intrinsic-factor and Pancreatic-Diseases

This monograph on the clinical chemistry of vitamin B12 reviews the literature on daily requirements, methods for measurement, the effects of drugs on vitamin B12 metabolism absorption, pregnancy, clinical conditions associated with vitamin B12 deficiency, errors of metabolism, and reactions to vitamin therapy. Although only very small quantities of vitamin B12 are required to satisfy the daily requirement, a sufficient supply is stored in the liver to meet normal requirements for at least a 3-year period. A number of drugs are known to affect the absorption of vitamin B12, including neomycin, potassium chloride, p-aminosalicylic acid, and colchicine. Significantly reduced serum concentrations of vitamin B12 have been noted in users of oral contraceptives (OCs), although concentrations still remain within the limits of normal. It appears that the vitamin B12 level in OC users reestablishes itself at a different and somewhat lower level. Vitamin B12 binding protein appears to remain unchanged. A vitamin B12 deficiency is unusual in pregnant women who consume a normal, varied diet. On the other hand, lactating women whose diets are low in animal protein and dairy products may have problems providing enough vitamin B12 to meet their own and their infant's needs; supplementary oral vitamins should be considered.

Topics: Absorption; Adult; Alcoholism; Anemia, Pernicious; Ascorbic Acid; Autoantibodies; Biguanides; Biological Transport; Chemical Phenomena; Chemistry; Chlorpromazine; Contraceptives, Oral; Diet; Female; Gastrectomy; Gastritis; Humans; Intrinsic Factor; Malabsorption Syndromes; Male; Metabolism, Inborn Errors; Middle Aged; Neoplasms; Nervous System Diseases; Nitrous Oxide; Nutritional Requirements; Pancreatic Diseases; Parasitic Diseases; Pregnancy; Pregnancy Complications; Transcobalamins; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Animals; Calcium; Chronic Disease; Humans; Intestinal Absorption; Intrinsic Factor; Malabsorption Syndromes; Pancreatectomy; Pancreatic Diseases; Pancreatic Juice; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Animals; Chronic Disease; Humans; Hydrogen-Ion Concentration; Intestinal Absorption; Intestinal Secretions; Intestine, Small; Intrinsic Factor; Pancreas; Pancreatic Diseases; Pancreatic Juice; Rats; Vitamin B 12

Topics: Adolescent; Anemia; Animals; Biological Transport; Blind Loop Syndrome; Calcium; Gastric Mucosa; Gastritis; Guinea Pigs; Humans; Hydrogen-Ion Concentration; Ileum; Intestinal Absorption; Intestinal Diseases, Parasitic; Intestinal Mucosa; Intrinsic Factor; Male; Pancreatic Diseases; Radiation Effects; Rats; Thalassemia; Trypsin; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Animals; Bicarbonates; Binding Sites; Cations, Divalent; Dogs; Drug Synergism; Humans; Hydrogen-Ion Concentration; Ileum; Intestinal Mucosa; Intrinsic Factor; Iron; Malabsorption Syndromes; Pancreas; Pancreatectomy; Pancreatic Diseases; Pancreatic Juice; Pancreatin; Rats; Receptors, Drug; Vitamin B 12

Topics: Animals; Cobalt Isotopes; Disease Models, Animal; Intestinal Absorption; Intrinsic Factor; Malabsorption Syndromes; Pancreas; Pancreatectomy; Pancreatic Diseases; Rats; Tissue Extracts; Vitamin B 12

Topics: Antibodies; Antibodies, Anti-Idiotypic; Celiac Disease; Crohn Disease; Gastroenteritis; Gastrointestinal Diseases; Hepatitis; Humans; Hypersensitivity; Immunoglobulin G; Intestinal Diseases, Parasitic; Intrinsic Factor; Liver Diseases; Lymphocytes; Microscopy, Electron; Pancreatic Diseases; Virus Diseases

Topics: Adolescent; Anemia, Pernicious; Autoantibodies; Child; Chronic Disease; Female; Gastric Mucosa; Humans; Hydrogen-Ion Concentration; Ileum; Infant; Intestinal Mucosa; Intrinsic Factor; Malabsorption Syndromes; Male; Pancreatic Diseases; Pregnancy; Vitamin B 12 Deficiency

Crude preparations of hog gastric intrinsic factor or their own previously collected gastric juices administered with labeled vitamin B12 did not enhance vitamin B12 absorption in patients with vitamin B12 malabsorption secondary to pancreatic insufficiency. However, when these sources of gastric intrinsic factor were incubated with three times crystallized preparations of insolubilized bovine trypsin or chymotrypsin, the proteolytic enzymes were removed by centrifugation, and the preparations of gastric intrinsic factor were readministered to these patients, the absorption of vitamin B12 was markedly enhanced. Studies of hog gastric intrinsic factor before and after exposure to proteolytic enzymes failed to show any difference on Sephadex chromatography or polyacrylamide gel electrophoresis or on its affinity for vitamin B12 or the ileal receptor in guinea pigs. These investigations demonstrate that: (1) gastric intrinsic factor as secreted by subjects with pancreatic insufficiency or obtained from hog pyloric mucosal extracts is ineffective in promoting vitamin B12 absorption in patients with pancreatic insufficiency, (2) incubation of crude preparations of gastric intrinsic factor with insolubilized pancreatic proteases modified these preparations of gastric intrinsic factor in an as yet undefined manner, allowing them to enhance vitamin B12 absorption, and (3) in vitro studies using gut sacs or brush border preparations do not reflect the abnormality in vitamin B12 absorption associated with pancreatic dysfunction.

Topics: Anemia, Pernicious; Animals; Chymotrypsin; Clinical Trials as Topic; Female; Gastric Juice; Guinea Pigs; Humans; Intestinal Absorption; Intrinsic Factor; Pancreatic Diseases; Pancreatic Juice; Peptide Hydrolases; Swine; Trypsin; Vitamin B 12 Deficiency

The present paper outlines the classical concepts of transport and absorption of vitamin B12 and discusses findings which provide new insight into the important role of pancreatic enzymes in the absorption of the vitamin B12. In vivo experiments with healthy subjects and patients with exocrine pancreatic insufficiency demonstrate that the pancreatic enzymes do not activate "the precursor" intrinsic factor molecule but solely dissociate vitamin from the inactive R type proteins with a consequent coupling to the biologically active intrinsic factor.

Topics: Biological Transport; Humans; Ileum; Intestinal Absorption; Intrinsic Factor; Ligands; Pancreas; Pancreatic Diseases; Vitamin B 12

Topics: Blood Proteins; Humans; Intestinal Absorption; Intrinsic Factor; Pancreas; Pancreatic Diseases; Pancreatic Function Tests; Protein Binding; Schilling Test; Transcobalamins; Trypsin; Vitamin B 12

In vivo studies demonstrate that the pancreatic enzymes and the ionic environment in the upper gastrointestinal tract are essential determining factors for transport and absorption of cobalamin in man. Jejunal fluid was aspirated from healthy human volunteers after administration of cyano[57Co]cobalamin preparations. Immunochemical analysis of the aspirates demonstrated that all isotopic vitamin was transferred to a protein that is identical to the gastric intrinsic factor in terms of molecular mass (57,500), ionic nature (mean pI, 5.09), and reactivity with anti-intrinsic factor sera. However, in the aspirates from patients with exocrine pancreatic dysfunction the vitamin was found to be coupled > 60% to a protein identical to R proteins in terms of molecular mass (125,000), ionic nature (mean pI, 3.51), and reactivity with anti-R protein and anti-intrinsic factor sera. The preferential transfer of cobalamin to R proteins in the patients and to intrinsic factor in healthy subjects was associated, respectively, with low and normal levels of pancreatic enzymes in the intestine and these in turn were paralleled respectively by impaired and normal ileal absorption of cobalamin. These findings confirm the suggestion that the formation of unabsorbable cobalamin complexes may be the reason of impaired vitamin absorption in exocrine pancreatic insufficiency. Observations made with other selected patients demonstrate: (a) that decreased enzyme activity and nondegradation of R proteins may also be due to nonactivation of pancreatic zymogens in an acidic pH of the intestinal juice the vitamin transported to the jejunum couples to intrinsic factor when pancreatic function is normal, and to intrinsic factor and R protein in exocrine pancreatic insufficiency. The observations made with these selected patients may explain why not all patients with exocrine pancreatic insufficiency develop imparied cobalamin absorption, and also why the malabsorption is corrected by the administration of bicarbonate in certain patients.

Topics: Adult; Biological Transport; Blood Proteins; Digestive System; Gastric Juice; Gastrointestinal Motility; Humans; Hydrogen-Ion Concentration; Ileum; Intestinal Absorption; Intestinal Secretions; Intrinsic Factor; Male; Pancreatic Diseases; Transcobalamins; Vitamin B 12

Human bile incubated with vitamin B12 bound to intrinsic factor in human gastric juice will effectively dissociate this complex, and the vitamin will transfer to non-intrinsic factor unsaturated binding protein(s) contained in bile. Preincubation of the bile with pancreatic enzymes, particularly trypsin, and pepsin, decreases this effect of bile on the intrinsic factor--vitamin B12 complex by digesting the unsaturated binder(s) in the bile. These studies help explain why there is malabsorption of tracer amounts of vitamin B12 in some patients with pancreatic insufficiency, and why this abnormality is correctable by the administration of pancreatic extract.

Topics: Bile; Humans; Intrinsic Factor; Malabsorption Syndromes; Pancreatic Diseases; Pepsin A; Trypsin; Vitamin B 12; Vitamin B 12 Deficiency

Topics: Carrier Proteins; Chromatography, Gel; Cobalt Radioisotopes; Gastric Juice; Humans; Intestinal Secretions; Intrinsic Factor; Pancreatic Diseases; Pancreatic Juice; Vitamin B 12

Cobalamin (Cbl; vitamin B(12)) malabsorption in pancreatic insufficiency can be partially corrected by bicarbonate and completely corrected by pancreatic proteases but the mechanisms involved are unknown. Because saliva contains enough R-type Cbl-binding protein (R protein) to bind all of the dietary and biliary Cbl, it is possible that R protein acts as an inhibitor of Cbl absorption and that pancreatic proteases are required to alter R protein and prevent such inhibition. To test this hypothesis we studied the ability of R protein and intrinsic factor (IF) to compete for Cbl binding and ability of pancreatic proteases to alter this competition. Human salivary R protein bound Cbl with affinities that were 50- and 3-fold higher than those of human IF at pH 2 and 8, respectively. Cbl bound to IF was transferred to an equal amount of R protein with t((1/2))'s of 2 and 90 min at pH 2 and 8, respectively, and within several hours respective ratios of R protein-Cbl/IF-Cbl of 50 and 2 were observed. Cbl bound to R protein was not transferred to IF at either pH 2 or 8. Incubation of R protein with pancreatic proteases at pH 8 led to a 150-fold decrease in its affinity for Cbl. Incubation of R protein-Cbl with pancreatic proteases led to complete transfer of Cbl to IF within 10 min. Gel filtration studies with R protein-[(57)Co]Cbl and (125)I-R protein showed that pancreatic proteases partially degraded R protein. Pancreatic proteases differed in their ability to effect these changes with trypsin > chymotrypsin > elastase. Pancreatic proteases did not alter IF in any of the parameters mentioned above. Pepsin failed to alter either R protein or IF. THESE STUDIES SUGGEST THE FOLLOWING: (a) that Cbl is bound almost exclusively to R protein in the acid milieu of the stomach, rather than to IF as has been assumed previously; (b) that Cbl remains bound to R protein in the slightly alkaline environment of the intestine until pancreatic proteases partially degrade R protein and enable Cbl to become bound exclusively to IF; and (c) that the primary defect in Cbl absorption in pancreatic insufficiency is a lack of pancreatic proteases and a failure to alter R protein and effect the transfer of Cbl to IF. These studies also suggest that the partial correction of Cbl malabsorption observed with bicarbonate is due to neutralization of gastric HCl, since at slightly alkaline, pH IF can partially compete with R protein for the initial binding and retention of Cbl.

Topics: Carrier Proteins; Chymotrypsin; Endopeptidases; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Intestinal Absorption; Intrinsic Factor; Pancreas; Pancreatic Diseases; Pancreatic Elastase; Pancreatin; Pepsin A; Proteins; Trypsin; Vitamin B 12

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.

Topics: Adolescent; Adult; Binding, Competitive; Carrier Proteins; Cobamides; Female; Humans; Intestinal Absorption; Intrinsic Factor; Male; Middle Aged; Pancreatic Diseases; Schilling Test; Transcobalamins; Trypsin; Vitamin B 12

The mean absorption of vitamin B12 (Schilling test) was 13.1 +/- 1.0 (% +/- S.E.M.) in 21 patients with chronic pancreatic insufficiency and 17.6 +/- 1.4 in 13 control patients (p less than 0.01). There was no correlation between pancreatic bicarbonate production after secretion stimulation and vitamin B12 absorption in the patient group (r = 0.117). Human duodenal juice reduced the uptake of 57CoB12-rat intrinsic factor (IF) by perfused rat small intestinal segments in vivo (p less than 0.01) as well as the uptake of 57CoB12-human IF by purified guinea-pig intestinal brush borders in vitro (p less than 0.01). The results confirm reduced absorption of vitamin B12 in chronic pancreatic insufficiency, but the mechanism remains uncertain.

Topics: Adolescent; Adult; Aged; Animals; Bicarbonates; Chronic Disease; Duodenum; Female; Guinea Pigs; Hot Temperature; Humans; Intestinal Absorption; Intestinal Mucosa; Intrinsic Factor; Male; Middle Aged; Pancreatic Diseases; Pancreatic Juice; Rats; Schilling Test; Vitamin B 12

Topics: Adult; Anemia, Pernicious; Cobalt Isotopes; Female; Humans; Intrinsic Factor; Malabsorption Syndromes; Male; Middle Aged; Pancreatic Diseases; Pancreatic Extracts; Schilling Test; Vitamin B 12

Topics: Humans; Intestinal Absorption; Intrinsic Factor; Malabsorption Syndromes; Pancreas; Pancreatic Diseases; Pancreatic Extracts; Vitamin B 12

Topics: Administration, Oral; Antibodies; Bacteria; Calcium; Chronic Disease; Cobalt Isotopes; Feces; Hemoglobins; Humans; Hydrogen-Ion Concentration; Ileum; Intestinal Absorption; Intestinal Secretions; Intrinsic Factor; Jejunum; Lipid Metabolism; Lipids; Malabsorption Syndromes; Pancreas; Pancreatic Diseases; Pancreatic Extracts; Vitamin B 12

Topics: Adult; Bicarbonates; Binding Sites; Celiac Disease; Humans; Intestinal Absorption; Intrinsic Factor; Malabsorption Syndromes; Male; Pancreas; Pancreatic Diseases; Pancreatic Extracts; Vitamin B 12; Vitamin B 12 Deficiency