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Vitamin A: Can’t Get No Respect

Vitamin A: Can’t Get No Respect. Liz Lipski, PhD, CCN, CNS, CHN, LDN Maryland University of Integrative Health NANP Conference April 2014 Tucson. History. Ancient Egypt: night blindness Ancient Rome: fermented fish liver and fish guts 18 th Century: Europe cod liver oil

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Vitamin A: Can’t Get No Respect

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  1. Vitamin A: Can’t Get No Respect Liz Lipski, PhD, CCN, CNS, CHN, LDN Maryland University of Integrative Health NANP Conference April 2014 Tucson

  2. History • Ancient Egypt: night blindness • Ancient Rome: fermented fish liver and fish guts • 18th Century: Europe cod liver oil • 1913: two teams of researchers discovered: Osborne and Mendel/Yale and McCollum and Davis at U of Wisconsin

  3. Functions • Epithelial cell growth and repair • Vision • Immune Function • Cell differentiation • Bone growth • Reproduction • Integrity of epithelial tissue: skin, lungs, respiratory, urinary, GI • Regulation of adult genes • Embryonic development

  4. http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/visualcycle.htmlhttp://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/visualcycle.html

  5. Gene Expression • Isomers of retinoic acid have hormone-like action and affect gene expression http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/rxr.html

  6. Pre-Formed Vitamin A: Retinoids • Retinol: (an alcohol) precursor for retinoic acid and retinaldehyde, essential for proper mitochondrial oxidative phosphorylation • Retinal: (an aldehyde) converted to Retinoic acid • Retinoic acid: genetic transcription factors, cell development (RXR, • Retinaldehyde: vision • Pro-vitamin A: Specific carotenoids FASEB J. 2010 Feb;24(2):627-36. & http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/

  7. Sources of Pre-Formed Vitamin A= Retinoids • Liver: Can have up to 12,000 IU vitamin A in a single serving. • Kidneys • Dairy products • Eggs • Oily Fish: cod, halibut, shark, fish liver oils • Cod Liver oil: Children 1 tsp daily, adults 2-3 tsp daily.

  8. Provitamin A = Carotenoids • Provitamin A: • Beta-carotene (yellow/orange/green vegetables) • Alpha-carotene (carrots/red palm oil) • Beta-cryptoxanthin (red peppers, oranges, papaya) • Lycopene can be convered into B-carotene (tomatoes, wateremelon, pink grapefruit, red papaya, watermelon) • Not Provitamin A: • Lutein & Zeaxanthin: alone are deposited in macula (yellow/orange/green vegetables)

  9. Absorption • Pro-vitamin A: 80-90% absorbed • Pre-vitamin A: 40-60% absorbed • Needs zinc, magnesium and protein for conversion • Any GI disease that affects absorption of fats < vitamin A absorption: cystic fibrosis, liver cirrhosis and dx, celiac disease, gallbladder disease (leaky Gut?) pancreatic insufficiency, IBD, bypass surgery > risk for VAD in up to 60% of people. • Vegans, alcoholics, toddlers and preschool children living below poverty line, and recent immigrants have increased risk of VAD • Children with multiple infections may deplete stores http://emedicine.medscape.com/article/126004-overview#a0199; J Cyst Fibros. 2011 Jan;10(1):31-6, Campbell-McBride, GAPS

  10. Synergy

  11. Relationship to gut microbiome & enterocytes • Provitamin A is released from proteins in the stomach. These retinyl esters are hydrolyzed to retinol in the small intestine. • Better absorbed. • Carotenoids cleaved in intestinal mucose into retinaldehyde, then reduced to retinol, then esterified to retinyl esters. • Transported as micelles in lymphatic drainage of intestine to the blood stream then to the liver as components of chylomicrons. 50-80% of vitamin A is stored in the liver (bound to RBP). Rest stored in fat tissues, lungs, kindyes as retinyl esters, (commonly retinylpalmitate) • Mobilized from the liver (gets deesterified)…to blood vitamin A is bound to RBP and transtheyretin which transports it as a complex to tissues where it’s taken up and utilized • RPB is dependent on zinc and amino acids

  12. Carotenemia http://dermaamin.com/site/atlas-of-dermatology/3-c/237-carotenaemia-.html

  13. Activity of Vitamin A • RAE (Retinol Activity Equivalent) • 1 mcg RAE pure all-trans retinol = • 2 mcg RAE all-trans beta-carotene in oil = • 12 mcg of food based all trans beta-carotene= • 24 mcg of other food based provitamin A carotenoids

  14. RDA’s Vitamin A • Infants aged 1 year or younger - 375 mcg • Children aged 1-3 years - 400 mcg • Children aged 4-6 years - 500 mcg • Children aged 7-10 years - 700 mcg • All males older than 10 years - 1000 mcg • All females older than 10 years - 800 mcg

  15. http://www.webmd.com/vitamins-and-supplements/lifestyle-guide-11/supplement-guide-vitamin-ahttp://www.webmd.com/vitamins-and-supplements/lifestyle-guide-11/supplement-guide-vitamin-a

  16. Storage of Vitamin A • 50-80% in liver • 20-50% in fat tissue, lungs, and kidneys • Adult can store 1 year’s worth • Children store a few week’s worth

  17. Testing for Vitamin A • Serum Retinol Levels NHANES reference range: 30-72 microg/dL • Nutritional Physical: signs and symptoms • Bleaching J Cyst Fibros. 2008 Mar;7(2):137-41.

  18. Global Insufficiencies MultScler. 2013 Jul;19(8):1046-51.

  19. Global VAD • 250 million children at risk VAD • Malnourished children • > risk of death from measles and xerophtalmia • ¼-1/2 million children go blind from VAD • Reduce measles mortality by 50% • Diarrhea mortality by 33% • All cause mortality by 23%

  20. Symptoms of VAD • Repeated miscarriage • Impaired sperm production • Fatigue • Increased infections • Reduced immune function • < growth rate and bone development in children • Blind spots/blindness • Slow adaptation to darkness/night bision • Dry skin: keratosis • Dry hair • Pruitis • Broken fingernails • Keratomalacia • Xeropthalmia • Corneal performation • Blocked hair follacles (folicular hyperkeratosis) • Anemia

  21. Night Blindness • Zinc • Vitamin A

  22. VAD • Abnormal epithelial cells: thin out, dry out, • Keratosis

  23. Liver Transplant Patients • End stage liver disease: 69.8% of liver transplant patients had VAD Liver Transpl. 2013 Jun;19(6):627-33.

  24. Alcholism • Aochol dehydrogenase catalyzes the conversion of retinol to retinaldehyde which is oxidized to become retinoic acid. • Alcohol impedes conversion or retinol to retinoic acid

  25. Deficiency/Insufficiency of Vitamin A • Incidence • Symptoms • Conditions • Not enough in diet • Defective absorptionor metabolism • Increased need: • Serum retinol levels are controlled homeostatically: when serum levels are low, tissues are really depleted.

  26. Genomic effect of Vitamin A • regulation of adult genes. It functions as an activator of gene expression by retinoid alpha-receptor transcription factor and ligand-dependent transcription factor. http://emedicine.medscape.com/article/126004-overview

  27. Vitamin A and Vitamin D • Cellular response to vitamin D regulated by VDR • “superfamily” of nuclear transcription factors: VDR, retinoid, thyroid hormone • Vitamin D turns on a switch in the VDR that binds AND the retinoid X receptor Zhong M, Kawaguchi R, Ter-Stepanian M, Kassai M, Sun H (2013) Plasma Retinol Binding Protein. PLoS ONE 8(1 ): e73838. doi:10.1371/journal.pone.0073838

  28. Vimaleswaran et al.BMC Genetics 2014 15:37   doi:10.1186/1471-2156-15-37

  29. Therapeutic Usage • VAD: protein deficiency, diabetes, hyperthyroid, fever, liver disease**, cystic fibrosis, abetalipoproteinemia (genetic disease) • May be effective: • Preventing postmenopausal breast cancer (diet yes/sups?) • < risk of malaria, measles, diarrhea in children • < problems in pregnancy in malnourished women • Prevention of cataracts • Used with vitamin E after laser eye surgery

  30. Therapeutic Usages • Skin: acne, eczema, warts • Hearing loss • Smelling loss • Tinnitus • Infections: colds, malaria, measles, TB • Eyes: blepharitis, conjunctivitis, night blindness, Retinitis, Siccasyndrome • Acute promyelocytic leukemia Gaby, A. Nutritional Medicine; http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/ • Burns • Cancer? • Celiac disease • Critical illness • Diabetes • Downs syndrome • Dysfunctional uterine bleeding • Hyperthyroidism • Oral leukoplakia • Peptic ulcer

  31. Anemia in Children • Jiminez et al. 200,000 IU dose of vitamin A to children with vitamin A deficiency (VAD) • 30 days. > HMG, MCH, serum retinol • Rates of anemia fell 17.6-13.2% • Low Vitamin A levels: > in 25-13.2%

  32. Supplementation • 5000-10,000 IU • Common forms: retinylpalmitate, retinyl acetate, beta-carotene, mixed carotenoids • 25,000 IU/day therapeutically • Physician Rx: Up to 300,000 IU/day short term) Oil based vitamin A supplements less toxic than water-miscible, emulsified, or solid (dry) preparations • Carotenoids: no toxic dose level known. Just carotenemia. • Test for Liver enzymes and serum calcium with high dose vitamin A supplementation Gaby, A. Nutritional Medicine; http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/

  33. Basic Supplementation • Pre-formed vitamin A up to 2500 IU/day • Betacarotene/carotenoids 2500 IU/day

  34. Vitamin A & Osteoporosis • Vitamin A supplementation > risk of osteoporosis and fracture • Level: 1500 IU/day pre-formed vitamin A • Not associated with carotenoids • Why: interfere with vitamin D? • < BMD also present in elderly who don’t get enough vitamin A in their diet http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/

  35. WHO & UNICEF joint statements • Vitamin A given to all children who have measles, especially if <2years old • Cochrane Review: daily treatment with 200,000 IU of vitamin A for 2 days or more reduces mortality rates in small children with measles.

  36. American College of Pediatrics • Use vitamin A supplements in children aged 6-24 months who have measles (hospitalized) • All hospitalized children older than 6 months

  37. Kids with Cystic Fibrosis • Vitamin A given routinely • Several studies indicate higher than expected levels. • 58-78% subjects had > DRI tolerable upper intake level • J Cyst Fibros. 2008 Mar;7(2):137-41. • J Cyst Fibros. 2008 Mar;7(2):137-41.

  38. Vitamin A and Thyroid Disease • Acta Med Austriaca. 1993;20(1-2):17-20. • [Beta-carotene, vitamin A and carrier proteins in thyroid diseases]. • [Article in German] • Aktuna D1, Buchinger W, Langsteger W, Meister E, Sternad H, Lorenz O, Eber O. • Author information • Abstract • The conversion of beta-carotene (provitamin A) to 2 molecules of vitamin A (retinol) is accelerated by thyroxine and hyperthyroidism, respectively. The characteristic yellow tint of the skin in hypothyroidism is due to hyper-beta-carotenemia. Both in hyper- and hypothyroidism in a retinol deficiency has been observed in literature. In a series of 36 patients (16 hyper-, 8 hypo-, and 12 euthyroid) serum samples were analyzed for retinol and beta-carotene levels (high pressure liquid chromatography) as well as retinol binding protein (radial immune diffusion), prealbumin (nephelometry), and serum zinc values (atomic absorption spectrometry) were established. The beta-carotene serum level in the hypothyroid group (mean 1.1 microgram/ml) was significantly higher (p < 0.05) in relation to euthyroid controls (0.6 microgram/ml), the hyperthyroid group showed significantly lower values (0.3 microgram/ml). RBP and prealbumin concentrations were significantly lower (p < 0.05) in hyperthyroid as against eu- and hypothyroid patients. Surprisingly, in all 3 groups the retinol levels were not significantly different, although the hyperthyroid group was slightly lower (0.6 microgram/ml) than the mean value of 0.7 micrograms/ml in the other groups. A vitamin A and protein rich food, customary in Central Europe, seems to rule out any vitamin A deficiency both in hyper- and hypothyroidism. However, the beta-carotene values are significantly higher in hypothyroidism, while in hyperthyroidism they were lower. As intrahepatic zinc content plays an important role in the synthesis of RBP and its secretion together with retinol, we also analyzed this component: The serum zinc levels in hyperthyroid patients were clearly higher (79.1 micrograms/dl) than in the hypothyroid group with 57 micrograms/dl (p < 0.05).

  39. Conditions: Vitamin A insufficiency • Hypothyroid: Thyroid hormone helps with conversion of betacarotene into retinol • Liver disease • Alcoholism • Gastric or intestinal surgery • Parasites • Malabsorption • Children with Type I diabetes taking a fiber supplement Gaby, A. Nutritional Medicine

  40. Toxicity of Vitamin A • Symptoms • Peeling or itching skin, brittle nails, yellowish skin, hair loss, bone/joint pain • Massive dose: nausea, vomiting, head pressure, mental changes • Conditions • Liver problems, osteoporosis, CNS disorders. • High sunlight can metabolize vitamin A to > free radicals > DNA strand cleavage ToxicolInd Health. 2005 Sep;21(7-8):167-75. Gaby, A. Nutritional Medicine

  41. Vitamin A Toxicity: Teratogen • Pregnant women: dosages not more than 3000 IU retinol daily. • Nonpregnant women: given 30,000 IU vitamin A palmitate daily for 21 days “without safety concern.” • Non-pregnant women: 4000, 10,000, or 30,000 IU 3 weeks; range or slightly above early pregnancy ranges. Levels not within or just slightly above normal physiological range. Hartmann S, et al. Ann Nutr Metab. 2005 May-Jun;49(3): 155-64

  42. Vitamin A: Toxicity in Monkeys • No observed adverse effect level (NOAEL) 7500 IU per kilo body weight. • Lowest observed adverse effect level (LOAEL) for developmental toxicity: 20,000 IU/kg • Comment: 30,000 IU/day not teratogenic in humans Weigand, UW, Hartmann, S, Hummler H. Int J Vitam Nutr Res. 1998;68(6):411-6.

  43. Toxicity • Acute vitamin A toxicity: 25,000 IU/kg of body weight or 1.75 million IU for a 150 pound person • Chronic toxicity: 50,000 IU daily for 2.5 years, or 150,000-600,000 IU daily for 2 months to 8.5 years. • Liver disease or alcoholics: toxicity < 50,000 IU daily

  44. Drug-Nutrient Interactions • Coumadin (warfarin) synergistic • Vitamin A skin creams: Retin A, Accutane • Tetracycline, Declomycin, Minocin (only in high doses causes problems) • Excessive drinking • Liver harming medications amplifies liver damage (Tylenol, amiodarone, Tegratol, isoniazid, methotrexate, methyldopa, Diflucan, Dilantin, Sporanox, erythromycin, Mevacor, prevastatin, Zocor, etc.

  45. Pregnancy • No increased need for vitamin A: body stores meet the need • Can be a teratogen first trimester • RDA 800 mcg women • Lactation: 1300 mcg 6 months, then 1200 mcg 6-12 months

  46. Post Partum Depression: Too much Vitamin A? • Breastfeeding protects by depleting stores of high vitamin A below a threhold. • Pregnant women accumulate retinoids in liver and breast to prepare for lactation. Higher levels associated with cognitive disturbances and mood disorders including depression and suicide. • 6 months of lactation = to 76% of toxic dose vitamin A J Affect Disord. 2013 Sep 25;150(3):1129-35.

  47. Hypervitamin A Levels • End Stage Kidney disease: typically high levels. Do not supplement • Gaby, A. Nutritional Medicine

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