+) plays a critical role in regulating acidity within the secretory compartments of isolated gastric glands. Here, we investigate the content, distribution and demand for Zn(2+) in gastric mucosa under baseline conditions and its regulation during secretory stimulation. METHODS AND FINDINGS: Content and distribution of zinc were evaluated in sections of whole gastric mucosa using X-ray fluorescence microscopy. Significant stores of Zn(2+) were identified in neural elements of the muscularis, glandular areas enriched in parietal cells, and apical regions of the surface epithelium. In in vivo studies, extraction of the low abundance isotope, (70)Zn(2+), from the circulation was demonstrated in samples of mucosal tissue 24 hours or 72 hours after infusion (250 microg/kg). In in vitro studies, uptake of (70)Zn(2+) from media was demonstrated in isolated rabbit gastric glands following exposure to concentrations as low as 10 nM. In additional studies, demand of individual gastric parietal cells for Zn(2+) was monitored using the fluorescent zinc reporter, fluozin-3, by measuring increases in free intracellular concentrations of Zn(2+) during exposure to standard extracellular concentrations of Zn(2+) (10 microM) for standard intervals of time. Under resting conditions, demand for extracellular Zn(2+) increased with exposure to secretagogues (forskolin, carbachol/histamine) and under conditions associated with increased intracellular Ca(2+). Uptake of Zn(2+) was abolished following removal of extracellular Ca(2+) or depletion of intracellular Ca(2+) stores, suggesting that demand for extracellular Zn(2+) increases and depends on influx of extracellular Ca(2+). CONCLUSIONS: This study is the first to characterize the content and distribution of Zn(2+) in an organ of the gastrointestinal tract. Our findings offer the novel interpretation, that Ca(2+) integrates basolateral demand for Zn(2+) with stimulation of secretion of HCl into the lumen of the gastric gland. Similar connections may be detectable in other secretory cells and tissues.


ECL-cell histamine mobilization in conscious rats: effects of locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators

            (Norlen, Bernsand et al. 2001) Download

1. The ECL cells control gastric acid secretion by mobilizing histamine in response to circulating gastrin. In addition, the ECL cells are thought to operate under nervous control and to be influenced by local inflammatory processes. 2. The purpose of the present study was to monitor histamine mobilization from ECL cells in conscious rats in response to locally applied regulatory peptides, candidate neurotransmitters and inflammatory mediators. 3. Microdialysis probes were implanted in the submucosa of the acid-producing part of the rat stomach. Three days later, the agents to be tested were administered via the microdialysis probe and their effects on basal (48 h fast) and stimulated (intravenous infusion of gastrin-17, 3 nmol kg(-1) h(-1)) mobilization of ECL-cell histamine was monitored by continuous measurement of histamine in the perfusate (radioimmunoassay). 4. Locally administered gastrin-17 and sulfated cholecystokinin-8 mobilized histamine as did pituitary adenylate cyclase-activating peptide-27, vasoactive intestinal peptide, peptide YY, met-enkephalin, endothelin and noradrenaline, adrenaline and isoprenaline. 5. While gastrin, sulfated-cholecystokinin-8, met-enkephalin and isoprenaline induced a sustained elevation of the submucosal histamine concentration, endothelin, peptide YY, pituitary adenylate cyclase activating peptide, vasoactive intestinal peptide, noradrenaline and adrenaline induced a transient elevation. 6. Calcitonin gene-related peptide, galanin, somatostatin and the prostanoid misoprostol inhibited gastrin-stimulated histamine mobilization. 7. The gut hormones neurotensin and secretin and the neuropeptides gastrin-releasing peptide, neuropeptide Y and substance P failed to affect ECL-cell histamine mobilization, while motilin and neuromedin U-25 had weak stimulatory effects. Also acetylcholine, carbachol, serotonin and the amino acid neurotransmitters aspartate, gamma-aminobutyric acid, glutamate and glycine were inactive or weakly active as was bradykinin. 8. In summary, a range of circulating hormones, local hormones, catecholamines, neuropeptides and inflammatory mediators participate in controlling the activity of rat stomach ECL cells in situ.


The vagus regulates histamine mobilization from rat stomach ECL cells by controlling their sensitivity to gastrin

            (Norlen, Ericsson et al. 2005) Download

The ECL cells in the oxyntic mucosa secrete histamine in response to gastrin, stimulating parietal cells to produce acid. Do they also operate under nervous control? The present study examines histamine mobilization from rat stomach ECL cells in situ in response to acute vagal excitation and to food or gastrin following vagal or sympathetic denervation. Applying the technique of microdialysis, we monitored the release of histamine by radioimmunoassay. Microdialysis probes were placed in the submucosa on either side of the stomach, 3 days before experiments. The rats were awake during microdialysis except when subjected to electrical vagal stimulation. One-sided electrical vagal stimulation raised serum gastrin and mobilized gastric histamine. However, gastrin receptor blockade prevented the histamine mobilization, indicating that circulating gastrin accounts for the response. Vagal excitation by hypoglycaemia (insulin) or pylorus ligation did not mobilize either gastrin or histamine. The histamine response to food was almost abolished by gastrin receptor blockade, and it was halved on the denervated side after unilateral subdiaphragmatic vagotomy. While the histamine response to a near-maximally effective dose of gastrin was unaffected by vagotomy, the response to low gastrin doses was reduced significantly. Abdominal ganglionic sympathectomy failed to affect the histamine response to either food or gastrin. In conclusion, gastrin is responsible for most of the food-evoked mobilization of ECL-cell histamine. The histamine response to electrical vagal stimulation reflects the effect of circulating gastrin rather than a direct action of the vagus on the ECL cells. Vagal denervation was accompanied by an impaired histamine response to food intake, probably reflecting the right-ward shift of the serum gastrin concentration-histamine response curve. The results suggest that the vagus controls the sensitivity of the ECL cells to gastrin.

Is Vitamin B3 Dependency a Causal Factor in the Development of Hypochlorhydria and Achlorhydria

            (Prousky 2001) Download

It is well known by many clinicians in the field of complementary and alternative medicine that vitamin B3 has numerous therapeutic indications. The many review articles, case reports, and books authored by Hoffer fully elucidate the known and theoretical benefits of vitamin B3 administration for the treatment of AIDS, alcoholism, arthritis, cancer, cardiovascular disease, childhood learning and behavioral disorders, longevity, post-traumatic stress disorder, schizophrenia and senility. Despite the breadth of Hoffer¹s work, there has been no direct description regarding the usefulness of vitamin B3 for the treatment of hypochlorhydria and achlorhydria conditions denoting a lack and absence of stomach (gastric) acid secretion.

Non-immunological defence mechanisms of the gut

         (Sarker and Gyr 1992) Download

Non-immunological defence mechanisms represent an important line of intestinal defence in addition to humoral and cellular immunity. This review summarises the evidence for the role of the non-immunological defence system. Protective factors that have been amply documented are gastric juice, intestinal motility, and intestinal flora. Components of pancreatic juice, lysozyme, and epithelial cell turnover may also be involved. Special attention is given to gastric acid, infection with Helicobacter pylori, and hypochlorhydria and their association with infectious diarrhoea. Epidemic hypochlorhydria is discussed since this increases sensitivity to intestinal infections in third world countries.

New non-invasive test of gastric acid secretion for use in children

         (Thomas, Eastham et al. 1993) Download

Loss of the gastric acid barrier may lead to recurrent enteric infections, small intestinal bacterial overgrowth, persistent diarrhoea, and thus malnutrition. To investigate this possibility, a new, non-invasive test of gastric acid secretion was developed ideal for field use in the developing world, where chronic diarrhoea and undernutrition are common. The test relies on the capacity of the kidney to retain H+ during gastric acid secretion, leading to a post-prandial urine 'alkaline tide'. Gastric intubation studies of seven healthy adult volunteers showed a direct relation between changes in gastric acid secretion and changes in urine acid output (measured as the H+/creatinine molar ratio in spot urine samples). Subjects who secreted gastric acid in response to stimulation with a sham feed showed a fall in urine acid output > 0.5 mmol H+/mmol creatinine (range -7.4 to -1.52 mean -1.12). The most reproducible decrease in urine acid output in response to normal food was observed around the time breakfast was usually eaten and was abolished by 36 hours of treatment with ranitidine. Breakfast time reductions in postprandial urine acid output in 22 healthy English children were comparable with those in healthy adults, and significantly different from values in achlorhydric adults. They were much more variable, however, in 106 Gambian children in whom values spanned both normochlorhydric and achlorhydric ranges (-12.7 to +1.8). Measuring changes in urine acid output at breakfast time provides a reliable indirect measure of gastric acid secretion that can be used in field conditions, enabling the relation between gastric acid output and the development of diarrhoeal diseases to be investigated.


Autoantibodies to parietal cells as predictors of atrophic body gastritis: a five-year prospective study in patients with autoimmune thyroid diseases

            (Tozzoli, Kodermaz et al. 2010) Download

Autoimmune thyroid diseases (AITD) can be associated with autoimmune gastritis (AIG), but the frequency of this association is poorly characterized. We performed a prospective study to: a) characterize the frequency of parietal cell (PCA) and intrinsic factor (IFA) autoantibodies in AITD patients; b) evaluate the development of histologically- and functionally-proven AIG after five years and to assess the predictive role of PCA for AIG at baseline; and c) analyze the trend of PCA levels in the course of the disease. We studied 208 consecutive adult patients affected by AITD (166 Hashimoto's thyroiditis, 42 Graves' disease). PCA, IFA and plasma gastrin levels were measured with ELISA methods at baseline and after 5years. At baseline, 51/208 (24.5%) AITD patients were positive for PCA and 10/208 (4.8%) for IFA. 25 out of 54 PCA/IFA-positive AITD patients (all without gastric or haematologic symptoms) agreed to participate in the follow-up study. After 5years, 6 (24%) of these 25 patients showed a histologically proven AIG, with lymphocytic infiltration and/or atrophy of body gastric mucosa. The trend analysis of PCA concentration showed that autoantibody levels rise progressively over time, reach a peak level and then fall, according to the progressive destruction of gastric mucosa and to the disappearance of the target autoantigen (proton pump). The presence of PCA predicts the development of autoimmune gastritis in AITD patients. Antibody levels measured with a sensitive quantitative immunometric method are useful for early diagnosis and early treatment of the disease.

Dynamic regulation of gastric autoimmunity by thyroid hormone

         (Wang, Griggs et al. 1998) Download

Neonatal thymectomy (NTX) of BALB/c mice between days 1 and 3 post-birth leads to a high incidence of autoimmune gastritis involving T cells and autoantibodies. Although progress has been made in understanding various immunological events associated with that disease process, much remains to be learned about the regulatory factors which control autoimmune gastritis. In this study we have examined the potential for neuroendocrine hormones of the hypothalamus-pituitary-thyroid (HPT) axis to alter the outcome of experimental autoimmune gastritis in NTX mice. As reported here, thyroxine administered to young adult NTX mice during an active phase of disease development dramatically reduced the incidence of gastritis and the overall severity of disease, and lowered the levels of anti-parietal cell antibodies. In contrast, treatment of young NTX mice with thyroxine or other HPT hormones prior to the onset of disease had no beneficial effect on gastritis, but instead resulted in significantly higher anti-parietal cell antibody levels compared to non-hormone-treated NTX mice or to NTX mice treated as adults. Reverse transcriptase spectratype analyses of 22 Vbeta gene junctional sites revealed pronounced oligoclonality and limited junctional diversity in stomach lymphocytes from untreated NTX mice compared to normal mice or thyroxine-treated NTX mice. These findings identify a set of dynamic immune-endocrine interactions, linked to critical development-dependent events, that are involved in the expression and regulation of peripheral autoimmunity.

Ghrelin and gastric acid secretion

         (Yakabi, Kawashima et al. 2008) Download

Ghrelin, a novel growth hormone-releasing peptide, was originally isolated from rat and human stomach. Ghrelin has been known to increase the secretion of growth hormone (GH), food intake, and body weight gain when administered peripherally or centrally. Ghrelin is also known to stimulate the gastric motility and the secretion of gastric acid. In the previous studies, the action of ghrelin on acid secretion was shown to be as strong as that of histamine and gastrin in in-vivo experiment. In the studies, the mechanism for the action of ghrelin was also investigated. It was shown that vagotomy completely inhibited the action of ghrelin on the secretion of gastric acid suggesting that vagal nerve is involved in the mechanism for the action of ghrelin on acid secretion. As famotidine did not inhibit ghrelin-induced acid secretion in the study by Masuda et al, they concluded that histamine was not involved in the action of ghrelin on acid secretion. However, we have shown that famotidine completely inhibited ghrelin-induced acid secretion and histidine decarboxylase (HDC) mRNA was increased in gastric mucosa by ghrelin injection which is inhibited by vagotomy Our results indicate that histamine is involved in the action of ghrelin on acid secretion. Furthermore synergistic action of gastrin and ghrelin on gastric acid secretion was shown. Although gastrin has important roles in postprandial secretion of gastric acid, ghrelin may be related to acid secretion during fasting period or at night. However, further studies are needed to elucidate the physiological role of ghrelin in acid secretion.


Reduced pepsin A processing of sonic hedgehog in parietal cells precedes gastric atrophy and transformation

            (Zavros, Waghray et al. 2007) Download

Sonic hedgehog (Shh) is not only essential to the development of the gastrointestinal tract, but is also necessary to maintain the characteristic acid-secreting phenotype of the adult stomach. Gastrin is the only hormone capable of stimulating gastric acid and is thus required to maintain functional parietal cells. We have shown previously that gastrin-null mice display gastric atrophy and metaplasia prior to progression to distal, intestinal-type gastric cancer. Because reduced levels of Shh peptide correlate with gastric atrophy, we examined whether gastrin regulates Shh expression in parietal cells. We show here that gastrin stimulates Shh gene expression and acid-dependent processing of the 45-kDa Shh precursor to the 19-kDa secreted peptide in primary parietal cell cultures. This cleavage was blocked by the proton pump inhibitor omeprazole and mediated by the acid-activated protease pepsin A. Pepsin A was also the protease responsible for processing Shh in tissue extracts from human stomach. By contrast, extracts prepared from neoplastic gastric mucosa had reduced levels of pepsin A and did not process Shh. Therefore processing of Shh in the normal stomach is hormonally regulated, acid-dependent, and mediated by the aspartic protease pepsin A. Moreover parietal cell atrophy, a known pre-neoplastic lesion, correlates with loss of Shh processing.


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