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The prevalence and significance of circulating antibodies to gastric intrinsic factor and parietal cells in gastric carcinoma.

The prevalence of circulating antibodies to gastric intrinsic factor and parietal cells was examined in 60 patients with histologically proven gastric carcinoma and was found not to differ from the prevalence of these antibodies in control subjects of similar age and sex distribution.Amongst the 60 patients with gastric carcinoma seven were thought to have actual or potential pernicious anaemia. The absence of an increased prevalence of antigastric antibodies in gastric carcinoma indicates that gastritis itself, whether autoimmune or not, is the likely common denominator underlying the predisposition to gastric carcinoma in both pernicious anaemia and chronic atrophic gastritis.

Adolescent↗

The value of the intrinsic factor antibody test in diagnosing pernicious anaemia.

OBJECTIVE: Assessment of the usefulness of the intrinsic factor antibody (IF Ab) test in comparison to the Schilling test in diagnosing pernicious anaemia (PA) in patients with vitamin B12 deficiency. DESIGN: This study was designed to compare the If Ab test to the Schilling test using results obtained of patients presenting with megaloblastic anaemia and low serum vitamin B12 levels to a large referral hospital. SETTING: The Chris Hani Baragwanath Hospital, Soweto, Gauteng, South Africa. SUBJECTS: Results from 77 patients with megaloblastic anaemia, low serum vitamin B12 levels and with both Schilling and IF Ab test results available were included. MAIN OUTCOME MEASURES: The sensitivity and specificity of the IF Ab test was compared to the Schilling test with regard to making a diagnosis of PA in patients presenting with megaloblastic anaemia and low serum vitamin B12 levels. RESULTS: Relevant statistical analysis showed that in the correct clinical setting, a confident diagnosis of PA could be made without Schilling tests in patients with megaloblastic anaemia, vitamin B12 deficiency and positive IF Ab tests. In a small proportion of patients in whom the IF Ab is negative, Schilling tests still need to be performed. CONCLUSION: With the increased concern over rising medical costs and where limited facilities are available, the IF Ab, in the correct clinical setting, is a cost effective and reliable test for diagnosis of PA.

Anemia, Pernicious↗

Intrinsic factors for unbound theophylline.

The developmental changes of the ratio of unbound theophylline to total serum concentration have been demonstrated, suggesting clinical usefulness. However, the molecules that can replace the theophylline binding sites of albumin could influence theophylline-binding affinity. We evaluated the intrinsic factors influencing the unbound theophylline ratio. The results suggested that physicians should note that a more intense response might be obtained in children with various intrinsic factors even at the same total theophylline concentration.

Adolescent↗

Effect of cimetidine on intrinsic factor secretion stimulated by different doses of pentagastrin in patients with impaired renal function.

Gastric intrinsic factor (IF) secretion was examined in five patients with impaired renal function during stepwise increasing doses (0.02, 0.2, and 2.0 micrograms/kg/h) of intravenous infusion of pentagastrin alone or in combination with continuous intravenous infusion of cimetidine (05 mg/kg/h) after and initial bolus of 1.5 mg/kg. Whereas cimetidine caused a moderate reduction of maximally stimulated IF output, the output during submaximal stimulation was reduced to basal levels by cimetidine. The results suggest that IF insufficiency may occur during cimetidine treatment in patients with impaired renal function on long-term treatment with H2-blockers.

Adult↗

Prostaglandin E analogue inhibition of intrinsic factor release.

In many mammalian species (including humans) the parietal cell secretes both acid and intrinsic factor (IF). The aim of this study was to examine the direct effect of prostaglandin E analogues on basal and stimulated IF release in isolated, enriched rabbit parietal cells. The effects of graded concentrations (10(-12) to 10(-6) M) of 16,16-dimethyl prostaglandin E2 (DMPGE2) and 16-methyl,16-hydroxyl prostaglandin E1 (misoprostol) on submaximal histamine-stimulated (10(-6) M) secretion were tested. Both analogues failed to alter basal release of IF or aminopyrine accumulation (indirect measure of acid secretion). Increasing concentrations of DMPGE2 resulted in a dose-dependent inhibition of IF release (22 +/- 8% decrease at 10(-9) M; p less than 0.05) and a maximal effective response at 10(-7) M (54 +/- 9%; p less than 0.005). Dose-dependent inhibition of IF secretion was also observed with increasing concentrations of misoprostol, with a 22 +/- 7% decrease at 10(-9) M (p less than 0.05) and maximal effective inhibition at 10(-6) M (47 +/- 8%; p less than 0.01). Misoprostol and DMPGE2 inhibition of acid secretion paralleled IF release. Prostaglandin analogues appear to block IF release potently in histamine-stimulated parietal cells.

Alprostadil↗

Cellular localization and hormonal regulation of pancreatic intrinsic factor secretion in dogs.

Gastric mucosal cells are considered to be the principal site of intrinsic factor (IF) production in most mammals. Recent observations in dogs suggest that the pancreas is the major site of IF production in this species. The present study was undertaken to determine the cellular origins of canine pancreatic IF by combining in situ hybridization with immunocytochemistry and to examine the potential role of physiological pancreatic secretagogues, cholecystokinin octapeptide (CCK-8) and secretin, as mediators of canine pancreatic IF secretion. A human IF cDNA probe (J. Hewitt et al., Genomics 10: 432-440, 1991), validated for use in the dog, identified IF mRNA in parietal cells in the gastric fundus, gastric gland cells in the pyloric antrum, and in secretory duct cells of the pancreas. Immunocytochemistry using antibody against rat IF confirmed that these cells, as well as secretory ducts of salivary glands, synthesized an immunoreactive protein. In stimulated secretions of anesthetized dogs, mean 45-min outputs of IF, haptocorrin, and trypsinogen were 13-, 8-, and 16-fold greater during stimulation with CCK-8 than with secretin. No synergistic effects of combined stimulation were observed for IF or haptocorrin, although a synergistic effect was observed for trypsinogen. These findings demonstrate that IF is synthesized in the canine stomach, pancreas, and probably salivary glands and that CCK-8 mediates IF secretion from pancreatic duct cells.

Animals↗

Factors intrinsic to the neuron can induce and maintain its ability to promote axonal outgrowth: a role for BCL2?

The adult CNS provides a poor environment for axonal growth and regeneration. The question of to what extent the loss of axonal growth occurring as the brain matures is dependent on factors intrinsic or extrinsic to the growing neuron is still unanswered. Examination of axonal growth from neural transplants provides insight into the roles of growth factors, inhibitory molecules, growth-promoting substrates and the differences between CNS and PNS environments in the regulation of neurite extension. The data that imply a role for BCL2 and related molecules in such processes are reviewed in this article, which analyzes the factors intrinsic to the neuron that control its capacity for axonal growth.

Animals↗

Regulation of gastric mucosal pepsinogen and intrinsic factor contents, and their mRNA levels during starvation and refeeding in rats.

Gastric mucosal pepsinogen and intrinsic factor (IF) contents, and their mRNA levels during starvation and refeeding were studied. During starvation for 4 d, gastric mucosal pepsinogen and IF contents significantly decreased, whereas pepsinogen and IF mRNA levels increased by 30-50%. These results suggested that the mRNAs of pepsinogen and IF could be preserved for a long time so as to prepare for refeeding. After ceasing the starvation for 72 h, gastric mucosal pepsinogen and IF contents were significantly decreased at 1 h after refeeding, and their mRNA levels were increased by 20-30% at 30 min after refeeding. We examined whether the refeeding-induced changes in gastric mucosal pepsinogen and IF contents and their mRNA levels could be reproduced by the exogenous administration of secretagogues. They were not found to be affected by the administration of each secretagogue during starvation for 72 h at 30 min. However, by the simultaneous administration of 2 or 3 secretagogues (carbachol, cholecystokinin octapeptide (CCK-8) or secretin), the contents of pepsinogen and IF decreased to 70-80% and 50-80% of the control, respectively. However, their mRNA levels increased to 140-160% and 120-135% of the control, respectively. Therefore, refeeding-induced changes in pepsinogen and IF contents and their mRNA levels were partially reproduced by exogenously administered secretagogues. This showed that food intake influences huge changes in neural, hormonal and physical conditions on the stomach. It was indicated that the secretagogues stimulated not only pepsinogen and IF secretion, but also had a tendency to increase their mRNA.

Animals↗

Intrinsic factor secretion from isolated gastric mucosal cells of rat and man--two different patterns of secretagogue control.

Intrinsic Factor (IF) secretion was studied using isolated gastric mucosal cells from rat and man. In the rat, IF was localized to the chief cells and its secretion responded most efficaciously to carbachol. DbcAMP and hexoprenaline were less powerful, whereas histamine and pentagastrin lacked any effect. In man, IF secretion derived from the parietal cells and was increasingly enhanced by hexoprenaline, pentagastrin, carbachol, histamine and dbcAMP. In both species, IF secretion differs with respect to its cellular origin and the pattern of secretagogue control: IF release from rat chief cells is due to muscarinic receptor excitation, whereas IF release from human parietal cells responds predominantly to histamine-H2-receptor activation and seems to be mediated by the cAMP system.

Adenylyl Cyclases↗

Urinary autoantibodies against intrinsic factor in pernicious anaemia patients.

In radioimmunoassay seven concentrated urines of penicious anaemia (PA) patients were positive for intrinsic factor (IF). Four were studied by gel filtration. Two contained both binding and blocking antibodies against IF, one had only blocking antibodies and one lacked both types of antibodies. The antibodies were mainly of the IgG-type. No such antibodies were found in the urine of a healthy person. None of the urines studied contained enough protein to be classified as proteinuric. Not until the interferences of the autoantibodies in the IF assay can be eliminated is the assay of value in the diagnosis of PA.

Anemia, Pernicious↗

Identification of a 4-base deletion in the gene in inherited intrinsic factor deficiency.

A 4-base deletion has been identified in the coding region of the gene for gastric intrinsic factor (IF) in an 11-year-old girl with severe anemia and cobalamin (Cbl) deficiency. The bone marrow showed frank megaloblastic morphology, and the Schilling test indicated a failure to absorb Cbl that was corrected by coadministration of IF. Pentagastrin administration induced acid secretion, but the gastric juice lacked IF as determined by CbI binding, by fractionation of protein-bound CbI, and by immunoprecipitation with anti-IF antiserum. Individual exons were amplified by the polymerase chain reaction by using primers to the flanking intronic regions, and the nucleotide sequence analysis identified a 4-base deletion (c183_186delGAAT) spanning positions 104 to 107 in exon 2, resulting in premature termination of translation. This mutation also eliminates a site for Bst XI endonuclease and introduces a site for BsaBI for identifying this deletion in hereditary IF deficiency.

Anemia, Megaloblastic↗

Effect of placental lactogen on the number of intrinsic factor receptors in the pregnant mouse.

Experiments were designed to identify the factor in serum which has been shown to result in an increased number of intrinsic factor (IF) receptors in the small intestine of the mouse in late pregnancy. IF receptors for cobalamin (Cbl) were measured by determining the quantity of IF-57CoCbl bound in ileal homogenates. A Scatchard plot of the binding data confirmed that there was an increase in the number of IF receptors and revealed that there was a reduction in their affinity constant (K alpha). The K alpha for pregnant mice was 0.7 x 10(12) M-1 compared with 2.8 x 10(12) M-1 in nonpregnant mice. The number of receptors decreased between 2 and 4 hr after hysterectomy (Hx) in day 19 pregnant mice. Hourly injections of human placental lactogen (PL) maintained IF-Cbl binding at pregnant levels in the Hx mice. Growth hormone but not prolactin produced a similar response. The smallest quantity of PL which was effective was 1 microgram. Placental lactogen did not have an effect on IF-Cbl binding in nonpregnant female mice. Neither hypophysectomy nor ovariectomy affected IF-Cbl. It is proposed that placental lactogen is the serum factor which is responsible for the increased number of IF receptors in the pregnant mouse.

Animals↗

Binding of intrinsic factor to ileal brush border membrane in the rat.

The rat ileal brush border membrane binds both free [125I]-intrinsic factor (IF) and the IF-[57Co]cobalamin (cbl) complex. This binding is observed with IF isolated from rat stomach, but not from IF isolated from hog, canine and human stomachs. The binding of rat-IF[57Co]cbl can be blocked with free rat IF but not with hog IF. The IF-cbl complex binds at a higher affinity (Ka = 0.15 X 10(9) M-1) compared to that of free IF (Ka = 0.9 X 10(9) M-1). Rat IF-cbl also binds efficiently to human and canine ileal membranes. While antibody to the canine ileal receptor blocks the binding of rat, human or hog IF-[57Co]cbl to human and canine ileal membranes, it does not affect the binding of rat IF-[57Co]cbl to rat ileal membranes. These findings demonstrate that the rat ileal receptor is different from canine and human ileal receptors.

Animals↗

The inhibitory effect of bile on the binding of vitamin B12 to intrinsic factor. An in vivo study in rats.

To investigate whether bile reduces the amount of vitamin B12 bound by intrinsic factor (IF) in the intestinal juice in vivo, choledochocolic fistulae were made in 9 rats, and 10 rats were sham-operated. Small-intestinal juice was collected 1 h after gastric instillation of 57CoB12. The percentage of 57CoB12 bound by IF in the intestinal juice was markedly increased in fistula rats (median, 86%; range, 75-91%) as compared with sham-operated rats (35%; 12-50%) (p less than 0.001). In a second experiment we investigated whether bile enhances the intestinal uptake of the IF-B12 complex. Aliquots of the radioactive intestinal juice collected from the sham- and fistula-operated rats were separately instilled into tied intestinal loops created in 19 rats. The percentage of the instilled radioactivity taken up per 10 cm of the loop was significantly higher when juice from fistula-operated rats was instilled (median, 12.4; range, 4.3-18.7) than when juice from sham-operated rats was instilled (3.3; 1.4-6.2) (p less than 0.001).

Animals↗

[Heterogeneity of the gastric intrinsic factor autoantibodies of types I and II].

Variable results were obtained in a study of the immunologic reaction of the intrinsic factor (IF)-autoantibodies (IFA) to the human, hog and rat IF antigens. Effectively, some IFA I were unable to block completely all the binding sites of B12 to IF. As to the IFA II, some did not show a total effectiveness in neutralizing the activity of IF in certain human gastric juices. In another study conducted on patients with pernicious anemia, the antibodies obtained from their sera reacted differently to the hog and rat IF; some reacted identically to homologous and heterologous IF others were less and even not effective on the heterologous IF. From these results it was suggested that, within the two main branches of IFA, there would be subdivided groups with selective effect on different antigenic sites of IF.

Animals↗

Cobalamin release from intrinsic factor and transfer to transcobalamin II within the rat enterocyte.

To ascertain the mechanism of release of cobalamin (Cbl) from intrinsic factor (IF) and subsequent formation of transcobalamin II (TC-II)-Cbl complex, we studied the intracellular distribution of 57Co-labeled Cbl after its uptake in suckling and adult rats. The amount of Cbl bound to IF, to the IF-Cbl receptor via IF, and to TC-II was determined by immunoprecipitation with monospecific antisera raised to these proteins. IF-Cbl receptor activity was found to be very low in suckling rats up to 12 days after birth. Oral administration of leupeptin in amounts known to alter protein turnover had no effect on the release of Cbl from IF nor did it inhibit the formation of the TC-II-Cbl complex in either adult or suckling animals. However, oral administration of chloroquine resulted in a transient increase in the intestinal concentration of Cbl in both adult and suckling rats and in total inhibition of Cbl released from IF in adults rats. Chloroquine prevented completely the transfer of Cbl to TC-II in adult rats and inhibited the transfer by 50% in suckling rats. These data demonstrate that in adult mucosa utilizing receptor-mediated endocytosis, Cbl is transferred from IF to TC-II. This transfer does not require the IF-Cbl receptor, as it occurs in suckling rats. Finally, transfer of Cbl to TC-II is decreased by a drug that alters vesicular pH. Because Cbl can be released at acid pH from IF, it is proposed that release of Cbl from IF and its transfer to TC-II occurs in an acidic vesicle.

Administration, Oral↗