Vitamin D Flashcards
precalciferol
a precursor to vitamin D3 (cholecalciferol).
Derived from 7-dehydrocholesterol exposed to UVB light.
After thermal isomerization it becomes cholecalciferol.
cholecalciferol
Vitamin D3
(the unactivated form of vitamin D)
the form found in animal foods and
the form synthesized in the body from 7-dehydrocholesterol (which exposed to UVB light becomes precalciferol and after thermal isomerization cholecalciferol)
calcidiol
also called 25-OH D
or
25-OH cholecalciferol
Precursor to the active form of vitamin D. Results from the hydroxylation of cholecalciferol in the liver by 25-hydroxylase enzyme.
This is the main form of vitamin D in the body
calcitriol
The activated form of vitamin D
also called 1,25-OH(2) D
or
1,25 dihydroxycholecalciferol
Results from hydroxylation of 25-OH D in the kidney by 1-hydroxylase
ergocalciferol
Vitamin D2
can be synthetic or from plants (shitake mushrooms)
ergosterol
The precursor to Vitamin D2 ergocalciferol
Why is it wrong to call cholecalciferol a vitamin?
It is derived from cholesterol and is a seco-steroid (a steroid with a broken ring).
What are the main dietary forms of vitamin D?
D3 cholecalciferol (from animal foods or endogenous production)
D2 ergocalciferol (from plant or synthetic sources)
The forms are different only in their side chains.
calcitonin
Calcitonin is a hormone released by the thyroid gland
Calcitonin can lower serum calcium and phosphorus by inhibiting bone resorption and accelerating uptake of calcium and phosphate into bone matrix
calbindin
a calcium binding protein
calbindin C9k is found in the intestines and binds calcium in the enterocytes
calbindin C28k is found in the kidney enhances resorption of calcium in the kidney tubules
osteocalcin
a protein found in bone an dentin.
Osteocalcin is secreted by osteoblasts.
osteopontin
extracellular structural protein in bone
secreted by osteoblasts
calciferol
general term for vitamin D
includes cholecalciferol and ergocalciferol
7-dehydrocholesterol
precursor for vitamin D synthesis in the skin
precholecalciferol
previtamin D3
produced in the skin when 7-dehydrocholesterol is exposed to UVB light
after thermal isomerization precholecalciferol is converted to cholecalciferol
Are vitamins D3 and D2 physiologically the same?
The two forms of vitamin D differ only in their side chain. They have the same effect as a treatment for rickets.
They are both metabolized by the same hydroxylase enzymes.
The metabolism of D2 produces additional metabolites not generated by vitamin D3 and is thought to be less efficient in calcitriol production than D3. (Study results vary, but it appears that pharmacologic doses of D2 (such as 50,000 IU) are catabolized more quickly by cytochrome P-450 enzymes in the liver and intestine.)
The hydroxylase enzymes that activate vitamin D belong to which family of enzymes?
Cytochrome P450 enzymes
How is vitamin D synthesized in the body?
7-dehydrocholesterol in the skin is exposed to UVB light and becomes
precholecalciferol (previtamin D3) which then undergoes thermal isomerization (which can take a few hours to a few days) and becomes
cholecalciferol (vitamin D3)
Can excess (toxic) amounts of vitamin D be produced endogenously?
No
excess production of vitamin D3 is prevented by the generation of inactive metabolites
these include lumisterol and tachysterol
What are good food sources of cholecalciferol?
Vitamin D3 (cholecalciferol) is found in a small number of animal foods
liver, especially beef
eggs
fatty fish and their oils (includes salmon, tuna, herring, and sardines)
fortified foods
milk
yogurt, cheese, butter
margerine
orange juice
some breakfast cereals and breads
What are food sources of ergocalciferol?
a few plant foods
shitake mushrooms
also may be found in fortified foods
milk and dairy products
margerine
orange juice
some breakfast cereals and breads
Is vitamin D stable?
yes.
Vitamin D is fairly stable and is not subject to loss due to cooking, storage, or processing.
What digestion is required for vitamin D?
None.
How is vitamin D absorbed?
Vitamin D gathers in micelles with fats (aided by bile salts)
Micelles are absorbed by passive diffusion into the enterocyte
Most vitamin D is absorbed in the ileum (distal small intestine)
Vitamin D is incorporated into chylomicrons for export to the lymph system then into the blood
What percent of dietary vitamin D is absorbed?
about 50%
How is vitamin D transported in the body?
Dietary vitamin D
- transported by chylomicrons
- Some is delivered to adipose and muscle tissues
- Chylomicron remnants are taken up by the liver
Endogenously produced vitamin D
- vitamin D made in the skin diffused into the blood and attaches to the vitamin D binding protein
- transported in the blood bound to vitamin D binding protein
- vitamin D bound to DBP is delivered primarily to the liver
- some may be taken up by adipose tissue and muscle
What is the first step in the activation of cholecalciferol?
In the liver cholecalciferol is hydroxylated by 25-hydroxylase (a cytochrome P450 enzyme) forming
25-OH D or calcidiol
25-OH D is released into blood attached to vitamin D binding protein
What is the second step in the activation of vitamin D?
Calcidiol (25-OH D) from the blood is taken up by the kidneys in response to an increase in parathyroid hormone (released when serum calcium is low)
PTH stimulates the synthesis of 1-hydroxylase enzyme
production of 1,25-OH(2) D (or calcitriol or 1,25 dihydrocholecalciferol) is increased
Much of the 1,25-OH(2) D is release by the kidneys into the blood where it binds to DBP and travels to other tissues
(Other tissues can also make their own 1,25-OH(2) D if serum 25-OH D levels are adequate)
What 2 hormones are primarily responsible for regulating the production of 1,25-OH(2) D?
Parathyroid hormone (PTH) - increases production
- released in response to low serum calcium
- also released in response to low serum phosphorus
- stimulates the synthesis of 1-hydroxylase and increased production of 1,25-OH(2) D
Fibroblast-like Growth Factor 23 (FGF 23) - decreases production
- secreted by osteocytes and osteoblasts
- reduces synthesis of 1-hydroxylase and production of 1,25-OH(2) D
Besides PTH and FGF23 what factors influence production of 1,25-OH(2) D?
Inhibitors 1,25-OH(2) D Production
- high serum calcium levels
- high serum phosphorus levels
- high serum 1,25-OH(2) D
Where is vitamin D stored?
The blood
- contains the largest pool of 25-OH D and is the major storage site
- in the blood 25-OH D has a half-life of 15 days to 3 weeks
Other storage sites
- adipose tissue (primarily cholecalciferol)
- muscle (both cholecalciferol and 25-OH D)
What are the main functions of vitamin D in the body?
Calcium homeostasis (primary role)
Phosphorus homeostasis
Cell differentiation, proliferation and growth
Muscle function
What disorders may be helped by adequate vitamin D levels?
Blood pressure regulation
Vitamin D suppresses expression of renin gene which lowers production of angiotensin and lowers blood pressure
Heart Disease
LDL and HDL cholesterol levels - 25-OH D levels above 30 ng/mL appear to decrease LDL and increase HDL levels which may decrease risk of heart disease
Autoimmune conditions
Rhuematoid arthritis, Crohn’s disease, multiple sclerosis, and type 1 diabetes have been associated with inadequate vitamin D status.
Pancreatic beta cell function and insulin secretion
vitamin D plays a role in b-cell protection and has been positively associated with insulin sensitivity.
How does vitamin D increase serum calcium levels?
PTH is released in response to low serum Ca levels.
PTH stimulates production of the 1-hydroxylase enzyme
1-hydroxylase actives 25-OH D producing 1,25-OH(2) D
1,25-OH(2) D acts in
- the Kidney - increases reabsorption of calcium by increasing production of calbindin D28k and TRPV5
- the intestine to increase absorption of calcium (increases expression of calbindin D9k (Ca transport protein) and TRVP6 (protein for absorption of Ca))
- Bone - mobilize Ca from bone to serum by increasing osteoclast activity (calcitriol stimulates osteoblasts to produce cytokine RANKL which stimulates differentiation and production of osteoclasts.
How are serum calcium levels decreased?
Secretion of PTH decreased
- elevation in serum calcitriol decreases transcription of PTH gene
- elevation in serum Ca inhibits secretion of PTH
- FGF 23 secreted by osteocytes and osteoblasts
Calcitonin released from the thyroid gland
- inhibits activity of osteoclasts
- inhibits reabsorption of Ca by kidneys
How does calcitriol influence phosphorus metabolism?
Intestine
-increases activity of brush border alkaline phosphatase which frees more phosphorus for absorption
- increases number of carriers so phosphorus absorption increased
Bone
- promotes resorption of phosphorus from bone
Kidney
- calcitriol enhances resorption of phosphorus
How does vitamin D influence cell differentiation and proliferation?
Vitamin D
Promotes cell differentiation
(the process by which immature less specialized cells become mature functional cells)
Inhibits proliferation of cells
(the increase in cell numbers due to cellular division)
How does vitamin D affect psoriasis?
Psoriasis is characterized by enhanced cell proliferation and failed differentiation of keratinocytes.
Vitamin D inhibits proliferation of the epidermis
And induces normal differentiation of keratinocytes
What role might vitamin D play in prevention of malignancy?
Calcitriol down-regulates cancer cell growth (proliferation)
and induces apoptosis
What is the effect of vitamin D deficiency on muscle health?
Myopathy (muscle weakness and pain) is common in people with vitamin D deficiency.
People with vitamin D deficiency are also more prone to falls.
Muscle biopsies of people with vitamin D deficiency show atrophy of fast-twitch (type 2) muscle fibers. These are the type used to prevent falling.
How is vitamin D excreted?
Most ~70% of vitamin D metabolites are conjugated and excreted in the bile.
The 24 hydroxylated form is converted to calcitroic acid and then excreted in the bile.
Less than 30% is excreted in the urine.
What nutrients does vitamin D interact with?
Calcium
Phosphorus
Vitamin K (activates osteocalcin which binds Ca and helps to mineralize bone.)
What is the RDA for vitamin D?
Adult men and women 600 IU (15 mcg)
Adults over 70 years old 800 IU (20 mcg)
1 IU - 0.25 mcg
1 mcg = 40 IU
What is the UL for vitamin D?
4000 IU (100 mcg) for all over 9 years old
How much sunshine is needed to provide adequate vitamin D from endogenous production?
5 to 15 minutes between the hours of 10 am and 3 pm during the months of Spring, Summer and Fall
Full sun exposure in a fair skinned individual can generate 10,000 to 20,000 IU vitamin D in 15 to 30 minutes.
When might endogenous production of vitamin D be inadequate?
- during the winter months
- at latitudes North of 35 degrees (SF 37.7, Boston 42)
- in people with dark skin (the higher melanin content of their skin blocks UVB rays and longer exposure time is needed to produce adequate vitamin D).
- Older people (due to lower production of 7-dehydrocholesterol and diminished organ function
- when sun exposure (UVB light)is blocked by clothes, windows, polution
Is there a risk of toxicity from endogenous production of vitamin D?
No.
- Cutaneous production peaks around 20,000 IU (5,000 mcg)
- Full body exposure to UVB raises serum levels to 40 to 80 ng/mL (100 - 200 nmol/L)
- Levels greater than 200 ng/mL (500 nmol/L) are associated with toxicity.
- Excess vitamin D is converted to inactive metabolites
What are the main deficiency disease associated with vitamin D deficiency?
Rickets (in infants and children)
Osteomalacia (in adults)
What are the main signs and symptoms of rickets (3)?
In infants in children
- Failure of bone to mineralize
- epiphyseal cartilage continues to grow and enlarge without replacement by bone matrix and minerals
resulting in enlarged wrists, ankles, and knees
- long bones of legs bow and knees knock when weight bearing activity begins - Seizures
- Growth retardation
What are the signs and symptoms of osteomalacia?
Associated with vitamin D deficiency in adults and older children. Results from prolonged elevation of PTH secondary to low 25-OH D and serum Ca.
Bone resorption is increased but remineralization is impaired.
Signs and symptoms
1. bone pain
2. Soft bone
3. muscle weakness and pain
4. indicators of bone resporption
-hydroxyproline
-N-telopeptide
-Pyridinoline
-deoxypridinoline
What groups are at risk of vitamin D deficiency (6)?
- the elderly
- 7-dehydrocholesterol production declines and
- they may avoid sun exposure - infants
- human milk is low in vitamin D,
- they may not get sun exposure
- vitamin D supplements are recommended for breast fed infants - people with disorders characterized by fat malabsorption
- Crohn’s disease, Celiac disease, pancreatitis, liver disease - people with disorders affecting function of liver, kidneys, or parathyroid gland
- obese individuals
- overweight and obese individuals appear to store more vitamin D in their adipose tissue and may require larger doses to reach an appropriate serum concentration - dark skinned individuals living in Northern latitudes or anyone not getting adequate sun exposure
What is the recommended treatment for inadequate vitamin D levels?
For people with normal organ function
High dose supplement 50,000 IU (1,240 mcg) once per week for eight weeks
1,000 IU (25 mcg) per day for several months.
How much do serum levels of 25-OH D increase with supplementation?
It is estimated that for every 100 IU vitamin D taken serum 25-OH D levels increase by 1 ng/mL
What are signs and symptoms of vitamin D toxicity?
hypercalcemia
calcinosis (calcification of soft tissues including kidneys, heart, lungs, and blood vessels)
hyperphosphatemia
hypertension
anorexia
nausea
weakness
headache
renal dysfunction
seen with intake of 10,000 IU per day for several months
What serum level of 25-OH D is associated with maximum calcium absorption?
30 - 32 ng/mL (75 - 80 nmol/L)
What is the conversion between ng/Ml and nmol/L?
1 ng/mL = 2.5 nmol/L
What tests are used to assess vitamin D levels?
Serum 25-OH D
Deficiency 200 ng/mL (500 nmol/L)
(but some evidence shows >60 ng/mL (150 nmol/L) may be adverse to health
What serum level of 25-OH D is considered sufficient?
30 - 40 ng/mL (75 - 100 nmol/L)
This is the level needed for bone health
What serum level of 25-OH D is considered toxic?
Toxicity >200 ng/mL (500 nmol/L)
(but some evidence shows >60 ng/mL (150 nmol/L) may be adverse to health
What daily intake of supplemental vitamin D may be required to achieve serum 25-OH D > 30 ng/mL?
1000 to 2000 IU per day
