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- the different families/forms of fat soluble vitamins
- eg. vitamin A has at least six vitamer chemicals that all qualify as "vitamin A", each with slightly different property
- e/a set of vitamers has some forms that are active & some forms that contribute to toxicity
Short-chain Fatty Acids
- a sub-group of fatty acids with aliphatic tails of 2-6 carbons
- they are produced in small amounts when dietary fiber is fermented in the colon
- they are primarily absorbed through the portal vein during lipid digestion (while long-chain fatty acids are packed into chylomicrons & enter lymphatic capillaries)
- eg. Formic acid. Acetic acid, Butyric acid, Propionic acid
Medium-chain Triacylglycerides (MCTs)
- medium-chain (8-10 carbons) fatty acid esters of glycerol
- they passively diffuse from the GI tract to the portal system (longer fatty acids are absorbed into the lymphatic system)
- they don't require modification like long-chain fatty acids or very-long-chain fatty acids nor do they require bile salts for digestion
- *malnutrition patients are treated with MCTs because they do not require energy for absorption, utilization, or storage
- are found in palm kernel oil, coconut oil, & camphor tree drupes
Where does ALL absorption of fat soluble vitamins occur?
- the small intestine
- except for some forms of vitamin K (menaquinones) produced by bacteria & absorbed in the COLON
- digestion + absorption of fat soluble vitamins requires normal digestion of fat by pancreatic enzymes & micelle formation by bile acids
- fat soluble vitamins in vegetables or fruit eaten without fat have REDUCED bioavailability
- family = retinoids, which refers to retinol, metabolites in the body, & synthetic analogs
- it plays a role in reproduction & bone growth
What role does vitamin A play in vision?
- the retina requires retinal to adapt to dim light because 11-cis-retinal is a critical part of the rhodopsin molecule of the rods
- also retinoic acid is required for normal corneal differentiation
How does a vitamin A deficiency affect eyesight?
- it can cause diminished night vision
- dryness (xeropthalmia)
- Bitot’s spots (accumulation of keratinized tissue on the cornea) which if left untreated will lead to blindness
What role does vitamin A play in cell division & differentiation?
retinoic acid is required for gene expression of enzymes & structural proteins
What effect does Vitamin A deficiency have on the immune system?
vitamin A DEFICIENCY increases the risk of viral ailments such as measles or respiratory infections
How do carotenoids acts as antioxidants?
- an example would be the role of leutine in retina: it scavenges free radicals generated during phototransduction
- *age related Macular Degeneration is more likely to occur in people deficient in leutine & other pigments in the retina
What are the two dietary sources of vitamin A?
- 1. Vitamin A: a family of compounds related to Retinol (retinol itself = pre-formed vitamin A)
- 2. Provitamin A Carotenoids: precursors that can be converted to vitamin A in the intestine + elsewhere
Out of the 600 carotenoids identified, what three are provitamin A carotenoids that are cleaved to form retinol?
- 1. α-carotene
- 2. β-carotene
- 3. β-cryptoxanthin
- aka out of all the carotenoids only 3 form vitamin A
What are the biological properties of non-provitamin A carotenoids?
- they protect against cancer
- there's no vitamin A activity involved
- eg. lutein, lycopene, & zeaxanthin
provitamin A carotenoid cleavage
- central cleavage --> creates vitamin A
- eccentric cleavage --> creates 2 molecules that don't have vitamin A activity
- this process is regulated by vitamin A stores THEMSELVES
- ingesting retinol/pre-formed vitamin A is more efficient than central cleavage of carotenoids
What food sources contain pre-formed vitamin A?
- animal foods: [polar bear] liver, meat, poultry, fish, dairy, eggs, animal oils, & fortified foods such as cereals
- this pre-formed vitamin A exists as retinyl esters or retinol
- it naturally occurs in milk but removing fat (making skim milk) takes out the vitamin A --> it is later fortified in skin milk
- is not added back in whole milk because it's already present
What food sources contain provitamin A carotenoids?
- brightly colored fruits, green leafy vegetables, vegetable oils, eggs, & fortified foods such as cereals
- carotenoids are why egg yolks are yellow
How is Retinol absorbed?
- retinol absorption is carrier mediated & facilitated by pancreatic lipase + bile
- transport from the intestine to the liver occurs in chylomicrons
- about 70-90% of pre-formed vitamin is absorbed
How is β-carotene absorbed?
- passively in micelles
- it has poor average absorption of ~10-20%
- however depleted vitamin A stores may up-regulate absorption & central cleavage to vitamin A in enterocytes or other tissues
Which is more readily converted to retinol, β-carotene in supplements or food?
β-carotene in supplements is converted to retinol more effectively than β-carotene in food due to reduced bioavailability in food
Where are approximately 50-80% of body stores of vitamin A?
- the liver
- retinol is released from liver stores bound to retinol binding protein (RBP) or in lipoproteins & secreted into circulation
- retinol binding protein (RBP) is cleared by the kidney
- once in a cell, retinol is converted to its active form retinoic acid
- retinoic acid acts on nuclear receptors
- vitamin A metabolites are excreted in urine & bile if liver stores are high
Why do obese people have LOWER concentrations of carotenoids?
- because it gets sequestered in their large fat stores & can't get out into the circulation
- obese males can also have low sperm levels & vitamin A deficiency can lead to decreased spermatogenesis
Vitamin A Deficiency
- primary deficiency: accompanies protein energy malnutrition (PEM) & zinc deficiency
- secondary deficiency: low fat diets, disorders of fat digestion/absorption such as pancreatic insufficiency, low bile production, SI diseases
- generally occurs with poor diet, malabsorptive disorders, or parasite infestation
- mild deficiency treatment: oral supplements + correcting dietary or other reasons for deficiency
- moderate to severe deficiency treatment: parenteral vitamin A
Who would be a good candidate for intermittent parenteral vitamin A?
patients with fat malabsorption syndromes
Vitamin A Deficiency Chart
- stunting: kids that have an abnormally low height for weight at a certain age
- wasting: low weight for a height at a certain age
Vitamin A Toxicity
- occurs with excess ingestion of pre-formed vitamin A OR w/ impaired excretion of vitamin metabolites
- is almost always due to supplement use, but CAN occur with very high intake of vitamin A containing foods
- is mostly due to chronic excess but acute toxicity can be caused by supplement overdoses
- • Headache, dizziness, loss of muscle coordination, & eventual coma
- • Liver damage -> eventual cirrhosis
- • Teratogenicity
- • Osteoporosis
What is a condition where vitamin A excretion may be impaired?
- Chronic Kidney Disease - RBP is not well cleared by dialysis machines
- this predisposes a person to vitamin A toxicity so supplementation with pre-formed Vitamin A aren't recommended long-term
Why don't provitamin A carotenoids result in vitamin A toxicity?
- because their cleavage to vitamin A can be down-regulated when the body detects enough vitamin A already present
- excess provitamin A carotenoids instead results only in hypercarotenemia (excess pigmentation of skin)
- unlike jaundice, this orange discoloration of the skin doesn't affect the sclerae of the eye - they remain white
What is the relationship between β-carotene supplementation in smokers & lung cancer?
- smokers who take β-carotene supplements have an INCREASED risk of lung cancer
- therefore in general routine supplementation β-carotene is not recommended
- *one condition in which carotenoid supplements might IMPROVE outcome is age related macular degeneration*
Vitamin A Recommendations
- its RDA is based on intake necessary to maintain adequate liver stores of vitamin A
- its UL is based on risk of liver disease & in women of childbearing age the risk of teratogenicity
- there are NO DRI for carotenoids
- it can be found in plants, fungi, invertebrates, & supplements
- if you irradiate mushrooms (fungi) them with UV light [aka give them a tan] they produce Vitamin D2
- this form isn't endogenously synthesized
- it comes from SYNTHESIS IN THE SKIN, animal foods (fatty fish, liver, whole milk, other dairy products), fortified foods (eg. skim milk, orange juice, cereal), & supplements
How is Vitamin D synthesized if not derived from dietary D2 or D3?
- it's made in the skin from 7-dehydrocholesterol (which is the last intermediate before cholesterol is formed) when 7-DCH is hit by solar UVB radiation (UV light)
- this process is regulated BY the amount of vitamin D already stored in the body (in the liver); if a lot is already present 7-DHC isn't converted
25-hydroxyvitamin D [25(OH)D]
- a pre-hormone produced in the liver by hydroxylation of vitamin D3 by cholecalciferol 25-hydroxylase
- *its levels are used to determine a patient's vitamin D status because it is a stable form that can exist for weeks in the body
- it has a half-life of 15 days
1,25(OH)2D [1,25-dihydroxyvitamin D]
- the ACTIVE form of vitamin D made in the kidneys by hydroxylating 25-hydroxyvitamin D
- this active form moves to the intestine & increases absorption of calcium (+ phosphate & vitamin D)
- it's not a good indication of vitamin D status b/c a person will have normal levels until SEVERE deficiency
- half-life = 4-6 hours
Vitamin D Form Order
- Vitamin D2, Vitamin D3, or 7-dehydrocholesterol
- 25(OH)D 25-hydroxyvitamin D (form in the liver)
- 1,25(OH)2D *ACTIVE FORM
- 1,25-dihydroxyvitamin D
- (formed in the kidney)
What stimulates the hydroxylation of 25-hydroxyvitamin D to the active form of vitamin D, 1,25(OH)2D?
- Parathyroid Hormone
- which itself is secreted from the parathyroid when blood calcium levels are LOW
parathyroid hormone (PTH)
- hormone made by parathyroid gland chief cells that INCREASES blood calcium (opposes the action of calcitonin)
- increases osteoclast activity - bone breakdown & liberation of calcium
- stimulates vitamin D activation in kidney, which stimulates calcium resorption in GI tract & kidney)
- *is a vital hormone
How are vitamin D metabolites excreted?
primarily in bile into the feces, but some metabolites are excreted in urine
Roles of Vitamin D
- the traditional roles include calcium (& phosphorous) homeostasis, bone health, & muscle function [which is heavily dependent on normal intracellular calcium levels]
- vitamin D is also thought to influence cancer (colon, prostate, breast), diabetes type 2, cardiovascular disease (blood pressure), immune function, & depression
- however the dietary recommendations of vitamin D (20 ng/mL) are still based only on its effect on bone health, not on any of its emerging roles
What role does vitamin D play in immune function? Cancer? Diabetes?
- in macrophages, vitamin D stimulates the release of a compound that kills bacteria (eg. tuberculosis)
- vitamin D inhibits angiogenisis in tumors cells & may also regulate apoptosis & cell death
- it may regulate insulin secretion from pancreas or induce insulin sensitivity
What are risk factors for deficiency of vitamin D derived from 7-dehydrocholesterol?
- anything that decreases the skin's ability to synthesize vitamin D:
- 1. aging (impaired synthesis)
- 2. limited sun exposure (no UV rays to convert)
- 3. dark skin (UV rays are less well absorbed)
What are risk factors for dietary vitamin D deficiency?
- Infants who are exclusively breastfed
- Lactose intolerance
- Fat malabsorption
- Obesity (D is also stored in but possibly not release from adipose as well as the liver)
- End stage liver or kidney disease
- Medications such as corticosteroids & anticonvulsants
What is the relationship between body fat & vitamin D levels?
- as body fat decreases, SO does vitamin D
- low vitamin D levels translate to low Calcium levels as a result of poor Calcium absorption
- active vitamin D is what goes to the intestine & increases absorption of Calcium - no Vit D, no Ca2+
- this can lead to secondary hyperparathyroidism, when excessive PTH is secreted to try to compensate for low Calcium levels
What does Vitamin D deficiency cause?
- poor Calcium absorption & therefore low Ca2+ levels
- the PTH secreted to activate vitamin D only functions to increase osteoclast activity & facilitate bone demineralization to maintain Ca2+ levels
- in children this leads to Rickets, & in adults this leads to Osteomalacia
- softening of bones in immature mammals due to deficiency or impaired metabolism of vitamin D, phosphorus or calcium
- can lead to fractures & deformity
- is characterized by growth retardation + bowing of lower extremities
- softening of the bones caused by defective bone mineralization secondary to low levels of phosphorus & calcium
- is characterized by diffuse bone & muscle pain, muscle weakness, & frailty
- long term osteomalacia increases the risk of osteoporosis
- is caused by vitamin D deficiency which can lead to overactive resorption of calcium from the bone as a result of hyperparathyroidism
What do supplements containing calcium & vitamin D protect against?
- bone mineral loss & bone fracture
- they should be considered for those who don't meet dietary goals
How are vitamin D deficiencies treated?
- oral supplementation w/ the doses dependent on severity of deficiency
- hydroxylated forms of vitamin D (at the 1, the 25, or both sites) are prescription medications that can be used for patients w/ parathyroid, liver, or renal disease
What are symptoms of excess vitamin D?
- Calciuria & kidney stones
- Soft Tissue Calcification
- Impaired GI Motility
- Polyuria (excessive urination)
- Polydipsia (excessive thirst)
- this CAN'T be caused from UV exposure - it's caused by supplements or medications
How can vitamin D status be assessed besides by measuring 25-OH vitamin D?
- Calcium levels
- Parathyroid hormone levels
- giving a DEXA scan to check bone mineral density
Vitamin E - BioChem definition
- terminates free radical oxidation of unsaturated fatty acids
- double bonds in PUFAs (poly-unsaturated fatty acids) are good at stabilizing free radicals, meaning they SPOIL quickly
- vitamin E can take up free radicals & prevents PUFAs from spoiling
- the reduced form of vitamin E is regenerated in a reaction using vitamin C & glutathione
- a family of compounds that exhibit the antioxidant activity of α-tocopherol & tocotrienol derivatives
- alpha, beta, gamma & delta forms exist based on different side chain stereoisomers
What type of vitamin E occurs naturally?
- RRR α-tocopherol
- it's the only biologically active form & the only one that contributes to the vitamin E RDA
- ALL α-tocopherol forms contribute to toxicity risk defined by the UL
- other forms are may be present in food to a lesser extent or can be synthesized for use in supplements
What foods contain vitamin E?
- wheat germ, vegetable oils, nuts, seeds, green leafy vegetables, olives, fortified foods (cereal), & supplements
- it is added to some foods to function as an antioxidant
Vitamin E Absorption, Trnsprt, Metabolism
- it is absorbed as part of micelles in the small intestine
- it is secreted from enterocytes as part of chylomicrons, where it can be transferred to other lipoproteins, enter cell membranes, or be taken up by the liver
- from the liver vitamin E can be secreted straight into the plasma or as part of VLDL (lipoproteins)
- in addition to liver, it can also be stored in adipose tissue
α-tocopherol transfer protein (TTP)
- a liver protein that facilitates transfer of α-tocopherol from the liver into the plasma
- genetic abnormalities of TTP result in an inability to export vitamin E from the liver & therefore systemic deficiency of vitamin E even though adequate stores may be present
What are the biological roles of vitamin E?
- 1. Antioxidant - it prevents RBC hemolysis & lipid peroxidation (is reduced by vitamin C)
- 2. Immune Function
- 3. DNA Repair
What is the RDA for vitamin E based on?
the amount necessary to prevent hemolysis of red blood cells in response to oxidative stress
What puts someone at RISK for vitamin E deficiency?
- Dietary insufficiency
- Premature infants w/ very low birth weight
- Fat malabsorption
- α-tocopherol transfer protein (TTP) defects
- a rare autosomal recessive disorder that interferes with the normal absorption of fat + fat-soluble vitamins from food
- it is caused by a mutation in microsomal triglyceride transfer protein resulting in deficiencies in the apolipoproteins B-48 and B-100 used in the synthesis and exportation of chylomicrons & VLDL (respectively)
What are SYMPTOMS of vitamin E deficiency?
- 1. Peripheral neuropathy
- 2. Spinocerebellar Ataxia with vitamin E deficiency (AVED) due to TTP mutations
- 3. Myopathy
- 4. Retinopathy
- 5. Immune dysfunction
- 5. RBC hemolysis
Vitamin E Excess
- caused by: OVER-SUPPLEMENTATION
- results in: bleeding (hemorrhage due to a possible interaction w/ vitamin K - mainly an issue in surgery), worsened risk or outcome for some cancers, & an increased risk of mortality if levels go above 400 IU/day
How is vitamin E excreted?
- in bile and subsequently in feces
- some is also lost in urine & through sebaceous gland secretions
Vitamin K - BioChem definition
- a cofactor in γ-carboxylation required for prothrombin & other blood clotting factors to function
- is PRO BLOOD CLOTTING
- is given to premie babies who lack it to prevent hemorrhaging disease
What are the 2 forms of Vitamin K?
- 1. Phylloquinone (K1): common US form from plants
- 2. Menaquinones (K2, MK): come from fermented foods, animal feeds
- *side chains are what distinguishe the two forms
What foods are good sources of phylloquinone (K1)?
- Green leafy vegetables (kale)
- Green vegetables (broccoli)
- Vegetable oils (eg. soy bean but not olive oil)
- Fortified foods (breakfast cereal = main source for kids)
What foods are good sources of menaquinones (K2)?
- Some fermented foods
- Animal foods
- Intestinal bacteria ("we" can make it, just like we can synthesize D3)
Vitamin K is absorbed from the intestinal lumen in ________, secreted from enterocytes with dietary fat in ___________, transported in the serum in __________, stored in the ________, & its metabolites are excreted primarily in ____.
- absorbed from intestine lumen in: micelles
- secreted from enterocytes as: chylomicrons
- serum transported in: lipoproteins
- stored in: the liver
- excreted in: bile
What reaction is vitamin K a cofactor for?
- the γ-carboxylation of glutamic acid to form carboxyglutamic acid (Gla)
- the carboxylation allows calcium to bind to vitamin K dependent blood coagulation factors (II, IV, VII, X, Protein C, & Protein S) & clot blood
- after acting as a cofactor vitamin K exists in epoxide form
- warfarin blocks the regeneration of active vitamin K through the vitamin K cycle, lengthening the time it takes for a blood clot to form
- an anti-coagulant given to people who get blood clots easily
- consistent intake of vitamin K is recommended when on the drug
- a person's vitamin K cycle polymorphisms predict dosage & response to warfarin
How are Vitamin K levels measured?
- using prothrombin time: a measure of the extrinsic pathway of coagulation
- the body regulates the production of clotting factors, therefore excess vitamin K doesn't result in excessive clotting
- blood levels reflect recent intake not stores, which is why such info is rarely used to assess vitamin K levels
Risk Factors for Vitamin K Deficiency
- Liver disease (difficulty absorbing/storing the vitamin)
- Fat malabsorption
- Malabsorptive disorders
- Poor intake
- Surgical resection of the small intestine
Symptoms of Vitamin K Deficiency
- Bleeding abnormally
- Embryopathy caused by warfarin (a teratogen) use or severe deficiency in mothers
- Disorders of soft tissue and bone calcification (caused by warfarin)
- *people at greatest risk are babies born in home births
- caused by warfarin use & severe vitamin K deficiency
- Chondrodysplasia punctata (bony deformities with excess calcification
- Nasal hypoplasia (depressed nose bridge)
- Mental retardation
What is the UL of vitamin K?
- it has NO UL & no toxicity
- high intake of vitamin K does NOT promote abnormal coagulation