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Journal of Clinical Medicine Jun 2022Autoimmune gastritis (AIG) is chronic atrophic gastritis caused by an autoimmune mechanism of unknown etiology and presents with various pathological conditions by... (Review)
Review
Autoimmune gastritis (AIG) is chronic atrophic gastritis caused by an autoimmune mechanism of unknown etiology and presents with various pathological conditions by causing an achlorhydria state through parietal cell damage. The most characteristic endoscopic finding in AIG is advanced corpus-dominant mucosal atrophy. A recent study that examined several cases in Japan revealed the presence of endoscopic features other than corpus-dominant advanced atrophy. Remnants of oxyntic mucosa and sticky adherent dense mucus were found in ≥30% of cases, and hyperplastic polyps were found in ≥20% of cases. In image-enhanced endoscopy (IEE), white globe appearance (WGA) was observed in 32% of AIG cases. Additionally, some reports have stated that the findings in AIG cases using IEE showed cast-off skin appearance (CSA) and foveola type mucosa; however, a consensus is yet to be achieved. These endoscopic results were found in cases of advanced-stage AIG. There have been few reports concerning early-stage AIG cases. In these few reports, all of the cases were pathologically diagnosed as early AIG. In all of the cases, the pathological findings almost always showed neither parietal cell destruction nor atrophy. Endoscopic findings such as "mosaic pattern with slight swelling of the areae gastricae", "diffuse reddened and edematous gastric fundic gland mucosa", and "pseudopolyp-like nodules" may be common characteristics of early images. In such early cases, high antibody titers, no atrophic changes, and few clinical abnormal findings were shown. Endoscopists are expected to update their knowledge regarding AIG diagnosis with the evolution of imaging equipment.
PubMed: 35743593
DOI: 10.3390/jcm11123523 -
Digestive and Liver Disease : Official... Sep 2023Gastric polyps represent an abnormal proliferation of the gastric mucosa. Chronic atrophic autoimmune gastritis (CAAG) targets parietal cells and results in...
BACKGROUND
Gastric polyps represent an abnormal proliferation of the gastric mucosa. Chronic atrophic autoimmune gastritis (CAAG) targets parietal cells and results in hypo-achlorhydria and hypergastrinemia, which exerts a proliferative effect on the gastric mucosa.
AIMS
We investigate the incidence of gastric polyps in CAAG patients.
METHODS
This is a single-center retrospective study examining patients with confirmed CAAG from January 1990 until June 2022. Demographic, clinical, biochemical, and serological data were collected for each included patient. The histopathological characteristics of the detected polyps were recorded.
RESULTS
A total of 176 CAAG patients were included. Eighty-nine (50.5%) had 163 incidental polyps. Seventy-six patients (85%) had 130 non-endocrine lesions, among which 118 (90.7%) were inflammatory, 6 (4.6%) adenomatous, and 4 (3%) fundic; 33 patients (37%) had gastric neuroendocrine neoplasms (gNENs), and 21 (23.6%) both; one had MALToma and one gastric adenocarcinoma. Higher circulating levels of gastrin and chromogranin A were observed among patients with polyps (median 668 vs 893 pg/ml p = 0.0237, 146 vs 207 ng/ml p = 0.0027, respectively).
CONCLUSION
CAAG implies a high incidence of gNENs and exocrine lesions. Gastrin plays a possible trophic role on the mucosa. Further evidence is needed to validate its predictive role for increased polyp risk in CAAG.
Topics: Humans; Gastrins; Retrospective Studies; Autoimmune Diseases; Gastritis; Gastritis, Atrophic; Gastric Mucosa; Stomach Neoplasms; Precancerous Conditions; Polyps
PubMed: 36858908
DOI: 10.1016/j.dld.2023.02.008 -
Dysphagia Apr 2022Caustic ingestion can lead to structural changes in the upper gastro-intestinal tract. However, there is limited data on the effect of caustic ingestion on gastric...
Caustic ingestion can lead to structural changes in the upper gastro-intestinal tract. However, there is limited data on the effect of caustic ingestion on gastric secretion. This study was planned to determine changes in gastric acid output after sham feeding in patients with caustic induced esophageal stricture and to compare it with healthy controls. It was a prospective study done at tertiary care center in North India. Consecutive patients with caustic induced esophageal stricture were evaluated for the study. Gastric secretory function was estimated in the basal state and after modified sham feeding. These results were compared with age-matched controls. The mean age of the included patients (n = 18) was 30.11 ± 9.19 years and 13 patients were male. 16 (88%) patients had history of acid ingestion. Patients with caustic sequelae had significantly lower basal and stimulated acid secretion compared to controls (n = 10) (5.84 ± 2.44 mmol/hr; p < 0.01 and 17.16 ± 7.53 mmol/hr; p < 0.01; respectively). Patients with lower esophageal stricture (n = 8) had significantly lower increase in acid output compared to patients with stricture elsewhere in esophagus (0.20 ± 0.3 vs. 2.31 ± 1.74 mmol/hr, p < 0.01). Patients with lower esophageal involvement had significantly lower stimulated acid secretion and increase in acid secretion compared to controls (4.74 ± 4.67 vs. 17.16 ± 7.53 mmol/hr; p < 0.01 and 20 ± 0.3 vs. 2.09 ± 0.88 mmol/hr; p < 0.01; respectively).
Topics: Adult; Caustics; Esophageal Stenosis; Female; Gastric Acid; Humans; Male; Prospective Studies; Young Adult
PubMed: 33905046
DOI: 10.1007/s00455-021-10285-5 -
Bioscience Reports Feb 2020Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H+, K+-adenosine triphosphatase (ATPase), the enzyme...
Parietal cells of the gastric mucosa contain a complex and extensive secretory membrane system that harbors gastric H+, K+-adenosine triphosphatase (ATPase), the enzyme primarily responsible for gastric lumen acidification. Here, we describe the characterization of mice deficient in the H+, K+-ATPase α subunit (Atp4a-/-) to determine the role of this protein in the biosynthesis of this membrane system and the biology of the gastric mucosa. Atp4a-/- mice were produced by gene targeting. Wild-type (WT) and Atp4a-/- mice, paired for age, were examined at 10, 12, 14 and 16 weeks for histopathology, and the expression of mucin 2 (MUC2), α-methylacyl-CoA racemase (AMACR), Ki-67 and p53 proteins was analyzed by immunohistochemistry. For further information, phosphoinositide 3-kinase (PI3K), phosphorylated-protein kinase B (p-AKT), mechanistic target of rapamycin (mTOR), hypoxia-inducible factor 1α (HIF-1α), lactate dehydrogenase A (LDHA) and sirtuin 6 (SIRT6) were detected by Western blotting. Compared with the WT mice, hypochlorhydric Atp4a-/- mice developed parietal cell atrophy and significant antral inflammation (lymphocyte infiltration) and intestinal metaplasia (IM) with elevated MUC2 expression. Areas of dysplasia in the Atp4a-/- mouse stomach showed increased AMACR and Ki-67 expression. Consistent with elevated antral proliferation, tissue isolated from Atp4a-/- mice showed elevated p53 expression. Next, we examined the mechanism by which the deficiency of the H+, K+-ATPase α subunit has an effect on the gastric mucosa. We found that the expression of phosphorylated-PI3K, p-AKT, phosphorylated-mTOR, HIF-1α, LDHA and SIRT6 was significantly higher in tissue from the Atp4a-/- mice compared with the WT mice (P<0.05). The H+, K+-ATPase α subunit is required for acid-secretory activity of parietal cells in vivo, the normal development and cellular homeostasis of the gastric mucosa, and attainment of the normal structure of the secretory membranes. Chronic achlorhydria and hypergastrinemia in aged Atp4a-/- mice produced progressive hyperplasia and mucolytic and IM, and activated the Warburg effect via PI3K/AKT/mTOR signaling.
Topics: Achlorhydria; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Chronic Disease; Energy Metabolism; H(+)-K(+)-Exchanging ATPase; Metaplasia; Mice, Inbred C57BL; Mice, Knockout; Mucin-2; Parietal Cells, Gastric; Phosphatidylinositol 3-Kinase; Precancerous Conditions; Proto-Oncogene Proteins c-akt; Signal Transduction; Stomach Neoplasms; TOR Serine-Threonine Kinases; Time Factors
PubMed: 31904088
DOI: 10.1042/BSR20181881 -
Endocrine Journal Oct 2022VIPomas are generally rare functioning pancreatic neuroendocrine tumors (PanNETs) that cause watery diarrhea, hypokalemia, and achlorhydria. Due to their extreme rarity,...
VIPomas are generally rare functioning pancreatic neuroendocrine tumors (PanNETs) that cause watery diarrhea, hypokalemia, and achlorhydria. Due to their extreme rarity, the clinicopathological features and outcomes of VIPomas have not been well reported. This study aimed to determine the diagnostic and therapeutic characteristics and prognosis of VIPomas and to compare them with other PanNETs at a Japanese reference hospital. Medical records of 293 patients with PanNETs were collected. Patient and tumor characteristics and outcomes were retrospectively reviewed. This cohort had only 1.4% (four patients) of patients with VIPomas, and three of these patients changed from non-functioning (NF-) PanNETs during their disease course. Recurrences of hormonal symptoms were observed in all patients despite the initial controls, and all of them died from their disease, more specifically mainly from hormonal symptoms. Compared to the other PanNETs, VIPomas were all located at the pancreatic tail, were larger, and had a higher Ki-67 index and more metastasis. The median survival time was significantly shorter for patients with VIPoma than for those with NF-PanNET (5.9 vs. 26.7 years, p < 0.0001), insulinoma (21.8 years, p < 0.0001), and gastrinoma (12.3 years, p = 0.0325). This study presents the possibility of shifting from non-symptomatic to symptomatic VIPomas as they grow or of transforming from NF-PanNETs to VIPomas. VIPomas should be considered in patients with relatively large NF-PanNETs, especially those located in the pancreatic tail, when diarrhea is continuously observed. As hormonal symptoms are an important cause of death in VIPomas, long-term symptomatic control, which is relatively difficult, is of great significance.
Topics: Humans; Vipoma; Neuroendocrine Tumors; Retrospective Studies; Pancreatic Neoplasms; Vasoactive Intestinal Peptide; Diarrhea
PubMed: 35644576
DOI: 10.1507/endocrj.EJ22-0111 -
Drug Development and Industrial Pharmacy Mar 2022Development and optimization of orally administered drug products often require bio-predictive tools to help with informing formulation and manufacturing decisions.... (Review)
Review
Development and optimization of orally administered drug products often require bio-predictive tools to help with informing formulation and manufacturing decisions. Reliable bio-predictive dissolution toolkits not only allow rational development of target formulations without having to conduct excessive studies but also help in detecting critical material attributes (CMAs), critical formulation variables (CFVs), or critical process parameters (CPPs) that could impact a drug's performance. To provide early insights for scientists on the development of a bio-predictive method for drug product development, this review summarizes current phase-appropriate bio-predictive dissolution approaches applicable to address typical concerns on solubility-limited absorption, food effect, achlorhydria, development of extended-release formulation, clinically relevant specification, and biowaiver. The selection of an method which can capture the key rate-limiting step(s) of the dissolution and/or absorption is considered to have a better chance to produce a meaningful correlation (IVIVC) or relationship (IVIVR).
Topics: Administration, Oral; Delayed-Action Preparations; Dosage Forms; Drug Development; Solubility
PubMed: 35786119
DOI: 10.1080/03639045.2022.2098315 -
Food Research International (Ottawa,... Jul 2022We applied in vitro models of gastrointestinal (GI) digestion simulating the conditions of the GI tract of healthy adults and elderly individuals with achlorhydria (EA)...
We applied in vitro models of gastrointestinal (GI) digestion simulating the conditions of the GI tract of healthy adults and elderly individuals with achlorhydria (EA) to investigate differences in the digestibility of meat (chicken, beef and pork) and soy proteins. Digestibility was significantly affected by EA alterations. Peptidomics analyses revealed significant differences in peptide profiles between control and EA conditions, including number, length distribution, clustering, and differentially abundant peptides (DAPs). Our results revealed that the differences in meat peptide profiles diminished going from the gastric to intestinal phase. For soy protein, the marked differences between control and EA conditions were maintained in the gastric and intestinal phases. Higher numbers of potentially bioactive peptides were generated under the control condition compared to the EA condition. The present study provides insight into the distinct peptide profiles generated by in vitro digestion of meat and soy proteins under adult and EA GI conditions.
Topics: Adult; Aged; Animal Proteins, Dietary; Animals; Digestion; Humans; Meat; Peptides; Soybean Proteins
PubMed: 35761537
DOI: 10.1016/j.foodres.2022.111215 -
Cellular and Molecular Gastroenterology... 2020In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs)....
BACKGROUND & AIMS
In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling.
METHODS
We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGS gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples.
RESULTS
Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGS cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGS cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5.
CONCLUSIONS
In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide.
Topics: Animals; Benzodiazepines; Benzodiazepinones; Cell Line, Tumor; Disease Models, Animal; Gastric Mucosa; Gastrins; Gene Knockdown Techniques; Humans; Mice; Mice, Transgenic; Neuroendocrine Tumors; Organoids; Phenylurea Compounds; Pregnancy-Associated Plasma Protein-A; Primary Cell Culture; Receptor, Cholecystokinin B; Stomach Neoplasms; Treatment Outcome
PubMed: 32004755
DOI: 10.1016/j.jcmgh.2020.01.010 -
PloS One 2021Hypochlorhydria (gastric pH >4) increases susceptibility to diarrhoea, iron deficiency, and gastric cancer. We sought to clarify the prevalence of this condition and its...
BACKGROUND
Hypochlorhydria (gastric pH >4) increases susceptibility to diarrhoea, iron deficiency, and gastric cancer. We sought to clarify the prevalence of this condition and its predisposing factors in Zambia by pooling data from previous studies conducted in hospital and community settings.
METHODS
Gastric pH was measured in participants from five separate studies by collecting gastric aspirate from fasted adults and children under 3 years of age undergoing gastroscopy. Gastric pH was correlated with serological testing for Human Immunodeficiency Virus (HIV) and Helicobacter pylori (H. pylori) infections.
RESULTS
We studied 597 individuals (487 adults and 110 children). Hypochlorhydria was present in 53% of adults and 31% of children. HIV infection was detected in 41% of adults and 11% of children. H. pylori serology was available for 366 individuals: 93% of adults and 6% of children were seropositive. In univariate analysis, hypochlorhydria was significantly associated with HIV seropositivity (OR 1.7; 95% CI 1.2-2.4; p = 0.004) and H. pylori antibody seropositivity (OR 4.9; 95% CI 2.8-8.6; p<0.0001), and with advancing age in HIV negative individuals (p = 0.0001). In multivariable analysis, only H. pylori was associated with hypochlorhydria (OR 4.0; 95% CI 2.2-7.2; p<0.0001) while excluding possible exposure to proton pump inhibitors.
CONCLUSIONS
Hypochlorhydria is common in our population, with H. pylori being the dominant factor. Only young HIV seronegative individuals had a low prevalence of hypochlorhydria. This may have implications for the risk of other health conditions including gastric cancer.
Topics: Achlorhydria; Adult; Aged; Child; Child, Preschool; Endoscopy; Female; Gastroscopy; HIV; HIV Infections; Helicobacter Infections; Helicobacter pylori; Humans; Hydrogen-Ion Concentration; Infant; Male; Middle Aged; Risk Factors; Stomach; Stomach Neoplasms
PubMed: 34449790
DOI: 10.1371/journal.pone.0256487 -
Molecular Pharmaceutics Sep 2021Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. drug dissolution depends on the GI...
Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. drug dissolution depends on the GI tract's physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. and Bermejo, M. ). The dissolution of an ionizable drug may benefit from manipulating variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (, proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds' dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties ( solubility and p) and its interplay with the pH modifier p or ps. As an example of this complex interaction, for basic drugs with high p and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as p, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to multi-compartment dissolution vessels and are validated by experiments in the gastrointestinal simulator. This model's predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both and conditions.
Topics: Administration, Oral; Betaine; Biological Availability; Chemistry, Pharmaceutical; Computer Simulation; Drug Design; Drug Liberation; Excipients; Fumarates; Gastrointestinal Absorption; Humans; Hydrogen-Ion Concentration; Models, Biological; Solubility; Tartrates
PubMed: 34428047
DOI: 10.1021/acs.molpharmaceut.1c00262