Vitamin B12
Common Names: Vitamin B12; HydroxycyanocobalaminPlease read the disclaimer concerning the intent
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References
Aymard JP, Aymard B, Netter P, Bannwarth B, Trechot P, Streiff F. Haematological adverse effects of histamine H2-receptor antagonists.
Med Toxicol Adverse Drug Exp 1988 Nov-Dec;3(6):430-448.
Abstract: Histamine H2-receptor antagonists are widely used in the treatment of gastrointestinal diseases related to gastric acid hypersecretion. Cimetidine was introduced into medical practice in 1976 and ranitidine, famotidine and nizatidine in 1981, 1985 and 1987, respectively. Haematological adverse effects are relatively uncommon and most have been reported in cases of cimetidine administration. These adverse effects are reviewed under 4 main headings: (a) blood cytopenias and leucocytosis; (b) coagulation disorders related to drug interactions with oral anticoagulants; (c) reduction of dietary iron absorption; and (d) reduction of dietary cobalamin absorption. 85 reported cases of blood cytopenias attributed to these drugs are reviewed, of which 75 (88%) were associated with cimetidine therapy. In postmarketing surveillance studies, the incidence of cimetidine-associated blood cytopenia has been evaluated at about 2.3 per 100,000 patients. Neutropenia and agranulocytosis are by far the most frequently encountered. Whatever the drug or the type of cytopenia, this adverse effect is almost always rapidly reversible when treatment is stopped. Moreover, in several cases other factors such as underlying diseases or additional drugs could have been responsible, at least partly, for the cytopenia. The pathophysiological basis of these adverse effects remains poorly explained. Various mechanisms have been proposed, which in some cases are probably associated: (a) direct toxicity for haemopoietic stem cells; (b) drug-induced immune reactions leading to blood or bone marrow cell damage, and (c) drug interactions, with increased and prolonged action of potentially haematotoxic drugs. Mechanisms (a) and (c) appear to be of particular clinical importance in cases of impaired renal elimination of H2-receptor antagonists. Cimetidine and probably to a lesser extent ranitidine potentiate the action of oral anticoagulants of both coumarin and indanedione structure. This may result in haemorrhagic complications. Such action is a consequence of the reduced hepatic metabolism of oral anticoagulants through a dose-dependent, reversible inhibition of cytochrome P450. Malabsorption of dietary iron and cobalamin appears to result from inhibition of gastric secretion by the H2-receptor antagonists. This is of no clinical importance in short term treatment, but long term use of H2-receptor antagonists may theoretically contribute to the occurrence of iron or cobalamin deficiency anaemia.
Baum MK, Shor-Posner G, Lu Y, Rosner B, Sauberlich HE, Fletcher MA, Szapocznik J, Eisdorfer C, Buring JE, Hennekens CH. Micronutrients and HIV-1 disease progression.
AIDS. 1995 Sep;9(9):1051-1056.
Abstract: OBJECTIVE: To determine whether nutritional status affects immunological markers of HIV-1 disease progression. DESIGN: A longitudinal study, to evaluate the relationship between plasma levels of nutrients and CD4 cell counts, along and in combination with beta 2-microglobulin (beta 2M; AIDS index) over an 18-month follow-up. METHODS: Biochemical measurements of nutritional status including plasma proteins, zinc, iron and vitamins B1, B2, B6, B12 (cobalamin), A, E, C and folate and immunological markers [lymphocyte subpopulations (CD4) and beta 2M] were obtained in 108 HIV-1-seropositive homosexual men at baseline and over three 6-month time periods. Changes in nutrient status (e.g., normal to deficient, deficient to normal), were compared with immunological parameters in the same time periods using an autoregressive model. RESULTS: Development of deficiency of vitamin A or vitamin B12 was associated with a decline in CD4 cell count (P = 0.0255 and 0.0377, respectively), while normalization of vitamin A, vitamin B12 and zinc was associated with higher CD4 cell counts (P = 0.0492, 0.0061 and 0.0112, respectively). These findings were largely unaffected by zidovudine use. For vitamin B12, low baseline status significantly predicted accelerated HIV-1 disease progression determined by CD4 cell count (P = 0.041) and the AIDS index (P = 0.005). CONCLUSIONS: These data suggest that micronutrient deficiencies are associated with HIV-1 disease progression and raise the possibility that normalization might increase symptom-free survival.
Bays HE, Dujovne CA. Drug interactions of lipid-altering drugs. Drug
Saf. 1998 Nov;19(5):355-371. (Review)
Bellou A, Aimone-Gastin I, De Korwin JD, Bronowicki JP, Moneret-Vautrin A, Nicolas JP, Bigard MA, Gueant JL. Cobalamin deficiency with megaloblastic anaemia in one patient under long-term omeprazole therapy. J Intern Med 1996 Sep;240(3):161-164.
Abstract: The first case of cobalamin deficiency with megaloblastic anaemia in a patient under long-term omeprazole therapy is presented. This patient received omeprazole at a daily dose of 40-60 mg for 4 years as treatment for a gastro-oesophagal reflux complicated by peptic oesophagitis. Seric vitamin B12 was dramatically decreased at 80 pmol L-1. The Schilling test was normal (13%) with crystalline [57Co] cobalamin and it was at 0% with [57Co] cobalamin-labelled trout meat. All other assimilation tests were normal except an expiratory hydrogen breath test performed with lactulose. The haematological status was restored after intramuscular treatment with cobalamin. In conclusion, prolonged omeprazole therapy can be responsible for a cobalamin deficiency due to protein-bound cobalamin malabsorption.
Berger W. Incidence of severe side effects during therapy with sulfonylureas and biguanides.
Horm Metab Res Suppl 1985;15:111-115.
The most important side-effect of sulfonylureas is hypoglycaemia. According to surveys in Switzerland and in Sweden it occurs at a frequency of about 2 cases per 10,000 treatment years. Mortality is high, about 10%. The syndrome of inappropriate ADH-secretion has been observed almost exclusively during treatment with chlorpropamide. Asymptomatic cases of SIADH-syndrome are quite frequent, hyponatraemia has been observed in 6-10% of diabetics treated with chlorpropamide. The most dangerous side-effect of biguanides is lactic acidosis. It occurs significantly more frequent during treatment with phenformin compared to metformin. Metformin has been reported to lead to lactic acidosis in 0.4 cases per 10,000 treatment years; mortality is about 30%. Mortality of phenformin-associated lactic acidosis is even higher, 70%. Both biguanides, phenformin and metformin, cause relatively frequently vitamin B12-malabsorption (in about 1/3 of the cases). However, symptomatic vitamin B12-deficiency is extremely rare.
Brattstrom L, Israelsson B, Olsson A, Andersson A, Hultberg B. Plasma homocysteine in women on oral oestrogen-containing contraceptives and in men with oestrogen-treated prostatic carcinoma.
Scand J Clin Lab Invest 1992 Jun;52(4):283-287.
Abstract: The mechanism by which oral oestrogen-containing contraceptives in women and oestrogen treatment of prostatic carcinoma in men increases the risk of vascular disease is unclear. These agents decrease serum concentrations of vitamin B12, pyridoxal 5-phosphate, and folate, all of which are essential for the metabolism of the atherogenic amino acid homocysteine. We found serum vitamin B12 concentrations to be lower in 17 women using oral contraceptives (219 +/- 84 pmol l-1) than in 13 age-matched female controls (385 +/- 129, p less than 0.001), but similar values were obtained in the two groups both for fasting plasma homocysteine concentrations (9.1 +/- 2.4 vs 9.2 +/- 3.6 mumol l-1) and for the increase in these concentrations after methionine loading (19.2 +/- 7.5 vs 17.8 +/- 5.2 mumol l-1). In five men with prostatic carcinoma, high-dose oestrogen treatment decreased serum vitamin B12 concentrations by a mean of 30% (p less than 0.05) within 4 weeks, during which fasting plasma homocysteine concentrations decreased (13.8 +/- 4.5 vs 10.5 +/- 2.8 mumol l-1) and response to methionine loading increased (12.4 +/- 3.4 vs 17.3 +/- 5.1 mumol l-1), though the latter changes were non-significant. Our findings do not support the hypothesis that hyperhomocysteinemia explains cardiovascular risk in women using oral oestrogen-containing contraceptives, or in oestrogen-treated men with prostatic carcinoma.
Bremenep SM, Alferova VA, Zgurskaia GN, Zubkova EI, Pipko AS, Rogova KP. [Changes in metabolism of vitamins B6, Bl2, PP, pantothenic acid and vitamin C in patients with chronic colitis of various etiology treated with tetracycline]. Antibiotiki 1967 Apr;12(4):343-347. [Article in Russian]
Campbell P. Vitamin B-12 in the treatment of viral hepatitis. Am J Med Sci. 1952;224:252.
Abstract: IV B-12 brought about rapid return of appetite and liver size to normal in patients with viral hepatitis. In addition, the serum bilirubin returned to normal earlier (in 10 weeks compared to 18), and the mean duration of illness was reduced from 54 to 48 days.
Carslaw N. Vitamin B-12 in psoriasis. Brit. Med J. 1963;1:611. (Letter)
Abstract: Vitamin B-12, saline or triamcinolone were infused into psoriatic lesions (epidermis and mid-dermis) with a hypodermic needle. Triamcinolon caused rapid regression of lesions, while normal saline had no effect. Of the 8 patients who received the B-12, 6 showed regression of the lesion.
Coronato A, Glass GB. Depression of the intestinal uptake of radio-vitamin B 12 by
cholestyramine. Proc Soc Exp Biol Med 1973 Apr;142(4):1341-1344.
Crosby WH. Oral cyanocobalamin without intrinsic factor for pernicious anemia. Arch Intern Med 1980;140:1582.
Cullen RW, Oace SM. Neomycin has no persistent sparing effect on vitamin B-12 status in pectin-fed rats.
J Nutr. 1989 Oct;119(10):1399-1403.
Abstract: In the present study, rats were depleted of vitamin B-12 with fiber-free or 5% pectin diets, with or without neomycin. Through use of this intestinal antibiotic reported to "spare" vitamin B-12, we sought to determine if bacterial fermentation of pectin might explain our previous observations of negative effects of pectin on vitamin B-12 status. However, neomycin did not lessen interference by pectin with vitamin B-12 metabolism. Pectin increased urinary methylmalonate and decreased propionate oxidation to a greater extent in the presence than in the absence of neomycin. Also, regardless of the presence of neomycin, the biologic half-life of injected [57Co]vitamin B-12 was 58 d for rats fed the fiber-free diets and only 38 d for rats fed 5% pectin diets. Neomycin delayed early fecal excretion of 57Co but had no persistent effect. Thus, neomycin-sensitive bacteria do not mediate the negative effects of pectin on vitamin B-12 status. Pectin may interfere directly with vitamin B-12 absorption or may stimulate vitamin B-12 uptake or propionate production by microbial species that have adapted to neomycin.
Duell PB, Malinow MR. Homocyst(e)ine: an important risk factor for atherosclerotic vascular disease.
Curr Opin Lipidol 1997 Feb;8(1):28-34. (Review)
Abstract: Homocysteine is an intermediate compound formed duringmetabolism of methionine. The results of many recent studies have indicated that elevated plasma levels of homocyst(e)ine are associated with increased risk of coronary atherosclerosis, cerebrovascular disease, peripheral vascular disease, and thrombosis. The plasma level of homocyst(e)ine is dependent on genetically regulated levels of essential enzymes and the intake of folic acid, vitamin B6 (pyridoxine), and vitamin B12 (cobalamin). Impaired renal function, increased age, and pharmacologic agents (e.g. nitrous oxide, methotrexate) can contribute to increased levels of homocyst(e)ine. Plausible mechanisms by which homocyst(e)ine might contribute to atherogenesis include promotion of platelet activation and enhanced coagulability, increased smooth muscle cell proliferation, cytotoxicity, induction of endothelial dysfunction, and stimulation of LDL oxidation. Levels of homocysteine can be reduced with pharmacologic doses of folic acid, pyridoxine, vitamin B12, or betaine, but further research is required to determine the efficacy of this intervention in reducing morbidity and mortality associated with atherosclerotic vascular disease.
Dutta SK. Vitamin B12 malabsorption and omeprazole therapy. J Am Coll Nutr 1994 Dec;13(6):544-545. (Comment)
Ehrenfeld M, Levy M, Sharon P, Rachmilewitz D, Eliakim M. Gastrointestinal effects of long-term colchicine therapy in patients with recurrent polyserositis (familial mediterranean fever).
Dig Dis Sci 1982 Aug;27(8):723-727.
Abstract: Twelve patients with recurrent polyserositis (RP, familial Mediterranean fever) on colchicine prophylaxis (1.0-2.0 mg daily) for three years or more were evaluated for the presence of gastrointestinal effects possibly attributable to the drug. Two patients had bulky stools, two others had transient diarrhea, and one had heartburn. Serum vitamin B12, calcium, and carotene levels were normal in all cases, and D-xylose absorption was normal in 11 of the 12. Three patients had mild steatorrhea (7.5, 7.9, and 9.9 g daily). Jejunal biopsies from these and a fourth patient with bulky stools but normal fecal fat excretion showed no abnormal histological changes. However, (Na + K)-ATPase activity was significantly decreased in all four cases. Colchicine had to be discontinued in only one of the 12 cases. It is concluded that mild steatorrhea and enzyme inhibition may occur in patients on long-term colchicine prophylaxis and that careful periodic observations for this and other adverse effects is imperative in such patients.
Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of tiredness.
Br J Nutr 1973 Sep;30(2):277-283.
Abstract: 28 men and women who complained of tiredness but had normal serum B-12 levels and no physical findings were given injections of Hydroxycobalamin 5mg 2x day for 2 weeks followed by a 2 week rest period and then a similar course of placebo injection or the same regimen in reverse order. Those who received placebo first felt significantly better in regard to general well being when they started the second period when they received the B-12. The other group felt better immediately but not upon the second series of placebo (they felt no different).
Elsborg L. Vitamin B12 and Folic Acid in Crohn's Disease. Dan Med Bull 1982; 29:362-365.
Falguera M, Perez-Mur J, Puig T, Cao G. Study of the role of vitamin B12 and folinic acid supplementation in preventing hematologic toxicity of zidovudine.
Eur J Haematol. 1995 Aug;55(2):97-102.
Abstract: A prospective, randomized study was conducted to evaluate the role of vitamin B12 and folinic acid supplementation in preventing zidovudine (ZDV)-induced bone marrow suppression. Seventy-five human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts < 500/mm3 were randomized to receive either ZDV (500 mg daily) alone (group I, n = 38) or in combination with folinic acid (15 mg daily) and intramascular vitamin B12 (1000 micrograms monthly) (group II, n = 37). Finally, 15 patients were excluded from the study (noncompliance 14, death 1); thus, 60 patients (31 in group I and 29 in group II) were eligible for analysis. No significant differences between groups were found at enrollment. During the study, vitamin B12 and folate levels were significantly higher in group II patients; however, no differences in hemoglobin, hematocrit, mean corpuscular volume, and white-cell, neutrophil and platelet counts were observed between groups at 3, 6, 9 and 12 months. Severe hematologic toxicity (neutrophil count < 1000/mm3 and/or hemoglobin < 8 g/dl) occurred in 4 patients assigned to group I and 7 assigned to group II. There was no correlation between vitamin B12 or folate levels and development of myelosuppression. Vitamin B12 and folinic acid supplementation of ZDV therapy does not seem useful in preventing or reducing ZDV-induced myelotoxicity in the overall treated population, although a beneficial effect in certain subgroups of patients cannot be excluded.
Farmer JA, Gotto AM Jr. Antihyperlipidaemic agents. Drug interactions of clinical significance.
Drug Saf 1994 Nov;11(5):301-309.
Abstract: The available antihyperlipidaemic drugs are generally safe and effective, and major systemic adverse effects are uncommon. However, because of their complex mechanisms of action, careful monitoring is required to identify and correct potential drug interactions. Bile acid sequestrants are the most difficult of these agents to administer concomitantly, because their nonspecific binding results in decreased bioavailability of a number of other drugs, including thiazide diuretics, digitalis preparations, beta-blockers, coumarin anticoagulants, thyroid hormones, fibric acid derivatives and certain oral antihyperglycaemia agents. Although the incidence is low, nicotinic acid may cause hepatic necrosis and so should not be used with drugs that adversely affect hepatic structure or function. With the HMG-CoA reductase inhibitors, relatively new agents for which clinical data are still being accumulated, the major problems appears to be rhabdomyolysis, associated with the concomitant use of cyclosporin, fibric acid derivatives or erythromycin, and mild, intermittent hepatic abnormalities that may be potentiated by other hepatotoxic drugs. Fibrates also have the potential to cause rhabdomyolysis, although generally only in combination with HMG-CoA reductase inhibitors, and are subject to binding by concomitantly administered bile acid sequestrants. The major interaction involving probucol is a possible additive effect with drugs or clinical conditions that alter the prolongation of the QTc interval, increasing the potential for polymorphic ventricular tachycardia.
Farmer JA, Gotto AM Jr. Choosing the right lipid-regulating agent. A guide to selection.
Drugs 1996 Nov;52(5):649-661.
Fava M, Borus JS, Alpert JE, Nierenberg AA, Rosenbaum JF, Bottiglieri T. Folate, vitamin B12, and homocysteine in major depressive disorder.
Am J Psychiatry 1997 Mar;154(3):426-428.
Abstract: OBJECTIVE: The authors examined the relationships between levels of three metabolites (folate, vitamin B12, and homocysteine) and both depressive subtype and response to fluoxetine treatment in depressed patients. METHOD: Fluoxetine, 20 mg/day for 8 weeks, was given to 213 outpatients with major depressive disorder. At baseline, depressive subtypes were assessed, and a blood sample was collected from each patient. Serum metabolite levels were assayed. Response to treatment was determined by percentage change in score on the 17-item Hamilton Depression Rating Scale. RESULTS: Subjects with low folate levels were more likely to have melancholic depression and were significantly less likely to respond to fluoxetine. Homocysteine and B12 levels were not associated with depressive subtype or treatment response. CONCLUSIONS: Overall, the results are consistent with findings linking low folate levels to poorer response to antidepressant treatment. Folate levels might be considered in the evaluation of depressed patients who do not respond to antidepressant treatment.
Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on vitamin B12 absorption.
Ann Pharmacother 1992 Oct;26(10):1283-1286.
Abstract: OBJECTIVE: To discuss the potential of histamine H2-receptor antagonists (H2RAs) to cause malabsorption of vitamin B12 (cyanocobalamin). DATA SOURCES: Pertinent literature was identified via a MEDLINE search. Journals and references cited in published articles also were used as data sources. STUDY SELECTION: Studies evaluating the effect of H2RAs on vitamin B12 absorption were reviewed. DATA SYNTHESIS: H2RAs decrease acid secretion by the gastric parietal cells. Gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources. Intrinsic factor (IF), also produced by gastric parietal cells, is required for vitamin B12 absorption from the gastrointestinal tract. Although H2RAs have not conclusively been shown to decrease IF secretion, studies have demonstrated a significant reduction in food-bound vitamin B12 absorption secondary to decreased acid secretion in patients taking these drugs. CONCLUSIONS: H2RAs have the potential to cause vitamin B12 deficiency. This may be important in patients with inadequate stores of vitamin B12 (e.g., poor diet), particularly those receiving H2RA therapy continuously for more than two years. Healthcare providers should be aware of this potential adverse effect.
Goldberg TH. Oral vitamin B12 supplementation for elderly patients with B12 deficiency.
J Am Geriatr Soc 1995;43:SA73.
Hartshorn, EA. Effect of Histamine H2-Receptor Antagonists on Vitamin B12 Absorption.
Ann Pharmacother 1992;26:1283-1286.
Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc. 1985 Jan;44(1 Pt 1):124-129. (Review)
Hjelt K, Brynskov J, Hippe E, Lundstrom P, Munck O. Oral contraceptives and the cobalamin (vitamin B12) metabolism. Acta Obstet Gynecol Scand
1985;64(1):59-63.
The mean concentrations of serum (S)-cobalamin (vitamin B12) and S-unsaturated B12 binding capacity (UBBC) were significantly decreased in 101 women (mean age: 30.4 years) taking oral contraceptives (OC) of the combination type, compared to 113 controls. OC users more frequently showed decreased concentrations of S-cobalamin (less than 200 pmol/l) than did their controls. However, the incidence of particularly low concentrations (less than 150 pmol/l) in OC users was not increased. To study a possible dose-dependent effect, 27 women (mean age: 50.5 years) given high-dose estrogen preparations (1-4 mg estrogen) were compared with 31 controls. The two groups showed no difference with regard to S-cobalamin, but the mean S- and plasma-UBBC levels were significantly decreased in the high-dose estrogen group. 12 OC users with decreased S-cobalamin (less than 200 pmol/l), 9 OC users with normal S-cobalamin and 10 controls were studied more intensively. The mean hemoglobin concentration was significantly decreased in those OC users having decreased S-cobalamin. On the contrary, the absorption and excretion of radiolabeled cobalamin and the concentrations of erythrocyte-folate, S-iron and -transferrin did not show any difference between the groups, and all results were normal, by and large. No characteristic changes in plasma volume were found. It is concluded that routine measurement of S-cobalamin in women taking OC is not justified.
Holt GA. Food and Drug Interactions. Chicago: Precept Press, 1998.
Houston DK, Johnson MA, Nozza RJ, et al. Age-related hearing loss, vitamin B-12, and folate in elderly women.
Am J Clin Nutr 1999;69:564-571.
Jain, Mukerji. Observations on the therapeutic value of intravenous B12 in infective hepatitis.
J Indian Med Assoc 1960;35:502-505.
Abstract: 13/26 patients with viral hepatitis selected alternately received B12 100mcg IV daily in addition to standard treatment. While liver function tests were unmodified, the experimental group had less anorexia and jaundice and the mean duration of illness was 34.5 days compared to 45.8 days in the controls.
Kaufman W. The use of vitamin therapy to reverse certain concomitants of aging. J Am Geriatr Soc 1955;3:927-936.
Klemes. Vitamin B-12 in acute subdeltoid bursitis. Indust. Med. Land Surg. 1957;26:290-292.
Abstract: 40 acute patients received vitamin B-12 1000mcg daily for 7-10days; then 3x weekly for 2-3wks; then 1-2x weekly for 2-3wks (depending upon their rate of progress). All but 2 or 3 improved with rapid relief of pain and subjective symptoms, sometimes within a few hours. Complete relief was often noted in several days. Follow-up radiographs of cases of calcific bursitis showed considerable resorption of calcium deposits.
Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol 1987 Jan;2(1):10-32.
Abstract: Cholestyramine, colestipol, clofibrate, gemfibrozil, nicotinic acid (niacin), probucol, neomycin, and dextrothyroxine are the most commonly used drugs in the treatment of hyperlipoproteinaemic disorders. While adverse reaction data are available for all of them, definitive data regarding the frequency and severity of potential adverse effects from well-controlled trials using large numbers of patients (greater than 1000) are available only for cholestyramine, clofibrate, nicotinic acid and dextrothyroxine. In adult patients treated with cholestyramine, gastrointestinal complaints, especially constipation, abdominal pain and unpalatability are most frequently observed. Continued administration along with dietary manipulation (e.g. addition of dietary fibre) and/or stool softeners results in diminished complaints during long term therapy. Large doses of cholestyramine (greater than 32 g/day) may be associated with malabsorption of fat-soluble vitamins. Most significantly, osteomalacia and, on rare occasions, haemorrhagic diathesis are reported with cholestyramine impairment of vitamin D and vitamin K absorption, respectively. Paediatric patients have been reported to experience hyperchloraemic metabolic acidosis or gastrointestinal obstruction. Concurrent administration of acidic drugs may result in their reduced bioavailability. Serious adverse reactions to clofibrate will probably limit its role in the future. Of particular concern are ventricular arrhythmias, induction of cholelithiasis and cholecystitis, and the potential for promoting gastrointestinal malignancy which far outweigh the reported benefits in preventing new or recurrent myocardial infarction, cardiovascular death and overall death. Patients with renal disease are particularly prone to myositis, secondary to alterations in protein binding and impaired renal excretion of clofibrate. Drug interactions with coumarin anticoagulants and sulphonylurea compounds may produce bleeding episodes and hypoglycaemia, respectively. Nicotinic acid produces frequent adverse effects, but they are usually not serious, tend to decrease with time, and can be managed easily. Dermal and gastrointestinal reactions are most common. Truncal and facial flushing are reported in 90 to 100% of treated patients in large clinical trials. Significant elevations of liver enzymes, serum glucose, and serum uric acid are occasionally seen with nicotinic acid therapy. Liver enzyme elevations are more common in patients given large dosage increases over short periods of time, and in patients treated with sustained release formulations.
Kondo H. Haematological effects of oral cobalamin preparations on patients with megaloblastic anemia.
Acta Haematol 1998;99:200-205.
Koop H. Review article: metabolic consequences of long-term inhibition of acid secretion by omeprazole.
Aliment Pharmacol Ther 1992 Aug;6(4):399-406.
Abstract: Metabolic sequelae of profound and long-lasting inhibition of gastric acid secretion by omeprazole have largely been neglected. Data from long-term studies suggest that vitamin B12 stores decrease slightly over several years, although this was not clinically relevant within the first 4 years of therapy. Additionally, it cannot be completely ruled out that patients with an increased iron demand may develop iron deficiency, but data available at present do not provide any evidence that iron malabsorption is to be expected under normal conditions. Protein homeostasis and calcium metabolism seem to be unaffected by long-term omeprazole therapy. Based upon present experience, serum cobalamin concentration should be monitored in patients undergoing omeprazole therapy for several years.
Koop H, Bachem MG. Serum iron, ferritin, and vitamin B12 during prolonged omeprazole therapy.
J Clin Gastroenterol 1992 Jun;14(4):288-292.
Abstract: Since gastric acid plays an important role in the absorption process of iron and vitamin B12, we determined levels of iron, ferritin, vitamin B12, and folic acid in 75 serum samples obtained during continuous omeprazole therapy (6-48 months after start of therapy) from 34 patients with peptic diseases (primarily reflux esophagitis). Serum iron and ferritin levels were decreased in two and three patients, respectively, but there is little evidence that omeprazole administration was causally related to these findings. Serum vitamin B12 and folic acid levels were normal in all cases. We conclude that iron, vitamin B12, and folic acid malabsorption is unlikely to occur, at least within the initial 3-4 years of continuous omeprazole therapy.
Kornberg A, Segal R, Theitler J, Yona R, Kaufman S. Folic acid deficiency, megaloblastic anemia and peripheral polyneuropathy due to oral contraceptives.
Isr J Med Sci 1989 Mar;25(3):142-145.
Abstract: A 34-year-old woman developed megaloblastic anemia and peripheral polyneuropathy following the use of oral contraceptives for 4 years. Low levels of folic acid and vitamin B12 were found. Both the complete recovery after therapy with the vitamins, and the absence of other causes of vitamin B12 and folate deficiency, suggest that the vitamin deficiencies were caused by the oral contraceptives and resulted in the rare combination of megaloblastic anemia and polyneuropathy. The poor response to vitamin B12 alone, and the development of anemia and polyneuropathy 4 months after cessation of vitamin B12 therapy suggest that folate deficiency was the primary problem.
Krogh Jensen M, Ekelund S, Svendsen L. Folate and homocysteine status and haemolysis in patients treated with sulphasalazine for arthritis.
Scand J Clin Lab Invest 1996 Aug;56(5):421-429.
Abstract: In an attempt to estimate the frequency of folate deficiency and haemolysis in a group of 25 outpatients with arthritis treated with sulphasalazine (SASP), haematological measurements, including plasma total homocysteine (tHcy) which is a sensitive marker of folate deficiency, serum folate (S-folate), erythrocyte (RBC) folate, S-cobalamin and routine indices of haemolysis were performed. No patient had been taking folate-containing vitamins for at least 8 weeks prior to the study. Compared to a group of 72 healthy hospital staff, the median plasma tHcy was significantly higher in the patient group (8.8 mumol 1(-1) vs. 6.8 mumol 1(-1); p = 0.003). Five patients (20%) had plasma tHcy levels that exceeded the upper normal limit of plasma tHcy (median+2 SD of the reference group). Median S-folate was significantly lower in the patient group (6.0 nmol 1(-1) vs. 8.5 nmol 1(-1); p < 0.001), and 11 (44%) patients had depressed S-folate. Only three (12%) patients had RBC folate values below the reference interval. There was no difference in the levels of RBC folate between the two groups. A comparison of S-cobalamin levels in the two groups disclosed a significantly lower level in the patient group. However, no patient had cobalamin deficiency as assessed by S-cobalamin and S-methylmalonate measurements. Thus, it is unlikely that any patient had increased plasma tHcy due to cobalamin deficiency. Of 24 patients having a HbA1c measurement performed, 12 (50%) had decreased levels indicating chronic haemolysis. Only seven (28%) patients had reticulocytosis. HbA1c was positively correlated to haptoglobin levels (r = 0.77; p < 0.001) and negatively correlated to the percentage of reticulocytes (r = -0.50; p = 0.02). The percentage of reticulocytes was negatively correlated to haptoglobin levels (r = -0.42; p = 0.04). The chronic haemolysis of the patients' blood due to SASP might explain the similar RBC folate values in the two groups because of a relatively higher folate content of young erythrocytes. In conclusion, our results support previous findings of folate deficiency and haemolysis occurring in a considerable fraction of patients receiving treatment with SASP. Measurements of plasma tHcy suggest that a substantial number of patients may have folate deficiency at the tissue level.
Kuncl RW, et al. Colchicine neuropathy or vitamin B12 deficiency neuropathy?
New Engl J Med 1987;317:1290-1291. (Letter)
Kuncl RW, George EB. Toxic neuropathies and myopathies. Curr Opin Neurol 1993 Oct;6(5):695-704. (Review)
Lapp CW, Cheney PR. The rationale for using high-dose cobalamin (vitamin B12).
CFIDS Chronicle Physicians’ Forum, 1993;Fall:19-20.
Lavy NW. Omeprazole and vitamin B12. Ann Intern Med 1994 Jul 1;121(1):74. (Comment)
Lederle FA. Oral cobalamin for pernicious anemia—medicine’s best kept secret?
JAMA 1991;265:94-95. (Comment)
Leeb BF, Witzmann G, Ogris E, Studnicka-Benke A, Andel I, Schweitzer H, Smolen JS. Folic acid and cyanocobalamin levels in serum and erythrocytes during low-dose methotrexate therapy of rheumatoid arthritis and psoriatic arthritis patients.
Clin Exp Rheumatol 1995 Jul-Aug;13(4):459-463.
Abstract: OBJECTIVE. To compare folic acid (FA) levels in patients being treated with methotrexate (MTX) with those of untreated patients in order to investigate potential folate depletion by MTX and its possible relationship to the drug's efficacy. METHODS. In 33 patients on low-dose MTX therapy and in 24 controls, FA and cyanocobalamin (B12) levels were determined in serum and red blood cells (RBC). In addition, MTX levels in the RBC and serum were measured, and clinical and laboratory measures of disease activity were evaluated. RESULTS. MTX treated patients had lower FA levels than controls (median 4.36 vs 7.37 ng/ml, p < 0.001). A significant correlation between serum FA and MTX/RBC (p < 0.01) and between the weekly dose and MTX/RBC (p < 0.01) was seen. There was apparently no correlation between FA and the cumulative total MTX. MTX patients had lower B12/RBC levels than the controls (p < 0.001); the serum levels of B12 were not different. Clinical features, ESR and CRP did not correlate with FA, B12 or MTX levels. CONCLUSIONS. The degree of folate depletion during MTX therapy depends primarily upon the weekly administered dose. Folate depletion may be related to B12 deficiency in RBC. Since FA levels were not related to parameters of disease activity it is conceivable that MTX does not exert its action in RA primarily by inhibiting dihydrofolatereductase. Therefore, additional folate compounds, if necessary, should not lead to a reduction in the efficacy of MTX.
Lindenbaum J. Drugs and vitamin B12 and folate metabolism. Curr Concepts Nutr
1983;12:73-87. (Review)
Lindenbaum J, Rosenberg IH, Wilson PWF, et al. Prevalence of cobalamin deficiency in the Framingham elderly population.
Am J Clin Nutr 1994;60:2-11.
Longstreth GF, Newcomer AD. Drug-induced malabsorption. Mayo Clin Proc 1975 May;50(5):284-293.
Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (Vitamin B12).
Ann Intern Med 1994 Feb 1;120(3):211-215.
Abstract: OBJECTIVE: To evaluate protein-bound cyanocobalamin (vitamin B12) absorption before and after omeprazole (Prilosec) therapy in healthy male volunteers. DESIGN: Clinical trial in which each volunteer served as his own control. SETTING: Outpatient department of a university medical center. PARTICIPANTS: Ten healthy, male volunteers 22 to 50 years old. INTERVENTION: Each participant had a modified Schilling test (protein-bound cyanocobalamin) and a gastric analysis, as well as measurements of serum vitamin B12, gastrin, and folate levels. Five patients were then randomly assigned to take either 20 mg or 40 mg of omeprazole daily. After 2 weeks of omeprazole therapy, these tests were repeated. MEASUREMENTS: The modified Schilling test, gastric analysis, serum gastrin level, folate level, and cyanocobalamin level. RESULTS: At the end of the 2-week treatment period, cyanocobalamin absorption decreased from 3.2% to 0.9% (P = 0.031) in participants receiving 20 mg of omeprazole daily. In patients taking 40 mg of omeprazole daily, cyanocobalamin absorption decreased from 3.4% to 0.4% (P < 0.05). CONCLUSIONS: Omeprazole therapy acutely decreased cyanocobalamin absorption in a dose-dependent manner.
Marz R. Medical Nutrition From Marz. Second Edition. Portland, OR. 1997.
Mayer J. Iatrogenic malnutrition. Postgrad Med. 1971 Mar;49(3):247-249.
Mikhail TH, Ibrahim KM, Awadallah R, Mona E,. The effect of vitamin B12 on tetracycline-induced fatty liver.
Z Ernahrungswiss 1980 Sep;19(3):173-178.
Abstract: The effect of vitamin B12 on the metabolic alterations due to tetracycline toxicity was studied experimentally on laboratory animals. Treatment of Sprague-Dawley rats with 120 or 250 mg tetracycline (i.p.) per kg per day for two or three days caused an accumulation of lipids, mainly triglycerides in the liver of 75% of animals studied, while phospholipid level tend to decrease. These doses are approximately twice and four times the recommended maximum dose for man. In the present work no direct relationship was observed between dose of tetracycline and hepatic accumulation of triglyceride, although livers of rats treated with 250 mg tetracycline/kg appeared uniformly pale yellow. Elevated serum triglyceride was found predominantly in rats treated with 120 mg/kg, while there was no obvious difference between serum triglyceride of rats treated with 250 mg tetracycline and control rats, indicating a block in the release of hepatic triglycerides. Where protection by vitamin B12 was studied, the vitamin was given i.m. (50 microgram/animal) 3 hours before the injection of 120 mg tetracycline per kg. There was a good evidence that lipid abnormalities caused by tetracycline improved by vitamin B12. Thus both hepatic and serum total lipid and triglycerides were significantly lower than those of rats treated with tetracycline, although hepatic total cholesterol was significantly increased as in case of tetracycline only.
Palopoli JJ, Waxman J. Colchicine neuropathy or vitamin B12 deficiency neuropathy?
N Engl J Med 1987 Nov 12;317(20):1290-1291. (Letter)
Polliotti BM, Panigel M, Miller RK. Free vitamin B12 and transcobalamin II-vitamin B12 complex uptake by the visceral yolk sac of the Sprague-Dawley rat: effect of inhibitors.
Reprod Toxicol 1997 Jul;11(4):617-626.
Prasad AS, Lei KY, Moghissi KS, Stryker JC, Oberleas D. Effect of oral contraceptives on nutrients. III. Vitamins B6, B12, and folic acid.
Am J Obstet Gynecol 1976 Aug 15;125(8):1063-1069.
Abstract: The interactions of oral contraceptive agents (OCA's) with vitamins were studied in a large population of women. In the upper socioeconomic groups, higher incidences of abnormal clinical signs related to vitamin deficiencies were seen in OCA users than in the control subjects. Plasma pyridoxal phosphate and red cell and serum folate were lower in subjects using OCA's in the upper socioeconomic group as compared to levels in the control subjects. Reduction in erythrocyte glutamic oxalacetic transaminase (EGOT) activity and elevation in the EGOT-stimulation test were observed in subjects using OCA's in both upper and lower socioeconomic groups. These observations suggest a relatively deficient state with respect to vitamins B6 and folic acid in OCA users. No significant effect on serum vitamin B12 was observed as a result of OCA administration.
Pronsky Z. Powers and Moore's Food-Medications Interactions. Ninth Edition. Food-Medication Interactions. Pottstown, PA, 1991.
Rana S, D’Amico F, Merenstein JH. Relationship of vitamin B12 deficiency with incontinence in older people.
J Am Geriatr Soc 1998;46:931. (Letter)
Reynolds EH, Chanarin I, Milner G, Matthews DM. Anticonvulsant therapy, folic acid and vitamin B12 metabolism and mental symptoms.
Epilepsia. 1966 Dec;7(4):261-270.
Robinson C, Weigly E. Basic Nutrition and Diet Therapy. New York: Macmillan, 1984.
Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989.
Roe DA. Drug-induced Nutritional Deficiencies. 2nd ed. Westport, CT: Avi Publishing, 1985: 158-159.
Roe DA. Essential hyperlipemia with xanthomatosis: effects of cholestyramine and clofibrate.
Arch Dermatol 1968 Apr;97(4):436-445.
Roe DA. Risk factors in drug-induced nutritional deficiencies. In: Roe DA, Campbell T, eds.
Drugs and Nutrients: The Interactive Effects. New York: Marcel Decker, 1984: 505-523.
Saltzman JR, Kemp JA, Golner BB, Pedrosa MC, Dallal GE, Russell RM. Effect of hypochlorhydria due to omeprazole treatment or atrophic gastritis on protein-bound vitamin B12 absorption.
J Am Coll Nutr 1994 Dec;13(6):584-591.
Abstract: OBJECTIVE: To investigate the effects of hypochlorhydria and acidic drink ingestion on protein-bound vitamin B12 absorption in elderly subjects. METHODS: Absorption of protein-bound vitamin B12 was examined in elderly normal subjects (n = 8), and in hypochlorhydric subjects due to omeprazole treatment (n = 8) or with atrophic gastritis (n = 3). Subjects underwent absorption tests of protein-bound vitamin B12 ingested with water, cranberry juice and 0.1 N hydrochloric acid. RESULTS: Protein-bound vitamin B12 absorption was lower in the omeprazole-treated group (0.50%) compared to the normal group (1.21%; p < 0.001). With cranberry juice ingestion, the omeprazole-treated group showed an increase in absorbed protein-bound vitamin B12 (p = 0.025). With dilute hydrochloric acid ingestion, there was a further increase in vitamin B12 absorption (p < 0.001). CONCLUSION: Omeprazole causes protein-bound vitamin B12 malabsorption, and ingestion of an acidic drink improves protein-bound vitamin B12 absorption.
Schenk BE, Festen HP, Kuipers EJ, et al. Effect of short-and long-term treatment with omeprazole on the absorption and serum levels of cobalamin.
Aliment Pharmacol Ther 1996;10:541-45.
Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser PA, Walter-Sack I. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment.
Epilepsia 1999 Mar;40(3):345-350.
Abstract: PURPOSE: Homocysteine is an experimental convulsant and an established risk factor in atherosclerosis. A nutritional deficiency of vitamin B6, vitamin B12, or folate leads to increased homocysteine plasma concentrations. During treatment with carbamazepine (CBZ), phenytoin, or phenobarbital, a deficiency in these vitamins is common. The objective of the study was to test the hypothesis that antiepileptic drug (AED) treatment is associated with increased homocysteine plasma concentrations. METHODS: A total of 51 consecutive outpatients of our epilepsy clinic receiving stable, individually adjusted AED treatment and 51 sex- and age-matched controls were enrolled in the study. Concentrations of total homocysteine and vitamin B6 were measured in plasma; vitamin B12 and folate were measured in the serum of fasted subjects. RESULTS: Patients and controls differed significantly in concentrations of folate ( 13.5+/-1.0 vs. 17.4+/-0.8 nM and vitamin B6 (39.7+/-3.4 vs. 66.2+/-7.5 nM), whereas serum concentrations of vitamin B12 were similar. The homocysteine plasma concentration was significantly increased to 14.7+/-3.0 microM in patients compared with controls (9.5+/-0.5 microM; p < 0.05, Wilcoxon rank-sum test). The number of patients with concentrations of >15 microM was significantly higher in the patient group than among controls. The same result was obtained if only patients with CBZ monotherapy were included. Patients with increased homocysteine plasma concentrations had lower folate concentrations. CONCLUSIONS: These data support the hypothesis that prolonged AED treatment may increase plasma concentrations of homocysteine, although the alternative explanation that increased homocysteine plasma concentrations are associated with the disease and not the treatment cannot be completely excluded at the moment.
Shojania AM, Wylie B. The effect of oral contraceptives on vitamin B12 metabolism.
Am J Obstet Gynecol 1979 Sep 1;135(1):129-134.
Abstract: Serum vitamin vitamin B12 levels were determined in 199 women who were on a regimen of oral contraceptives of either the combination or sequential type and in a control group of 196 women. The group using oral contraceptive agents (OCA) had significantly lower serum levels of vitamin B12 vitamin as compared to those of the control group. A total of 19 women using OCAs had serum vitamin B12 levels that were lower than normal values. However, the Schilling test and urinary methylmalonate excretion in this group were normal. The OCA group had a significantly lower total serum vitamin B12 binding capacity, a lower total transcobalamin I level, and a higher transcobalamin III level. Our study suggests that the fall of serum vitamin B12 in OCA users is due to the changes in vitamin B12 binders of serum and does not represent vitamin B12 deficiency. Therefore, according to our data, there is no justification for vitamin B12 supplementation in users of oral contraceptives.
Snower DP, Weil SC. Changing etiology of macrocytosis. Zidovudine as a frequent causative factor.
Am J Clin Pathol 1993 Jan;99(1):57-60.
Abstract: Macrocytosis is most commonly associated with vitamin B12 and folate deficiencies, followed by alcoholism, liver disease, and malignant neoplasms. Many laboratories have observed that in recent years macrocytosis increasingly has been associated with zidovudine treatment of acquired immune deficiency syndrome. One hundred consecutive inpatients in a large metropolitan urban hospital with mean corpuscular volumes greater than 110 fL were studied; 44% were patients with acquired immune deficiency syndrome being treated with zidovudine, 19% were alcoholics, and 12% had malignant neoplasms. Only 3% were folate deficient and just 4% were vitamin B12 deficient. This study suggests that zidovudine has become the most common cause of macrocytosis in the hospitalized urban patient population and that vitamin B12 and folate deficiencies have decreased in proportion.
Steegers-Theunissen RP, Van Rossum JM, Steegers EA, Thomas CM, Eskes TK. Sub-50 oral contraceptives affect folate kinetics.
Gynecol Obstet Invest 1993;36(4):230-233.
Abstract: The effects of long-term use of oral contraceptives containing less than 50 micrograms of estrogen (sub-50 OCs) on the kinetics of folic acid monoglutamate, vitamin B12 levels, and iron status have been studied in 29 OC users (Marvelon) and in 13 women without OC use serving as controls. At 210 min after oral folate loading the median serum folate concentration was significantly lower in OC users when compared to the control group. OC users showed significantly higher total iron binding capacity and significantly lower serum vitamin B12 concentrations. This data demonstrates that sub-50 OCs significantly affect folate kinetics and vitamin B12 levels. However, the folate and vitamin B12 status does not seem to be at risk.
Stewart CA, Termanini B, Sutliff VE, Serrano J, Yu F, Gibril F, Jensen RT. Iron absorption in patients with Zollinger-Ellison syndrome treated with long-term gastric acid antisecretory therapy.
Aliment Pharmacol Ther 1998 Jan;12(1):83-98.
Abstract: BACKGROUND: Gastric acid secretion is important for absorption of dietary non-haem iron, and iron deficiency is common in gastric hyposecretory states such as after gastric resection. It is not known if prolonged, continuous treatment with potent acid suppressants such as omeprazole will lead to iron deficiency or lower body iron stores. AIM: To assess iron stores and the occurrence of iron deficiency anaemia in patients with Zollinger-Ellison syndrome (ZES) treated long-term with gastric antisecretory drugs. METHODS: One hundred and nine patients with ZES but without previous gastric resections were studied. All patients underwent assessment of acid control on antisecretory agents, determination of tumour extent, evaluation of haematological parameters (Hct, haemoglobin, WBC, MCV, MCHC), and determination of serum iron parameters (iron, ferritin, transferrin, iron/ transferrin ratio). Acid control values for the last 4 years were reviewed, the presence or absence of acid hyposecretion determined using three different criteria and this result correlated with haematological and iron parameters. RESULTS: Eighty-nine patients were taking omeprazole, nine patients were taking histamine H2-antagonists and 11 patients were taking no drugs following curative resection. The mean duration of omeprazole treatment was 5.7 years (range 0.7-12.5 years) and total duration of any treatment was 10.1 years (range 0.7-21 years). Acid hyposecretion was present by at least one criterion in 45% of patients. There were no significant differences between patients with or without acid hyposecretion, taking or not taking omeprazole, having different durations of omeprazole treatment or different durations of total time receiving any antisecretory treatment, for any serum iron parameter, haematological parameter, or for the frequency of iron deficiency. Males and females did not differ in percentage with low ferritin levels or percentage with iron deficiency. CONCLUSIONS: Continuous treatment with omeprazole for 6 years or continuous treatment with any gastric antisecretory drug for 10 years does not cause decreased body iron stores or iron deficiency. These results suggest that, in contrast to recent results which show yearly monitoring of vitamin B12 in such patients is needed, such monitoring for iron parameters is not necessary.
Stopa EG, O'Brien R, Katz M. Effect of colchicine on guinea pig intrinsic factor-vitamin B12 receptor.
Gastroenterology 1979 Feb;76(2):309-314.
Abstract: Colchicine can induce the malabsorption of vitamin B12 and other nutrients. Previous investigations have suggested but not proved that this malabsorption was due to a lesion in the ileal mucosa. Employing the receptor assay of M. Katz and B. A. Cooper (J Clin Invest 54:733-739, 1974), the authors have observed a dose-related, reversible reduction in the quantity of intrinsic factor-vitamin B12 (IF-B12) receptor (from 5.78 ng to 1.3 ng of B12 binding) in the intestinal mucosa of guinea pigs fed 0.05-0.25 mg/100 g colchicine/day for 3 days. Malabsorption of vitamin B12 was also demonstrated in vivo in similarly treated animals. Increasing intestinal motility with cascara sagrada had no effect on the IF-B12 receptor. The quantity of IF-B12 receptor and the amount of vitamin B12 absorbed increased markedly to greater than normal levels during recovery from a 3-day course of colchicine. The total number of intestinal cells decreased after colchicine administration and increased during recovery; however, the fluctuations observed were not sufficient to explain the changes in the quantity of receptor. Histologic examination of the ileal mucosa showed a decrease in the population of villus cells after colchicine. The correlation between the changes in receptor quantity and in vivo B12-absorption prove that the IF-B12 receptor is a critical limiting factor in B12 absorption.
Streeter AM, Goulston KJ, Bathur FA, Hilmer RS, Crane GG, Pheils MT. Cimetidine and malabsorption of cobalamin.
Dig Dis Sci 1982 Jan;27(1):13-16.
Termanini B, Gibril F, Sutliff VE, Yu F, Venzon DJ, Jensen RT. Effect of long-term gastric acid suppressive therapy on serum vitamin B12 levels in patients with Zollinger-Ellison syndrome.
Am J Med 1998 May;104(5):422-430.
Abstract: BACKGROUND AND AIMS: Long-term treatment with H(+)-K(+)-adenotriphosphatase (ATPase) inhibitors, such as omeprazole or lansoprazole, for severe gastroesophageal reflux disease is now widely used. Whether such treatment will result in vitamin B12 deficiency is controversial. We studied whether long-term treatment with omeprazole alters serum vitamin B12 levels in patients with Zollinger-Ellison syndrome. METHODS: In 131 consecutive patients treated with either omeprazole (n = 111) or histamine H2-receptor antagonists (n = 20), serum vitamin B12 and folate levels and complete blood counts were determined after acid secretion had been controlled for at least 6 months. These studies were repeated yearly. Serum vitamin B12 and folate levels were correlated with the type of antisecretory drug and the extent of inhibition of acid secretion. RESULTS: The mean duration of omeprazole treatment was 4.5 years, and for H2-receptor antagonists 10 years. Vitamin B12 levels, but not serum folate levels or any hematological parameter, were significantly (P = 0.03) lower in patients treated with omeprazole, especially those with omeprazole-induced sustained hyposecretion (P = 0.0014) or complete achlorhydria (P < 0.0001). In 68 patients with two determinations at least 5 years apart, vitamin B12 levels decreased significantly (30%; P = 0.001) only in patients rendered achlorhydric. The duration of omeprazole treatment was inversely correlated with vitamin B12 levels (P = 0.013), but not folate levels. Eight patients (6%) developed subnormal B12 levels during follow-up. CONCLUSIONS: Long-term omeprazole treatment leads to significant decreases in serum vitamin B12 but not folate levels. These results suggest patients with Zollinger-Ellison syndrome treated with H(+)-K(+)-ATPase inhibitors should have serum vitamin B12 levels monitored. Furthermore, these results raise the possibility that other patients treated chronically with H(+)-K(+)-ATPase inhibitors may develop B12 deficiency.
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Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Apr 1997.
Threlkeld DS, ed. Gastrointestinal Drugs, Histamine H2 Antagonists. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Sep 1995.
Threlkeld DS, ed. Hormones, Oral Contraceptives. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Jul 1994.
Trovato A, Nuhlicek DN, Midtling JE. Drug-nutrient interactions. Am Fam Physician
1991 Nov;44(5):1651-1658.(Review)
Tuckerman M, Turco S. Human Nutrition. Philadelphia: Lea and Febiger, 1983, 215-222.
USDA: Composition of Foods. USDA Handbook #8 Washington DC, ARS, USDA, 1976-1986
Verhaeverbeke I, Mets T, Mulkens K, Vandewoulde M. Normalization of low vitamin B12 serum levels in older people by oral treatment.
J Am Geriatr Soc 1997;45:124-125. (Letter)
Waif SO, Jansen CJ, Crabtree RE, et al. Oral vitamin B12 without intrinsic factor in the treatment of pernicious anemia.
Ann Intern Med 1963;58:810-817.
Webb DI, Chodos RB, Mahar CQ, Faloon WW. Mechanism of vitamin B12 malabsorption in patients receiving colchicine.
N Engl J Med 1968 Oct 17;279(16):845-850.
Watkins DW, Khalafi R, Cassidy MM, Vahouny GV. Alterations in calcium, magnesium, iron, and zinc metabolism by dietary cholestyramine.
Dig Dis Sci 1985 May;30(5):477-482.
Abstract: Cholestyramine is an effective drug for the reduction of plasma cholesterol because of its ability to sequester intestinal bile acids. Since metabolic alterations, including diminished intestinal absorption of vitamin D and osteomalacia have been reported with long-term use of this resin, the influence of cholestyramine on dietary balance of four mineral elements has been investigated. Wistar-strain rats were fed either a 2% cholestyramine or control diet for one month. Dietary intakes and fecal and urinary excretions of calcium, magnesium, iron, and zinc were determined using atomic absorption spectrophotometry during three, 3-day balance periods. Cholestyramine-fed rats had a net negative balance for calcium and a lower net positive balance for magnesium, iron, and zinc than the controls. Other effects of cholestyramine were an increased urinary excretion of calcium and magnesium, a decreased urinary zinc, and an alkalinization of urine. Blood and tissue cation content was unchanged except for a reduction in serum magnesium with resin feeding. Alterations in calcium, magnesium, and zinc metabolism might be explained by inadequate vitamin D absorption from the intestine followed by an increased secretion of parathyroid hormone. A diminished iron absorption due to resin binding could account for the reported disturbance in iron balance.
Werbach MR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997. (Review).
West RJ, Lloyd JK. The effect of cholestyramine on intestinal absorption. Gut. 1975 Feb;16(2):93-98.
Abstract: Cholestyramine in a mean dosage of 0-6 g/kg/day has been given to 18 children with familial hypercholesterolaemia for between one and two and a half years. With prolonged treatment folate deficiency occurred, as evidenced by a fall in the mean serum folate concentration from 7-7 ng/ml before treatment to 4-4 ng/ml for patients on treatment for over one year; a corresponding lowering of red cell folate was also seen. Oral folic acid 5 mg daily overcame this depletion, and should be given to all patients on long-term anion exchange resins. Prothrombin time has remained normal in all patients; there has been a significant decrease in the mean serum concentrations of vitamins A and E and of inorganic phosphorus over the first two years of treatment, although values remain within the normal range. The routine administration of fat-soluble vitamins appears unnecessary but it is prudent to measure prothrombin time and serum vitamins A and E at intervals. In children who were having a normal intake of dietary fat five out of seven tested had faecal fat of over 5 g/day while on cholestyramine. No child has developed diarrhoea, and growth has been normal. The concentrations of serum iron, vitamin B12, plasma calcium, and protein did not change significantly in any patient.
Wynn V. Vitamins and oral contraceptive use. Lancet 1975 Mar 8;1(7906):561-564.
Abstract: Reports concerning the interaction between steroidal contraceptives (the combined pill) and vitamins indicate that in users the mean serum-vitamin-A level is raised and the mean serum-vitamin-B2 (riboflavine), vitamin-B6 (pyridoxine), vitamine-C, folic-acid, and vitamin-B12 levels are reduced. Other vitamins have been insufficiently studied for comment. Biochemical evidence of co-enzyme deficiency has been reported for vitamin B2, vitamin B6, and folic acid. Clinical effects due to vitamin deficiency have been described for vitamin B6--namely, depression and impaired glucose tolerance. Folic-acid deficiency with megaloblastic anaemia has been reported in only 21 cases.