Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition.
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Vitamin A is a pivotal biochemical factor required for normal proliferation and differentiation as well as for specialized functions, such as vision. The dietary intake of 1500 IU/day is recommended in the first year of life. Here, we report the case of an infant who had been given 62 000 IU/day for 80 days. The infant showed several clinical signs of retinol intoxication, including severe anemia and thrombocytopenia. Bone marrow showed a remarkably reduced number of erythroid and megakaryocytic cells. The interruption of vitamin A treatment was immediately followed by clinical and biochemical recovery. To clarify whether the effects of retinol are due to a direct action on bone marrow cell proliferation, we investigated the activity of retinol (both the drug and the pure molecule) on the growth of K-562, a multipotent hematopoietic cell line, and on bone marrow mesenchymal stem cells. We observed that vitamin A strongly inhibited the proliferation of the cells at concentrations similar to those reached in vivo. Subsequent biochemical analyses of the cell cycle suggested that the effect was mediated by the up-regulation of cyclin-dependent kinase inhibitors, p21(Cip1) and p27(Kip1). These are the first findings to demonstrate that infant hypervitaminosis A causes a severe anemia and thrombocytopenia and that this is probably due to the direct effect of the molecule on the growth of all bone marrow cellular components. Our data also suggest potential bone marrow functional alterations after excessive vitamin A intake because of emerging social habits. (+info)
Short-term vitamin A supplementation does not affect bone turnover in men.
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Limited data in humans and animals indicate that excess vitamin A stimulates bone resorption and inhibits bone formation, effects that over time might lead to bone loss and fracture. Thus, it is possible that vitamin A supplementation is a currently unrecognized risk factor for the development of osteoporosis. To further evaluate this possibility, a prospective, randomized, single-blind study of vitamin A supplementation was conducted in 80 healthy men age 18-58 y. One half received 7576 microg (25,000 IU) of retinol palmitate daily with their evening meal; the others took a placebo. Blood was collected from fasting subjects and serum prepared at baseline and after 2, 4 and 6 wk of supplementation. Serum bone specific alkaline phosphatase (BSAP) and N-Telopeptide of type 1 collagen (NTx) were measured at all time points. Serum osteocalcin (Oc) was measured at baseline and after 6 wk of supplementation. BSAP, NTx and Oc did not differ between the supplemented and placebo-treated groups over the course of the study. In conclusion, short-term vitamin A supplementation at this dosage in healthy men does not alter serum markers of skeletal turnover. Thus, it is unlikely that short-term administration of vitamin A would contribute to the development of osteoporosis. Whether long-term vitamin A supplementation might have adverse skeletal effects remains to be determined. (+info)
In vivo studies of altered expression patterns of p53 and proliferative control genes in chronic vitamin A deficiency and hypervitaminosis.
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Several clinical trials have revealed that individuals who were given beta-carotene and vitamin A did not have a reduced risk of cancer compared to those given placebo; rather, vitamin A could actually have caused an adverse effect in the lungs of smokers [Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens, F.L., Valanis, B., Williams, J.H., Barnhart, S. & Hammar, S. N. Engl. J. Med (1996) 334, 1150-1155; Hennekens, C.H., Buring, J.E., Manson, J.E., Stampfer, M., Rosner, B., Cook, N.R., Belanger, C., LaMotte, F., Gaziano, J.M., Ridker, P.M., Willet, W. & Peto, R. (1996) N. Engl. J. Med. 334, 1145-1149]. Using differential display techniques, an initial survey using rats showed that liver RNA expression of c-H-Ras was decreased and p53 increased in rats with chronic vitamin A deficiency. These findings prompted us to evaluate the expression of c-Jun, p53 and p21WAF1/CIF1 (by RT-PCR) in liver and lung of rats. This study showed that c-Jun levels were lower and that p53 and p21WAF1/CIF1 levels were higher in chronic vitamin A deficiency. Vitamin A supplementation increased expression of c-Jun, while decreasing the expression of p53 and p21WAF1/CIF1. Western-blot analysis demonstrated that c-Jun and p53 showed a similar pattern to that found in the RT-PCR analyses. Binding of retinoic acid receptors (RAR) to the c-Jun promoter was decreased in chronic vitamin A deficiency when compared to control hepatocytes, but contrasting results were found with acute vitamin A supplementated cells. DNA fragmentation and cytochrome c release from mitochondria were analyzed and no changes were found. In lung, an increase in the expression of c-Jun produced a significant increase in cyclin D1 expression. These results may explain, at least in part, the conflicting results found in patients supplemented with vitamin A and illustrate that the changes are not restricted to lung. Furthermore, these results suggest that pharmacological vitamin A supplementation may increase the risk of adverse effects including the risk of oncogenesis. (+info)
Adult cockatiels (Nymphicus hollandicus) at maintenance are more sensitive to diets containing excess vitamin A than to vitamin A-deficient diets.
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The purpose of this experiment was to examine the physiological responses of adult cockatiels at maintenance to dietary vitamin A (VA) concentrations, and to identify concentrations associated with deficiency and toxicity. Adult cockatiels at maintenance (n = 22, 2-3 y of age) were fed a diet of 0, 600, 3000 or 30,000 microg VA/kg (0, 2000, 10,000 or 100,000 IU), and monitored for signs of VA deficiency or toxicity for up to 706 d. The analyzed diet concentrations were 0, 835, 2815 and 24,549 microg/kg, respectively. After 269 d, birds fed the 30,000 microg/kg VA diet had greater plasma retinal concentrations, markedly intensified vocalization patterns, pancreatitis and multifocal accumulation of lymphocytes in the lamina propria of the duodenum compared to birds fed the 600 microg/kg diet (P < 0.05). The 3000 microg/kg VA diet induced increased plasma retinol, splenic hemosiderosis and altered vocalization patterns (P < 0.05), although not as striking as those induced by the 30,000 microg/kg VA diet. The secondary antibody response was reduced after 225 d and vocalization patterns were altered in birds fed 0 microg/kg VA (P < 0.05), but after almost 2 y there were no changes in body condition, plasma retinol, organ pathology or classical signs of deficiency such as squamous metaplasia of nasal epithelia. Thus, adult cockatiels at maintenance were more susceptible to VA toxicity than to VA deficiency and concentrations > or = 3000 microg VA/kg diet can cause toxicity. It is possible that disturbances in VA nutrition contribute to the widespread incidence of behavioral problems reported in companion birds. (+info)
Alleviation of vitamin A deficiency with palm fruit and its products.
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The decreased dietary diversity wrought from the adoption of the settled, agrarian system to replace the hunter-gather and pastoralist lifestyles assured a stable supply of protein and calories from grains and tubers while creating a vulnerability for humans to suffer micronutrient deficiencies. The vitamin A from animal tissue is more bioavailable to humans than the provitamin A in the matrix of green plants. Provitamin A carotenes achieve a dietary vitamin A efficacy nearly equivalent to that of the preformed vitamin only in the context of an oily matrix. The homeostatic regulation of carotene bioconversion by the intestine, moreover, prevents any excess toxic accumulation of vitamin A from provitamin A sources. The efficacy and safety of the palm fruit (genus Elaeis) as a source of vitamin A, in addition to its cultural recognition as a food, are more consistent with the gentler concept of "alleviation" of the public health problem of hypovitaminosis A, then the more aggressive, medical model of "eradication" with its greater potential for risk and collateral damage. The palm fruit and its derivatives achieve new opportunities for creative contribution and sustained use in formats of supplementation (prophylactic in children and women, for lactation), food-to-food fortification (in bakery goods and snacks, as condiments), and even in food diversification strategies. Experience in India, South Africa, and Guatemala begins to define and delineate the opportunities and limitations for the palm fruit to contribute to the alleviation of endemic vitamin A deficiency. (+info)
Antagonism of hypervitaminosis A-induced anterior neural tube closure defects with a methyl-donor deficiency in murine whole-embryo culture.
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The interaction of a dietary excess of vitamin A (retinoid) and deficiency of methyl-donor compounds was examined in murine early-organogenesis embryonic development. Female mice were fed one of six diets from the time of vaginal plug detection until gestational d 8.0, when embryos were removed and grown in whole embryo culture for 46 h, using serum from rats fed the same diet for 36 d as the culture medium. The six diets were either methyl-donor deficient (designated -FCM: devoid of folic acid, choline and supplemental L-methionine, but having methionine as a component of the protein portion of the diet) or methyl-donor sufficient (designated +FCM: containing folic acid, choline and L-methionine supplementation), in combination with one of three concentrations of retinyl palmitate (0.016, 0.416 or 4.016 g/kg diet). The high dose of retinyl palmitate induced a failure of anterior neuropore closure and hypoplasia of the visceral arches, both of which were significantly ameliorated by simultaneous administration of the methyl-donor-deficient diet. The primary acidic retinoid detected in the rat serum was 9,13-di-cis-retinoic acid, although we hypothesize that teratogenic retinoids were formed by embryonic biotransformation of the retinyl esters to toxic metabolites. Biochemical measurements of metabolites in relevant pathways were performed. We propose that the amelioration of these malformations may be used to determine biochemical pathways critical for retinoid teratogenesis. (+info)
Water-miscible, emulsified, and solid forms of retinol supplements are more toxic than oil-based preparations.
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BACKGROUND: It is well established that an excessive intake of retinol (vitamin A) is toxic; however, it has been > 25 y since the last extensive treatise of case reports on this subject. OBJECTIVE: The objectives were to identify and evaluate all individual cases of retinol toxicity published in the scientific literature that assessed the thresholds and symptoms induced by high intakes of retinol and to compare the toxicity of different physical forms of retinol preparations. DESIGN: We performed a meta-analysis of case reports on toxicity claimed to be induced by intakes of excessive amounts of dietary retinol (ie, retinol and retinyl esters in foods or supplements). Using free text and MESH (medical subheading) strategies in PubMed, we identified 248 articles in the scientific literature. From these initial articles we identified other relevant citations. The final database consisted of 259 cases in which individual data on dose, sex, age, time of exposure, and symptoms are reported. RESULTS: Chronic hypervitaminosis A is induced after daily doses of 2 mg retinol/kg in oil-based preparations for many months or years. In contrast, doses as low as 0.2 mg retinol. kg(-1). d(-1) in water-miscible, emulsified, and solid preparations for only a few weeks caused chronic hypervitaminosis A. Thus, water-miscible, emulsified, and solid preparations of retinol are approximately 10 times as toxic as are oil-based retinol preparations. The safe upper single dose of retinol in oil or liver seems to be approximately 4-6 mg/kg body wt. These thresholds do not vary considerably with age. CONCLUSIONS: The results of the present study indicate that the physical form of retinol supplements is a major determinant of toxicity. The use of water-miscible, emulsified, and solid preparations of retinol should therefore be carefully considered before being used in supplements and fortifications. (+info)
Hepatotoxicity of alcohol-induced polar retinol metabolites involves apoptosis via loss of mitochondrial membrane potential.
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Chronic alcohol consumption depletes hepatic vitamin A stores. However, vitamin A supplementation is hepatotoxic, which is further potentiated by concomitant alcohol consumption. It was suggested that polar retinol metabolites generated by alcohol-inducible cytochrome P4502E1 aggravate liver damage. However, experimental evidence supporting this hypothesis is lacking. To elucidate the effects of polar retinol metabolites on cultured HepG2 cells and primary rat hepatocytes, polar retinol metabolites were extracted from liver tissues of rats fed either an alcoholic or isocaloric control Lieber-DeCarli diet. Cell toxicity assays included morphology assessment, trypan blue exclusion test, and LDH/AST leakage. Staining for DAPI and acridine orange, FACS analysis, and Western blot for cleaved caspase-9 and -3 were used to detect apoptosis. Polar retinol metabolites caused marked cytotoxicity in a concentration- and time-dependent manner in both cell types reflected by morphological changes, a dramatic increase in trypan blue positive cells, and LDH/AST leakage. Toxicity was due to apoptosis, as demonstrated by a time-dependent increase of sub-G1 cellular events, a rapid loss of mitochondrial membrane potential, and a time-dependent activation of caspase-9 and -3. No toxicity was found with equivalent doses of the control extract from nonalcoholic rats. We demonstrate that polar retinol metabolites cause marked hepatocyte death through the induction of apoptosis. (+info)