CAUTION: MULTIVITAMINS MAY BE TOXICKristal BenallyMegan GleasonHeather KhoEmma Pindra

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Multivitamins• OK, lets be honest. When was the last time you took

multivitamins?• What did they actually contain? • According to Standford.edu the content list is long. → → → • Observe the Maximum Safety Intake• Aren’t vitamins good for us?• Why are there safety limits for what’s good for us?• As Toolson said on the first day of class;

“Everything is toxic, its the dose that determines whether it is beneficial or not. There is no free lunch.”

http://www.ksl.stanford.edu/people/kpfleger/multivitamins/cached/www.mothernature.com_cg_multi_vitamins.asp.html

Vitamin Safety Margins• We blazed through the long list of vitamins available and found that Vitamins A, C, E, and D had

multiple reports of toxicity. We chose these vitamins keeping in mind their prevalence in multivitamins.

• Vitamin A toxicity can cause skin discoloration, bone abnormalities, vomiting, diarrhea, and teratogenic effects.

• Caused by increased concentrations of retinyl esters within the liver.• Vitamin C toxicity causes diarrhea, vomiting, and stomach cramps.

• Due to overloading of iron molecules in the small intestine.• Vitamin E toxicity produces increased risk of hemorrhaging.

• Mechanism is not yet known.• Vitamin D toxicity can cause anorexia, weight loss, polyuria, heart arrhythmias, increased calcium

concentrations in the blood, and kidney stones. • Primarily caused by increase calcium absorption in the GI tract.

• Mechanisms of vitamin toxicity are not fully understood, however, there have been several hypothesized mechanisms. The most supported mechanisms are discussed here.

Vitamin A (Retinol)• Fat-soluble vitamin

• Two Forms found in daily diet

• Preformed- Found in animal products

• Eggs, meats/fish, and dairy products

• Pro-vitamin- Found in plant-based foods, most common form is beta-carotene.

• Sweet potatoes, carrots, dark leafy greens, winter squashes, lettuce

• Dried apricots, cantaloupe, bell peppers, tropical fruits

• Dietary supplement forms

• Retinyl acetate or retinyl palmitate (preformed)

• Beta-carotene (pro-vitamin)

• Combination of preformed and pro-vitamin A

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http://www.medindia.net/patients/lifestyleandwellness/images/vitamin-a-rich-foods.jpg

Recommended Dietary Allowance• Dosage Units: Recommended daily allowance for vitamin A are given as mcg of retinol activity

equivalents (RAE) to account for the different forms of vitamin A.

• 1 IU retinol = 0.3 mcg RAE

• 1 IU -carotene from dietary supplements = 0.15 mcg RAEβ

• 1 IU -carotene from food = 0.05 mcg RAEβ

• 1 IU -carotene or -carotene = 0.025 mcg RAEɑ β

http://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/

Vitamin A- Biochemical Functions• Metabolic Pathways

Retinyl ester ↔ Retinol/Vitamin A ↔ Retinal → Retinoic Acid

• Retinyl Ester: Stored in the liver until further notice.

• Retinol: Transported from liver to tissues through the plasma. Retinol binds to Retinol Binding Protein (RBP) then once in the plasma RBP binds to transthyretin (TTR) to form a Holo-RBP-TTR complex.

• Retinal: Aldehyde group, 11-cis retinal, binds with Opsin to form Rhodopsin.

• Retinoic Acid: Acid binds and activates two nuclear protein receptors, retinoic acid receptor (RAR) and retinoid X receptor (RXR), which induce gene transcription.

• Improves vision by providing retinal in the synthesis of rhodopsin.

• Stimulation to the function of the immune system and increases resistance to infections.

• Maintains healthy skin by increasing cell proliferation of epithelial cells.

• Vitamin A supports cell growth and differentiation which is important in development of a fetus.

• Influencing the development of bone growth by actively regulating osteoblasts and osteoclasts.

Interactions• Vitamin A Toxicity

• Excessive amounts of storage form of Vitamin A in the liver causing it to become saturated. Retinyl esters begin to diffuse into the bloodstream causing random reactions with cell membranes rather than with Holo-RBP-TTR complex.

• Can be caused by Accutane

• Carotenemia- increased pro-vitamin A intake causes skin to turn yellow-orange

• Hypervitaminosis A- increased intake of preformed vitamin A causing retinyl esters to circulate with plasma lipoproteins.

• Symptoms

• Acute: Nausea, vomiting, diarrhea, weakness, increased intracranial pressure.

• Chronic: Skin desquamation, chronic fatigue, double vision, liver damage, bone abnormalities, joint pain, alopecia, coma, renal dysfunction.

Metabolism- Normal Dosage• Active retinol form must be

deactivated by transformation into retinyl esters.

• Retinyl esters are a form of storage which could later be transformed back into retinol for either gene transcription or rhodopsin synthesis.

• Retinyl esters are stored in the stellate cells within the liver.

• Hence, fat-soluble vitamin.

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Metabolism- Over consumption• Increased intake of Vitamin A causes large

concentrations of retinyl esters after transformation. • Over loading of retinyl esters in the stellate cells causes

saturation of the liver.• Retinyl esters begin to leak out of the liver and invade

the bloodstream causing liver and renal damage. • Increased levels of Vitamin A have been reported to

interact with the metabolism of Vitamin D, E, and K. • Hypervitaminosis A disrupts cell proliferation and

differentiation in fetal development which can lead to teratogenic effects.

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Treatment• Immediately ceasing vitamin A intake• Intravenous fluids and diuretics to counteract effects of

diarrhea and vomiting.• Immediate lumbar puncture as treatment for intracranial

pressure

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Vitamin C (Ascorbic Acid) Fruits with the highest sources of vitamin C

• Citrus fruits and juices, such as orange and grapefruit• Cantaloupe• Kiwi • Mango• Papaya• Pineapple• Strawberries, raspberries, blueberries, cranberries• Watermelon

• Vitamin C is currently being added to some cereals and beverages, such as milk. For the best intake of vitamin C is to eat the vitamin containing fruits and vegetables raw, instead of cooked

• Deficiency of Vitamin C could lead to various tissue in the body to break down, general health and repair of the body also become affected, and with persistent deficiency can lead to scurvy.

Vegetables which contain a high source of Vitamin C

• Broccoli, Brussels sprouts, cauliflower

• Green and red peppers

• Spinach, cabbage, turnip greens, and other leafy greens

• Sweet and white potatoes

• Tomatoes and tomato juice

• Winter squash

Recommended Dietary Allowance Infants and children

• 0-6 months 40 mg/day• 7-12 months 50

mg/day• 1-3 years 15 mg/day• 4-8 years 25 mg/day• 9-13 years 45 mg/day

• It is suggested to not exceed 2 grams/day

• Overconsumption of vitamin C is rare due as it is readily soluble, with excess removal by kidneys

• Vitamin C is used in the body to reduce copper and iron

• Vitamin C is also used as a protective antioxidant

Adolescents• Girls 14-18 years 65 mg/day• Pregnant teens 80 mg/day• Lactating teens 115 mg/day• Boys 14-18 years 75 mg/day

Adults• Men 19+ 90 mg/day• Women 19+ 75 mg/day• Pregnant women 85 mg/day• Lactating women 120

mg/day

Vitamin C - Biochemical Function• Amino acid and protein

metabolism • Collagen synthesis

• Connective tissue essential for wound healing

• Thyroxine Synthesis• Thyroid hormone vital to

digestion, heart + muscle function, brain development

• Neurotransmitter synthesis:• Epinephrine + norepinephrine

(utilizing tyrosine derived cofactor)

• Key facilitator in absorption of nonheme iron

• Highly effective antioxidant • Protects against DNA mutations• Regenerates and recycles other

antioxidants (vitamin E alpha-tocopherol)

• Promotes and maintains immunocompetence

Mechanism of Absorption• Vitamin C is absorbed in the lumen of small intestine via

active transport processes • Tissue saturation increases proportionally with vitamin c

uptake • Vitamin C retained via renal-tubular reabsorption

mechanism; excess vitamin c excreted via urine

• Oxidation of Vitamin C from L-ascorbic acid to Dehydro-L- ascorbic acid releases two donor electrons which become available for other biochemical reactions.JAMA. 1999;281(15):1415-1423. doi:10.1001/jama.281.15.1415

Copyright © 2015 American Medical Association. All rights reserved.

Ascorbic acid enhances the absorption of nonheme iron

• Non-heme iron enters the GI tracts in Ferric form Fe³⁺• Fe³⁺ is not bioavailable and has to be converted into

ferrous iron Fe²⁺ • This reduction is assisted by Ascorbic acid and its release

of electrons • Ascorbic acid reduces Fe³⁺ in the lumen of the small

intestine

Vitamin C Toxicity Though very rare if vitamin C is over consumed it can cause • Diarrhea• Nausea• Stomach cramps

Usually treated by stopping further supplement intake

Increased dosage of vitamin C increases iron uptake conferring a therapeutic benefit to anemic individuals

However, individuals with hemochromatosis are susceptible to iron overload and consequently must monitor their vitamin C intake

Vitamin E ● Potent fat soluble antioxidant

● Only vitamin actively maintained in human body

● Food sources: nuts, seeds, green leafy vegetables, vegetable oils, fish, tofu

● Alpha-tocopherol is the most abundant and metabolically active component of vitamin E (only component maintained in plasma) in both whole foods and supplements

90% Americans are deficient (reported average 6.9mg/day in contrast to RDA of 15 mg/day)

Recommended Daily Allowance (RDA)● 1 mg alpha-tocopherol equates to 1.49

IU natural and 2.22 IU synthetic form of vitamin E

● People need 50% more IU of synthetic alpha tocopherol (from supplements) to obtain same amount from whole foods

● Supplements have >100 IU (significantly more than RDA)

● 1999-2000 National Health and Nutrition Examination Survey found that 11.3% adults took vitamin E supplements containing at least 400 IU

http://ods.od.nih.gov/factsheets/VitaminE-HealthProfessional/#en6

Function • Antioxidant (neutralizes free radicals)

• Prevents cell damage• Prevents lipo peroxidation

• maintains cell membrane integrity• protects against cardiovascular

diseases

• Immunity• supports cellular mediated response

(promotes immature T cell differentiation)

• Blood• Formation of erythrocytes• Prevents clot formation (via vasodilation)

• Disease prevention• Prevents LDL oxidation which upon

aggregation in vessels results in atherosclerosis

• Decreased risk of dementia• Slower progression of Alzheimers

• Brain health• Maintains normal levels of DHA

(omega 3 fatty acid required for structural formation and maintenance of brain matter)

Chemical Properties |▪ Alpha–tocopherol is most metabolically active form of Vitamin E

•Predominant form in supplements•Primary antioxidant for LDL’s (maintains plasma membrane integrity) and protects against chronic diseases •Upon neutralizing a free radical, antioxidant property of alpha-tocopherol restored by Vitamin C

▪Gamma-tocopherol while less metabolically pronounced lower levels within humans, is most common form in American diets ▪Potent scavenger of lipoprotein electrophiles ▪Possesses anti inflammatory properties (unlike the alpha form)

Exists in 8 forms, as tocopherols + tocotrienols (alpha, beta, gamma, and delta)

Mechanism of Absorption 1. Vitamin E requires de-esterification in stomach 2. Aggregation of vitamins by micelles 3. Bile salts emulsify the vitamin into water soluble form4. Small intestine enterocytes absorb alpha-tocopherol 5. Transportation from GI to liver via chylomicrons (lipoproteins) and erythrocytes in the blood and lymph6. Liver incorporates alpha tocopherol into LDL’s and HDL’s for subsequent distribution to respective organs

Vitamin E toxicity▪ Overconsumption of vitamin E from whole food sources is rare▪ Toxicity primarily from excessive vitamin E supplementation

▪ Recommended daily dose of 1000 mg/day (1500 IU)

▪Primary toxic effect : Increased bleeding▪Reduced platelet aggregation and blood coagulation(clotting)▪Especially critical during trauma or injury ▪increased risk of hemorrhaging (internal + external) ▪Increased risk of hemorrhagic stroke (22%)▪However, research shows decreased risk of ischemic stroke (10%)

▪Drug interactions must be carefully considered▪Anticoagulants (ex. Warfarin, Plavix) and non steroid anti inflammatory drugs

(ex. Aspirin, ibuprofen) may result in increased hemorrhaging

Ultimately, while vitamin E supplementation does demonstrate various benefits, natural forms of vitamin E (from whole foods) provide much greater therapeutic benefits with significantly reduced risk for toxicity.

Vitamin D• Vitamin D is a fat-soluble vitamin.

• Two dietary forms: D2 (ergocalciferol, from yeast and plant sterol) and D3

(cholecalciferol, from a precursor for cholesterol when generated in the skin)• Whole food sources:

• Flesh of some fish: salmon, tuna, mackerel• Fish liver oils (best source)• Beef liver, egg yolks, cheese (small amounts)• Some mushrooms (grown under controlled exposure of UV light)

• Another source of Vitamin D is the sun-- exposure to ultraviolet rays triggers endogenous Vitamin D production

• The main source of Vitamin D comes from food fortified with Vitamin D:• Milk, some yogurts, most breakfast cereals, some brands of orange juice, and infant

formulas

Recommended Daily Allowances• Vitamin D intake should not reach excess

of 250-1000 mcg/day over a prolonged period of time

• Excess intake due to over supplementation rather than from food sources or sun exposure

• However, too much sun exposure can result in the photogdegradation of D3 (formed previtamin) prior to it being able to be utilized

Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academy Press, 2010.

Vitamin D: Biochemical Functions The body uses Vitamin D for a number of functions:

• Calcium absorption in the gut• Maintains calcium and phosphate serum concentration for normal

mineralization of bones• Used in bone growth and remodeling• Modulation of cell growth• Modulation of protein coding genes

•proteins involved in cell proliferation, differentiation, and apoptosis

• Neuromuscular and immune function• Reduction of inflammation

Vitamin D: Biochemical Functions• Vitamin D is measured in the body by serum 25(OH)D

concentrations in the blood.

• This serum level is the indicator for Adequate Intake (AI) of Vitamin D.

Vitamin D: Mechanism of AbsorptionMetabolic Pathway

• From skin/digestive tract D3 enters the circulatory system

• Accumulates in the liver and undergoes the first hydroxylation: 25(OH)D

• Then moves to the kidneys and undergoes another hydroxylation into the biologically active form of Vitamin D: 1, 25(OH)2 D

http://www.nature.com/nrc/journal/v7/n9/fig_tab/nrc2196_F1.html

Vitamin D: Interactions• Vitamin D deficiencies are the more common interaction or lack of,

however rare, it is possible to intake too much, Hypervitaminosis D, and have it reach upper intake levels.

• Symptoms (non-specific) include:• Anorexia• Weight loss• Polyuria• Heart arrhythmias• Increased calcium levels in the blood (that can lead to):

• Vascular and tissue calcification, that damages the heart, kidneys, and blood vessels

• Kidney stones (in postmenopausal women)

Vitamin D: Interactions• Vitamin D intoxication (VDI) is another possible diagnosis when serum

25(OH)D levels are above the upper intake levels.• This is primarily caused in pediatrics who are being treated for Rickets

without having serum 25(OH)D levels checked before treatment.• VDI is indicated by hypercalcemia, depending on the severity of

hypercalcemia symptoms can be observed in:• GI, renal, central nervous, cardiovascular, and musculoskeletal

systems• Eyes and skin

Vitamin D: Toxicity TreatmentHypervitaminosis D and Vitamin D Intoxication

• Correct hypercalcemia• Discontinue intake of Vitamin D• Switch to low Calcium/Phosphorus diet

• IV fluids• Loop diuretics• Glucocorticoids or Prednisolone (steroids)• Calcitonin (hormone reducing blood calcium levels)• Possible hospitalization for treatment and observation (if VDI is severe)

Conclusion• Overall Vitamin toxicity can be either very rare or highly

dangerous. • Hypervitaminosis A, C, E, or D can lead to serious

problems as previously stated.• Vomiting, diarrhea, stomach cramps, skin

discoloration, intracranial pressure, teratogenic effects, heart arrhythmias, kidney stones, and increased hemorrhaging (just to name a few).

• Take home message: Take vitamin supplements when needed and as directed. AND…

There is no such thing as free lunch

Thanks for reading.

Vitamin A Sources• http://www.nlm.nih.gov/medlineplus/ency/article/002400.htm• http://ods.od.nih.gov/factsheets/VitaminA-HealthProfessional/#h2• https://www.ebi.ac.uk/interpro/potm/2005_6/Page2.htm• http://www.healthaliciousness.com/articles/food-sources-of-vitamin-A.php• http://www.fao.org/docrep/004/y2809e/y2809e0d.htm#bm13.8• http://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiency-dependenc

y-and-toxicity/vitamin-a• http://flipper.diff.org/app./items/info/6430• http://emedicine.medscape.com/article/819426-clinical• Gropper, Sareen S., and Jack L. Smith, 2013, Advanced Nutrition and Human Metabolism, Wadsworth,

Belmont, CA, 371 p.

Vitamin C Sources • Maiken Lindblad , Pernille Tveden-Nyborg and Jens Lykkesfeldt. Regulation of Vitamin C

Homeostasis during Deficiency. Nutrients 2013, 5(8), 2860-2879; doi:10.3390/nu5082860• http://www.drugbank.ca/drugs/DB00126• http://jama.jamanetwork.com.libproxy.unm.edu/article.aspx?articleid=189543• http://eds.b.ebscohost.com.libproxy.unm.edu/eds/detail/detail?sid=dac8655b-9212-4093-83c3-8

07c56f908ee%40sessionmgr198&vid=0&hid=111&bdata=JnNpdGU9ZWRzLWxpdmUmc2NvcGU9c2l0ZQ%3d%3d#db=e000xna&AN=398814

• http://www.annualreviews.org.libproxy.unm.edu/doi/abs/10.1146/annurev.nu.14.070194.002103• http://www.mdpi.com/2072-6643/5/8/2860/htm• http://ajcn.nutrition.org/content/73/1/93.full• http://www.wjgnet.com/1007-9327/13/4716.pdf• http://www.ncbi.nlm.nih.gov/pubmed/6940487

Vitamin E Sources • http://www.hsph.harvard.edu/nutritionsource/vitamin-e/• https://www.uic.edu/classes/phar/phar332/Clinical_Cases/vitamin%20cases/vitamin%20E/Vit%

20E%20Physiology.htmhttp://healthyeating.sfgate.com/can-happen-someone-taking-excessive-amounts-vitamin-supplements-7485.html

• http://www.livestrong.com/article/417483-what-does-vitamin-e-do-for-the-body/• http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/vitamine.html• http://www.ncbi.nlm.nih.gov/pubmed/11722951• http://ajcn.nutrition.org/content/74/6/714.long

Vitamin D Sources• http://www.merckmanuals.com/professional/nutritional-disorders/vitamin-deficiency-dependenc

y-and-toxicity/vitamin-d

• http://www.nal.usda.gov/fnic/DRI/Essential_Guide/DRIEssentialGuideNutReq.pdf Vitamin D, p. 225-234

• http://www.nature.com/nrc/journal/v7/n9/fig_tab/nrc2196_F1.html

• http://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/#en2

• http://www.turkishjournalpediatrics.org/?fullTextId=1031&lang=eng, Ozkan, B., Hatun, S., and Bereket, A. Vitamin D Intoxication. Turkish Journal of Pediatrics. 2012, 54:93-98.