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Vitamin A: Cant Get No Respect Liz Lipski, PhD, CCN, CNS, CHN, LDN Maryland University of Integrative Health NANP Conference April 2014 Tucson

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

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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

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

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

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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/ http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/

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Dietary Vitamin A + fat (pro or pre formed) Micellized/conversion requires lipase on brush borders Passive absorption by enterocytes Lymph to bloodLiver or Tissue

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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.

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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)

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CarotenesCarotene enzymeRetinal Intestines, also liver, lung, kidneys, retina Retinol

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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 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#a0199http://emedicine.medscape.com/article/126004-overview#a0199; J Cyst Fibros.J Cyst Fibros. 2011 Jan;10(1):31-6, Campbell-McBride, GAPS

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Synergy

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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 retinyl palmitate) 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 its taken up and utilized RPB is dependent on zinc and amino acids

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

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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

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RDAs 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

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

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FoodServing Vitamin A, RAEVitamin A, IURetinol, mcgRetinol, IU Cod liver oil1 teaspoon1,350 mcg4,500 IU1,350 mcg4,500 IU Fortified breakfast cereals 1 serving150-230 mcg500-767 IU150-230 mcg500-767 IU Egg1 large91 mcg303 IU89 mcg296 IU Butter1 tablespoon97 mcg323 IU95 mcg317 IU Whole milk1 cup (8 fl oz.)68 mcg227 IU68 mcg227 IU 2% fat milk (vitamin A added) 1 cup (8 fl oz)134 mcg447 IU134 mcg447 IU Nonfat milk (vitamin A added) 1 cup (8 fl oz.)149 mcg497 IU149 mcg497 IU Sweet potato, canned 1/2 cup, mashed 555 mcg1,848 IU00 Sweet potato, baked 1/2 cup961 mcg3,203 IU00 Pumpkin, canned 1/2 cup953 mcg3,177 IU00 Carrot (raw) 1/2 cup, chopped 538 mcg1,793 IU00 Cantaloupe 1/2 medium melon 467 mcg1,555 IU00 Mango1 fruit79 mcg263 IU00 Spinach 1/2 cup, cooked 472 mcg1,572 IU00 Broccoli 1/2 cup, cooked 60 mcg200 IU00 Kale 1/2 cup, cooked 443 mcg1,475 IU00 Collards 1/2 cup, cooked 386 mcg1,285 IU00 Squash, butternut 1/2 cup, cooked 572 mcg1,907 IU00 Make handout

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Storage of Vitamin A 50-80% in liver 20-50% in fat tissue, lungs, and kidneys Adult can store 1 years worth Children store a few weeks worth

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

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Global Insufficiencies Mult Scler.Mult Scler. 2013 Jul;19(8):1046-51.

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

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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

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Night Blindness Zinc Vitamin A

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VAD Abnormal epithelial cells: thin out, dry out, Keratosis

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

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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

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

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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 http://emedicine.medscape.com/article/126004-overview

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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

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

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Case History: Vitamin D Deficiency

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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

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

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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%

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Supplementation 5000-10,000 IU Common forms: retinyl palmitate, 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/

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

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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 dont get enough vitamin A in their diet http://lpi.oregonstate.edu/infocenter/vitamins/vitaminA/

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WHO & UNICEF joint statements Vitamin A given to all children who have measles, especially if

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. J Cyst Fibros. 2008 Mar;7(2):137-41. J Cyst Fibros.

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Vitamin A and Thyroid Disease Acta Med Austriaca. 1993;20(1-2):17-20. Acta Med Austriaca. [Beta-carotene, vitamin A and carrier proteins in thyroid diseases]. [Article in German] Aktuna D 1, Buchinger W, Langsteger W, Meister E, Sternad H, Lorenz O, Eber O. Aktuna DBuchinger WLangsteger WMeister ESternad HLorenz OEber 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).

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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

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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 Toxicol Ind Health.Toxicol Ind Health. 2005 Sep;21(7-8):167-75. Gaby, A. Nutritional Medicine

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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): 155-64Ann Nutr Metab.

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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.Int J Vitam Nutr Res.

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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

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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.

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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

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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.J Affect Disord. 2013 Sep 25;150(3):1129-35.

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

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Nutrient Interactions Zinc deficiency: poor protein synthesis, impairs retinol transport from the liver to tissues Iron deficiency: vitamin A alone will not improve vitamin A deficiency when there is also iron deficiency Vitamin E: enhances absorption and tissue uptake Vitamin A toxicity: impairs vitamin K synthesis High dose vitamin A reduces iodine uptake to thyroid (50,000 IU daily) Gaby, A. Nutritional Medicine

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High Vitamin A side Effects Fatigue Joint pain Muscle aches Dry skin Bone pain Dry eyes

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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

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Vitamin A: Cant Get No Respect Liz Lipski, PhD, CCN, CNS, CHN, LDN Maryland University of Integrative Health NANP Conference April 2014 Tucson