Protein-bound Vitamin B12 Research Articles

Characterization of vitamin B12 compounds from marine foods

Vitamin B12 is synthesized by only certain bacteria and archaea but not by animals or plants. In marine environments, bacterial vitamin B12 is transferred and concentrated into fish and shellfish bodies by plankton in the marine food chain. Moreover, marine macrophytic red algae, Porphyra spp. specifically contain substantial amounts of vitamin B12, due to microbial interaction. Although some meats or viscera of edible fish and shellfish are excellent sources of biologically active vitamin B12, an inactive corrinoid, pseudovitamin B12, was found in some edible shellfish using liquid chromatography/electrospray ionization–tandem mass spectrometry. To prevent elderly people from developing vitamin B12 deficiency due to food protein-bound vitamin B12 malabsorption, we present a survey of marine foods containing free vitamin B12. The results of our study suggest that bonito and clam extracts (or soup stocks), which contain considerable amounts of free vitamin B12 are useful not only as seasonings and flavorings but also as excellent sources of free vitamin B12.

Vitamin B12 deficiency and use of acid-suppressive drugs: The association revisited

Vitamin B12 is a water-soluble nutrient involved in several important physiologic processes. Deficiency may lead to a variety of manifestations, such as megaloblastic anemia and neurologic deficits.1 Gastric acid plays a role in vitamin B12 absorption by activating proteolytic enzymes in the stomach, such as pepsin, which free protein-bound vitamin B12 from food sources to make it available for absorption.2,3

Determination of Vitamin B 12 in meat products by RP-HPLC after enrichment and purification on an immunoaffinity column

A quantitative method for the determination of Vitamin B12 in meat products by RP-HPLC and UV detection was developed and compared to the reference method (microbiological assay, MBA). Vitamin B12 was extracted with 50 mM sodium acetate buffer in the presence of sodium cyanide. For the quantification of total Vitamin B12, it was necessary to release protein-bound Vitamin B12 by pepsin treatment. Cyanocobalamin was detected as total Vitamin B12 after purification and enrichment on an immunoaffinity column. The calibration with five concentrations of Vitamin B12 was linear with a regression coefficient r2 > 0.99. The method was validated at three different concentration levels (5–15 ng/g) with salami showing good recovery rates between 80 and 108% and low relative standard deviations between 1.50 and 7.26% (n = 6). The detection limit was found to be 2 ng/g. The Vitamin B12 levels of 50 meat products measured by the developed procedure were similar or significantly lower than those determined by the MBA.

Vitamin B12Deficiency and Depression in the Elderly

Vitamin B₁₂Deficiency and Depression in the Elderly

What is an Adequate Dose of Oral Vitamin B<SUB>12</SUB> in Older People with Poor Vitamin B<SUB>12</SUB> Status?

The prevalence of vitamin B12 deficiency increases in the elderly, mainly because atrophic gastritis decreases the production of the acid and digestive enzymes needed to cleave protein-bound vitamin B12 from the natural chemical form of vitamin B12 found in meat, poultry, fish, and dairy foods. Depending on the biochemical criterion that is used, 5% to more than 20% of older adults have marginal or frank vitamin B12 deficiency. Adults over 50 years of age should meet the Recommended Dietary Allowance by consuming vitamin B12 in the crystalline form, which does not require gastric acid or enzymes for initial digestion. A recent clinical trial suggests that an oral dose of 500 μg/d of crystalline vitamin B12 is needed to reverse biochemical signs of vitamin B12 deficiency in older adults.

What is an Adequate Dose of Oral Vitamin B12in Older People with Poor Vitamin B12Status?

The prevalence of vitamin B12 deficiency increases in the elderly, mainly because atrophic gastritis decreases the production of the acid and digestive enzymes needed to cleave protein-bound vitamin B12 from the natural chemical form of vitamin B12 found in meat, poultry, fish, and dairy foods. Depending on the biochemical criterion that is used, 5% to more than 20% of older adults have marginal or frank vitamin B12 deficiency. Adults over 50 years of age should meet the Recommended Dietary Allowance by consuming vitamin B12 in the crystalline form, which does not require gastric acid or enzymes for initial digestion. A recent clinical trial suggests that an oral dose of 500 microg/d of crystalline vitamin B12 is needed to reverse biochemical signs of vitamin B12 deficiency in older adults.

Vitamin B12 Deficiency Associated with Histamine2-Receptor Antagonists and a Proton-Pump Inhibitor

OBJECTIVE:To report a case of vitamin B12 deficiency associated with long-term use (∼4½ y) of histamine2 (H2)-receptor antagonists and a proton-pump inhibitor (PPI) in a patient with gastroesophageal reflux.CASE SUMMARY:A 78-year-old nonvegetarian white woman with symptomatic gastroesophageal reflux (GER) was started on cimetidine 300 mg 4 × daily in February 1990 and took various other antisecretory medications over the course of the next 4½ years. She had a normal serum vitamin B12 concentration of 413 pg/mL in August 1992. In June 1994, her serum vitamin B12 concentration was found to be in the low normal range at 256 pg/mL. Biochemical markers of vitamin B12–dependent enzyme activity were measured at that time, and methylmalonic acid (MMA) and homocysteine (HCYS) were elevated at 757 nmol/L and 27.3 μmol/L, respectively. Serum folate was within the normal range at 4.9 ng/mL, and serum creatinine was slightly elevated at 1.4 mg/dL. MMA and HCYS concentrations decreased dramatically with oral replacement of vitamin B12 1000 μg/d, which confirmed vitamin B12 deficiency. Oral replacement also demonstrated that the woman was able to adequately absorb nonprotein—bound vitamin B12 from the gastrointestinal tract, suggesting that her deficiency was a result of food—cobalamin malabsorption. The accumulation of MMA and HCYS was not a consequence of renal dysfunction, since both metabolites dramatically decreased with vitamin B12 replacement.DISCUSSION:Malabsorption of dietary protein-bound vitamin B12 has been demonstrated with the use of H2-receptor antagonists and PPIs. One previous case report of vitamin B12 deficiency resulting from long-term use of omeprazole has been published. The malabsorption of dietary vitamin B12 is thought to be a result of its impaired release from food protein, which requires gastric acid and pepsin as the initial step in the absorption process.CONCLUSIONS:The use of H2-receptor antagonists and/or PPIs may impair the absorption of protein-bound dietary vitamin B12 and could contribute to the development of vitamin B12 deficiency with prolonged use. Patients taking these medications for extended periods of time, particularly >4 years, should be monitored for vitamin B12 status.

Changes in gastric mucosa and luminal environment during acid-suppressive therapy: a review in depth.

Acid-suppressive therapy and subsequent changes in gastric mucosa and luminal environment rank highly amongst the investigated issues in gastroenterology over the past two to three decades. Herewith, we present an overview of these intragastric changes, particularly during long-term administration of acid-suppresive medication and concurrent infection with Helicobacter pylori. Current evidence indicates that: i) Long-term acid suppression facilitates the development of fundic ECL cell hyperplasia, especially in the presence of Helicobacter pylori. No neoplastic changes directly attributable to acid suppression have so far been demonstrated in humans. ii) Acid-suppressive therapy increases the risk of enteric infections. iii) Acid-suppressive therapy does not alter fat and mineral bioavailability, but may decrease the absorption of protein-bound vitamin B12. iv) Acid suppression invariably results in intragastric overgrowth of non-Helicobacter pylori bacterial species. The concurrent infection with Helicobacter pylori may promote this bacterial overgrowth and the intragastric formation of N-nitrosamines. v) Acid-suppressive therapy alters the natural course of Helicobacter pylori gastritis, transforming the antral-predominant pattern into a body-predominant pattern, which in turn may progress to body gland atrophy. The pathophysiology of this phenomenon is currently under investigation. vi) In view of the potential adverse effects of acid suppression in the presence of Helicobacter pylori, the screen-and-treat strategy is advocated for Helicobacter pylori in subjects considered for long-term treatment.

Vitamin B12 deficiency in the elderly.

Vitamin B12 deficiency is estimated to affect 10%-15% of people over the age of 60, and the laboratory diagnosis is usually based on low serum vitamin B12 levels or elevated serum methylmalonic acid and homocysteine levels. Although elderly people with low vitamin B12 status frequently lack the classical signs and symptoms of vitamin B12 deficiency, e.g. megaloblastic anemia, precise evaluation and treatment in this population is important. Absorption of crystalline vitamin B12 does not decline with advancing age. However, compared with the younger population, absorption of protein-bound vitamin B12 is decreased in the elderly, owing to a high prevalence of atrophic gastritis in this age group. Atrophic gastritis results in a low acid-pepsin secretion by the gastric mucosa, which in turn results in a reduced release of free vitamin B12 from food proteins. Furthermore, hypochlorhydria in atrophic gastritis results in bacterial overgrowth of the stomach and small intestine, and these bacteria may bind vitamin B12 for their own use. The ability to absorb crystalline vitamin B12 remains intact in older people with atrophic gastritis. The 1998 recommended daily allowance for vitamin B12 is 2.4 micrograms, but elderly people should try to obtain their vitamin B12 from either supplements or fortified foods (e.g. fortified ready-to-eat breakfast cereals) to ensure adequate absorption from the gastrointestinal tract. Because the American food supply is now being fortified with folic acid, concern is increasing about neurologic exacerbation in individuals with marginal vitamin B12 status and high-dose folate intake.

Prospective evaluation of protein bound vitamin B12(cobalamin) malabsorption in the elderly using trout flesh labelled in vivo with 57Co-cobalamin

Background—The frequency of dietary protein bound vitamin B12 malabsorption in elderly patients remains controversial.Aims—To evaluate this malabsorption in elderly hospitalised patients using a modified Schilling test.Patients—Fourteen elderly patients with low...

12 Cobalamin and folate deficiency in the elderly

Elderly persons are more likely to have low values for serum and erythrocyte folate, and for serum cobalamin. Many of those with low vitamin levels have biochemical abnormalities consistent with true deficiency, including increased formiminoglutamic acid excretion, abnormal marrow deoxyuridine suppression, and raised serum levels of methylmalonic acid and homocysteine. Therapy with the appropriate vitamin reverses the biochemical defect. Despite this, the clinical consequences for most elderly persons are remarkably few. True megaloblastic anaemia is rare, and the small number of therapeutic trials to date have not improved the levels of haemoglobin in the treated subjects, although the mean corpuscular volume has decreased significantly. There has been recent concern that these low blood vitamin levels might be important causes of nervous system damage, but studies specifically of the elderly have not demonstrated overall improvements in neurological function following therapy. Vascular damage from high blood homocysteine levels secondary to cobalamin or folate deficiency remains a potential hazard. Dietary insufficiency, malabsorption of protein-bound vitamin B12 secondary to atrophic gastritis, and defective absorption of folyl polyglutamates seem the likeliest possible causes. Pernicious anaemia, although a common cause of severe megaloblastic anaemia in the elderly, is an infrequent cause for the low cobalamin levels in population studies. Although the benefits are uncertain, the balance of the evidence suggests that one should treat elderly persons with low values of cobalamin or folate. Crystalline vitamin B12 and folic acid are absorbed normally and are therefore suitable for replacement therapy, provided that pernicious anaemia is excluded.

Detection of Protein Bound Vitamin B12 Malabsorption

The Schilling test is used to identify the cause of vitamin B12 malabsorption in patients with low serum vitamin B12 levels. The initial step required for vitamin B12 absorption is a process of separation from the protein complexes of food. The crystalline Co-57 vitamin B12 used in the Schilling test does not reproduce this physiologic process. Thus, a crystalline stage I Schilling test may be normal even in the face of cobalamin malabsorption. An adjunctive stage I Schilling test using Co-57 vitamin B12 bound to protein has been developed. The authors describe a patient with protein-bound vitamin B12 malabsorption whose crystalline Co-57 vitamin B12 stage I Schilling test was normal. A subsequent stage I Schilling test using Co-57 vitamin B12 bound to chicken serum revealed significant cobalamin malabsorption. A review of the history and literature of this diagnostic test using protein bound vitamin B12 is also presented.

Letters: Omeprazole and Vitamin B_12

Letters1 July 1994Letters: Omeprazole and Vitamin B12Stefan P. Marcuard, MDStefan P. Marcuard, MDEast Carolina University School of Medicine; Greenville, NC 27858-4354Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-121-1-199407010-00022 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail IN RESPONSE:Our study design to evaluate protein-bound B12 absorption before and during treatment with omeprazole is appropriate and is known as “self-pairing” [1, 2]. This method eliminates the variability between study patients and “controls.” Although we agree that a placebo group would have strengthened our results, our straightforward study design is adequate to show changes in vitamin B12 absorption during omeprazole therapy.Dr. Lavy's comments indicate a misunderstanding of vitamin B12 digestion and absorption. To correct protein-bound vitamin B12 malabsorption, hydrochloric acid (not vitamin B12) is added to the modified Schilling tests. In fact, this has been done by ...

Reversal of protein-bound vitamin B12 malabsorption with antibiotics in atrophic gastritis

The role of bacteria in the bioavailability of proteinbound vitamin B12 was examined in eight elderly subjects who had atrophic gastritis and in eight normal controls. On separate days and in random order, vitamin B12 absorption tests were performed using either radiolabeled crystalline or proteinbound vitamin B12. At the same time, bacterial samples were collected from the upper gastrointestinal tract. The tests and gastrointestinal aspirates were performed before and during tetracycline therapy. Crystalline vitamin B12 was absorbed to the same extent in the two study groups. Atrophic gastritis subjects absorbed significantly less proteinbound vitamin B12 than normal controls (mean ±SEM, 0.7% ± 0.2% vs. 1.9% ± 0.5%, respectively). However, protein-bound vitamin B12 absorption in these subjects normalized after antibiotic therapy. These results suggest that the small amounts of vitamin B12 released from the protein binders is readily absorbed (as shown in vitro) and/or metabolized by bacteria.

Mechanisms of vitamin B12 deficiency in elderly inpatients.

A protein-bound Schilling test incorporating chick serum was used to study 16 elderly vitamin B12-deficient inpatients. Thirteen of these also underwent standard Schilling tests. They were compared with an age-matched control group of non-deficient inpatients. The lower limit of normal for assimilation of protein-bound vitamin B12 was 0.7%. Fourteen out of 16 deficient patients assimilated protein-bound vitamin B12 subnormally. Twelve of these were fully Schilling tested. Five assimilated free B12 normally, and five responded to intrinsic factor. One patient did not respond to intrinsic factor and had jejunal diverticulosis and one could not be categorized. One of two patients with normal assimilation had a borderline vitamin B12 intake. No subjects had neurological sequelae and only three were anaemic. In this population, B12 deficiency is usually asymptomatic but nearly always results from impaired assimilation possibly justifying replacement therapy. Schilling testing only affects treatment if there is other evidence of small-bowel dysfunction.

The absorption of free vitamin B12 and R protein-bound vitamin B12 in the diagnosis of pancreatic exocrine insufficiency in rats.

Vitamin B12 (B12) absorption was studied in rats following biliopancreatic duct ligation. The absorption of free B12, as well as of hog R protein-bound B12, was markedly impaired after both intragastric and intraduodenal administration in these rats. The intraduodenal administration of a mixture of pancreatic extract and sodium bicarbonate (NaHCO3) improved the absorption of both free and R protein-bound B12. However, pancreatic extract without NaHCO3 was ineffective in this respect. Intraduodenal administration of NaHCO3 without pancreatic extract worsened the R protein-bound B12 absorption. This finding would indicate that the degradation of R protein by proteolytic enzymes, in the intestine of rats with pancreatic juice exclusion, is inhibited by NaHCO3.

Experiences with dual protein bound aqueous vitamin B12 absorption test in subjects with low serum vitamin B12 concentrations.

A dual isotope vitamin B12 absorption test in which vitamin B12 is given both in aqueous solution and bound to protein (chicken serum), was evaluated in 26 controls and 68 patients with subnormal serum vitamin B12 concentrations (19 with pernicious anaemia, 13 with iron deficiency, seven after partial gastrectomy, seven with malabsorptive states, five with folate deficiency, four with chronic alcoholism and 13 in whom no cause was apparent). In control patients protein bound absorption decreased with age; isotope excretion was 1.0% or over in those aged under 60 and 0.5% or over in those aged 60 and above. Malabsorption of protein bound vitamin B12 with normal aqueous absorption occurred in five patients with iron deficiency, three with alcoholism, two after partial gastrectomy, two with folate deficiency and in one with a malabsorptive state. In alcoholics abstinence produced an improvement in protein bound absorption. All patients in the group for whom no cause could be found for the subnormal serum vitamin B12 concentration had normal aqueous absorption but four had malabsorption of protein bound vitamin. Although the dual isotope test gave reproducible results and was consistent with the standard Schilling test some anomalies were detected; nine patients had reduced aqueous absorption with normal protein bound absorption. Despite this the dual test may prove useful in determining the importance of a subnormal vitamin B12 concentration where the cause is not clinically apparent. Further development is needed before it can be considered for routine use.

Incidence and clinical significance of protein-bound vitamin B12 malabsorption.

Patient records from January 1975 to December 1984 were analysed to assess the possible incidence of protein-bound vitamin B12 malabsorption. This condition is characterised by a low serum vitamin B12 level and a normal Schilling test but impaired absorption of vitamin B12 bound to protein. We found that 48 (25%) patients with a low serum cobalamin level unexplained by other causes had a normal Schilling test. Megaloblastic haemopoiesis was found in 25 of these. From this group, all 10 patients who had a test of protein-bound vitamin B12 absorption showed impaired absorption. Protein-bound vitamin B12 malabsorption may represent an early phase of pernicious anaemia when hypochlorhydria precedes intrinsic factor deficiency and should be tested for when the serum vitamin B12 level is decreased and the Schilling test is normal.

Concurrent administration of cimetidine and enteric‐coated prednisolone: effect on plasma levels of prednisolone.

British Journal of Clinical PharmacologyVolume 10, Issue 1 p. 87-89 Free Access Concurrent administration of cimetidine and enteric-coated prednisolone: effect on plasma levels of prednisolone. PJ Morrison, PJ MorrisonSearch for more papers by this authorHJ Rogers, HJ RogersSearch for more papers by this authorID Bradbrook, ID BradbrookSearch for more papers by this authorC Parsons, C ParsonsSearch for more papers by this author PJ Morrison, PJ MorrisonSearch for more papers by this authorHJ Rogers, HJ RogersSearch for more papers by this authorID Bradbrook, ID BradbrookSearch for more papers by this authorC Parsons, C ParsonsSearch for more papers by this author First published: July 1980 https://doi.org/10.1111/j.1365-2125.1980.tb00506.xCitations: 15AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References BODEMAR, G., NORLANDER, B., FRANSSON, L. & WALEN, A. (1979). The absorption of cimetidine before and during maintenance treatment with cimetidine and the influence of a meal on the absorption of cimetidine—studies in patients with peptic ulcer disease. Br. J. clin. Pharmac., 7, 23– 32. BRECKENRIDGE, A.M., CHALLINER, M., MOSSMAN, S., PARK, B.K., SERLIN, M.J., SIBEON, R.G., WILLIAMS, J.R.B. & WILLOUGHBY, J.M.T. (1979). Cimetidine: interaction with warfarin in man. Br. J. clin. Pharmac., 8, 392– 393p. BURLAND, W.L., DUNCAN, W.A.M., HESSELBO, T., MILLS, J.G., SHARPE, P.C., HAGGIE, S.J. & WYLLIE, J.H. (1975). Pharmacological evaluation of cimetidine, a new histamine H2-receptor antagonist, in healthy man. Br. J. clin. Pharmac., 2, 481– 486. CONN, H.O. & BLITZER, B.L. (1976). Nonassociation of adrenocorticosteroid therapy and peptic ulcer. N. Engl. J. Med., 294, 473– 479. FISHER, P., HOUSE, F., INNS, P., MORRISON, P.J., ROGERS, H.J. & BRADBROOK, I.D. (1980). Effect of cimetidine on the absorption of orally administered tetracycline. Br. J. clin. Pharmac., 9, 153– 158. FRIED, J. & ZIETZ, S. (1973). Curve fitting by Spline and Akima methods: possibility of interpolation error and its suppression. Phys. Med. Biol., 18, 550– 558. GIBALDI, M. (1977). Biopharmaceutics and clinical pharmacokinetics, p. 49. Philadelphia: Lea & Febiger. KAMMERER, W.H., FREIBERGER, R.H. & RIVELIS, A.L. (1958). Peptic ulcer in rheumatoid patients on corticosteroid therapy. Arth. Rheum., 1, 122– 141. LEE, D.A.H., TAYLOR, G.M., WALKER, J.G. & JAMES, V.H.T. (1979). The effect of food and tablet formulation on plasma prednisolone levels following administration of enteric-coated tablets. Br. J. clin. Pharmac., 7, 523– 528. MORRISON, P.J., BRADBROOK, I.D. & ROGERS, H.J. (1977). Plasma prednisolone levels from enteric and non-enteric coated tablets estimated by an original technique. Br. J. clin. Pharmac., 4, 597– 603. RANDOLPH, W.C., OSBORNE, V.L., WALKENSTEIN, S.S. & INTOCCIA, A.T. (1977). High pressure liquid chromatographic analysis of cimetidine, a histamine H2-receptor antagonist in blood and urine. J. pharm. Sci., 66, 1148– 1150. STERNBERG, W., KING, C. & TOSKES, P. (1978). Cimetidine inhibits the absorption of protein-bound vitamin B12 but not crystalline vitamin B12. Gastroenterology, 74, 1099. Citing Literature Volume10, Issue1July 1980Pages 87-89 ReferencesRelatedInformation

Clinically significant vitamin B12 deficiency secondary to malabsorption of protein-bound vitamin B12

Protein- (chicken serum) bound [57Co]cyanocobalamin absorption was evaluated in five hypochlorhydric patients who had developed B12 deficiency despite having normal absorption of unbound crystalline vitamin B12. All five patients had decreased urinary excretion of protein-bound B12 (0.06--0.34%) as compared to twelve normal controls (0.61--5.6%), P less than .001. Improvement in protein-bound B12 absorption in four of the five patients occurred with the exogenous administration of hydrochloric acid, pepsin, gastric intrinsic factor, or a combination thereof. Vitamin B12 deficiency developing in the setting of hypochlorhydria may result from deficiency of acid-peptic digestion of B12 bound to protein and/or a relative deficiency of intrinsic factor. This digestive defect is not detected with tests which measure the absorption of unbound crystalline B12 but is detected by a simple test which employs B12 bound to chicken serum as the form of protein-bound B12.