Morphology of G Cells in Hypergastrinemic Cotton Rats

In a strain of inbred cotton rats, 25-50% of females develop spontaneous gastric hypochlorhydria and  hypergastrinemia. Hypergastrinemic animals develop ECL cell derived gastric carcinomas located in the  oxyntic mucosa, thus being an interesting animal model for studying the role of gastrin in gastric carcinogenesis.  The response to gastric hypoacidity in cotton rats as regards the level of hypergastrinemia is far  more pronounced than in the more commonly used laboratory rat. It is unknown whether the pronounced  hypergastrinemic response in cotton rats is due to a greater population of G cells or a greater capacity of  hormone synthesis in each G cell. The aim of the study was therefore to examine G cell population and  ultrastructure in normogastrinemic and hypergastrinemic cotton rats by the use of immunhistochemical  methods applied on both light- and electron-microscopy. Five hypergastrinemic vs. five normogastrinemic  cotton rats were compared. Cotton rats with gastric hypochlorhydria have a 55-fold increase in serum gastrin levels and a 6-fold  increase in G cell number, but this is not accompanied by significant changes in G cell ultrastructure. The  lack of ultrastructural changes in these activated G cells indicates that previously reported changes in  chronic stimulated G cells are just one of several ways G cells are activated.

Animal Models to Study the Role of Long-Term Hypergastrinemia in Gastric Carcinogenesis

Patients with chronic hypergastrinemia due to chronic atrophic gastritis or gastrinomas have an increased risk of developing gastric malignancy, and it has been questioned whether also patients with hypergastrinemia caused by long-term use of acid inhibiting drugs are at risk. Gastric carcinogenesis in humans is affected by numerous factors and progresses slowly over years. When using animal models with the possibility of intervention, a complex process can be dissected by studying the role of hypergastrinemia in carcinogenesis within a relatively short period of time. We have reviewed findings from relevant models where gastric changes in animal models of long-term hypergastrinemia have been investigated. In all species where long-term hypergastrinemia has been induced, there is an increased risk of gastric malignancy. There is evidence that hypergastrinemia is a common causative factor in carcinogenesis in the oxyntic mucosa, while other cofactors may vary in the different models

Classification of tumours

Tumours are classified according to the most differentiated cells with the exception of carcinomas where a few tumour cells show neuroendocrine differentiation. In this case these cells are regarded as redifferentiated tumour cells, and the tumour is not classified as neuroendocrine. However, it is now clear that normal neuroendocrine cells can divide, and that continuous stimulation of such cells results in tumour formation, which during time becomes increasingly malignant. To understand tumourigenesis, it is of utmost importance to recognize the cell of origin of the tumour since knowledge of the growth regulation of that cell may give information about development and thus possible prevention and prophylaxis of the tumour. It may also have implications for the treatment. The successful treatment of gastrointestinal stromal tumours by a tyrosine kinase inhibitor is an example of the importance of a correct cellular classification of a tumour. In the future tumours should not just be classified as for instance adenocarcinomas of an organ, but more precisely as a carcinoma originating from a certain cell type of that organ

The peroxisome proliferator-activated receptor (PPAR) alpha agonist fenofibrate maintains bone mass, while the PPAR gamma agonist pioglitazone exaggerates bone loss, in ovariectomized rats

<p>Abstract</p> <p>Background</p> <p>Activation of peroxisome proliferator-activated receptor (PPAR)gamma is associated with bone loss and increased fracture risk, while PPARalpha activation seems to have positive skeletal effects. To further explore these effects we have examined the effect of the PPARalpha agonists fenofibrate and Wyeth 14643, and the PPARgamma agonist pioglitazone, on bone mineral density (BMD), bone architecture and biomechanical strength in ovariectomized rats.</p> <p>Methods</p> <p>Fifty-five female Sprague-Dawley rats were assigned to five groups. One group was sham-operated and given vehicle (methylcellulose), the other groups were ovariectomized and given vehicle, fenofibrate, Wyeth 14643 and pioglitazone, respectively, daily for four months. Whole body and femoral BMD were measured by dual X-ray absorptiometry (DXA), and biomechanical testing of femurs, and micro-computed tomography (microCT) of the femoral shaft and head, were performed.</p> <p>Results</p> <p>Whole body and femoral BMD were significantly higher in sham controls and ovariectomized animals given fenofibrate, compared to ovariectomized controls. Ovariectomized rats given Wyeth 14643, maintained whole body BMD at sham levels, while rats on pioglitazone had lower whole body and femoral BMD, impaired bone quality and less mechanical strength compared to sham and ovariectomized controls. In contrast, cortical volume, trabecular bone volume and thickness, and endocortical volume were maintained at sham levels in rats given fenofibrate.</p> <p>Conclusions</p> <p>The PPARalpha agonist fenofibrate, and to a lesser extent the PPARaplha agonist Wyeth 14643, maintained BMD and bone architecture at sham levels, while the PPARgamma agonist pioglitazone exaggerated bone loss and negatively affected bone architecture, in ovariectomized rats.</p

Role of Autoimmune Gastritis in Gastric Cancer

It has been known for 70 years that gastric cancer occurs mainly in a stomach with gastritis. Gastritis was previously so prevalent that it was regarded as an aging phenomenon. Since the description of Helicobacter pylori (Hp) as the main cause of gastritis and peptic ulcer disease (1), Hp was soon accepted as the most important gastric carcinogen (2). The mechanism by which Hp induces gastric cancer has not been found despite intensive research for 30 years. However, a major breakthrough was achieved when Uemura et al. (3) described that Hp predisposes to gastric cancer only when having induced atrophy of the oxyntic mucosa. This led us to propose that hypergastrinemia due to reduced acid secretion leading to gastric hypoacidity was the pathogenic factor in Hp-associated gastric cancer (4). Autoimmune gastritis (AI) has been accepted as a separate type of gastritis having a much lower prevalence than Hp gastritis. Hp and AI gastritis have special traits (Table 1), but no test that can definitively discriminate between the 2 types

Gastritis, Gastric Polyps and Gastric Cancer

Gastric cancer is still an important disease causing many deaths worldwide, although there has been a marked reduction in prevalence during the last few decades. The decline in gastric cancer prevalence is due to a reduction in Helicobacter pylori infection which has occurred for at least 50 years. The most probable mechanism for the carcinogenic effect of H. pylori is hypergastrinemia since H. pylori infected individuals do not have increased risk of gastric cancer before the development of oxyntic atrophy. When atrophy has developed, the carcinogenic process continues independent of H. pylori. Autoimmune gastritis also induces oxyntic atrophy leading to marked hypergastrinemia and development of ECL cell neoplasia as well as adenocarcinoma. Similarly, long-term treatment with efficient inhibitors of acid secretion like the proton pump inhibitors (PPIs) predisposes to ECL cell neoplasia of a different degree of malignancy. Contrasting the colon where most cancers develop from polyps, most polyps in the stomach have a low malignant potential. Nevertheless, gastric polyps may also give rise to cancer and have some risk factors and mechanisms in common with gastric cancer. In this overview the most common gastric polyps, i.e., hyperplastic polyps, adenomatous polyps and fundic gland polyps will be discussed with respect to etiology and particularly use of PPIs and relation to gastric carcinogenesis

Types of Gastric Carcinomas

Gastric cancer has reduced prevalence, but poor prognoses. To improve treatment, better knowledge of carcinogenesis and cells of origin should be sought. Stomach cancers are typically localized to one of the three mucosae; cardial, oxyntic and antral. Moreover, not only the stem cell, but the ECL cell may proliferate and give rise to tumours. According to Laurén, the classification of gastric carcinomas seems to reflect biological important differences and possible different cell of origin since the two subtypes, intestinal and diffuse, do not transform into the other and show different epidemiology. The stem cell probably gives rise to the intestinal type, whereas the ECL cell may be important in the diffuse type. Elevation of gastrin may be the carcinogenic factor for Helicobacter pylori as well as the recently described increased risk of gastric cancer due to proton pump inhibitor treatment. Therefore, it is essential to determine the role of the gastrin target cell, the ECL cell, in gastric carcinogenesis. Clinical trials with gastrin antagonists could improve prognoses in those with gastrin receptor positive tumours. However, further studies on gastric carcinomas applying relative available methods and with the highest sensitivity are warranted to improve our knowledge of gastric carcinogenesis.publishedVersion© 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/

Is empiric proton pump inhibition in patients with symptoms of extraesophageal gastroesophageal reflux justified?

Abstract Background The prevalence of gastroesophageal reflux disease (GERD) has had a marked increase in Western countries with a paralleling interest in extraesophageal (EE) manifestations of GERD, including laryngopharyngeal reflux (LPR). There are considerable differences in clinical practice between gastroenterologists, otolaryngologists and pulmonologists. Methods In this narrative review we address some of these controversies concerning EE manifestations of GERD and LPR. Results It is disputed whether there is causal relationship between reflux and the numerous symptoms and conditions suggested to be EE manifestations of GERD. Similarly, the pathophysiology is uncertain and there are disagreements concerning diagnostic criteria. Consequently, it is challenging to provide evidence-based treatment recommendations. A significant number of patients are given a trial course with a proton pump inhibitor (PPI) for several months before symptoms are evaluated. In randomized controlled trials (RCTs) and meta-analyses of RCTs PPI treatment does not seem to be advantageous over placebo, and the evidence supporting that patients without verified GERD have any benefit of PPI treatment is negligible. There is a large increase in both over the counter and prescribed PPI use in several countries and a significant proportion of this use is without any symptomatic benefit for the patients. Whereas short-term treatment has few side effects, there is concern about side-effects after long-term use. Although empiric PPI treatment for suspected EE manifestations of GERD instead of prior esophageal 24-hour pH and impedance monitoring is included in several guidelines by various societies, this practice contributes to overtreatment with PPI. Conclusion We argue that the current knowledge suggests that diagnostic testing with pH and impedance monitoring rather than empiric PPI treatment should be chosen in a higher proportion of patients presenting with symptoms possibly attributable to EE reflux

The phylogeny and biological function of gastric juice-microbiological consequences of removing gastric acid

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

Do Gastric Signet Ring Cell Carcinomas and ECL-Cell Neuroendocrine Tumours Have a Common Origin?

Gastric cancer is a heterogenous group of tumours, and a better understanding of the carcinogenesis and cellular origin of the various sub-types could affect prevention and future treatment. Gastric neuroendocrine tumours (NETs) and adenocarcinomas that develop in the gastric corpus and fundus of patients with chronic atrophic gastritis have atrophic gastritis, hypoacidity, and hypergastrinemia as common risk factors and a shared cellular origin has been suggested. In particular, signet ring cell carcinomas have previously been suggested to be of neuroendocrine origin. We present a case of a combined gastric NET and signet ring cell carcinoma in a patient with hypergastrinemia due to autoimmune chronic atrophic gastritis. The occurrence of such a combined tumour strengthens the evidence that gastric NETs and signet ring cell carcinomas develop from a common origin