Abstract
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.
Full text
PDF










Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Allen R. H., Seetharam B., Podell E., Alpers D. H. Effect of proteolytic enzymes on the binding of cobalamin to R protein and intrinsic factor. In vitro evidence that a failure to partially degrade R protein is responsible for cobalamin malabsorption in pancreatic insufficiency. J Clin Invest. 1978 Jan;61(1):47–54. doi: 10.1172/JCI108924. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Burger R. L., Allen R. H. Characterization of vitamin B12-binding proteins isolated from human milk and saliva by affinity chromatography. J Biol Chem. 1974 Nov 25;249(22):7220–7227. [PubMed] [Google Scholar]
- CONLEY C. L., KREVANS J. R., MCINTYRE P. A., SACHS M. V. Pathogenesis and treatment of macrocytic anemia; information obtained with radioactive vitamin B12. AMA Arch Intern Med. 1956 Nov;98(5):541–549. doi: 10.1001/archinte.1956.00250290001001. [DOI] [PubMed] [Google Scholar]
- Cotter R., Rothenberg S. P., Weiss J. P. Dissociation of the intrinsic factor--vitamin B12 complex by bile: contributing factor to B12 malabsorption in pancreatic insufficiency. Scand J Gastroenterol. 1979;14(5):545–550. doi: 10.3109/00365527909181387. [DOI] [PubMed] [Google Scholar]
- DESNUELLE P., CONSTANTIN M. J., BALDY J. Technique potentiométrique pour la measure de l'activité de la lipase pancréatique. Bull Soc Chim Biol (Paris) 1955;37(2-3):285–290. [PubMed] [Google Scholar]
- GOTTLIEBLAU K. S., WASSERMAN L. R., HERBERT V. RAPID CHARCOAL ASSAY FOR INTRINSIC FACTOR (IF), GASTRIC JUICE UNSATURATED B12 BINDING CAPACITY, ANTIBODY TO IF, AND SERUM UNSATURATED B12 BINDING CAPACITY. Blood. 1965 Jun;25:875–884. [PubMed] [Google Scholar]
- GRASBECK R. Studies on the vitamin B12-binding principle and other biocolloids of human gastric juice. Acta Med Scand Suppl. 1956;314:1–87. [PubMed] [Google Scholar]
- GREENWOOD F. C., HUNTER W. M., GLOVER J. S. THE PREPARATION OF I-131-LABELLED HUMAN GROWTH HORMONE OF HIGH SPECIFIC RADIOACTIVITY. Biochem J. 1963 Oct;89:114–123. doi: 10.1042/bj0890114. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gastroent S. J. The absorption of vitamin B12 in chronic pancreatic insufficiency. Scand J Gastroenterol. 1977;12(3):257–259. [PubMed] [Google Scholar]
- Gräsbeck R., Salonen E. M. Vitamin B12. Prog Food Nutr Sci. 1976;2(5):193–231. [PubMed] [Google Scholar]
- HUMMEL B. C. A modified spectrophotometric determination of chymotrypsin, trypsin, and thrombin. Can J Biochem Physiol. 1959 Dec;37:1393–1399. [PubMed] [Google Scholar]
- Hooper D. C., Alpers D. H., Burger R. L., Mehlman C. S., Allen R. H. Characterization of ileal vitamin B12 Binding using homogeneous human and hog intrinsic factors. J Clin Invest. 1973 Dec;52(12):3074–3083. doi: 10.1172/JCI107506. [DOI] [PMC free article] [PubMed] [Google Scholar]
- King C. E., Leibach J., Toskes P. P. Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12. Dig Dis Sci. 1979 May;24(5):397–402. doi: 10.1007/BF01297127. [DOI] [PubMed] [Google Scholar]
- Kolhouse J. F., Kondo H., Allen N. C., Podell E., Allen R. H. Cobalamin analogues are present in human plasma and can mask cobalamin deficiency because current radioisotope dilution assays are not specific for true cobalamin. N Engl J Med. 1978 Oct 12;299(15):785–792. doi: 10.1056/NEJM197810122991501. [DOI] [PubMed] [Google Scholar]
- Kraut J. Serine proteases: structure and mechanism of catalysis. Annu Rev Biochem. 1977;46:331–358. doi: 10.1146/annurev.bi.46.070177.001555. [DOI] [PubMed] [Google Scholar]
- LOWENSTEIN L., COOPER B. A., BRUNTON L., GARTHA S. An immunologic basis for acquired resistance to oral administration of hog intrinsic factor and vitamin B12 in pernicious anemia. J Clin Invest. 1961 Sep;40:1656–1662. doi: 10.1172/JCI104388. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LeBauer E., Smith K., Greenberger N. J. Pancreatic insufficiency and vitamin B 12 malabsorption. Arch Intern Med. 1968 Nov;122(5):423–425. [PubMed] [Google Scholar]
- Marcoullis G., Gräsbeck R. Solubilised intrinsic factor receptor from pig ileum and its characteristics. Biochim Biophys Acta. 1977 Jan 24;496(1):36–51. doi: 10.1016/0304-4165(77)90113-1. [DOI] [PubMed] [Google Scholar]
- Marcoullis G., Gräsbeck R. Vitamin B12-binding proteins in human gastric mucosa. General pattern and demonstration of intrinsic factor isoproteins typical of mucosa. Scand J Clin Lab Invest. 1975 Jan;35(1):5–11. doi: 10.1080/00365517509067998. [DOI] [PubMed] [Google Scholar]
- Marcoullis G., Merivuori H., Gräsbeck R. Comparative studies on intrinsic factor and cobalophilin in different parts of the gastrointestinal tract of the pig. Biochem J. 1978 Sep 1;173(3):705–712. doi: 10.1042/bj1730705f. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Marcoullis G., Rothenberg S. P., Labombardi V. J. Preparation and characterization of proteins in the alimentary tract of the dog which bind cobalamin and intrinsic factor. J Biol Chem. 1980 Mar 10;255(5):1824–1829. [PubMed] [Google Scholar]
- Marcoullis G., Salonen E. M., Gräsbeck R. Isolation of vitamin B-12-binding proteins by combined immuno and affinity chromatography. Comparative studies on the isolated and unisolated proteins. Biochim Biophys Acta. 1977 Dec 20;495(2):336–348. doi: 10.1016/0005-2795(77)90389-0. [DOI] [PubMed] [Google Scholar]
- Mathan V. I., Babior B. M., Donaldson R. M., Jr Kinetics of the attachment of intrinsic factor-bound cobamides to ileal receptors. J Clin Invest. 1974 Sep;54(3):598–608. doi: 10.1172/JCI107797. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Matuchansky C., Rambaud J. C., Modigliani R., Bernier J. J. Letter: Vitamin B12 malabsorption in chronic pancreatitis. Gastroenterology. 1974 Aug;67(2):406–407. [PubMed] [Google Scholar]
- PERMAN G., GULLBERG R., REIZENSTEIN P. G., SNELLMAN B., ALLGEN L. G. A study of absorption patterns in malabsorption syndromes. Acta Med Scand. 1960 Oct 17;168:117–125. doi: 10.1111/j.0954-6820.1960.tb06652.x. [DOI] [PubMed] [Google Scholar]
- Parmentier Y., Marcoullis G., Nicolas J. P. The intraluminal transport of vitamin B12 and the exocrine pancreatic insufficiency. Proc Soc Exp Biol Med. 1979 Apr;160(4):396–400. doi: 10.3181/00379727-160-40457. [DOI] [PubMed] [Google Scholar]
- Rothenberg S. P., Kantha K. R., Ficarra A. Autoantibodies to intrinsic factor: their determination and clinical usefulness. J Lab Clin Med. 1971 Mar;77(3):476–484. [PubMed] [Google Scholar]
- SCHILLING R. F. Intrinsic factor studies II. The effect of gastric juice on the urinary excretion of radioactivity after the oral administration of radioactive vitamin B12. J Lab Clin Med. 1953 Dec;42(6):860–866. [PubMed] [Google Scholar]
- Stenman U. H. Intrinsic factor and the vitamin B12 binding proteins. Clin Haematol. 1976 Oct;5(3):473–495. [PubMed] [Google Scholar]
- Toskes P. P., Deren J. J. Vitamin B 12 absorption and malabsorption. Gastroenterology. 1973 Oct;65(4):662–683. [PubMed] [Google Scholar]
- Toskes P. P., Hansell J., Cerda J., Deren J. J. Vitamin B 12 malabsorption in chronic pancreatic insufficiency. N Engl J Med. 1971 Mar 25;284(12):627–632. doi: 10.1056/NEJM197103252841202. [DOI] [PubMed] [Google Scholar]
- Toskes P. P., Smith G. W., Francis G. M., Sander E. G. Evidence that pancreatic proteases enhance vitamin B12 absorption by acting on curde preparations of hog gastric intrinsic factor and human gastric juice. Gastroenterology. 1977 Jan;72(1):31–36. [PubMed] [Google Scholar]
- VEEGER W., ABELS J., HELLEMANS N., NIEWEG H. O. Effect of sodium bicarbonate and pancreatin on the absorption of vitamin B12 and fat in pancreatic insufficiency. N Engl J Med. 1962 Dec 27;267:1341–1344. doi: 10.1056/NEJM196212272672604. [DOI] [PubMed] [Google Scholar]
- VEEGER W., ABELS J., HELLEMANS N., NIEWEG H. O. Effect of sodium bicarbonate and pancreatin on the absorption of vitamin B12 and fat in pancreatic insufficiency. N Engl J Med. 1962 Dec 27;267:1341–1344. doi: 10.1056/NEJM196212272672604. [DOI] [PubMed] [Google Scholar]
- Von Der Lippe G., Andersen K. J., Schjönsby H. Intestinal absorption of vitamin B12 in patients with chronic pancreatic insufficiency and the effect of human duodenal juice on the intestinal uptake of vitamin B12. Scand J Gastroenterol. 1976;11(7):689–695. [PubMed] [Google Scholar]
- Waxman S., Schreiber C., Herbert V. Radioisotopic assay for measurement of serum folate levels. Blood. 1971 Aug;38(2):219–228. [PubMed] [Google Scholar]
