W14: Vit D, K, Cartenoids, Flavonoids, Polyphenols

Question 1

Which of the following statements is not true regarding vitamin D:

a. Vitamin D is synthesized in the skin in the presence of sunlight.
b. Vitamin D first goes to the liver to get hydroxylated at its 25th position, resulting in 25-hydroxyvitamin D₃.
c. 25-hydroxyvitamin D₃ goes to the kidneys to get hydroxylated at the 1st position. This forms the active form, ergocalciferol.

Answer 1

c. This forms the active form, calcitriol (everything else a-c is true).

When UVB rays (sun) hit the skin, it turns 7-Dehydrocholesterol (in the skin) into vitamin D3 (cholecalciferol).
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Cholecalciferol binds to vitamin D binding protein and is transported to the liver to be converted to 25(OH)VD (calcidiol), the storage form of vitamin D in the body. The enzyme involved here is 25-hydroxylase.
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When needed, 25(OH)VD is converted in the kidneys (with the help of 1alpha-hydroxylase) to the active form of vitamin D, calcitrol (1,25,dihydroxyvitamin D). ** This mainly occurs in the kidneys but also takes place in immune cells such as lymph nodes, alveoli, and alveolar macrophages (why optimal vitamin D is essential for COVID/lungs).

**Vitamin D is transported in chylomicrons

Question 2

The Vitamin D RDA for adults 19+ years is _____IU:

a. 400
b. 500
c. 600
d. 800

Answer 2

c. The RDA for adults 19 years and older is 600 IU (15 mcg) daily for men and women, and for adults >70 years it is 800 IU (20 mcg) daily.
* Vitamin D is usually measured in IU’s. 1mcg = 40 IU of vitamin D or calciferol.

UL: The Tolerable Upper Intake Level is the maximum daily intake unlikely to cause harmful effects on health. The UL for vitamin D for adults and children ages 9+ is 4,000 IU (100 mcg).

Question 3

Calcitriol (the active form of vitamin D) goes to the small intestine to tell the protein calbindin to absorb more Ca+ from food. What hormone plays a role in pumping out more calcitriol when this is needed?

a. aldosterone
b. parathyroid hormone
c. thyrotropin releasing hormone
d. calcitonin

Answer 3

b. parathyroid hormone.

When Ca+ goes down, PTH goes up. PTH goes to the kidney to act on the enzyme 1-hydroxylase, which responds by increasing Calcitriol.

Question 4

True or false - Vitamin D is a fat soluble, pro-hormone thats main role is to assist the process of increasing Ca+ absorption from food.

Answer 4

True-ish. It is a pro-hormone and fat soluble. However, while Ca+ regulation was originally thought to be the main purpose of vitamin D, we now know it does so much more, including roles in:

a. cell growth & differentiation
b. Autoimmunity/immune support
c. Ca+/phosphorus maintenance (intestinal absorption, and deposition into the bones, teeth, and cartilage).
d. Bone mineralization/remodeling
e. Neuromuscular function
f. May enhance secretion & action of insulin
g. regulating blood pressure (angiotensin system)
h. apoptosis

Question 5

True or false - Vitamin D receptor is found only on the intestine, bones, and kidneys.

Answer 5

False (though this was once thought to be true). VDR’s are also found on cardiac, muscle, pancreatic/beta cell, brain, hematopoietic, and immune tissues.

*In beta cells a vitamin D deficiency can cause insulin production dysfunction.

Question 6

A vitamin D deficiency in children is called Rickets. In adults, this is known as __________.

Hint, hint - osteo -something

Answer 6

Osteomalacia.

Rickets = bowed legs. 
Osteomalacia = softening of bones due to not mineralizing bones (back pain common).

Question 7

Fun fact - On a blood chemistry panel, providers run a 25-OH-D. This is looking at vitamin D after it comes out of the ________.

a. liver
b. kidneys
c. skin

Answer 7

a. liver (remember in the liver it is hydroxylated at the 25th position, in the kidneys it is hydroxylated at the 1st position).
* the 25 version has a 3 week half life (thus is pretty stable). The 1, 25 version has a short half life, thus is not tested, though this is the usable form. Additionally, the 1, 25 form is really looking at PTH since PTH increases production and activity of 1-hydroxlyase in the kidney which produces the 1, 25 version.

Question 8

Vitamin D toxicity can cause _____________:

a. hypercalcemia
b. hyperparathyroid disorder
c. hyperalbumin (in serum)

Answer 8

a. hypercalcemia (vitamin D increases Ca+ absorption).
* This can cause the following symptoms: fatigue, nausea, vomiting, atherosclerosis, arterial calcification, renal failure, polyurea, polydypsia, calcification of kidneys, and cardiac arrythmias. This can also cause calcification of soft tissues such as organs and blood vessels, possibly resulting in irreversible damage.
* Toxicity can also cause kidney stones, nausea, headaches, weakness, anorexia, frequent urination, weight loss, irregular heartbeat, and weak bones/muscles.
* Most of this information on these cards is from Dr. Walsch. He suggests really thinking about supplementing with vitamin D and suggests if we do we have patients take a low dose with other fat soluble vitamins. Highly recommend listening to his lecture on vitamin D. He questions- are low vitamin D levels seen worldwide protective in some way? Is it immune? Are we contributing to atherosclerosis due to Ca+ increasing by supplementing? Who knows.

Question 9

Vitamin D2, otherwise known as ______ is derived from ______, while vitamin D3, otherwise known as _______, is derived from food. FILL IN THE BLANKS WITH THE FOLLOWING LIST OF WORDS:

Plants, food, cholecalciferol, ergocalciferol.

Answer 9

Vitamin D2, otherwise known as ergocalciferol is derived from plants, while vitamin D3, otherwise known as cholecalciferol, is derived from food and exposure to sunlight.

*Vitamin D2 is a plant or yeast steroid commonly used to fortify milk, while D3 is found from animal sources + sun.

Question 10

Food sources of cholecalciferol include:

a. beef liver
b. cheese
c. egg yolks
d. fish (salmon, tuna, mackerel) and fish oils
e. all of the above

Answer 10

e. all of the above
* Mushrooms are the only plant food known to contain vitamin D. The amount varies widely depending on type and the amount of sunlight exposure during growth.

Question 11

Review: When calcium levels in the blood are low, the body releases ____, which stimulates the kidney to convert 25(OH)D to 1, 25(OH)2D. Elevations in the 1,25 form stimulate the GI tract to increase _____ absorption.

Answer 11

PTH, Calcium.

1, 25 VD stimulates the GI tract to increase calcium absorption rom about 10 to 30% AND phosphorous absorption from about 60 to 80%.

Question 12

Groups with increased risk for vitamin D deficiency (less than 20ng/mL) include (select all that apply):

a. breasted infants
b. older adults
c. obese individuals
d. people with dark skin
e. those with limited sun exposure

Answer 12

a-e

• strict vegetarians and those who have a milk allergy are also at risk.
• 5-30 minutes of sun exposure between 10am-3pm at least twice weekly without sunscreen is suggested.

Question 13

True or false? It is best to take vitamin D with vitamin K for best absorption.

Answer 13

True.

Current evidence supports the notion that joint supplementation of vitamins D and K might be more effective than the consumption of either alone for bone and cardiovascular health.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613455/

Question 14

All of the following are functions of vitamin K except:

a. blood clotting and coagulation
b. bone mineralization
c. regulation of blood calcium
d. hormone regulation

Answer 14

d. hormone regulation

Vitamin K functions as a coenzyme for vitamin K-dependent carboxylase, an enzyme required for the synthesis of proteins involved in hemostasis (blood clotting) and bone metabolism

1) Coagulation – several clotting factors are vitamin K dependent: II (2 - aka, prothrombin), VII (7), IX (9) and X (10), which are all synthesized in the liver. These clotting factors require vitamin K for the synthesis of calcium binding sites, which are required for their activation in the clotting cascade. Vit K is also needed for anticoagulation factor proteins C and S, which are involved in the reduction of clotting within the clotting cascade (to provide checks and balance).
2) Bone Mineralization – Several vit K-dept proteins in bone, including osteocalcin (aka bone GLA protein) and matrix GLA protein; osteocalcin binds calcium to mineralize bone, and matrix GLA protein helps prevent abnormal calcification. Synthesis of osteocalcin is regulated by calcitriol (active vit D).

Think of vitamin K as putting calcium where it belongs (makes calcium binding sites on clotting factors; pulls calcium into bone to mineralize it – by doing this, vit K regulates blood calcium and helps prevent calcification of arteries…..lower vit K status = higher risk of atherosclerosis; vit K can thus be used clinically for CVD support)

https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/
https://lpi.oregonstate.edu/mic/vitamins/vitamin-K
Bryan Walsh vit K lecture

Question 15

_________ is the predominant form of vitamin K from dietary sources while _______ is produced by gut microflora.

a. phylloquinone (K1); menaquinone (K2)
b. menaquinone (K2); phylloquinone (K1)
c. menaquinone (K2); menadione (K3)
d. phylloquinone (K1); menadione (K3)

Answer 15

a. phylloquinone (K1); menaquinone (K2)

K1 = made by plants

K2 = made by gut bacteria (and found in fermented foods); K2 is actually a family of molecules called menaquinones (MKs) - MK-4 through MK-13, (# is based on the length of their side chain). MK-4, MK-7, and MK-9 are the most well-studied menaquinones.

Vitamin K3 (menadione) = synthetic vitamin K which can be converted to MK-4 in the body (MK-4 is also synthesized by humans).

This is why it’s preferred to see K2 (as MK-4 and/or MK-7) in supplements - b/c K1 is readily available in foods (if eating a good diet), most people on SAD likely lack GI K2 production, and K2 may even be more potent than K1. K2 MK-7 is found in natto and has been seen to have increased bio activity vs. MK-4.

(Hark, p. 61)
https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/

Question 16

Why is an injection of vitamin K recommended for newborns?

Answer 16

To prevent ‘vitamin K deficiency bleeding’ (VKDB), which is a potentially fatal cause of bleeding in infants during the first few weeks of life. Infants are born with very little K - it doesn’t cross the placenta well and they lack the necessary gut bacteria to synthesize vitamin K adequately until ~1 week after birth - therefore, the newborn liver is unable to produce adequate levels of coagulation factors, and thus can’t form clots/stop bleeding properly. VKDB is associated with bleeding in the umbilicus, gastrointestinal tract, skin, nose, or as sudden intracranial bleeding (bleeding at undetectable sites contributes to the mortality). VKDB is known as “early VKDB” when it occurs in the first week of life. “Late VKDB” occurs at ages 2–12 weeks, especially in exclusively breastfed infants due to the low vitamin K content of breast milk or in infants with malabsorption problems. To prevent VKDB, a .05-1 mg injection of K1 is given to newborns shortly after birth. Infants born to moms on anticonvulsant meds to prevent seizures/psych illness are at increased risk.

https: //lpi.oregonstate.edu/mic/vitamins/vitamin-K
https: //ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/

Question 17

The AI for vitamin K for adults 19+ is:

a. 90 mcg/day for women; 120 mcg/day for men
b. 75 mcg/day for women and men
c. 60 mcg/day for women and men
d. 120 mcg/day for women; 150mcg/day for men

Answer 17

a. 90 mcg/day for women; 120 mcg/day for men

Up to 19yo, vitamin K reqs are the same for men and women - ranging from 2.0 mcg/day for 0-6 mo to 75 mcg/day for 14-18yo. (The AIs for infants are assuming breastfeeding and prophylactic vitamin K shot at birth)

https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/

Question 18

The TUL for vitamin K is:

a. 1g
b. 2g
c. 3g
d. There is no TUL for vitamin K

Answer 18

d. There is no TUL for vitamin K (including K1 and K2)

Note - Abnormal clotting is not related to excessive vitamin K intake, and there is no known toxicity associated with vitamin K1 or vitamin K2. HOWEVER - high amounts of synthetic vitamin K (K3) can result in hemolytic anemia and liver damage (usually via injection).

Question 19

True or false: vitamin K needs do not increase with pregnancy and lactation.

Answer 19

True - vitamin K needs stay the same in pregnancy and lactation (90mcg/day).

Question 20

An excellent food source of vitamin K is:

a. green leafy vegetables
b. dairy
c. meat
d. colorful root vegetables

Answer 20

a. green leafy vegetables

Other high sources include: natto (K2, MK-7), broccoli, okra, vegetable seed oils (canola, soybean)

Question 21

Vitamin K is absorbed in the _________ and requires bile salts for absorption.

a. duodenum
b. jejenum
c. ileum
d. all of the above

Answer 21

d. all of the above - Vitamin K is absorbed throughout the small intestine & requires bile acids (Vit K best absorbed with dietary fat - i.e. butter/olive oil with leafy greens).

From there, vitamin K is incorporated into chylomicrons, secreted into the lymphatic capillaries, transported to the liver, and repackaged into very low-density lipoproteins for tissue transport.

The body retains about 30% to 40% of an oral physiological dose, while about 20% is excreted in the urine and 40% to 50% in the feces via bile.

https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/

Question 22

Vitamin K deficiency increases the risk of all of the following except:

a. arterial calcification
b. easy/excessive bruising and bleeding
c. decreased bone mineral density
d. diabetes

Answer 22

d. diabetes

Symptoms of vit K deficiency = impaired blood clotting, easy bruising + bleeding (nose bleeds, bleeding gums, blood in urine/stool, very heavy menstrual bleeds)

Arterial calcification b/c excess blood calcium d/t lack of binding

Subclinical deficiency may be associated w/:
Decreased bone mineral density, increased fracture rates, CVD, arterial calcification, inflammation

Question 23

Vitamin K deficiency is rare in healthy adults, but may occur in all of the following cases except:

a. fat malabsorption
b. prolonged antibiotic therapy
c. severe liver disease/damage
d. elderly
e. breastfed infants
f. anticoagulant therapy
g. thyroid dysregulation

Answer 23

g. thyroid dysregulation

• • Prolonged antibiotic therapy = due to the disruption of the intestinal microbiota that produce vitamin K.
• • Severe liver disease/damage = results in lower blood levels of vitamin K-dependent clotting factors and an increased risk for uncontrolled bleeding (hemorrhage)
• • Elderly = malabsorption
• • Breastfed infants = due to the low vitamin K content of breast milk
• • Anticoagulant therapy = Anticoagulants such as Warfarin inhibit a step in the vitamin K cycle - thus preventing vitamin K recycling and contributing to vitamin K deficiency.

Clinical deficiency is considered “rare” bc 1) readily available in food 2) endogenous production and 3) can be recycled via the Vit K cycle. However, according to Bryan Walsh, some research suggests many people may have subclinical vitamin K deficiency (d/t SAD - lack of green leafy veggies; dysbiosis/medication intake - lack of GI vit K2 production).

https://lpi.oregonstate.edu/mic/vitamins/vitamin-K

Question 24

What other nutrient, along with vitamin K, is critical for blood clotting?

a. calcium
b. magnesium
c. zinc
d. copper

Answer 24

a. calcium - The ability to bind calcium ions is required for the activation of the several vitamin K-dependent clotting factors in the coagulation (clotting) cascade (which is a series of events, each dependent on the other, that stop bleeding through clot formation).

MORE DETAILS: 
Clotting factors (plasma proteins, #1-13) are made in the liver; these circulate inactive until injury, which activates the "clotting cascade" (i.e. clotting factor XII (12) activates 11 > 10 > 9, etc...to make fibrin, which is a fibrous mesh that impedes the flow of blood). 

Vit K is needed to add calcium binding sites onto specific clotting factors when these are being made in the liver (the binding of calcium on these sites is part of the activation of the clotting cascade - binding must happen to activate the next clotting factor in the cascade). Specifically, vitamin K allows the formation of calcium-binding gamma-carboxyglutamate (gla) that binds calcium and is required for the activity of factors VII, IX, X, and II (prothrombin), as well as osteocalcin and gla matrix protein.

So if deficient in vit K = can’t make Ca binding sites = decreases clotting capability = increased bleeding (calcium deficiency causes the same issue)

(Bryan Walsh - Vit K video)
Hark p. 61
https://lpi.oregonstate.edu/mic/vitamins/vitamin-K

Question 25

Large doses of which of the below interfere with the actions of vitamin K?

a. vit A
b. vit E
c. vit D
d. a & b
e. b & d

Answer 25

d. a & b - large doses of vitamin A and vitamin E

• • Vit A interferes w/ vit K absorption
• • Vit E may inhibit Vit K-dept carboxylase enzymes, metabolism of MK-4 > K1, and increases hepatic oxidation & excretion of all forms of Vit K. Excess vit E also decreases platelet aggregation (AKA it decreases clotting ability).

Question 26

True or false: Although vitamin K is a fat-soluble vitamin, the body stores very small amounts.

Answer 26

True. While the body has limited ability to store vitamin K, it’s recycled via the vitamin K cycle. The vitamin K cycle allows a small amount of vitamin K to be reused many times for protein carboxylation (via oxidation/reduction), thus decreasing the dietary requirement.

Anticoagulants such as Warfarin inhibit a step in the vitamin K cycle - thus preventing vitamin K recycling and contributing to vitamin K deficiency.

https: //lpi.oregonstate.edu/mic/vitamins/vitamin-K
http: //www.vivo.colostate.edu/hbooks/pathphys/topics/vitamink.html#:~:text=The%20Vitamin%20K%20Cycle,is%20reduced%20to%20vitamin%20KH2.

Question 27

The vitamin K status is reduced by all of the below except:

a. Antibiotics
b. Aspirin
c. Phenytoin/Dilantin
d. Warfarin/Coumadin/Jantoven
e. Xanax
f. Cholestyramine/Questran
g. Orlistat

Answer 27

e. Xanax

• • Antibiotics - can destroy vitamin K producing gut bacteria (consider supp. if antibiotic use is over several weeks & dietary vit K intake is lacking)
• • Aspirin = another of blood thinner (decreases platelet activation), so combining them furthers increases the risk of serious bleeding
• • Phenytoin (Dilantin = anticonvulsant) - anticonvulsants may reduce Vit K levels
• • Warfarin (Coumadin, Jantoven = blood thinner) - inhibits the recycling of Vit K (it’s a vitamin K antagonist), which can lead to Vit K deficiency. People taking warfarin/similar anticoagulants need to maintain a consistent intake of vitamin K because sudden changes in vitamin K intakes can increase or decrease the anticoagulant effect. Most commonly used for atrial fibrillation (A-fib – blood is more prone to coagulation d/t irregular contraction).
• • Bile acid sequestrants (Cholestyramine/Questran, Colestipol/Colestid) - used to reduce cholesterol levels by preventing reabsorption of bile acids, but also reduces absorption of fat soluble vits
• • Orlistat - weight loss drug that reduces absorption of dietary fat (including fat soluble vits). Combining orlistat with warfarin therapy might cause a significant increase in prothrombin time (how long it takes for a blood clot to form)

*In pregnant/breast-feeding women: Warfarin, anticonvulsants (i.e. phenytoin; brand name = Dilantin), anti-tuberculosis drugs (antibiotics - rifampin, isoniazid) can put newborn at increased risk of vit K deficiency

Fun fact - Coumadin = rat poison (kills rats by making them bleed out)

https://ods.od.nih.gov/factsheets/VitaminK-HealthProfessional/
https://lpi.oregonstate.edu/mic/vitamins/vitamin-K#drug-interactions
Bryan Walsh vit K video

Question 28

All of the below supplements are contraindicated with Warfarin (Coumadin, Jantoven) except:

a. Vitamin K
b. Vitamin E
c. Fish oil
d. St. John’s Wort
e. Gingko biloba
f. Bacopa

Answer 28

f. Bacopa

Other contraindicated herbs = Dong quai, garlic, ginseng, coenzyme Q10, cranberry, echinacea, garlic, goldenseal, green tea

Food = high levels of green leafy veggies/other vit K rich foods (i.e. wouldn’t want to do tons of green juicing), grapefruit

Many drugs are also contraindicated with Warfarin - always check interactions!

**Vit K = large quantities of dietary or supplemental vit K can overcome the anticoagulant effect of anticoagulants, thus patients taking these drugs are cautioned against consuming very large or highly variable quantities of vitamin K.

*Experts advise a reasonably constant dietary intake of vit K that meets the RDA (90 to 120 μg/day) for patients taking vitamin K antagonists like Warfarin. Because of the high variability in patients’ response to vitamin K antagonists, it has been suggested that daily supplementation of low-dose phylloquinone may improve the stability of anticoagulation therapy - daily phylloquinone (K1) supplements of up to 100 μg are considered safe for patients taking Warfarin (but therapeutic anticoagulant stability may be undermined by daily doses of K2 MK-7 as low as 10 to 20 μg). (Pauling Institute)

https: //lpi.oregonstate.edu/mic/vitamins/vitamin-K
https: //www.mayoclinic.org/diseases-conditions/deep-vein-thrombosis/in-depth/warfarin-side-effects/art-20047592
https: //www.drugs.com/warfarin.html#interactions

Question 29

The only clinically significant indicator of vitamin K status is:

a. prothrombin time
b. plasma phylloquinone
c. under-carboxylated osteocalcin
d. none of the above

Answer 29

a. prothrombin time (the time it takes for blood to clot)

In most cases, vitamin K status is not routinely assessed, except in individuals who take anticoagulants or have bleeding disorders - in which case, PT should be monitored.

Prothrombin time (PT) - also called Protime, PT/INR or INR - is a blood test used to help detect and diagnose a bleeding disorder or excessive clotting disorder; the international normalized ratio (INR) is calculated from a PT result and is used to monitor how well the blood-thinning medication Warfarin (Coumadin) is working to prevent blood clots. This test is run for patients taking warfarin or who have unexplained or prolonged bleeding or inappropriate blood clotting.