Midterm 2 (Lec 8) Flashcards
Vitamin D
Fat soluble - aka calciferol
2 forms;
- vitamin d3: cholecalciferol ( animal foods and from sun
- vitamin d2: ergocalciferol ( plant foods, converted to d3 for food fortification
Both forms are biologically inert and must be converted to other forms to be activated
Vitamin D activation
Vitamin D3 (cholecalciferol) must undergo two hydroxylations for activation :
- LIVER: vitamin D to 25OH-D3 (calcidiol) by 25-hydroxylase
- KIDNEY: 25(OH)D3 to 1,25(OH)2-D3 (calcitriol) by 1-alpha-hydroxylase
Vitamin D synthesis
Adequate sun exposure can eliminate dietary need yet still considered essential since sun exposure is not always available
Vitamin D synthesis decreased by:
- clothing
- sunscreen
- smoke/pollution
- age
- latitude
Vitamin D synthesis (sun)
Cholesterol -> sunlight -> vitamin D3
- occurs in our skin
Reasons for dietary vitamin D:
10-2
Distance from equator
Seasonal variation
UV photons get absorbed by ozone
Vitamin D absorption and transport
Absorption involved incorporation into chylomicrons (because it’s a fat soluble vitamin)
Transported bound to a protein - DBP (vitamin D binding protein) *needs binding protein since its fat soluble
Converted to active form in the kidney
Can be stored in the liver, other tissues as well especially adipose (vitamin D produced in sunny seasons can be stored for winter)
Vitamin D overall metabolic role
Maintains calcium and phosphorus homeostasis
- ensure that calcium and phosphorus are available in the blood that bathes the bones (bone health)
- acts as a STEROID HORMONE
- vitamin D endocrine system
Vitamin D as a steroid hormone
Specific cells in target organs with nuclear vitamin D receptor (VDR)
1. 1,25(OH)2-D3 travels to specific cell
2. Enters cell and binds to nuclear VDR
3. Binds to the actual DNA
4. Alters transcription rate of mRNA which code for synthesis of specific proteins - altering proteins to be able to bind vitamin D
Main target organs are intestine and bone
Other targets:
- brain and nervous systems
- pancrease, reproductive organs
- muscle, cartilage
- cancer cells
Vitamin D and calcium homeostasis
Tight regulation of calcium (and phosphorus) important for:
- bone growth
- maintenance of bone density
- nervous system
- blood clotting (remember vitamin K)
Complex system that involves
- vitamin D (steroid hormone role)
- parathyroid hormone (PTH)
Parathyroid hormone (PTH)
Peptide hormone produce by parathyroid glands
Key role in calcium homeostasis - also regulates phosphorus (same role as vitamin D)
Parathyroid gland contains a protein that acts as a SENSOR of blood calcium
- sensor protein will detect decreased blood calcium and increase PTH synthesis
“PTH synthesis tiggers increase of calcitrol formation in kidney - vitamin D cannot perform until PTH increases”
PTH effects
- Goal is to restore normal blood calcium and maintain phosphorus homeostasis
- Negative feedback loop created
- Primary target organs are kidney and bone
KIDNEY:
A) stimulates activation of vitamin D
- stimulates 1-alpha-hydroxylase
- 25OH-D3 -> 1,25(OH)2-D3 (calcitrol)
B) increases calcium reabsorprion
- decrease urinary calcium
- increase blood calcium
C) decreases phosphate reabsorption
- prevents hyperphosphatemia: which can inhibit conversion of vitamin D to its active form (calcitrol)
- when calcium is removed from bone, P is as well so we need t to keep P in check
- increases urinary phosphate
BONE
A) increases osteoclast activity
- increases bone resorption (bone breakdown)
- calcium and phosphorus are released
- increased blood calcium and phosphorus
Calcitrol 1,25(OH)2-D3
Goal is to restore normal blood calcium
Production in the kidney is stumbled by PTH
Acts on intestine and bone
1) INTESTINE
A) stimulates calcium absorption
- also need magnesium
- increase blood calcium
B) stimulates phosphorus absorption
- increases blood phosphorus
- BONW
A) increases osteoclast activity
- increases bone resorption (breakdown)
- calcium and phosphorus are released
- increase in blood calcium and phosphorus
Review of PTH and vitamin D
Both act to restore calcium homeostasis
PTH acts on kidney and bone
- kidney: stimulates 1-alpha-hydroxylase
- kidney: increases calcium reabsorption, decreases phosphorus reabsorption
- bone: increases osteoclast activity
1,25(OH)2D3 acts on intestine and bone
- intestine: increases calcium and phosphorus absorption
- bone: increases osteoclast activity, increases resorption, takes calcium out of bone
Hyperparathyroidism
Primary hyperparathyroidism
- direct problem with parathyroid glands
- non cancerous growth , cancer
Secondary hyperparathyroidism
- due to another condition that causes low blood calcium that then increases PTH (too much)
- could be conditions of calcium deficiency or vitamin D deficiency or chronic kidney failure
Week and poorly mineralized bones
Secondary hyperparathyroidism
One of the most common complications of chronic kidney disease
Kidney can’t activate vitamin D - chronic low blood calcium
Increased PTH, doesn’t work on kidney properly, can’t help to reabsorption calcium, decreased calcium reabsorption
Can’t excrete phosphate in kidney or decrease reabsorption - excess blood phosphate
Can cause bone disease due to bone turnover increasing osteoclast activity
How does vitamin D facilitate calcium absorption
Increasing calbindin synthesis
Calcium
Most abundant mineral in body - 99% in bones
Passive absorption
- doesn’t depend on vitamin D
- concentration dependent
Active transport absorption
- depends on vitamin D
- requires a transporter and energy
- requires a calbindin (calcium binding protein)
Calbindin
Free calcium is very toxic to inside of cells - need to move calcium across cell
Need to have calcium BOUND - calbindin binds calcium and acts as a shuttle for calcium through the cell
Facilitates calcium absorption across intestinal cell, also needs magnesium
Vitamin D increases calbindin synthesis
Factors affecting calcium absorption
ENHANCE absorption
- vitamin D: presence of calbindin (transport of calcium across intestinal cell)
- stomach acid
- supplements best absorbed with a meal
- optimal ratio of calcium to phosphorus
INHIBIT absorption
- vitamin D deficiency
- lack of stomach acid
- excess phosphorus
- high fiber diet
- phytic acid (storage form of phosphate - tends to be in high fiber foods)
- oxalate
Calcium metabolic role
Bone health (major role)
- bone tissue gains and loses minerals
- goal is to balance this
- teeth similar, fluoride acts as stabilizer
Regulator of cellular processes (minor role)
- muscle contraction, blood clotting
- nerve impulse transmission
- second messenger
Calcium as a second messenger
Signal transduction
Intracellular messenger of hormone action
Peptide hormone action
- hormone binds to receptor (first message)
- now need to transducer the signal inside the cell
- involves G proteins that need to be activated
- CALMODULIN is an intracellular protein (calcium receptor) that binds calcium allowing for activation of intracellular proteins and enzymes
CALMODULIN
Intracellular protein/ calcium receptor aka calcium dependent regulatory protein
Found in all cells - binds intracellular calcium
Allows for signal transduction to occur
Activates proteins and enzymes
Key in mechanism of section of numerous peptide hormones
Slide 32
Vitamin D food sources
Found naturally in very few foods - hard to get requirement through diet only
Fish, egg yolk, mushrooms
Fortified foods
Vitamin D and Calcium
With vitamin D deficiency:
- production of calbindin is decreased
- calcium absorption is decreased
- thus vitamin D and calcium are related
Specific syndromes related to vitamin D and calcium deficiencies:
- rickets (children)
- osteamalacia and osteoporosis (adults)
Rickets
Classic severe vitamin D deficiency disease in children
- Involves calcium- low blood calcium
- Still occurs in children world wide
Impaired mineralization of growing bones
- lumps on ribs due to unformed bone
- growth retardation, skeletal abnormalities
- bowlegs, knock needs, spine curvature, protruding belly
Muscle weakness and nervousness
- tetany (calcium involved in muscle contraction)
Factors that contribute towards rickets:
- poor diet
- low UV exposure (pollution, season, sunscreen, tall buildings)
Osteamalacia
Severe vitamin D deficiency; adult form of rickets
- also involved calcium: low blood calcium
- relatively rare
- could occur in women with: low calcium intake and low sun exposure, multiple pregnancies and lactation
remember bone is in a constant state of turnover
new bone matrix is laid down but NOT mineralized properly (defect in the mineralization of bone matrix)
- amount is not affected
- composition is affected
Softening of bones : bending of spine, bowing of legs
Osteoporosis
Disease related to calcium deficiency
Amount of bone - opposite of osteomalacia (no change in composition of bone, instead loss of overall amount of bone)
- reduced bone density
Increased susceptibility to fracture especially at wrist spine and hip
Types of bone
Bone made of 2 compartments :
- CORTICAL
- 80% of skeleton
- dense bone tissue, shafts of long bone, other hard shell of flat bones
- calcium loss is slow - TRABECULAR
- inner structural matrix
- at ends of long bones, inside cortical shell of flat bones
- loses calcium readily, calcium loss is faster
Type 1 osteoporosis
Rapid bone loss
Due to rapid loss of estrogen in women following menopause and decrease of testosterone in men with old age (50 to 70 years old)
More common in women “and than type 2” - called post menopausal osteoporosis
Primarily trabecular bone - wrist and spine fractures
Type 2 osteoporosis
Slower bone loss - > 70 years old
Due to aging factors
- reduced calcium absorption
- increases risk of falling
- increased bone mineral loss
Both trabecular and cortical bone
Hip fractures
Vitamin D status
Measurement of blood 25OH-D3 (calcidiol)
- > or equal to 50 nmol/L is sufficient amount
A biomarker of vitamin D exposure (from food supplements and sun exposure)
Vitamin D concern in older adults
Reduced dietary intake
Low use of supplements
Less time outside
Less cutaneous synthesis due to thinning of skin
Vitamin D and calcium toxicity
HYPERVITAMINOSIS D
- results in enhanced calcium absorption
Symptoms
- hypercalcemia
- loss of appetite, anorexia
- fatigue, irritability
- headache
- calcinosis
No documented cases due to excess sun: process is self limiting
CALCINOSIS
- deposition of calcium in soft tissues
- blood vessels
- heart, kidney, lungs
- kidney stones
- tissue around joints
Vitamin D and non skeletal health outcomes
Very active area of research
- cancers, CVD
- diabetes, immunity
Multiple sclerosis
- substantial evidence to support a role for vitamin D
- lower rates of MS closer to the equator and in people who get more sun exposure/ have higher vitamin D status
Vitamin D and Covid 19
Active area of research
Lower rates of Covid 19 closer to equator
Inverse associations of Covid with 25(OH)D3
Similar risk factors for Covid and vitamin D deficiency
- may relate to vitamin D’s role as a hormonal modulator of immune cells which all have vitamin D receptors
