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Increased Needs:

pregnancy, lactation

DM

Alcohol, IBD

Clinical Connections

wound healing

cholesterol: lipid lowering effects of pantethine

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Burning Foot syndrome:

neuritis w/ burning sensation, worse w/ warmth, bettwe w/ cold

Skin irritation, vomiting, fatigue weakness cramping

Rare, only in severe deficiency

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Shares a transporter w/ biotin & lipoic acid (possible competition)

OCPs may increase need

Pantethine (B5 derivative) w/ statins or nicotinic acid increases lipid lowering effects

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Sensitive to heat & freezing, also to acid & alkaline environments

processing / refining grains will cause loss

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Nearly all plant & animal foods (pantos)

Beef liver (high)

sunflower seeds

trout, chicken,

avocado, sweet potato

lentils

eggs

Endogenous: microbial synthesis in colon (amount absorbed is unclear)

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Coenzyme A (CoA) is made from B5

Energy production: is involved in citric acid cycle in the form of acetyl-CoA & succinyl CoA

Nutrient metabolism: role in synthesis of essential fats, cholesterol, steroid hormones, vitamins A & D

Acetylation: introduces an acetyl functional group

acetylcholine synthesis - BRAIN function !

acetylation of histones enhances gene expression & promotes transcription

sugar, protein, some drugs - detox

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Pantothenic Acid

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Few

Dimercaprol (chelating agent): can bind w/ certain metals such as iron & selenium , forming a complex that is toxic to kidneys

Valproic acid (anticonvulsant drug) & cisplatin (chemotherapeutic agent)

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Cancer: shown protective effect of higher selenium level, however no benefit shown w/ supplementation

Type II DM: some evidence has shown may increase risk of type II DM

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primarily occurs in areas where selenium does not occur in soil i.e. China, central Africa , parts of Europe

Keshan Disease: cardiomyopathy, CHF

infection w/ cozxackie virus = a cofactor -> lack of selenium makes the virus more virulent

Kashin-Beck disease: osteoarthropathy

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Over 25 selenoproteins -> most function as antioxidants

Glutathione Peroxidase: catalyzes removal of hydrogen peroxides, selenium is an integral part of this enzyme

Selenoprotein P: transports selenium to tissues & acts as an antioxidant in the blood

Methionine Sulfoxide Reductase (Selenoprotein R): reduces oxidized methionine, created when free radicals oxidize methionine residues in protein (damages the protein)

Theioredoxin Reductase & more

Other selenoproteins involved in functions such as maintaining / inducing cytochrome P450 system, DNA repair, muscle growth, enzyme activation, immune function, etc.

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Does not require digestion, efficiently absorbed in small intestine

Absorption enhanced by: vitamins A, C, & E

Absorption inhibited by: heavy metals & phytic acid

Storage: stored in relatively high amounts in thyroid, kidneys, liver, heart, pancreas, muscle, lungs, brain, bones & RBC

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Brazil nuts (Richest source)

Meats

Broccoli

Wheat

Garlic

Eggs

Seafood (unless contains mercury)

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Complimentary action w/ Selenium

Higher concentrations of one can reduce effects of lower concentrations of the other

Also complementary w/ Vit C

Vit C can regenerate vitamin E after it's oxidized

Polyunsaturated fatty acids

Requirement for Vit E increases or decreases when the amount of pUFA goes up or down

Vitamin E inhibits B-carotene absorption and metabolism

Impairs vitamin K abs & metabolism

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Rare
Occurs in

Premature infants

Fat malabsorption states (cystic fibrosis)

Hepatobiliary disorders

Severe malnutrition

Genetic defects affecting a-tocopherol transfer protein

Smokers

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Alkylating agents & anti-tumor antibiotics

Anticoagulants & anti-platelet drugs, herbs, & supplements

Cytochrome P450 substrates

Statins & niacin

Vitamin K

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CVD:

inhibits oxidation of LDL

may inhibit platelet aggregation, prevent blood from clotting

Diabetes Mellitus

Cancer: theoretically due to antioxidant properties

Eye Health:

may slow progression of age-related macular degeneration if taken w/ vitamin C, beta-carotene, zinc and copper

Cataracts

Alzheimer's: supplementation did not slow progression of Alz

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Antioxidant role:

protects membranes from destruction by preventing oxidation of unsaturated fatty acids in the phospholipids of membranes

Free radical termination

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Superior sources: Unprocessed plant oils:

wheat germ oil (highest amount)

sunflower, safflower, canola, olive cottonseed whole grains, legumes, nut butters, some fruits & veggies

High fat meats (inferior sources)

Vit E is destroyed by air, light and heat so processed oils, roasted nuts will not contain active form

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Tocopherols: have saturated side chains

Tocotrienols: have unsaturated side chains

Only alpha-tocopherol has biologic activity

RRR-a-tocopherol = most biologically active form

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Cold & Flu prevention

promotes chemotaxis & proliferation of macrophages & lymphocytes

increases activity of NK cells

antihistamine

many studies show Vit C has not been shown to prevent the common cold or reduce its symptoms but can reduce duration of symptoms

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Strong inverse association between plasma ascorbic acid & mortality from all causes, CVD & ischemic heart disease

Higher vitamin C levels associate w/ decreased risks of cancer & all causes of mortality

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Scurvy: < 10 mg vitamin C/ daily for 1 month can lead to symptoms
plasma concentrating < 0.2 mg/dL

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Antioxidant
Pre-oxidant activity

In vitro at very high concentrations, but in normal physiological concentrations, unlikely

High dose IV vitamin C - used for adjunctive treatment in cancer

Reducing agent

Maintains iron & copper atoms metalloenzymes in their reduced state

These metalloenzymes catalyze rxns involved in

collagen synthesis

carnitine synthesis

tyrosine synthesis + catabolism

NT synthesis

hormone synthesis

Microsomal Metabolism

hydroxylation rxns that help the liver's detoxification of exogenous substrates or xenobiotics- drugs, carcinogens, pesticides, food additives, pollutants, etc

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Vit C w/ bioflavonoids

no evidence of increased absorption

Ascorbic acid & metabolites (ESTER-C)

no evidence of increased absorption

gentler on GI, non-acidic

Ascorbyl palmitate

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Fruits & Vegetables: especially asparagus, papaya, oranges, cantaloup, cauliflower, broccoli, brussels, green peppers, grapefruit, kale, lemons, strawberries, kiwi, limes, banana, pineapple, potato, rose hips

Also very high in buckwheat leaf juice & adrenal gland

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Ascorbic acid & dehydroascorbic acid (DHAA)

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Has the potential to affect how the body metabolizes B vitamins. May be increased for dietary folate, B6, B12

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Morning Sickness: considered a 1st line treatment for nausea & vomiting of pregnancy (don't take on empty stomach)

Premenstrual Syndrome: some studies suggest efficacy w/ high doses

Depression: appears helpful, probably as part of a B-complex

remember, OCPs deplete B6 and many other B's

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Associated with

Increased risk of immune dysfunction

CVD

systemic inflammation

cognitive decline & alz

Depressive disorders

cancer, kidney stones

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Ethanol: impairs conversion of pyridoxine & pyridoxamine to PLP & acetaldehyde degrades PLP

Inhibition of activity: long-term NSAID use, anticonvulsants, anti-tuberculosis drugs, L-dopa, OCPS (have na impact on many micronutrients)

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Plant:

Pyridoxine & pryidoxine phosphate

Nuts & seeds: sunflower seeds, walnuts, hazelnuts, pecans

Fruits & vegetables: bananas, potatoes, avocados, spinach , kale

Legumes: Soybeans, lentils, chickpeas, lima beans

Whole grains: what germ, buckwheat

Animal:

Pyridoxal & pyridoxamine & phosphorylated forms

Especially fish, beef, pork, chicken

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Nervous system

Component of NT synthesis

decarboxylation of GABA, serotonin, dopamine

Co-enzyme for 100s of enzymes

Transamination (transfers an amino group)

Coenzyme for ALT & AST -> key to liver function

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Active form: Pyridoxal 5-phosphate (P5P)

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CVD: elevated homocysteine is directly correlated w/ increased risk of CVD

May decrease cancer risk by liberating foalte

B12 deficiency is associated w/ increased risk of AL=lz & Dementia

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Early: megaloblastic anemia + elevated homocysteine

Late: loss of coordination, balance, sensation changes in extremities, irritability, memory problems, psychosis ,dementia

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Meds that reduce acidity

Can reduce release of protein bound B12

Can also lead to SIBO , flora competes for B12 absorption

PPIs especially

Metformin, Cholestryamine, Cochicine, some antibiotics

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Elevated homocysteine or MMA

Folate deficiency symptoms because of folate trap - folate not in a usable form

Low energy

Numbness & tingling of the hands or feet

memory loss

depression/ mood issues

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Therapeutic applications - Potential Problems 

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Therapeutic applications - Potential Problems 

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Hypochlorhydria (acid-reducing medications, aging)

stomach acid is necessary for the release of B12 from food

bacterial overgrowth (bacteria also use B12)

H. Pylori Infection

can cause atrophic gastritis or ulcers & can also lead to SIBO

Loss of gastric parietal cells that make intrinsic factor

autoimmunity to those cells or to intrinsic factor (pernicious anemia)

Hashimoto's

Pancreatic insufficiency:

Cobalamin remains bound to R protein

Malabsorption

Impairs absorption from food (Celiac, other IBDs)

Surgeries for IBD

(Crohn's, UC) removing terminal ileum removes the absorption site for B12

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Stomach- key!

Stomach acid (HCL/Hydrochloric acid) & pepsin free B12 from food

Then the free B12 binds to R proteins

Duodenum

R proteins are hydrolyzed by proteases -> releases free B12

Free cobalamin binds to intrinsic factor in the small intestine

Terminal Ileum (Distal Small Intestine)

Intrinsic factor-B12 complex binds to receptors is absorbed by endocytosis

Note- many chances for issues to come up!

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Animal (main source):

Organ meats & some shellfish

Dairy

Less bioavailable in eggs

Plant/Fortified foods:

Nutritional yeast

Fermented beans & vegetables

Nori/ seaweed has substantial amounts

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Cofactor roles

Helps convert homocysteine to methionine as cofactor methionine synthase

Converts methylmalonic CoA to succinyl CoA in mitochondria as a cofactor for L methylmalonic CoA mutase

Produces hemoglobin, indirectly contributes to DNA synthesis

Nutrient metabolism & energy production

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Major forms:

Meythlcobalamin: active form

Cyanocobalamin: common supplemental form

5'Deoxyadenosylcobalamin: active form

Hydroxycobalamin

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Macrocytic (megaloblastic) Anemia

High MCV< high MCH, elevated homocysteine

Fatigue, weakness, HA's, trouble concentration, heart palp

Oxygen carrying capacity is reduced

Impaired DNA Synthesis

Other cells w/ rapid turnover will not work well,

shortened villi & thinning of mucosa in SI -> diarrhea + malabsorption

Increased risk of neural tube defects in pregnancy

Depression/ Anxiety/ Alzheimer's

Low levels of folate related to Alz

Low levels of folate AND B12 related to depression

Elevated homocysteine - above issues + cardiovascular

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Plant:

Leafy greens: spinach, kale, aspragus, broccoli

Legumes: lentils, black0eyes peas, soy beans, kidney beans

Whole grains: rice germ, wheat germ, barley

Nuts & seeds: walnuts, hazelnuts, almonds

Animal:

Mainly beef liver

Bacterial production

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Ethanol: inhibits digestion & absorption

Methotrexate (used for autoimmune diseases) is a folate agonist, inhibits DHFR

Toxicity: 1000 ug from fortification can mask megaloblastic anemia in B12 deficicncy, will resolve the anemia but not the B12 deficiency

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B12, B2 work w/ SAM regeneration pathway, B6 downstream

Zinc is needed to digest folate

Folate trap: occurs w/ low B12

Low B12 -> affects methionine reductase -> traps folate in a form that's not usable by the body! (pay attention to B12 levels!)

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Labs

RBC folate: reflects folate stores, better indicator of folate levels but

Serum folate: reflects diet

Altered needs:

pregnancy, lactation, malabsorption (anything that impairs GI function), potentially MTHFR variant carriers

Prevention*

Adverse pregnancy outcomes: neural tube defects, CV malformation, orofacial clefts

CVD: inversely correlated w/ CVD< elevated homocysteine directly correlated

Cancer: may increase or decrease risk

Alzheimers

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Folate lost w/ heat, oxidation, UV light

Folic acid = more heat stable, better absorption (near 100% absorption if taken away from food)

Raw foods w/ folate like greens will increase bioavailability for those at risk

Absorption: mixed diet folate: 80% available compared to folic acid

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Helps break down homocysteine

Necessary for DNA repair & gene expression

Nutrient metabolism & energy production

Hematopoiesis

Deeper dive:

Folate is a methyl carrier - 5MTHF transfers a methyl group to homocysteine via B12 to generate methionine --> SAM

SAM is involved in many rxns!

neural function, catecholamine synthesis (dopamine, NE, epinephrine)

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Folate is not folic acid!

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Facial dermatitis (red, scaly)

Anorexia, nausea, alopecia (body-wide), brittle nails, myalgias

Depression, lethargy, peripheral neuropathy, seizures, ataxia

Diabetes: deficiency causes impaired glucose metabolism, this is why biotin will be in blood sugar supplements

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Multiple Sclerosis: high-dose biotin may result in clinical improvement

Alopecia & Onychorrhexis: hair loss may improve, brittle nails may be strengthened

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Altered Needs:

pregnancy, lactation, high raw egg white consumption

smoking, liver disease, inflammatory bowel disease, alcohol use disorder

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Panothenic acid & ALA compete for the same carrier (SMVT)

Avidin in raw egg whits binds biotin tightly -> effect eliminated by cooking egg whites

Alcohol use disorder: may decrease absorption

Antibiotics: interfere w/ GI absorption

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Plant:

Nuts & seeds: walnuts, pecans, almonds

Whole grains: rice bran, barley, oatmeal

Legumes: soy beans, peanuts, black eyed peas

Animal

Liver, dairy, egg yolk, fish, meat

Endogenous:

Bacterial synthesis in colon by microbiome

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Coenzyme for carboxylases that catalyze metabolic rxns -> nutrient metabolism & energy production

Gene expression: biotinylation of histones -> uncoils them & makes them available for transcription

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Decreased niacin levels associated w/ increased risk of some cancers

CVD: lipid-altering agent,

2-6 qd used to treat high cholesterol (nicotinic acid form)

Some evidence for reduced risk of MI

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If given w/ statins --> increases risk of myopathy & rhabdomyolysis

Alcohol use disorder -> decreased conversion of Trp

OCPs increase efficiency of B3 synthesis from Trp -> reduces need!

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Deficiency: Pellagra (rare)
Altered needs:

pregnancy, lactation, corn based diet (without proper prep),

bariatric surgery, chemo, malabsorption (chronic diarrhea, IBD, etc), alcohol use disorder

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Can be synthesized from tryptophan (60 mg tryp = 1 mg niacin)

Removed from refined grains

In corn, not released by digestion unless treated w/ lime water/ alkaline / acidic solution

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Plant:

Nuts & seeds: sesame seeds, sunflower seeds, pine nuts, almonds

Whole grains: rice brain, wheat bran, wild rice

Legumes: peanuts, split peas

Animal:

Fish, liver, meat, poultry, eggs

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Dietary precursor of NAD (nicotinamide adenine di-nucleotide)

NAD+/ NADP as co-enzymes (> 400 rxns!)

Oxidizing / reducing agent that enables macronutrient metabolism & energy production

Beta oxidation

Alcohol oxidation

Regenerate Vit C & Glutathione

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Two forms:
Nicotinic acid: more common in foods
Nicotimamide: more common in supplements

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Decreased thiamin levels associated w/

increased risk of cataracts

altered glucose metabolism in the brain -> Alzheimer's

rapidly dividing tumors

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Severe deficiency: Beriberi
Altered needs:

fever, pregnancy, location, growth in adolescence, intense physical activity, malnutrition

older adults, malaria, bariatric surgery

alcohol use disorder

malabsorption issues

Excessive loss seen in kidney failure w/ hemodialysis, diuretics, alcohol use disorder

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Thiaminases found in some raw fish can cleave thiamin --> inactivate it & reduce bioavailability

Oxidized by polyhydroxyphenols found in coffee, tea, blueberries, black currants, brussel sprouts, red cabbage

Prevent this with antioxidants like Vitamin C

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Active Form: Thiamin Diphosphate TDP

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Very unstable, sensitive to heat & alkaline environment (pH> 8)

Baking, pasteurizing or boiling foods fortified w/ thiamin can reduce its content up to 50%

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Plant sources (free)

Nuts & seeds: sunflower seeds, pine nuts, brazil nuts

Legumes: soy beans, peanuts

Whole grains : wheat germ, buckwheat, oatmeal

Fortified foods

Animal sources (phosphorylated):

meat

poultry

fish

pork especially

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Energy production & nutrient metabolism

Coenzyme role: helps metabolize carbs, BCAAs, fatty acids

Nervous System Role:

Helps convert Acetyl CoA -> Acetylcholine

Acetylcholine is a NT -> key part of our brain, causes muscles to contract, activates pain responses, regulates endocrine & REM sleep

Myelin synthesis (requires Acetyl CoA)

NT release

Sodium regulation / transport, chloride activation