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At least 253 records · Page 14Linked to original sources
PubMed1992

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.

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.

Adolescent↗
PubMed1987

Somatostatin inhibition of intrinsic factor secretion from isolated guinea pig gastric glands.

The aim of our study was to examine the direct effect of somatostatin on histamine- and pentagastrin-stimulated intrinsic factor (IF) release in collagenase-dispersed guinea pig gastric glands. The effect of somatostatin (10(-11) M to 10(-6) M) on half-maximal doses of histamine (10(-6) M), pentagastrin (10(-6) M), and both histamine and pentagastrin together was tested. All tested concentrations of histamine significantly stimulated IF release. Pentagastrin (10(-10) M to 10(-6) M) inconsistently stimulated IF release. The quantity of IF release stimulated by histamine and pentagastrin together was approximately the additive sum of that produced by either agent alone. Somatostatin (10(-6) M) inhibited histamine-stimulated (10(-6) M) IF release by 69.9 +/- 7.2% and the combination of histamine (10(-6) M) and pentagastrin (10(-6) M) by 64.2 +/- 9.1%. This is the first in vitro demonstration that somatostatin inhibits IF release.

Animals↗
PubMed1984

Intrinsic factor secretion from isolated human gastric mucosal cells.

Human gastric mucosal cells were isolated from the resected fundic mucosa of peptic ulcer patients. The intracellular content and secretion of intrinsic factor were estimated by binding to cyano[57Co]cobalamin. The content was maximal in the enriched parietal cell fraction which also displayed the highest H+ production as measured by amino[14C] pyrine uptake. Secretagogues evoked full response after 15 min of incubation: pentagastrin (181% of basal secretion), carbachol (208%), histamine (250%) and dibutyryl cyclic adenosine monophosphate (304%). The phosphodiesterase inhibitor isobutylmethylxanthine was slightly more effective even than dibutyryl cAMP. The response to histamine was abolished by ranitidine, indicating activation of adenylate cyclase via histamine H2 receptors, but remained unaffected by atropine, which in turn blocked the carbachol effect, whereas ranitidine was ineffective. The mean formation rate was 8.4 fmol intrinsic factor/10(6) cells per h under basal conditions and 14.3 fmol in response to histamine.

1-Methyl-3-isobutylxanthine↗
PubMed1984

Influence of metal substitution on vitamin B12 binding to human intrinsic factor and transcobalamins I and II.

Metal-free, zinc, copper, and rhodium analogues of vitamin B12 were synthesized to further characterize structural requirements for the binding to human intrinsic factor, transcobalamin I, and transcobalamin II. Binding affinities of the various analogues were studied by competition against cyano[57Co]cobalamin. When albumin-coated charcoal was used for the separation of free and bound corrinoids, the relative 50% inhibition indexes were determined. The influence of metal substitution was similar among the three binding proteins. For analogues with a strong coordinative linkage between the heterocyclic base and the central metal ion, similar to that with cobalt (e.g., zincobalamin and cyanorhodibalamin), the indexes range from 0.65 to 2.35 for all three binding proteins. Analogues in which coordination is impossible (hydrogenobalamin and dicyanorhodibalamin) exhibit markedly reduced binding with indexes between 10 and 160. Cupribalamin shows 50% inhibition indexes ranging from 2.3 to 5.0, thus suggesting a weak coordinative bond between the copper ion and the 5,6-dimethylbenzimidazole moiety. These results emphasize the importance of the coordinative linkage between the central metal ion and the nucleotide moiety for optimal recognition by vitamin B12 binding proteins.

Binding Sites↗
PubMed1984

Parietal cell function of full-term and premature infants: unstimulated gastric acid and intrinsic factor secretion.

A 1-h basal collection of gastric secretions was taken from 14 healthy full-term infants (group I) and 10 premature infants (group II). Simultaneously, acid and intrinsic factor (IF) secretion was measured. In an additional group of 19 full-term infants (group III), 16 had IF detectable in their gastric secretions immediately at birth. Volumes of gastric juice (ml/kg/h) and IF secretion (ng/kg/h) were similar for group I and group II infants. Acid secretion (mEq/kg/h) was significantly less in group II (p less than 0.01). There was a linear correlation between acid secretion (mEq/kg/h) and IF secretion (ng/kg/h) for group I (r = 0.85, p less than 0.001). There was no correlation between the values for the premature infants in group II. The study documents that the parietal cell of the premature infant has the same capacity to secrete IF as the cell of the more mature infant. It also demonstrates the presence at birth of IF in gastric secretions, which suggests in utero secretion and independence from enteral feeding for stimulation.

Gastric Acid↗
PubMed2005

Autoantibodies against intrinsic factor (IF) measured with an ELISA using recombinant human IF as both catching and detecting reagent.

The aim was to develop and validate an assay for measuring autoantibodies against human intrinsic factor (IF). For this purpose 1.25 pmol of recombinant IF was coupled to each well. Samples (100 microL of plasma diluted 1:1) were incubated for 1 h, followed by 30 min with the detection reagent (biotinylated IF, 3.3 pmol/mL). Samples were obtained from healthy blood donors (n = 141) and patients with suspected vitamin B(12) deficiency (n = 355). The initial assay results (n = 99 samples) were in reasonable agreement with those obtained using a commercial assay (Diagnostic Products Corporation). All donors but one showed a negative result. For the patient populations the fraction of positive results decreased with increasing levels of serum vitamin B 12 : 0.67 for <100 pmol/L (n = 13), 0.17 for 100-150 pmol/L (n = 23), 0.06 for 151-200 pmol/L (n = 65) and <0.01 for >200 pmol/L (n = 254). The imprecision was 11% as judged by repeat analyses. All samples remained positive when the catching reagent was exchanged with vitamin B 12 -saturated IF, suggesting that the samples contained both blocking (type I) and non-blocking (type II)antibodies. Results obtained with IF as the detection reagent correlated to those obtained when anti-immunoglobulin G was used instead. In conclusion, an ELISA using recombinant IF as both catching and detection reagent seems suitable for the detection of IF autoantibodies in plasma.

Adult↗
PubMed1968

Malabsorption of hemoglobin iron in pernicious anemia: correction with intrinsic factor--containing substances.

Hemoglobin iron absorption in patients with treated prenicious anemia (PA) and concomitant iron deficiency was low compared to absorption in patients with iron deficiency alone. Crude and purified hog intrinsic factor (IF) concentrates doubled the absorption of hemoglobin iron in these patients as did normal (neutralized depepsinized) human gastric juice. Hemoglobin iron absorption was not significantly enhanced by PA gastric juice. Absorption of heme iron, like that of hemoglobin iron, was enhanced by normal neutralized depepsinized gastric juice. No enhancement of hemoglobin iron absorption by these substances was obtained in the normal or iron-deficient non-PA control subjects. Preincubation of the hog IF concentrate with antisera to IF significantly reduced the enhancement of hemoglobin iron absorption due to the concentrate. In vitro studies suggest that heme complexes with a substance present in IF-containing materials. Whether a gastric glycoprotein similar to IF serves as an intestinal transport factor for heme, similar to transport of vitamin B(12), or whether normal gastric juice acts by another mechanism cannot be determined at this time.

Anemia, Hypochromic↗
PubMed1993

Anti-intrinsic factor antibodies in systemic lupus erythematosus.

As the co-existence of pernicious anaemia (PA) and systemic lupus erythematosus (SLE) has been repeatedly reported, we have investigated the presence of anti-intrinsic factor antibodies (IFAb), the immunological hallmark of PA, in patients diagnosed with SLE. Serum cobalamin levels and IFAb were determined in 30 women diagnosed with SLE as well as in 45 controls. Cobalamin levels were low in 7/30 patients. IFAb were detected in 3/30 sera from patients but in none of the control sera. The presence of IFAb was associated with a low cobalamin concentration, anaemia and macrocytosis in only one patient. There was no evident relationship between the presence of IFAb and serological markers of SLE. We conclude that IFAb may appear in SLE patients, although the cobalamin deficiency described in SLE seems to be due to the presence of IFAb in only a minority of cases.

Adolescent↗
PubMed1979

Humoral and cellular immunity to intrinsic factor in myasthenia gravis.

Myasthenia gravis (MG) is an autoimmune disease often associated with other autoimmune disorders. A case history of MG with a coexisting atypical megaloblastic anaemia with vitamin B12 deficiency and anti Intrinsic Factor (IF) antibodies, led to a study of humoral and cellular immunity to IF in 81 MG patients. Within this series, 3 other patients had a disturbed humoral and cellular immunity to IF. These 3 patients presented no other features of pernicious anaemia. The possible origins and significance of the anti IF antibodies in MG patients are discussed.

Adolescent↗
PubMed2001

Transfer of cobalamin from intrinsic factor to transcobalamin II.

The process is obscure by which cobalamin (Cbl) in the endocytosed intrinsic factor (IF)-cobalamin (Cbl) complex is released and transferred to transcobalamin II (TCII) within the enterocyte. Using recombinant IF and TCII, binding of Cbl to IF at pH 5.0 was 70% of binding at pH 7.0, whereas for TCII alone, the value was only 12%. TCII binding activity was lost rapidly at lower pH, but this was not due to protease action. TCII incubated at pH 5.0 with cathepsin L was degraded and could not subsequently bind Cbl. Thus, transfer from IF to TCII is unlikely to occur within an acid compartment. Only 13-15% of bound Cbl was released at pH 5.0 and pH 6.0 from either rat IF, human IF, or human TCII. The K(a) of human or rat IF at pH 7.5 was 2.2 nM; for TCII, the value was 0.34 nM. At pH 7.5, Cbl transfers from IF to TCII, but only to a limited extent (21%), as detected by nondenaturing electrophoresis. Transfer of Cbl from IF to TCII could not be demonstrated at pH values of 5.0 or 6.0. Thus, luminal transfer of Cbl between IF and TCII is likely to be limited, but is possible. The most likely mechanism for intracellular transfer of Cbl from IF to TCII involves initial lysosomal proteolysis of IF, with subsequent Cbl binding to TCII in a more neutral cellular compartment.

Journal Article↗
PubMed2005

Hereditary juvenile cobalamin deficiency caused by mutations in the intrinsic factor gene.

Hereditary juvenile megaloblastic anemia due to vitamin B12 (cobalamin) deficiency is caused by intestinal malabsorption of cobalamin. In Imerslund-Grasbeck syndrome (IGS), cobalamin absorption is completely abolished and not corrected by the administration of intrinsic factor (IF); if untreated, the disease is fatal. Biallelic mutations either in the cubilin (CUBN) or amnionless (AMN) gene cause IGS. In a series of families clinically diagnosed with likely IGS, at least six displayed no evidence of mutations in CUBN or AMN. A genome-wide search for linkage followed by mutational analysis of candidate genes was performed in five of these families. A region in chromosome 11 showed evidence of linkage in four families. The gastric IF (GIF) gene located in this region harbored homozygous nonsense and missense mutations in these four families and in three additional families. The disease in these cases therefore should be classified as hereditary IF deficiency. Clinically, these patients resembled those with typical IGS; radiocobalamin absorption tests had been inconclusive regarding the nature of the defect. In the diagnosis of juvenile cobalamin deficiency, mutational analysis of the CUBN, AMN, and GIF genes provides a molecular characterization of the underlying defect and may be the diagnostic method of choice.

Chromosome Mapping↗
PubMed1978

Secretion of intrinsic factor and hydrochloric acid after 12 weeks' treatment with cimetidine.

A sample of 16 patients had pentagastrin stimulation studies performed before starting a 12 week course of cimetidine, and again 12 hours after completing the course. Basal and pentagastrin stimulated intrinsic factor secretion was assayed in 13 patients. There was no significant difference in the pattern of secretion after 12 weeks' treatment with cimetidine. The basal and peak acid outputs of all 16 patients were measured. No significant difference was found in the pattern of acid secretion after treatment. It appears that parietal cell secretory function is restored to normal within 12 hours of discontinuing a prolonged course of cimetidine.

Cimetidine↗
PubMed1978

Correction of cobalamin malabsorption in pancreatic insufficiency with a cobalamin analogue that binds with high affinity to R protein but not to intrinsic factor. In vivo evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency.

In vitro studies indicate that [(57)Co]cobalamin (Cbl) is preferentially bound to salivary R protein as opposed to intrinsic factor (IF) and that [(57)Co]Cbl bound to R protein is not transferred to IF at either pH 2 or pH 8. Incubation of R protein-[(57)Co]Cbl with pancreatic proteases causes a partial degradation of the R protein moiety and a rapid transfer of [(57)Co]Cbl to IF. We have postulated that the etiology of Cbl malabsorption in pancreatic insufficiency is an inability to partially degrade R protein because of a lack of pancreatic proteases. We have tested this hypothesis by determining the ability of a nonradioactive Cbl analogue, bound with high affinity by R protein but not by IF, to correct the malabsorption of [(57)Co]Cbl in patients with pancreatic insufficiency.R protein bound the Cbl analogue known as cobinamide with affinities that were the same and only 14-fold lower than those for Cbl at pH 8 and pH 2, respectively. Cobinamide was bound by IF with affinities that were 600,000- and 10,000-fold lower than those for Cbl at pH 8 and 2, respectively. The addition of 125 pmol of nonradioactive cobinamide to 0.5 pmol of [(57)Co]Cbl before being added to 1 pmol of R protein and 1 pmol of IF, markedly inhibited the ability of R protein to compete with IF for binding the [(57)Co]Cbl. Similar results were obtained with freshly aspirated gastric juice. This change was essentially indistinguishable from that observed previously when R protein or R protein-[(57)Co]Cbl was incubated in vitro with trypsin. The oral administration of 100 nmol of nonradioactive cobinamide in Schilling tests was equivalent to trypsin in its ability to completely correct the malabsorption of 0.4 nmol of [(57)Co]Cbl in three patients with pancreatic insufficiency. The fact that both trypsin and nonradioactive cobinamide inhibit the ability of R protein to compete with IF for [(57)Co]Cbl binding in vitro, and correct the mal-absorption of [(57)Co]Cbl in patients with pancreatic insufficiency in vivo, supports our hypothesis that the primary defect in Cbl absorption in this disease is an inability to partially degrade R protein because of a lack of pancreatic proteases.

Adolescent↗
PubMed2000

Transcytosis and coenzymatic conversion of [(57)Co]cobalamin bound to either endogenous transcobalamin II or exogenous intrinsic factor in caco-2 cells.

We have examined the intracellular route, coenzyme conversion and transcytosis rate of [(57) Co]-labeled cobalamin (Cbl) in function of its presentation to the apical side of Caco-2 cells, either free or bound to intrinsic factor (IF). The free-presented Cbl was progressively bound to endogenous transcobalamin II (TCII) which may stem, in part, from a basolateral to apical passage. Its transcytosis was TCII-mediated as it was abolished when antibodies to TCII were added to the apical medium. The apparent permeability coefficient (P(app)) was estimated at 20.8+/-3.6, 103.5+/-17.7, 0.9+/-0.3 x 10(-5) cm/h for TCII-Cbl, IF-Cbl and haptocorrin-Cbl, respectively. Chloroquine inhibited the transcytosis rate of both TCII and IF-bound Cbl in a dose-dependent manner. Approximately 80% of apical Cbl, bound to either exogenous IF or endogenous TCII, was transported to the basolateral side as intact cyano[(57)Co]Cbl whereas the remainder was converted into Ado-Cbl and CH(3)-Cbl within the cells, as shown by HPLC analyses of a 1,000-g pellet and a 12,000-g supernatant. Coenzymatic conversion was virtually abolished by chloroquine. In conclusion, we suggest that apically presented free Cbl is internalized via TCII-dependent transport. The apically internalized CN-Cbl, bound to either IF or TCII, is processed via an acidic vesicle and part of it is converted to coenzymes, whereas bulk of CN-Cbl is transcytosed intact.

Biological Transport↗
PubMed1992

Congenital intrinsic factor deficiency in a Spanish patient.

Vitamin B-12 deficiency was diagnosed in a 26-year-old man. Examinations performed to determine the etiology of the deficiency showed a vitamin B-12 malabsorption in the Schilling test which was corrected by adding intrinsic factor (IF) as well as normal gastric mucosa and acid secretion, although IF in gastric juice was absent. Family study showed normal serum vitamin B-12 levels in the parents, who are first cousins, and siblings. A gastric examination in the father and the sister showed decreased IF secretion, indicating heterozygosity for the disorder.

Adult↗
PubMed1985

Cobalamin malabsorption in three siblings due to an abnormal intrinsic factor that is markedly susceptible to acid and proteolysis.

Three siblings presented in their second year of life with megaloblastic anemia that responded to parenteral cobalamin (Cbl). Schilling tests were less than 1%, correcting to 5 to 15% after addition of hog intrinsic factor (IF). Gastric acid analysis and gastric biopsies were normal by light and electron microscopy. Gastric juice contained less than 3 pmol/ml of Cbl-binding ability due to IF (normal, 10-34 pmol/ml) and less than 2 pmol/ml of IF when measured with a radioimmunoassay (RIA) using normal human IF-[57Co]Cbl and rabbit anti-human IF serum (normal, 17-66 pmol/ml). However, RIA employing rabbit anti-hog IF serum gave values of 4-13 pmol/ml of IF (normal, 11-33 pmol/ml). This material had an apparent molecular weight of 40,000 (normal IF = 70,000). The IF from gastric biopsies appeared normal in terms of Cbl-binding ability, ileal binding, molecular weight, and both RIAs. This IF differed from normal mucosal IF, in that it lost its Cbl-binding ability when incubated at 37 degrees C at acid pH or in the presence of pepsin or trypsin. This loss was retarded when [57Co]Cbl was bound to the IF before these incubations. The stabilizing effects of neutralization and Cbl were also demonstrated in vivo. Schilling tests for the siblings of 0.4, 0.5, and 1.0% increased to 2.7, 5.7, and 4.3% (P less than 0.05), respectively, when the Schilling tests were repeated with the addition of NaHCO3 and cobinamide (which allows Cbl to bind immediately to IF). We conclude that Cbl malabsorption in these children is due to an abnormal IF that is markedly susceptible to acid and proteolytic enzymes which cause a decrease in its molecular weight and Cbl-binding ability and a loss of antigenic determinants that are recognized by the anti-human IF serum.

Anemia, Megaloblastic↗
PubMed2000

Production of gastric intrinsic factor, transcobalamin, and haptocorrin in opossum kidney cells.

Opossum kidney epithelial cells were shown previously to synthesize and secrete two cobalamin (Cbl)-binding proteins, presumed to be haptocorrin (Hc) and transcobalamin II (TCII). The present study examines the hypothesis that renal tubular cells also produce intrinsic factor (IF), and this production provides an explanation for the presence of IF in urine. By using antisera raised against human IF and against TCII, the presence of TCII was confirmed, and that of IF discovered in the media of opossum kidney (OK) cells in culture. The apparent molecular weight of IF and TCII was 68 and 43 kDa, respectively. Immunoreactivity on Western blot of the putative IF protein was blocked by recombinant human IF. When proteins secreted into the media were separated electrophoretically under nondenaturing conditions after binding with [(57)Co]Cbl, a broad major band migrated at a relative front independently of recombinant IF or TCII, and probably represents Hc, as the Cbl binding is blocked by cobinamide. Small amounts of bound [(57)Co]Cbl migrated in the position of both IF and TCII, when cobinamide was present. The presence of IF and TCII in OK cells was confirmed by immunohistology. Specific reactivity for IF (blocked by recombinant IF) was found in proximal tubules of opossum kidney, but not in other portions of the nephron, confirming the ability of anti-human IF antiserum to detect opossum IF. A 732-bp fragment of IF, nearly identical in sequence to rat IF, was isolated by RT-PCR from opossum kidney mRNA, and Western blot confirmed the presence of IF protein. The presence of IF was also documented in rat kidney by isolation of an RT-PCR fragment, immunocytochemistry, and Western blot. IF should be added to the list of renal (proximal) tubular antigens that are shared by other epithelia.

Animals↗