intrinsic-factor and Metaplasia

Autoimmune gastritis (AG) is a corpus-restricted chronic atrophic gastritis associated with intrinsic factor deficiency, either with or without pernicious anemia. Autoimmune gastritis is a microscopic disease because patients present with no or vague symptoms, and clinicians rarely find endoscopic changes. Autoimmune gastritis only becomes a clinical disease when pathologists diagnose it in gastric biopsies performed for a variety of clinical indications. Unfamiliarity with this disease can result in misdiagnosis of patients, and thus inadequate patient management.. To review the pathogenesis, clinical features, diagnostic criteria, differential diagnoses, sequelae, and surveillance recommendations for AG.. The sources of the study include a review of the pertinent literature for AG.. Autoimmune gastritis is an important disease characterized by a loss of oxyntic mucosa and presence of metaplastic epithelium and enterochromaffin-like cell hyperplasia. Awareness and proper diagnosis are critical to prevent mismanagement of patients.

Topics: Anemia, Pernicious; Autoimmune Diseases; Biopsy; Chronic Disease; Diagnosis, Differential; Diagnostic Errors; Epithelium; Gastritis, Atrophic; Humans; Hyperplasia; Intrinsic Factor; Metaplasia; Stomach

Topics: Amino Acids; Anemia, Pernicious; Animals; Carbohydrates; Embryo, Mammalian; Endopeptidases; Epithelial Cells; Epithelium; Fatty Acids; Female; Gastric Juice; Gastric Mucosa; Humans; Hyperglycemia; Intrinsic Factor; Male; Mast Cells; Metaplasia; Rats; RNA; Stomach Neoplasms; United States

Topics: Anemia, Pernicious; Antibodies; Atrophy; Autoimmune Diseases; Capillaries; Chronic Disease; Dyspepsia; Gastrectomy; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Humans; Hypertrophy; Intrinsic Factor; Metaplasia; Mitosis; Pentagastrin; Pepsin A; Peptic Ulcer; Pyloric Antrum; Radiography; Stomach; Stomach Neoplasms; Thyroid Diseases; Vagotomy

Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death.

Topics: Animals; Apoptosis; Atrophy; Azetidines; Cell Proliferation; Cellular Reprogramming; Chief Cells, Gastric; Diphtheria Toxin; Heparin-binding EGF-like Growth Factor; Intercellular Signaling Peptides and Proteins; Intrinsic Factor; Metaplasia; Mice; Parietal Cells, Gastric; Peptides; Piperazines; Plant Lectins; Stomach; Tamoxifen

Surveillance of intestinal metaplasia (IM) of the gastric mucosa should be limited to patients at high risk of gastric cancer. Patients with extensive IM are at increased cancer risk; however, the intragastric extent of IM is usually unknown at the time of the initial diagnosis.. To assess the predictive value of clinical, histologic, and serologic parameters for the intragastric extent of IM.. Prospective, multicenter study.. Eighty-eight patients with a previous diagnosis of IM of the gastric mucosa.. Surveillance gastroscopy with extensive random biopsy sampling.. Biopsy specimens were evaluated according to the Sydney classification system. In addition, serologic testing of Helicobacter pylori and cagA status, pepsinogens I and II, gastrin, and intrinsic factor antibodies was performed. The association between the available parameters and extensive IM was evaluated with logistic regression analysis.. In 51 patients (58%), IM was present in the biopsy specimens from at least 2 intragastric locations. The most important predictors of extensive IM were a family history of gastric cancer, alcohol use > or = 1 unit/d (1 glass, approximately 10 mL or 8 g ethanol), moderate or marked IM of the index biopsy specimen, and a pepsinogen I to II ratio < 3.0. A simple risk score based on these factors could identify extensive IM in 24 of 25 patients (sensitivity 96%).. A prospective cohort study should confirm the proposed risk stratification.. A risk score of clinical, histologic, and serologic parameters can predict extensive intragastric IM and may serve as a practical tool to select patients for surveillance endoscopy in routine clinical practice.

Topics: Adult; Aged; Antibodies, Bacterial; Antigens, Bacterial; Bacterial Proteins; Biopsy; Endoscopy, Gastrointestinal; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Helicobacter pylori; Humans; Intrinsic Factor; Male; Metaplasia; Middle Aged; Pepsinogen A; Pepsinogen C; Precancerous Conditions; Prognosis; Prospective Studies; Risk Factors; Stomach Neoplasms; Surveys and Questionnaires; Time Factors; Young Adult

The orderly differentiation of cell lineages within gastric glands is regulated by a complicated interplay of local mucosal growth factors and hormones. Histamine secreted from enterochromaffin-like cells plays an important role in not only stimulated gastric acid secretion but also coordination of intramucosal growth and lineage differentiation. We have examined histidine-decarboxylase (HDC)-deficient mice, which lack endogenous histamine synthesis, to evaluate the influence of histamine on differentiation of fundic mucosal lineages and the development of metaplasia following induction of acute oxyntic atrophy. Stomachs from HDC-deficient mice and wild-type mice were evaluated at 8 wk and 12 mo of age. DMP-777 was administrated orally to 6-wk-old mice for 1 to 14 days. Sections of gastric mucosa were stained with antibodies against Mist1, intrinsic factor, H/K-ATPase, trefoil factor 2 (TFF2), chromogranin A, and Ext1 and for the cell cycle marker phospho-histone H3. HDC-deficient mice at 8 wk of age demonstrated a prominent increase in chief cells expressing Mist1 and intrinsic factor. Importantly Mist1-positive mature chief cells were present in the midgland region as well as at the bases of fundic glands, indicating a premature differentiation of chief cells. Mice dually deficient for both HDC and gastrin showed a normal distribution of chief cells in fundic glands. Treatment of HDC-deficient mice with DMP-777 led to loss of parietal cells and an accelerated and exaggerated emergence of mucous cell metaplasia with the presence of dual intrinsic factor and TFF2-expressing cells throughout the gland length, indicative of the emergence of spasmolytic polypeptide-expressing metaplasia (SPEM) from chief cells. These findings indicate that histamine, in concert with gastrin, regulates the appropriate differentiation of chief cells from mucous neck cells as they migrate toward the bases of fundic glands. Nevertheless, histamine is not required for emergence of SPEM following acute oxyntic atrophy.

Topics: Age Factors; Animals; Azetidines; Basic Helix-Loop-Helix Transcription Factors; Cell Count; Cell Differentiation; Chief Cells, Gastric; Chromogranin A; Enterochromaffin-like Cells; Enzyme Inhibitors; Gastric Fundus; Gastric Mucosa; Gastrins; Histamine; Histidine Decarboxylase; Hyperplasia; Hypertrophy; Intrinsic Factor; Metaplasia; Mice; Mice, Inbred BALB C; Mice, Knockout; Mucins; Muscle Proteins; N-Acetylglucosaminyltransferases; Parietal Cells, Gastric; Peptides; Piperazines; Trefoil Factor-2

Loss of gastric parietal cells is a critical precursor to gastric metaplasia and neoplasia. However, the origin of metaplasia remains obscure. Acute parietal cell loss in gastrin-deficient mice treated with DMP-777 leads to the rapid emergence of spasmolytic polypeptide/trefoil factor family 2 (TFF2)-expressing metaplasia (SPEM) from the bases of fundic glands. We now sought to characterize more definitively the pathway for emergence of SPEM.. Emerging SPEM lineages in gastrin-deficient mice treated with DMP-777 were examined for immunolocalization of TFF2, intrinsic factor, and Mist1, and morphologically with electron microscopy. Emerging SPEM was isolated with laser-capture microdissection and RNA was analyzed using gene microarrays. Immunohistochemistry in mouse and human samples was used to confirm up-regulated transcripts.. DMP-777-induced SPEM was immunoreactive for TFF2 and the differentiated chief cell markers, Mist1 and intrinsic factor, suggesting that SPEM derived from transdifferentiation of chief cells. Microarray analysis of microdissected SPEM lineages induced by DMP-777 showed up-regulation of transcripts associated with G1/S cell-cycle transition including minichromosome maintenance deficient proteins, as well as a number of secreted factors, including human epididymis 4 (HE4). HE4, which was absent in the normal stomach, was expressed in SPEM of human and mouse and in intestinal metaplasia and gastric cancer in human beings.. Although traditionally metaplasia was thought to originate from normal mucosal progenitor cells, these studies indicate that SPEM evolves through either transdifferentiation of chief cells or activation of a basal cryptic progenitor. In addition, induction of metaplasia elicits the expression of secreted factors, such as HE4, relevant to gastric preneoplasia.

Topics: Animals; Atrophy; Basic Helix-Loop-Helix Transcription Factors; beta-Defensins; Carrier Proteins; Cell Cycle Proteins; Cell Transformation, Neoplastic; Chief Cells, Gastric; DNA-Binding Proteins; Epididymal Secretory Proteins; Fetal Proteins; Gastric Fundus; Gastric Mucosa; Gastrins; Humans; Intercellular Signaling Peptides and Proteins; Intrinsic Factor; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Knockout; Microtubule-Associated Proteins; Minichromosome Maintenance Complex Component 3; Mucins; Muscle Proteins; Nuclear Proteins; Parietal Cells, Gastric; Peptides; Precancerous Conditions; Stomach Neoplasms; Trefoil Factor-2

The loss of parietal cells from the gastric mucosa (oxyntic atrophy) is a critical step in the pathogenesis of chronic gastritis and gastric adenocarcinoma. Parietal cells are known to secrete epidermal growth factor receptor (EGFR) ligands, which are critical regulators of differentiation in the gastric mucosa. Although all of the actions of EGFR ligands are mediated through a common EGFR protein, individual ligands may produce different physiologic responses. Previous investigations have suggested that a deficit in EGFR signaling in waved-2 mice accelerates the emergence of metaplasia after induction of acute oxyntic atrophy. We sought to determine whether specific EGFR ligands regulate the metaplastic response to oxyntic atrophy.. To induce spasmolytic polypeptide-expressing metaplasia (SPEM), amphiregulin (AR) and transforming growth factor-alpha-deficient mice and their wild-type littermates were treated with DMP-777 for 0-14 days and for 14 days followed by 14 days of recovery off drug. We evaluated the gastric mucosal response to oxyntic atrophy using cell lineage-specific markers.. Although loss of transforming growth factor-alpha did not influence the induction of SPEM, loss of AR caused an acceleration and amplification in the induction of SPEM after acute oxyntic atrophy. Trefoil factor family 2/spasmolytic polypeptide and intrinsic factor dual-immunostaining cells significantly increased in the SPEM of AR-deficient mice. At the bases of glands, intrinsic factor immunoreactive cells also were costained for 5-bromo-2'-deoxyuridine, suggesting their re-entry into the cell cycle.. The absence of AR promoted the rapid emergence of SPEM in response to oxyntic atrophy.

Topics: Amphiregulin; Animals; Atrophy; Azetidines; EGF Family of Proteins; ErbB Receptors; Gastric Mucosa; Gastrins; Gene Expression Regulation; Glycoproteins; Intercellular Signaling Peptides and Proteins; Intrinsic Factor; Male; Metaplasia; Mice; Mice, Inbred C57BL; Mice, Knockout; Parietal Cells, Gastric; Peptides; Piperazines; S Phase; Somatostatin; Transforming Growth Factor alpha; Trefoil Factor-2

Gastric morphology, function, and immunology was studied in 68 patients with pernicious anemia (PA), 183 of their first-degree relatives, and 354 control subjects. The PA relatives and controls were comparable in age and sex distribution. In both groups, mean gastric acid output decreased and mean fasting serum gastrin levels and the prevalence of atrophic gastritis increased with age. The total prevalence of chronic gastritis was similar in the two groups, but severe atrophic gastritis of the body of the stomach (AGB), achlorhydria, parietal cell antibodies, and a raised fasting serum gastrin level were significantly more common in PA relatives than in controls. Of the PA relatives 23 had severe AGB which was indistinguishable from the gastric mucosal lesion found in PA probands and was, as a rule, accompanied by several other characteristics of type A gastritis. These included a normal antrum (78%), slight or absent inflammatory cell infiltration in the gastric mucosa (70%), achlorhydria (91%), high fasting serum gastrin level (83%), parietal cell antibodies (65%), and intrinsic factor antibodies (22%). The mean age and the proportion of subjects with slight and moderate AGB of all AGB subjects was significantly lower in PA relatives than in controls. This suggests an early onset and a rapid progression from mild to severe AGB in PA relatives. Thus, the PA relatives appear to consist of two populations, one with a high and one with little or no proneness to severe AGB. This bimodal distribution suggests the participation of a single major factor, probably genetic, in the pathogenesis of severe AGB in PA relatives.

Topics: Adolescent; Adult; Age Factors; Anemia, Pernicious; Atrophy; Autoantibodies; Consanguinity; Female; Gastric Juice; Gastric Mucosa; Gastrins; Gastritis; Humans; Intestines; Intrinsic Factor; Male; Metaplasia; Middle Aged; Pyloric Antrum; Vitamin B 12

Three hundred and one first-degree relatives (series) of 73 gastric carcinoma patients and 358 control relatives (controls) of 73 computer-matched probands from a general population were studied by direct-vision gastric biopsy and functional and immunological examinations. The controls were representative of the series with respect to age, sex, birth and dwelling place, and relationship of the relatives. Series and controls behaved similarly as to total prevalence of gastritis, age and sex distribution of gastritis, serum gastrin level, and circulating gastric antibodies. On the other hand, the total prevalence of hyperplastic polyps, atrophic gastritis of the body and antrum, severe atrophic gastritis of the body, intestinal metaplasia, epithelial atypia, and achlorhydria was significantly higher in the series than in the controls. In subjects below 50 years of age the prevalence of severe atrophic gastritis of the body, intestinal metaplasia, and epithelial atypia was also significantly higher in the series. In addition, the mean age of the subjects with atrophic gastritis, intestinal metaplasia, epithelial atypia, and achlorhydria was lower in the series than in controls; however, significant differences were found only in female subjects with epithelial atypia and atrophic gastritis of the body. The results suggest that the prevalence of signs often considered premalignant is significantly higher in carcinoma relatives than in controls and that these signs show a trend to occur at an earlier age in carcinoma relatives. This could explain the significantly higher than expected death rate from gastric carcinoma in close relatives with this disease, found in the present and in other series.

Topics: ABO Blood-Group System; Achlorhydria; Adolescent; Adult; Age Factors; Antibodies; Endoscopy; Epithelium; Female; Gastric Juice; Gastric Mucosa; Gastritis; Humans; Intestines; Intrinsic Factor; Male; Metaplasia; Middle Aged; Stomach Neoplasms

261 subjects with a normal body mucosa or with superficial gastritis used as controls for an atrophic gastritis series have been followed up for 23--27 years. Of them, 41 died during the earlier and 63 during the present follow-up period. In all, 141 subjects were reexamined in 1976--1977 and 16 answered a questionnaire. None of the subjects had gastric carcinoma or an adenomatous polyp. One patient diagnosed and reported earlier had died of gastric carcinoma during the present period of observation. Of the subjects with normal body mucosa 58% had developed superficial and 14% atrophic gastritis. Of those with superficial body gastritis 42% had developed atrophic gastritis and 18% showed an improvement of the gastritic changes. It should be noted, however, that earlier examinations were performed with blind biopsy and the present with direct vision gastroscopic biopsy. The state of the antral and body mucosa was similar in 53%, antral changes dominated in 33% and the changes in the body in 14%. Intestinal metaplasia was found in 36%, atypical epithelium in 6%, parietal cell antibodies in 0.5% and intrinsic factor antibodies in 0.5%. The fasting serum gastrin level was above 100 ng/ml in 10%. Only 2 cases fulfilled the morphological, functional and immunological criteria of type A gastritis. The present controls differed from the atrophic gastritis series in that the topography of gastritis was different and in that the incidence of metaplasia, atypia, gastric antibodies and high serum gastrin levels was markedly lower.

Topics: Antibodies; Atrophy; Biopsy; Female; Follow-Up Studies; Gastric Mucosa; Gastritis; Gastroscopy; Humans; Intestines; Intrinsic Factor; Male; Metaplasia; Middle Aged; Pyloric Antrum; Stomach Neoplasms; Time Factors

Mucosal biopsies from multiple sites in the stomachs of 21 patients with pernicious anaemia have been examined. The histological changes almost always involved the entire gastric mucosa, including that of the pyloric antrum. Metaplastic changes were almost universal and consisted of intestinal metaplasia in the body and antrum and pyloric metaplasia in the body. The severity of the pyloric metaplasia was such as to make the distinction between body and antrum on biopsy impossible. No relationship was found between serum gastrin activity and the histological appearances of the gastric antrum or body.

Topics: Adult; Aged; Anemia, Pernicious; Antibodies; Atrophy; Female; Gastric Mucosa; Gastrins; Gastritis; Humans; Hyperplasia; Intrinsic Factor; Male; Metaplasia; Middle Aged; Pyloric Antrum

Topics: Aged; Antibodies; Atrophy; Biopsy; Female; Follow-Up Studies; Gastric Mucosa; Gastrins; Gastritis; Humans; Intestinal Polyps; Intrinsic Factor; Male; Metaplasia; Middle Aged; Pyloric Antrum; Stomach; Stomach Diseases; Stomach Neoplasms

Topics: Adult; Aged; Chronic Disease; Electrophoresis, Starch Gel; Endopeptidases; Enzyme Precursors; Gastric Acidity Determination; Gastric Juice; Gastritis; Histamine; Humans; Intestinal Diseases; Intrinsic Factor; Metaplasia; Middle Aged; Peptide Hydrolases; Spectrophotometry

Topics: Anemia, Pernicious; Antibodies; Atrophy; Complement System Proteins; Diagnosis, Differential; Fluorescent Antibody Technique; gamma-Globulins; Gastric Mucosa; Gastritis; Humans; Intestinal Diseases; Intrinsic Factor; Metaplasia; Postgastrectomy Syndromes; Stomach Neoplasms