Ineffective hematopoiesis in folate-deficient mice.
Blood (UNITED STATES) May 1 1992, 79 (9) p2273-80
A folate-free amino acid-based diet provided an opportunity to characterize the effects of folate depletion on growth, tissue folate levels, and hematopoiesis of mice under well-standardized conditions. Weanling mice were fed a folate-free, amino acid-based diet supplemented with either 0 or 2 mg folic acid/kg diet for 35 to 48 days. Folate concentrations were decreased in liver, kidney, serum, and erythrocytes in mice fed the folate-free diet. The folate-deficient mice had anemia, reticulocytopenia, thrombocytopenia, and leukopenia, all of which reverted to normal after folic acid was reintroduced to the diet. Hematopoietic organs of folate-deficient mice had alterations that were similar to those seen in folate-deficient humans except that in mice, the hyperplasia of hematopoietic tissue occurred in the spleen rather than in the marrow. Ferrokinetic studies showed a normal 59Fe-transferrin half-life, but the percentage of 59Fe-incorporation into red blood cells at 48 hours was markedly subnormal. The number of committed hematopoietic progenitors at the stages of erythroid colony-forming units (CFUs), megakaryocyte CFUs, and granulocyte-macrophage CFUs were all increased in folate-deficient mice. However, the progeny of these progenitors was markedly decreased in folate-deficient mice. Thus, the folate-deficient mice had "ineffective hematopoiesis" leading to pancytopenia, and they therefore provide a murine model of megaloblastic anemia.
Premature infants require additional folate and vitamin B-12 to reduce the severity of the anemia of prematurity.
Am J Clin Nutr (UNITED STATES) Dec 1994, 60 (6) p930-5
One hundred eighty-four premature infants, < 1800 g at birth and < 36 wk gestation, were entered into a study investigating the role of additional folate and vitamin B-12 supplementation of the anemia of prematurity. All patients initially received vitamin E and iron in accordance with accepted standards. Patients were randomly assigned to four groups to receive orally 0.1 mg folate/d for 4 mo, 100 micrograms vitamin B-12 intramuscularly monthly for 4 mo, both supplements, or neither. All other activities including parenteral nutrition were carried out according to established practices, irrespective of study group. By 10-12 wk, infants treated with vitamin B-12 alone or combined with folate had higher hemoglobin values than the untreated (P < 0.0005) or solely folate-treated (P < 0.01) groups. These findings held true irrespective of wide variations in treatment and feeding practices. The only uncontrolled hematologic nutritional factor, selenium, showed a similar pattern of decline for 10-12 wk in all study patients, whether or not they received additional vitamin supplements.
Apoptosis mediates and thymidine prevents erythroblast destruction in folate deficiency anemia.
Proc Natl Acad Sci U S A (UNITED STATES) Apr 26 1994, 91 (9) p4067-71
Deficiency of the vitamin folic acid causes pancytopenia by decreasing the production of new blood cells. Although impaired DNA synthesis and destruction of hematopoietic cells have been implicated, the mechanism by which folate deficiency decreases blood cell production is uncertain. An in vitro model of folate-deficient erythropoiesis was developed by using proerythroblasts isolated from folate-deficient mice that were infected with Friend leukemia virus. Proerythroblasts from folate-deficient mice had one-tenth the total folate as did proerythroblasts from control mice. The folate-deficient proerythroblasts underwent apoptosis, a form of programmed cell death, after 20-32 h in culture in folate-deficient medium. At the time of apoptosis the cells had differentiated into the later erythroblast stages and some had begun hemoglobin synthesis. Addition of either folic acid or thymidine, but not deoxycytidine or inosine, to the folate-deficient medium prevented the apoptosis and permitted proliferation and differentiation of the proerythroblasts into reticulocytes. The prevention of apoptosis by thymidine indicates (i) that decreased thymidylate synthesis plays a role in erythroblast apoptosis and the anemia of folate deficiency and (ii) that DNA cleavage is likely to be a primary event in the apoptosis of folate-deficient erythroblasts. Apoptosis of erythroblasts in the late stages of differentiation leads to decreased erythrocyte production and to anemia. The increased erythropoietin produced in response to the anemia increases the number of erythroid progenitor cells in the differentiation stages preceding those in which the cells undergo apoptosis. This population shift to earlier stage erythroblasts and proerythroblasts is characteristic of bone marrows of individuals with folate deficiency anemia.
Interactions between folate and ascorbic acid in the guinea pig.
J Nutr (UNITED STATES) Apr 1982, 112 (4) p673-80
Possible interactions between folic acid (folate) and ascorbic acid (AA) have been suspected because megaloblastic anemia is occasionally observed in scorbutic patients, and it may or may not respond to folate treatment. Male weanling guinea pigs were fed diets containing high levels of folate and AA or diets deficient in one or both vitamins. A total of 36 animals, including 9 controls, were studied. When anorexia began to appear in the deficient groups, all animals were killed by exsanguination, and tissue samples (blood, liver, adrenal, kidney, spleen, and intestinal mucosa) were removed for AA and folate analyses. Folate and AA deficiency lowered tissue folate and AA levels, respectively. AA deficiency, either alone or in combination with folate restriction, did not affect tissue folate levels, nor did AA deficiency significantly exacerbate the anemia and leukopenia caused by folate deficiency. However, there was an unexpected decrease in AA levels in the liver and adrenal glands with folate deficiency. Although AA does not appear to be needed for normal folate metabolism, the lower AA levels associated with a folate deficiency are indicative of an interaction between the two vitamins.
Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study.
Am J Clin Nutr (UNITED STATES) Mar 1996, 63 (3) p306-14
We investigated the relations between plasma concentrations of homocysteine and vitamins B-12 and B-6 and folate, and scores from a battery of cognitive tests for 70 male subjects, aged 54-81 y, in the Normative Aging Study. Lower concentrations of vitamin B-12 (P=0.04) and folate (P=0.003) and higher concentrations of homocysteine (P=0.0009 ) were associated with poorer spatial copying skills. Plasma homocysteine was a stronger predictor of spatial copying performance than either vitamin B-12 or folate. The association of homocysteine with spatial copying performance was not explained by clinical diagnoses of vascular disease. Higher concentrations of vitamin B-6 were related to better performance on two measures of memory (P=0.03 and P=0.05). The results suggest that vitamins (and homocysteine) may have differential effects on cognitive abilities. Individual vitamins and homocysteine should be explored further as determinants of patterns of cognitive impairment.
Vitamin intake: A possible determinant of plasma homocyst(e)ine among middle-aged adults
Annals of Epidemiology (USA), 1997, 7/4 (285-293)
PURPOSE: Many epidemiologic studies have identified elevated plasma homocyst(e)ine as a risk factor for atherosclerosis and thromboembolic diseases. To examine the relationship between vitamin intakes and plasma homocyst(e)ine, we analyzed dietary intake data from a case-control study of 322 middle-aged individuals with atherosclerosis in the carotid artery and 318 control subjects without evidence of this disease. METHODS: All of these individuals were selected from a probability sample of 15,800 men and women who participated in the Atherosclerosis Risk in Communities (ARIC) study. RESULTS: Plasma homocyst(e)ine was inversely associated with intakes of folate, vitamin B6, and vitamin B12 (controls only for this vitamin)-the three key vitamins in homocyst(e)ine metabolism. Among nonusers of vitamin supplement products, on average each fertile increase in intake of these vitamins was associated with 0.4 to 0.7 micromol/L decrease in plasma homocyst(e)ine. An inverse association of plaine was also found with thiamin, riboflavin, calcium, phosphorus, and iron. Methionine and protein intake did not show any significant association with plasma homocyst(e)ine. CONCLUSIONS: In almost all analyses, cases and controls showed similar associations between dietary variables and plasma homocyst(e)ine. Plasma homocyst(e)ine among users of vitamin supplement products was 1.5 micromol/L lower than that among nonusers. Further studies to examine possible caused relationships among vitamin intake, plasma homocyst(e)ine, and cardiovascular disease are needed.
Atherogenesis and the homocysteine-folate-cobalamin triad: Do we need standardized analyses?
Journal of the American College of Nutrition (USA), 1997, 16/3 (258-267)
Background: Bioscientists, physicians and nutritionists are newly interested in the homocysteine folate cobalamin triad, in part because homocysteine may be important both in atherogenesis and thrombogenesis Homocysteine imbalance may be an early marker for cobalamin disorders because cobalamin is a cofactor in remethylation of homocysteine to methionine. Methods: In 139 men and 32 women of similar mean age of 65 years, we measured markers which have been cited as risk for atherosclerosis: serum homocysteine, folate, total cobalamin, holotranscobalamin I and II, (TCI and TCII), total serum cholesterol (SCHOL), high density lipoprotein cholesterol (HDLC), triglycerides (STG) as well as red blood cell (RBC) folate, food records and body composition by whole body counting of potassium-forty (40K). Results: Statistical relationships among the data showed healthy women had lower mean serum homocysteine and their mean RBC folate and TCI and TCII were higher than men. Eighty-three subjects had TCII much lower than 60 pg/ml (subnormal), yet only 11 of these men and two women had total cobalamin <200 pg/ml (abnormal). Fifty-two subjects with serum homocysteine greater than 17.5 nmol/ml had TCII less than 60 pg/ml, suggesting serum homocysteine may be a marker for early cobalamin negative balance. None of the subjects in the study had serum folate below abnormal values, i.e., less than 1.6 mg/ml. All subjects had RBC folate within normal range. Serum homocysteine showed inverse relationship with RBC folate and serum total cobalamin, TCI and TCII. Conclusions: 1) importance of using serum holotranscobalamin TCI and TCII as markers of cobalamin deficiency, 2) necessity to uke if strong comparisons are to be made among quantitative values of serum or plasma homocysteine, folate, cobalamin, and nutrients in food intake.
Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations.
Circulation (UNITED STATES) Dec 1 1996, 94 (11) p2743-8
BACKGROUND: A high level of total plasma homocysteine is a risk factor for atherosclerosis, which is an important cause of death in renal failure We evaluated the role of this as a risk factor for vascular complications of end-stage renal disease. METHODS AND RESULTS: Total fasting plasma homocysteine and other risk factors were documented in 176 dialysis patients (97 men, 79 women; mean age, 56.3 +/- 14.8 years). Folate, vitamin B12, and pyridoxal phosphate concentrations were also determined. The prevalence of high total homocysteine values was determined by comparison with a normal reference population, and the risk of associated vascular complications was estimated by multiple logistic regression. Total homocysteine concentration was higher in patients than in the normal population (26.6 +/- 1.5 versus 10.1 +/- 1.7 mumol/L; P < .01). Abnormally high concentrations (> 95th percentile for control subjects, 16.3 mumol/L) were seen in 149 patients (85%) with end-stage renal disease (P < .001). Patients with a homocysteine concentration in the upper two quintiles (> 27.8 mumol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; P = .007) of vascular complications. B vitamin levels were lower in patients with vascular complications than in those without. Vitamin B6 deficiency was more frequent in patients than in the normal reference population (18% versus 2%; P < .01). CONCLUSIONS: A high total plasma homocysteine concentration is an independent risk factor for atherosclerotic complications of end-stage renal disease. Such patients may benefit from higher doses of B vitamins than those currently recommended.
[Homocysteine, a less well-known risk factor in cardiac and vascular diseases]
Cas Lek Cesk (CZECH REPUBLIC) May 2 1996, 135 (9) p263-5
Hyperhomocyst(e)mia (Hcy) negatively influences vascular endothelium and coagulation factors. Association of Hcy with premature arteriosclerosis (rather than atherosclerosis), stroke, myocardial infarction and peripheral arterial and venous disease was proved in clinical and epidemiological studies, even as the association with conventional risk factors like age, male sex, smoking, hypertension and hypercholesterolemia. Vitamin substitution of folates, vitamin B6 and B12 decreases Hcy blood levels, however definite evidence is still lacking, whether it results in lower incidence and mortality from cardiovascular diseases. Therefore clinical and epidemiological studies are necessary. Before the grant-application we proved in a pilot study significantly higher Hcy levels in 97 patients with manifest ischaemic heart disease than in 37 controls.
Homocysteine and coronary atherosclerosis.
J Am Coll Cardiol (UNITED STATES) Mar 1 1996, 27 (3) p517-27
Homocysteine is increasingly recognized as a risk factor for coronary artery disease. An understanding of its metabolism and of the importance of vitamins B6 and B12 and folate as well as enzyme levels in its regulation will aid the development of therapeutic strategies that, by lowering circulating concentrations, may also lower risk. Possible mechanisms by which elevated homocysteine levels lead to the development and progression of vascular disease include effects on platelets, clotting factors and endothelium. This review presents the clinical and basic scientific evidence supporting the risk and mechanisms of vascular disease associated with elevated homocysteine concentrations as well as the results of preliminary therapeutic trials.
Is metabolic evidence for vitamin B-12 and folate deficiency more frequent in elderly patients with Alzheimer's disease?
J Gerontol A Biol Sci Med Sci (UNITED STATES) Mar 1997, 52 (2) pM76-9
BACKGROUND: It is still unclear whether there is an association between Alzheimer's disease and vitamin B-12 or folate deficiency. This study was designed to investigate whether patients with Alzheimer's disease are particularly prone to metabolically significant cobalamin or folate deficiency as compared to nondemented hospitalized controls and healthy elderly controls living at home. METHODS: Evaluation for the diagnosis of Alzheimer's disease, routine laboratory tests, serum folate and vitamin B-12, serum methylmalonic acid (MMA), total homocysteine (tHcy), and radiological tests was performed in 52 patients with Alzheimer's disease (AD), 50 nondemented hospitalized controls, and 49 healthy elderly subjects living at home. RESULTS: Serum vitamin B-12 and folate levels are comparable between patients with AD, hospitalized control patients, and subjects living at home. Patients with AD have the highest serum MMA and tHcy levels. The MMA levels of patients with AD and hospitalized controls are not different, but the mean tHcy level is significantly higher in patients with AD as compared to nondemented patients or subjects living at home. CONCLUSION: The interpretation of the vitamin B-12 and folate status in patients with AD depends largely on the methodology (i.e., serum vitamin vs metabolite levels) and the selection of the control group. Although patients with AD have the highest tHcy and MMA levels, metabolically significant vitamin B-12 and folate deficiency is also a substantial problem in nondemented elderly patients.
Folate, vitamin B12 and cognitive impairment in patients with Alzheimer's disease
ACTA PSYCHIATR. SCAND. (Denmark), 1992, 86/4 (301-305)
This study examines the relationship between folate, vitamin B12 and severity of cognitive impairment in patients with Alzheimer's disease (AD) as compared with other disorders associated with cognitive impairment. The patients were 97 consecutive referrals to an AD clinic. Forty patients had either possible or probable AD, 31 had other dementias (OD) and 26 had mild cognitive impairment (cognitively impaired, not demented; CIND). Patients had blood drawn for serum, red cell folate and B12, as well as other biochemical indicators of nutrition, within 24 h of the Mini-Mental State Examination (MMSE). In the AD group, only B12 was significantly correlated with MMSE. Using regression analysis, B12 contributed significantly to variance in MMSE. There was no correlation between MMSE and serum, red cell folate or B12 in the OD or CIND group and no significant correlation between MMSE and other nutritional indices in any group. These findings suggest the possibility of a specific relationship between B12 levels and severity of cognitive impairment in patients with AD.
Vitamin B12 and folate concentrations in serum and cerebrospinal fluid of neurological patients with special reference to multiple sclerosis and dementia
J. NEUROL. NEUROSURG. PSYCHIATRY (United Kingdom), 1990, 53/11 (951-954)
Vitamin B12 and folate concentrations were measured in serum and cerebrospinal fluid (CSF) in 293 neurological patients. Serum and CSF vitamin B12 concentrations showed a positive correlation. In individual patients CSF B12 concentrations varied considerably for a given serum concentration. The median serum vitamin B12 concentration of the Alzheimer's type dementia group was significantly lower compared with that of a control group. Lower median CSF vitamin B12 concentrations were found in groups of patients with multiple sclerosis and Alzheimer's type dementia. Five patients with heterogeneous clinical pictures had unexplained low serum and CSF B12 concentrations without macrocytosis. Two patients had very high serum B12 and low-normal CSF concentrations which could be explained by a blood-brain barrier transport defect. Serum and CSF folate concentrations did not show significant differences between the various groups.