Vitamin D

Question 1

Cholecalciferol (Vitamin D3) sources

Answer 1

o	Synthesis in skin – from sunlight
o	Animal sources:
•	Saltwater fish:  herring, salmon, tuna, and sardines - especially fish liver
•	Meat:  liver and beef
•	Egg yolks
•	Dairy:  milk, cheese and butter

Question 2

Ergocalciferol (Vitamin D2) sources

Answer 2

o Plant sources: mushrooms
o Fortified foods: milk and margarine
• Canada:
• Milk & margarine are required to be fortified by law
o Milk: 88 IU/250 ml – cow, evaporated, powdered, goat & plant
o Margarine: ≥530 IU/100 g
• Some yogurt & cheese if made with fortified milk
• United States:
• No foods require fortification by law
• Allowable foods include: milk, fruit juice, breads, ready to eat cereals, Olestra

Question 3

Ultraviolet synthesis of Vitamin D in plants

Answer 3

o Ergosterol absorbs photons producing previtamin D2

o Previtamin D2 has unstable bonds that rearrange with heat forming ergocalciferol

Question 4

Ultraviolet synthesis of Vitamin D in humans/animals

Answer 4

o 7-dehydrocholesterol (aka provitamin D3)
• Synthesized in the sebaceous glands of skin from cholesterol
• Secreted onto surface of skin and reabsorbed into epidermis and dermis
• Absorbs photons producing precalciferol
o Precalciferol (aka previtamin D3)
• Unstable bonds rearrange in 2-3 days resulting in cholecalciferol
o cholecalciferol (aka Vitamin D3, aka calciol)
• Diffuses from the skin into the blood
• Transported in the blood by an alpha-2 globulin vitamin D binding protein (DBP) aka transcalciferin

Question 5

Vitamin D digestion

Answer 5

Dietary vitamin D in association with dietary fats is packaged into micelles with the aid of bile salts

Question 6

Vitamin D absorption

Answer 6

• By passive diffusion

* Primarily in the distal small intestine

Question 7

Vitamin D transport from skin

Answer 7

o Diffuses into blood
o Picked up by DBP for transport
o Travels primarily to the liver but can be picked up by other tissues, especially muscle and adipose tissues

Question 8

Dietary vitamin D transport

Answer 8

o Incorporated into chylomicrons within the enterocytes for transport
o Chylomicron remnants then deliver vitamin D to the liver
o Some vitamin D from chylomicrons can be transferred from chylomicrons to DBP for delivery to extrahepatic tissues

Question 9

Vitamin D metabolism (25-hydroxy vitamin D3)

Answer 9

o Aka calcidiol
o Synthesized from vitamin D in the liver
• Enzyme required for conversion is: 25-hydroxylase
• Requires magnesium as a cofactor
o Most is released into the blood bound to DBP
o Main circulating form of vitamin D
• Accurately reflects vitamin D status from food and sunlight
o T1/2 = 10 days – 3 weeks

Question 10

Vitamin D metabolism (1,25-dihydroxy vitamin D3)

Answer 10

o Aka calcitriol
o Synthesized from 25-hydroxy vitamin D3 in kidney tubules
• Enzyme required for conversion is: 1-hydroxylase
o Active form of vitamin D
o Functions as a steroid hormone
o Transported in blood via DBP
o Binds to vitamin D receptors (VDR) on target tissues
o T1/2 = 4-6 hrs

Question 11

Regulation of vitamin D metabolism

Answer 11

•	1-hydroxylase activity
o	Increased by:
•	Parathyroid hormone
•	Low plasma calcium concentrations
•	Low 1,25(OH)2 D3 concentrations
o	Decreased by: 
•	High 1,25(OH)2 D3 concentrations
•	High phosphorus intake 
•	When 1,25-(OH)2 D3 levels are high:
o	1,25(OH)2 D3 is converted into 1,24,25(OH)3 D3 
o	25(OH) D3 is converted into 24,25(OH)2 D3

Question 12

Vitamin D storag

Answer 12

• Cholecalciferol is stored in the skin and adipose tissue

* 25-OH D3 is stored in the blood and muscle

Question 13

Vitamin D functions

Answer 13

Calcium homeostasis
Cell differentiation, proliferation and growth
Also roles in
-blood pressure
-immune system modulation
-pancreatic B cell function

Question 14

Vitamin D and calcium homeostasis

Answer 14

o Hypoclacemia stimulates secretion of PTH
o PTH stimulates 1-hydrolase activity in the kidney which converts 25-OH D3 to calcitriol
o Calcitriol binds to:
• Intestine cells → enhances intestinal Ca and P absorption
• Kidney cells → along with PTH stimulates Ca reabsorption in distal renal tubules
• Bone cells
• In hypocalcemic conditions PTH and calcitriol:
o Stimulate the production and maturation of osteoclasts, mobilizing Ca and P from bone
• In hypercalcemic conditions calctonin and calcitriol:
o Promote mineralization of Ca and P in the bone
o This is controlled by a negative Feedback loop
• Increasing serum calcium and calcitriol levels inhibit PTH secretion

Question 15

Vitamind D and cell differentiation, proliferation and growth

Answer 15

o Clacitriol is required for the differentiation of:
• Premyeloid WBCs and stem cells into macrophages and monocytes
• Stem cell monocytes in bone marrow into mature osteoclasts
• Skin epidermal cells
o Calcitriol inhibits the proliferation of:
• Fibroblasts, keratinocytes, and lymphocytes
• Abnormal intestinal, lymphatic, mammary, and skeletal cells
• Down regulates abnormal cell growth in some tissues and able to induce apoptosis if needed
• Low vitamin D levels are associated with increased risk of developing and dying of several cancers including: prostate, breast colon, ovarian, and non-Hodgkin’s lymphoma

Question 16

Vitamin D and blood pressure

Answer 16

• Vitamin D down regulates the production of renin and angiotensin

Question 17

Vitamin D and immune system modulation

Answer 17

• Autoimmune conditions
• Inadequate vitamin D levels are linked with rheumatoid arthritis, Crohn’s disease, multiple sclerosis, and type I diabetes
• Immune system function
• Cytokine production, lymphocyte and macrophage activity, monocyte maturation, and the production of certain antimicrobial peptides are mediated by vitamin D

Question 18

Vitamin D and pancreatic B cell function

Answer 18

• Higher 25-OH D3 levels are associated with decreased insulin secretion and increased insulin sensitivity

Question 19

Vitamin D mechanism of action

Answer 19

• Not fully understood
• 2 primary proposed mechanisms
o Functions as a steroid hormone
• Activation of signal transduction pathways linked to cell membrane VDRs
o Promotes genomic actions
• Interacts with nuclear VDRs influencing gene transcription

Question 20

Vitamin excretion

Answer 20

• Metabolites are excreted in feces (>70%) and urine

Question 21

Vitamin D skin production depends on

Answer 21

o	Season
o	Latitude
o	Time of day
o	Degree of pigmentation  
o	Age

Question 22

Vitamin D deficiency in children

Answer 22

Children = rickets 
o	Bone mineralization defects
•	Epiphyseal cartilage continues to grow without replacement by bone matrix and minerals	
•	Wrists, ankles, and knees enlarge
•	Legs bow and knees knock as walking begins
•	Spine becomes curved
•	Pelvic and thoracic deformities occur
o	Dental abnormalities 
o	Growth retardation
o	Muscle weakness
o	Seizures

Question 23

Vitamin D deficiency in adults

Answer 23

Adults = osteomalacia 
o	Bone mineralization defects
•	Secondary to changes in calcium and phosphate absorption and excretion
•	This stimulates PTH secretion
•	Which promotes bone resorption 
•	Bone matrix is preserved but remineralization is impaired
•	Bone pain and softening of the bones results
o	Muscle weakness
o	Low back pain
o	Diffuse aches and pains
o	Hyperesthesia
o	Fatigue
o	Head sweating

Question 24

Vitamin D deficiency increased risk

Answer 24

o	Insufficient sun exposure 
o	Living above 35 degrees latitude
o	The critically ill
o	Elderly, adolescents, and exclusively breastfed infants
o	Obesity 
o	Fat malabsorption 
o	Parathyroid disorders
o	Liver and kidney disease
o	Strict vegans

Question 25

Vitamin D clinical indications

Answer 25

• Osteoporosis
• Psoriasis
• Cancer prevention
• Influenza prevention

Question 26

Vitamin D preparations

Answer 26

• Ergocalciferol (D2)
o By prescription: 50,000 IU/pill, usually given once a week
• Cholecalciferol (D3)
o Preferred form for supplementation
• Natural form in humans
• More potent than D2
• More stable
• Less toxic
o Supplement: 400 - 1,000 IU/pill (Canada) - 50,000 IU/pill (US)
o Tablets, capsules, oil based liquids, emulsified liquids

Question 27

Vitamin D toxicity

Answer 27

• Tolerable Upper Intake Level
o 1997: 50 µg (2,000 IU)
o 2010: 100 µg (4,000 IU)
• This may still be overly conservative
• 10,000 IU has been proposed based on risk assessment
• All documented cases of toxicity have been with >40,000 IU/d (1 case report with 25,000 IU/d)
• D2 may be more toxic than D3
• Excessive sun exposure is not associated with risk of vitamin D toxicity

Question 28

Vitamin D toxicity symptoms

Answer 28

o	Hypercalcemia and hypercalciuria
o	Hyperphosphatemia
o	Anorexia, constipation, nausea and vomiting
o	Muscle weakness 
o	Hypertension and cardiac arrhythmias
o	Calcification of soft tissues
o	Renal dysfunction: polyuria, polydipsia, nephrolithiasis and renal failure
o	Mental confusion
o	Death

Question 29

Vitamin D nutrient interactions

Answer 29

• Calcium and Phosphorus
o Vitamin D increases their intestinal absorption
o Vitamin D promotes their deposition into bone
• Magnesium is required for conversion to the active form
• Vitamin K
o Osteocalcin and matrix Gla protein synthesis are stimulated by 1,25(OH)2 D3

Question 30

Vitamin D assessment of status

Answer 30

• Plasma concentration of 25-OH D3
o Deficient: 375 nmol/L
o Optimal: 125-200 nmol/L???
• Serum vitamin D levels
o Unreliable
o Very short t1/2 (~24 hrs)
o Only indicate recent intake or production
• Plasma concentration of 1,25(OH)2D3
o Unreliable d/t compensatory increase in PTH
o Levels often normal or elevated with vitamin D deficiency