retinol-palmitate and Hypervitaminosis-A

Vitamin A (VA) deficiency is a public health problem in many countries. The World Health Organization recommends high-dose VA supplements to children aged 6-59 months based on unequivocal evidence that supplements decreased mortality risk. VA supplements were meant as a temporary intervention until more sustainable approaches could be implemented. Fortification of processed foods with preformed VA is a means to improve VA status. The most recent addition of retinyl palmitate to cooking oil in countries that may also fortify margarine and milk will undoubtedly have a positive impact on VA status. However, quantitative measures have not been used to assess the underlying VA status of the groups who have adopted widespread fortification. The addition of preformed VA to otherwise adequate diets in VA may cause excessive total body stores. Monitoring population status will require accurate VA assessment to ensure that hypervitaminosis does not prevail. This perspective describes a cohort of rural Zambian children who have adequate diets in VA, mostly as provitamin A carotenoids; who were given high-dose VA supplements till the age of 5 years; who have access to VA-fortified sugar; and whose mothers had access to VA-fortified sugar throughout pregnancy and lactation. Many of these children turned orange during mango season, and this phenomenon occurred at estimated liver reserve concentrations >1 μmol retinol equivalents/g liver. It will be necessary to continue to monitor VA status, including all sectors of the population that have access to successful interventions, to optimize health with the intent to lower retinol content of fortified foods or better target VA supplementation to areas of most need.

Topics: beta Carotene; Child, Preschool; Diet; Dietary Supplements; Diterpenes; Dose-Response Relationship, Drug; Evidence-Based Medicine; Food, Fortified; Humans; Hypervitaminosis A; Infant; Mangifera; Nutritional Status; Recommended Dietary Allowances; Retinyl Esters; Rural Population; Seasons; Skin; Vitamin A; Zambia

This analysis was performed in Zambian children who had a high prevalence of hypervitaminosis A, defined as > 1.0 μmol retinol/g liver. Bone parameters included markers of bone formation (P1NP), bone resorption (CTX), parathyroid hormone, calcium, vitamin A, and vitamin D. Low dietary vitamin A intake increased P1NP.. Vitamin A (VA) interacts with bone health, but mechanisms require clarification. In countries where multiple interventions exist to eradicate VA deficiency, some groups are consuming excessive VA. Bone metabolism and inflammatory parameters were measured in Zambian children who had high prevalence of hypervitaminosis A determined by. Children (n = 143), 5 to 7 years, were recruited into a placebo-controlled biofortified orange maize feeding study for 90 days. Bone turnover (P1NP and CTX) and inflammatory (C-reactive protein (CRP) and alpha-1-acid glycoprotein) biomarkers were measured in fasting blood samples before and/or after intervention with the following: (1) VA at the recommended dietary allowance (400 μg retinol activity equivalents/day (as retinyl palmitate)), (2) maize enhanced with the provitamin A carotenoid β-carotene (2.86 mg/day), or (3) a placebo. Parathyroid hormone, calcium, and 25(OH)-vitamin D were measured at end line.. Bone formation, as measured by P1NP, increased (P < 0.0001) in the placebo group who consumed low preformed VA during the intervention. Bone resorption, measured by CTX, was not affected. P1NP and CTX were negatively associated with inflammation, most strongly with CRP. Serum calcium did not differ among groups and was low (7.29 ± 0.87 μg/dL). Serum 25(OH) D did not differ among groups (54.5 ± 15 nmol/L), with 91% < 75 nmol/L and 38% < 50 nmol/L.. Reduction of dietary preformed VA in Zambian children for 4 months improved bone formation. Chronic consumption of preformed VA caused hypervitaminosis A and may impair bone formation. In children, this could be associated with failure to accrue optimal peak bone mass.. The NIH Clinical Trial registry number is NCT01814891; https://clinicaltrials.gov/ct2/show/NCT01814891 .

Topics: Biomarkers; Bone Remodeling; C-Reactive Protein; Child; Child, Preschool; Diet; Diterpenes; Female; Humans; Hypervitaminosis A; Liver; Male; Nutritional Status; Osteogenesis; Parathyroid Hormone; Provitamins; Retinyl Esters; Vitamin A; Vitamins; Zea mays

Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the calcification process in vitro.. Using a combination of approaches, we defined calcific aortic valve disease pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular, and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated Sox9 repression and calcification is regulated by classical RA signaling and requires both RA and retinoid X receptors.. Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of calcific aortic valve disease in the human population.

Topics: Animals; Aortic Valve; Calcinosis; Cell Line; Chick Embryo; Collagen Type II; Dietary Supplements; Disease Models, Animal; Diterpenes; Gene Expression Profiling; Gene Expression Regulation; Heart Valve Diseases; Hypervitaminosis A; Mice; Mice, Inbred C57BL; Oligonucleotide Array Sequence Analysis; Osteogenesis; Osteopontin; Receptors, Retinoic Acid; Retinoid X Receptors; Retinyl Esters; RNA Interference; Signal Transduction; SOX9 Transcription Factor; Time Factors; Tissue Culture Techniques; Transfection; Tretinoin; Vitamin A; Vitamins

This investigation was aimed at the analysis of the shape and morpho-densitometric parameters of the erythrocytes in rats with experimental hypervitaminosis A. Male Wistar rats received 0.64 mg/g (1167 IU/g) of retinol palmitate (RP) in oil solution orally for 11 consecutive days. Rats fed oil alone and intact animals were used as control groups. At days 5 and 6 of the experiment, the first manifestations of hypervitaminosis A were observed (body mass loss, localized erythema and hemorrhages). In contrast to control groups, in rats with hypervitaminosis A, the area of erythrocyte cytoplasm decreased gradually in response to RP administration. Discocyte/spherocyte/stomatocyte ratio also changed dynamically: the proportion of discocytes progressively decreased, while the amount of spherocytes and stomatocytes increased. These results show that excess of the vitamin A alters the erythrocyte membrane structure. Integral optical density of erythrocyte cytoplasm in RP-treated rats as well as in oil-fed rats was lower than in intact animals. This may be an indirect evidence of the fall in erythrocyte hemoglobin content. The changes observed in erythrocytes of RP-treated rats may serve as an additional criterion for evaluation of hypervitaminosis A severity.

Topics: Animals; Cell Shape; Cytoplasm; Diterpenes; Erythrocyte Deformability; Erythrocyte Membrane; Erythrocytes; Hypervitaminosis A; Male; Models, Animal; Oils; Rats; Rats, Wistar; Retinyl Esters; Spherocytes; Vitamin A

In the present work the effect of intramuscular administration of 30.000, 50.000 and 100.000 IU of vitamin A palmitate daily for seven days, respectively, on the liver enzyme activity in 45 white male Wistar rats, aged 12 weeks and weighing 180-200 g, have been studied. The group control was integrated by 15 healthy rats with similar characteristics (strain, gender, age and weight) to treated animals. Food and water consumption and body weights were recorded at the end of the experimental period. Rats were observed for clinical signs of toxicity. At the end of the study, rats were sacrificed under ether anesthesia. Liver samples were taken for the determination of enzyme activity. Administration of excess of vitamin A produced a significant (p < 0.05) increase in the content of liver vitamin A, determined diverse and variable clinical signs (such as, anorexia, loss of body weight, alopecia, conjunctivitis, external and internal hemorrhages, skin abnormalities and death) and increased (p < 0.05) the activity of the following enzymes: alanine aminotransferase, aspartate aminotransferase, acid maltase (acid alpha-1,4-glucosidase), acid proteases, lactate dehydrogenase and alkaline phosphatase while glucose-6-phosphatase, glycogen phosphorylase, alpha-amylase, cholinesterase and arginase decreased (p < 0.05) as compared with untreated controls. These changes depend on the doses given of vitamin A. In conclusion, our results provide evidence that short-term administration of high doses of vitamin A determined diverse and variable clinical signs and produces a marked alteration of activity of liver enzymes.

Topics: Acute Disease; Animals; Antioxidants; Diterpenes; Hydrolases; Hypervitaminosis A; Injections, Intramuscular; Liver; Male; Oxidoreductases; Rats; Rats, Wistar; Retinyl Esters; Transferases; Vitamin A

Numerous vitamin supplements are available over-the-counter to the general public. Some such supplements are available as candy-like chewable preparations to encourage consumption by children. We report 3 cases of overdose of such preparations. Each patient had taken an estimated 200,000 to 300,000 IU of vitamin A. Their circulating vitamin A (retinol and retinyl palmitate) concentrations were monitored over a 6-month period. There were no clinical or biochemical complications noted. However, there were marked increases in both retinol and retinyl palmitate concentrations above age-related reference ranges. In particular, it took 1 to 3 weeks for the serum retinol concentrations to peak and many months for them to normalize. Parents should be warned about the dangers of excessive vitamin consumption. Clinicians should be aware of the late peak in serum retinol concentrations, which may lead to late complications of vitamin A overdose.

Topics: Biotransformation; Candy; Child, Preschool; Dietary Supplements; Diterpenes; Drug Overdose; Ergocalciferols; Follow-Up Studies; Hong Kong; Humans; Hypervitaminosis A; Male; Retinyl Esters; Risk; Tablets; Vitamin A

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.

Topics: Animals; Blotting, Western; Cell Division; Chronic Disease; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Diterpenes; DNA; Gene Expression Profiling; Gene Expression Regulation; Hypervitaminosis A; Liver; Lung; Macromolecular Substances; Precipitin Tests; Proto-Oncogene Proteins c-jun; Rats; Rats, Wistar; Receptors, Retinoic Acid; Retinyl Esters; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tumor Suppressor Protein p53; Vitamin A; Vitamin A Deficiency

We report the case of a 32-year-old man with portal hypertension without cirrhosis due to chronic vitamin A intoxication. Portal hypertension revealed by oesophageal varice rupture progressively worsened and ascites occurred 5 years after the patient stopped vitamin A intake. Initially, serum retinyl palmitate concentration was increased whereas serum retinol concentration was normal. There was no hepatic fibrosis on light microscopic examination of liver biopsy specimens. Five years after the patient stopped excessive vitamin A intake, serum retinol and retinol-binding protein concentrations were below the normal range even though there was an increased hepatic retinyl ester content. This was attributed to the late development of peri-sinusoidal fibrosis. This case mainly shows the importance of retinyl ester level determination: serum retinyl palmitate should be measured immediately after intoxication and hepatic retinyl esters should be measured initially and particularly later. Indeed, later serum and hepatic retinol levels in chronic hyper-vitaminosis A may be normal and lead to under-estimation of liver vitamin A overload.

Topics: Adult; Biopsy; Diterpenes; Esophageal and Gastric Varices; Humans; Hypertension, Portal; Hypervitaminosis A; Liver; Male; Retinol-Binding Proteins; Retinyl Esters; Vitamin A

Topics: Acute Disease; Chromatography, High Pressure Liquid; Diterpenes; Hepatitis; Humans; Hyperlipidemias; Hypervitaminosis A; Liver Cirrhosis; Reference Values; Retinyl Esters; Specimen Handling; Vitamin A

This study investigated the effects of vitamin A excess on hepatic galactosyltransferase (EC 2.4.1.13) activity in livers of rats achieved either by feeding of high levels of retinyl palmitate for 16 wk or gavaging with retinol in olive oil for 3 d. Both hypervitaminotic conditions were characterized by hepatic lipid accumulation. Golgi apparatus fractions were isolated and purity of the fractions was monitored by marker-enzyme analyses and electron microscopy. The quality of the fractions isolated from livers of rats receiving vitamin A excess was not different from that of fractions from control rats. An increase in fat-storing cells in liver, observed in vitamin A excess, coincided with the presence of a floating lipid layer present during isolation of the Golgi apparatus. Galactosyltransferase specific activity (with ovomucoid as acceptor) of Golgi apparatus of rats fed excess vitamin A was 27% of control with chronic feeding and 59% of control with administration by gavage. Activity of another luminally oriented protein, uridine 5'-diphosphate phosphatase, was increased under both in vivo regimens. Vitamin A content of Golgi apparatus, as determined by high performance liquid chromatography, correlated negatively with galactosyltransferase activity after both chronic and acute administration of excess vitamin A.

Topics: Acid Anhydride Hydrolases; Animals; Diterpenes; Galactosyltransferases; Golgi Apparatus; Hypervitaminosis A; Lipid Metabolism; Liver; Male; Microscopy, Electron; N-Acetyllactosamine Synthase; Phosphoric Monoester Hydrolases; Pyrophosphatases; Random Allocation; Rats; Rats, Inbred Strains; Retinyl Esters; Time Factors; Uridine Monophosphate; Vitamin A

The present study was designed to investigate the embryo-fetotoxicity of vitamin A in protein-energy malnourished animals. Retinyl palmitate (66, 99 and 132 mg/kg) suspended in corn oil was given by gavage to well-nourished and malnourished rats from gestational days 8 to 10 and cesarean sections were performed on day 20. All fetuses were weighed and examined for malformations before being prepared for skeletal evaluation. The proportion of malformed fetuses was higher in the malnourished group at each one of the three dose levels. The data indicate that malnourished animals are more susceptible to the toxic effects of retinyl esters.

Topics: Animals; Body Weight; Congenital Abnormalities; Diterpenes; Female; Hypervitaminosis A; Pregnancy; Protein-Energy Malnutrition; Rats; Rats, Inbred Strains; Retinyl Esters; Tretinoin; Vitamin A

Retinol and retinyl esters are measured in serum or plasma samples by gradient, normal-phase, adsorption "high-performance" liquid chromatography, with ultraviolet detection at 325 nm. The four major circulating retinyl esters in humans (esters of palmitate, stearate, oleate, and linoleate) are coeluted as a single peak. Retinyl acetate is included as an internal standard, to correct for variable recovery. Retinol values so measured correlated well (r = 0.88) with those by a widely used reversed-phase chromatographic technique (Clin Chem 1983;29:708-12). The mean retinol concentration was 570 (SEM 17) micrograms/L and the mean for retinyl esters was 33 (SEM 4) micrograms/L as determined in samples from 88 fasting young adults. Concentrations of retinol in plasma as low as 50 micrograms/L can be detected in 100-microL samples, as can 10 micrograms of retinyl esters per liter. Using this method, we measured absorption of low doses of vitamin A, which may provide a more physiological approach to assessment of fat malabsorption. Additionally, the procedure proved useful for quickly screening for vitamin A toxicity. Major advantages include small sample size, direct injection of the extract ed sample without evaporation, rapid elution pattern, co-elution of major retinyl esters as a single peak, and low limit of detection.

Topics: Adult; Animals; Child; Chromatography, High Pressure Liquid; Diterpenes; Female; Humans; Hypervitaminosis A; Male; Microchemistry; Plasma; Rats; Rats, Inbred Strains; Retinyl Esters; Vitamin A

The usual presenting features of vitamin A intoxication are pseuotumor cerebri, skeletal pain, desquamative dermatitis, and hepatic inflammation. Our patient was a nine-year-old female who had increasing cough, dyspnea, and abdominal distention for a short time prior to admission. She was said to have been treated with 10,000 units of vitamin A per day for skin rashes. Radiographic studies revealed a very large right sided pleural effusion, ascites, demineralized bones, and retarded skeletal maturation. The diagnosis of hypervitaminosis A was made. More detailed medical history confirmed that the child had, in actuality, received up to 300,000 units/day of vitamin A plus desiccated liver pills and carrot juice for the previous year. Clinical symptoms completely abated following acute medical treatment for ascites and cessation of vitamin A intake. Several months later, a sample of liver, obtained and preserved at the time of exploratory laparotomy, was homogenized and extracted with ethanol/hexane. The retinyl palmitate level was significantly elevated and consistent with vitamin A poisoning.

Topics: Age Determination by Skeleton; Ascites; Biopsy; Child; Diterpenes; Female; Humans; Hypervitaminosis A; Liver; Microscopy, Electron; Pleural Effusion; Radiography, Thoracic; Retinyl Esters; Skin Diseases; Vitamin A