Vitamin D
Before we look at the next function of vitamin D, we need to review the following terms: cell proliferation, cell differentiation and apoptosis.
- Cell proliferation: the increase in cell number as a result of cell growth and division. - Cell differentiation: how generic embryonic cells become specialized cells. This occurs through a process called gene expression. Gene expression is the specific combination of genes that are turned on or off (expressed or repressed) - Apoptosis: cell death
What are the blood levels of 25-OH D3 that are considered to indicate deficiency and insufficiency?
- Defic if less than 50 nmol/L - Insufficient if 50-74 nmol/L
What diseases contribute to vitamin D deficiency?
- Disorders characterized by fat-malabsorption like Crohn's, pancreatitis, and liver disease - Disorders affecting the parathyroid, liver, or kidneys
What are the problems associated with vitamin D toxicity?
- Hypercalcemia - Calcinosis - Calcification of soft tissues - Hyperphosphatemia, hypertension, anorexia, nausea, weakness, headache, renal dysfunction, in some cases death.
Describe the symptoms of rickets and the population at risk for this vitamin D deficiency disorder.
- In infants and young kids - Bowed legs, bone and muscle pain, rachetic rosary: boney deposits on ribs, enlarged joints (knees and wrists) - Seen most frequently in dark-skinned, breast fed infants/kids. Esp. those who's mom is vit D deficient
List the 3 historically important target tissues for the action of calcitriol. What other tissues are now known to have vitamin D receptors?
- Intestine, kidneys, bone - Pancreas, breast, pancreatic β-cells, lungs muscle, skin, heart, brain, colon, prostate, hematopoietic system, CNS, and the immune system
What factors regulate the synthesis of active vitamin D in the kidney?
- Low calcium concentration increases activation - High PTH increases activation - Fiberblast-like growth factor - High 1,25(OH)2P3 decreases activation - Pg.394
Describe the requirements for endogenous synthesis of adequate amounts of vitamin D and the factors that adversely affect its' synthesis.
- Need 5-15 min of exposure (hands and face) between 10 am and 3 pm in spring, summer and fall. - Best at latitude below 35 degrees (closer to the equator) - People with dark skin and the elderly do not convert as much vit D - Elderly are have impaired synthesis and often cover much of their skin
Briefly describe the digestion and absorption of vitamin D.
- Need bile from gallbladder (liver) to make a micelle to carry FSV and other lipids to the intestinal cell > chylomicron transport from intestinal cell > lymphatic system > to all body tissues > chylomicron remnant > to the liver, the liver can take D to 25OHD and send it out on DBP (D binding protein) - 25OHD attached to DBP in the liver > blood/kidney > Kidney will take 25OHD and convert it to 1,25OHD and attach it to a un-binding protein > blood - D in the skin + DBP > liver
Describe the treatment for vitamin D deficiency in people with normal organ function.
- Osteomalacia or low blood 25OHD: • 10,000 IU vitamin D once a week for 8 weeks with a meal that contains fat • ~2-3 months of 800-1,000 IU/day • At about 6 months after Dx, check blood 25OHD
There are LOTS of other functions for vitamin D. Let's list a few of the important ones.
- Regulating BP - Diminishing risk of heart disease - Some autoimmune conditions are linked to low vitamin D - Pancreatic beta cell protection - Insulin secretion
Describe the population at risk and the symptoms associated with osteomalacia.
- Seen primarily in the elderly and older kids - Bone and muscle pain - Decrease in bone re-mineralization = soft bones
How does long term anti-convulsant therapy affect vitamin D status?
- They may develop an impaired response to vitamin D and exhibit problems with calcium metabolism
List the conversion for vitamin D mcg and IU.
1 mcg = 40 IU or 1 IU = .025 mcg
List the steps and explain how vitamin D acts to INCREASE serum calcium levels by its action on the intestines, kidneys and bone. (Fig 10.14)
1) Blood: Initial stimulus from low blood calcium 2) Parathyroid gland: signals PT gland to release PTH 3) Kidney: increase of PTH in the blood 4) Stimulates kidneys to increase calcium reabsorption 5) Increase in blood calcium 6) #3 also stimulates renal-hydroxylase to convert 25-OH D to 1.25-(OH)2D (calcitriol) 7) Increase in blood calcitriol 8) Intestines: increase in calcitriol stimulates calcium absorption in intestine by increasing calbindin D9k synthesis, calcium transporter synthesis, calcium-ATPase exporters, and cluadin protein synthesis, among others 9) Increase in blood calcium 10) Bone: Increased PTH and calcium travels to the bone 11) PTH and calcitriol stimulate resorption of Ca and P from bone 12) End result is increased blood calcium
Steps in activation of vitamin D:
1) In the liver: 25OHD or 25OHD3 = 25 hydroxycholecalciferol, hydroxycalciterol, calcidiol 2) In the kidney: 1,25(OH)2D (active form) Also known as 1, 25 dihydroxycholecalciferol or calcitriol
Which form of vitamin D is the active one?
1,25(OH)2D
What is the UL for vitamin D?
4,000 IU (100 mcg)
What is the UL for DIETARY vitamin D
4,000 IU or 100 mcg
What is the RDA for adult males and females up to age 70?
600 IU
What type of a chemical structure is vitamin D?
A steroid based on cholesterol
What % of DIETARY vitamin D is typically absorbed?
About 50%
Why do breastfed infants need vitamin D supplementation?
Because human milk is low in vitamin D
What is another name for vitamin D?
Calciferol
Calcium and phosphorus are interrelated and calcitriol has effects on phosphorus homeostasis too! Explain the process by which calcitriol regulates phosphorus homeostasis. (Another little side note, high levels of PTH have some separate effects on phosphorus homeostasis which makes the issue of phosphorus metabolism a little more complicated, but I want you to focus on the actions of calcitriol by itself.)
Calcitriol acts on the same target organs as when maintaining calcium homeostasis. 1) In the intestine, calcitriol is thought to increase the activity of the brush border alkaline phosphatase, which hydrolyzes phosphate ester bonds to free the phosphorus and thus enable its absorption. It also regulates the number of carriers responsible for the sodium-dependent absorption of phosphorus at the brush border. 2) In bone, calcitriol promotes the resorption of phosphorus out of bone into the blood. 3) In the kidneys, it enhances phosphorus resorption in the distal tubules.
List and briefly describe how calcitriol interacts with PTH to DECREASE serum calcium
Calcitriol is indirectly involved. Increased calcitriol serum concentrations decreases PTH production through long and short feedback loops as well as via down-regulation by fribroblast growth factor. The long feedback loop is indirect. The short feedback group is direct: calcitriol decreases the transcription of the gene for preparathyroid hormone.
What happens to 25-OH D3 in the kidney?
Calcitriol is made.
What is the function of calcitriol in muscle? Why is this function so important?
Calcitriol is thought to function through genomic mechanisms to enhance calcium uptake and thus intracellular calcium concentrations. Specifically, the vitamin is thought to increase the transcription of genes for calcium ATPase pumps and for voltage-sensitive calcium channels. These changes are important for contraction and relaxation of muscles.
Describe the genomic mechanism by which calcitriol regulates gene expression. (see Fig 10.13)
Calcitrol binds to VDRE >changes in gene transcription>changes in protein synthesis
Little bit of background diversion before we go any farther - aka side lecture on calcium.
Changes in serum calcium concentrations and release of PTH stimulate calcitriol synthesis. Hypocalcemia stimulates secretion of PTH. Vitamin D, in high concentrations, influences PTH by interacting with VDRE in the promoter region of the PTH gene to inhibit its transcription. ????
What form of vitamin D is found in plants?
D2
How is calcitriol carried in the blood once it is released from the kidney?
DBP
This is a good time to distinguish between enriched and fortified because most (70%!) of you missed it on the last exam, so it is sure to show up again.
Fortified: beyond what was ever there Enriched: put back in original amts.
What is the main adverse effect of excessive vitamin D intake?
Hypercalcemia and calcinosis
What stimulates the kidneys to take up 25-OH D3?
Increased concentrations of parathyroid hormone (PTH)
How is vitamin D affected by cooking and processing?
It is not affected
List the foods of animal origin that contain naturally occurring vitamin D.
Liver, egg yolk, fatty fish
Briefly explain the non-genomic action of calcitriol.
Mediated by the activation of signal transduction pathways linked to cell membranes. Calcitrol binds to the cell membrane receptors in selected tissues and triggers a series of events through signal transduction which evokes rapid changes in some body processes. We know one vitamin D receptor - MARRS protein.
In the USA, what foods are typically FORTIFIED with vitamin D?
Milk, orange juice, some grain products, butter and margarine
What are the two broad categories for the actions of calcitriol?
Nongenomic and genomic
What form of vitamin D in the blood is used to assess status?
Serum 25-OH D concentrations
In addition to foods as a DIETARY source of vitamin D, humans have the capacity to meet some of their need for vitamin D via synthesis in the skin when exposed to sunlight (UVB). This is referred to as ENDOGENOUS synthesis. Look at Figure 10.11 and list the steps in this process.
Skin cholesterol >UVB>previtamin D>Vitamin D (calciferol)
Explain how calcitriol regulates cell growth, proliferation and differentiation.
The local presence of calcitriol within many non-calcium regulating tissues is thought to help maintain normal cell growth, differentiation, and proliferation. Pg. 397
What plant based food is a good source of vitamin D?
Tiny amounts except shitake mushrooms (as Vit. D2 which must be converted to D3 in humans)
What blood level of 25-OH D3 is considered toxic?
Toxic more than 500 nmol/L
Describe the process by which DIETARY vitamin D is transported to the liver and what happens there.
Vitamin D may be transferred by chylomicron to DBP. Tissues take up the vitamin from the chylomicrons, and chylomicron remnants deliver the remainder to the liver. The vitamin must be hydroxylated by cytochrome P-450 hydroxylases to begin the generation of vitamin D's active form.
What is DBP? Where is it synthesized and what does it do?
Vitamin D-binding protein is synthesized hepatically. Vitamin D that is made in the skin is picked up for transport by DBP. It primarily delivers to the liver, but may be picked up by other tissues.
Describe the process by which ENDOGENOUS (made in the body) vitamin D is transported to the liver and what happens there.
Vitamin D3 is made in the skin and slowly diffuses from the skin into the blood and is picked up from transport by DBP (transports about 60%). It is then delivered to the liver, but may be picked up by other tissues. The vitamin must be hydroxylated by cytochrome P-450 hydroxylases to begin the generation of vitamin D's active form.
What are the vitamin D precursors?
calciferol or cholecalciferol
Is vitamin D deficiency common in the USA?
yes