Everolimus Tablets (Afinitor) and Vitamin D

• Generic Name: everolimus
• Dosage Forms: n.a.
• Other Brand Names: Zortress, Afinitor, Afinitor Disperz

• It is used to treat cancer.
• It is used to treat certain kinds of kidney cysts.
• It is used to help control certain kinds of seizures.
• It may be given to you for other reasons. Talk with the doctor.

• Generic Name: cholecalciferol
• Dosage Forms: n.a.
• Other Brand Names: Aqueous Vitamin D, Bio-D-Mulsion, Bio-D-Mulsion Forte, BProtected Pedia D-Vite, D-Vi-Sol, Dialyvite Vitamin D 5000, Dialyvite Vitamin D3 Max, Pronutrients Vitamin D3, Opurity Vitamin D, VitaJoy Daily D Gummies, D3 Dots, VitaMelts Vitamin D, Replesta

Vitamin D has to be one of science’s most misunderstood vitamins.

For a start, it is not actually a vitamin, but a prohormone, which means that it is converted into a hormone by our body. It is also not just one substance, but five different substances, of which two have been identified as being the most important to humans. These are:

Vitamin D2 (ergocalciferol) Vitamin D3 (cholecalciferol).

In addition, research has discovered that vitamin D is not only vital for calcium absorption and bone growth and remodeling, but several other important processes as well, such as modulating cell growth and immune system function.

Vitamin D acts on our bones, intestines, kidneys and parathyroid glands to keep calcium in balance throughout our body. Vitamin D receptors are also located within our cardiovascular system, lungs, pancreas, skeletal muscle, skin, and reproductive organs. In summary, vitamin D is a prohormone that is essential for good health.

Only 10% of the vitamin D our body needs is obtained from food. The rest is made by our bodies when our skin is exposed to sunlight.

Vitamin D2 and D3 are two important forms of vitamin D. D2 comes from plants and D3 comes from mainly animal sources or it is made by our bodies when our skin is exposed to sunlight. D3 is better absorbed and more potent than D2. Fortified milk or juice is more likely to contain D2 because it is cheaper to produce.

Vitamin D2

Vitamin D2, also called ergocalciferol, is found naturally in mushrooms that have been exposed to the sun. Mushrooms contain a yeast compound called ergosterol, which is converted to ergocalciferol on exposure to UV light. Maitake mushrooms are one of the best sources of vitamin D2 at 786 IU per cup, followed closely by portobello mushrooms (634 IU/cup). Chanterelle mushrooms contain a lot less D2 (114 IU/cup). Vitamin D2 derived from mushrooms is vegetarian/vegan-friendly.

Vitamin D2 supplements can also be made synthetically by irradiating fungus and plant matter that naturally contain ergosterol. Drisdol is another name for supplemental vitamin D2. Supplemental D2 is cheaper to produce than supplemental D3; however, it is not as effective at raising levels of vitamin D in the blood nor as stable as synthetic vitamin D3. Vitamin D2 still requires conversion in the body to become D3 active.

Vitamin D3

Vitamin D3 is made when cholesterol in our skin is exposed to sunlight and it is also contained in small amounts in some animal-sourced foods.

Our skin stores a specific type of cholesterol, called 7-dehydrocholesterol, which is converted to previtamin D3 on exposure to UVB (wavelength 270-300nm). Another process changes this into cholecalciferol before it undergoes activation in the liver and kidneys to become active vitamin D. Active vitamin D is called 1,25 dihydroxyvitamin D3 (1,25(OH)D) or calcitriol.

The process of converting 7-dehydrocholesterol into active vitamin D3, although complex, is reasonably efficient and it has been estimated that only 10 minutes of summer sun on our hands and face is required to generate our daily requirement of 10 micrograms of vitamin D3.

Foods that naturally contain vitamin D3 include beef liver, cheese, cod liver oil, egg yolks, and fatty fish (such as mackerel, tuna, and salmon).

Supplements of vitamin D3 can be made by extracting cholesterol from lanolin derived from sheep wool, then subjecting it to a series of chemical reactions to yield 7-dehydrocholesterol. This is then irradiated to produce D3 (cholecalciferol). Supplements obtained from lanolin are not vegan-friendly; however, a D3 supplement extracted from lichen is vegan and vegetarian-friendly.

Vitamin D3 is more potent than D2 and binds to vitamin D receptors more effectively. It is also better absorbed and more easily converted into active D.

All forms of vitamin D2 and D3 obtained from our diet or from supplements require conversion in our liver and kidneys before being active in our body.

Vitamin D deficiency is measured with a blood test that measures 25(OH)D. This is the form of D3 that has undergone conversion by the liver; although it is still inactive and requires further conversion by the kidneys to active vitamin D3, 1,25(OH)D.

The reason 25(OH)D is measured is because it is the most stable form of D3. It is also the most abundant form and lasts several weeks in the body. It is a good representation of how much vitamin D has been obtained from both diet and sun exposure.

Conversely, 1,25(OH)D only lasts for a few hours in the body and levels are a thousand-fold less than those of 25(OH)D. Our body also has a way of increasing the production of active D3 by the kidneys during times of deficiency and insufficiency, so a blood test for 1,25(OH)D may appear normal or elevated even when your actual levels of vitamin D are low. However, in some disorders of calcium metabolism, the 1,25(OH)D test may be used.

25(OH)D levels will tell your doctor if you are deficient in vitamin D, borderline, sufficient, or vitamin D toxic.

See the flow chart above for an overview of the different forms of vitamin d.

Our skin makes vitamin D when it is exposed to the sun. It can also be obtained from foods containing vitamin D, and D2/D3 supplements.

Sources of vitamin D2 include:

Mushrooms Vitamin D2 supplements (made from irradiated mushrooms and plant material) Fortified foods containing D2 (eg, breakfast cereal, infant formula, margarine, orange juice, milk)

Sources of vitamin D3 include:

Exposing our skin to sunlight Butter Cheese Egg yolk Liver Oily fish (eg, mackerel, salmon, tuna) and fish oil Vitamin D3 supplements made using lanolin from sheep’s wool Vitamin D3 supplements made using lichen (vegan/vegetarian friendly) Fortified foods containing D3 (eg, breakfast cereal, infant formula, margarines, orange juice, milk)

Since D2 is cheaper to produce, it’s the most common form in fortified foods.

There is a bit of controversy regarding what is considered a low vitamin D level between different expert organizations. A vitamin D level measures levels of 25(OH)D in the blood (see the flowchart above for an overview of the different forms of vitamin d).

Most experts recommend:

Levels of 20-50 nanograms/milliliter (ng/ml) of 25(OH)D: Sufficient (good) Levels of 12-19 ng/ml: Borderline Levels of less than 12 ng/ml: Deficient (low)

However, not everybody agrees, and some organizations suggest different cut-off values.

The Institute of Medicine (IOM) states:

Levels above 20 ng/ml: Sufficient Levels below 20 ng/ml: Deficient

Note that several members of the IOM committee publicly stated that over screening for vitamin D deficiency was a problem which typically resulted in unnecessary treatment. They were not in agreement with a cut-off level of 20 ng/ml for deficiency and recommended a lower level of 12.5 ng/ml.

The Endocrine Society states:

Levels above 30 ng/ml: Sufficient; however, some assays are inaccurate and levels of 40-60 ng/ml better guarantee sufficiency Levels of 21-29 ng/ml: Insufficient Levels below 20 ng/ml: Deficient

Talk to your doctor about what he/she considers to be a low vitamin D level.

Vitamin D deficiency is when levels of vitamin D in your body fall below those recommended as necessary to ensure all the processes in your body that rely on vitamin D can function properly.

Currently, there is controversy regarding what is the cut-off level for vitamin D deficiency with recommendations ranging from less than 20 ng/ml of 25(OH)D to less than 12 ng/ml of 25(OH)D.

No, vitamin D is fat soluble. This means it is stored within our adipose (fat) tissue and small amounts can be mobilized if our daily intake temporarily falters. Other fat-soluble vitamins are vitamin A, vitamin E and vitamin K. Because it is fat soluble, vitamin D toxicity can occur if too much is taken.

Vitamin D deficiency is prevalent among obese people, because greater amounts of vitamin D are locked up in their adipose tissue (fat stores), rather than in the blood where it can be used. Obese people are also less likely to eat foods naturally high in vitamin D or expose their skin to sunlight.

The synthesis of active vitamin D is quite complex but involves sunlight, a specific type of cholesterol present in our skin, and modification first by our liver and then our kidneys.

Within our skin is a type of cholesterol called 7-dehydrocholesterol. When UVB rays of the wavelength range 290 to 315nm touch 7-dehydrocholesterol, they convert it into previtamin D3. This is then converted into cholecalciferol so that it can be transported to our liver for hydroxylation into calcidiol [25(OH)D]. Further hydroxylation happens in the kidneys to make 1,25(OH)D (calcitriol) which is the active form of vitamin D3.

The whole process of converting 7-dehydrocholesterol into active D3 is quite efficient and it has been reported that it takes 10 minutes of summer sun on the hands and face to generate 10 micrograms of vitamin D3 which is considered the daily requirement.

Production of vitamin D via our skin is efficient and represents an easy, reliable way for most people to get enough vitamin D.

Of course, how long you need to stay in the sun for depends on your age, skin type and color, the season, and the time of the day; but for most people, 10 minutes of summer skin on exposed skin, without sunblock, is considered sufficient.

Anything that interferes with the body’s ability to make vitamin D through the skin, including liver or kidney disease, can cause deficiency. Malabsorption syndromes or a diet low in foods containing vitamin D can also lower vitamin D levels.

The following factors may interfere with our body's ability to make vitamin D:

Chronic illness or disability that prevents regular sun exposure Living at latitudes above 37 degrees north or below 37 degrees south of the equator over winter, although this is controversial, and studies have shown only Caucasians show a correlation with low vitamin D levels and latitude. Skin color: Individuals with a darker skin produce less vitamin D with the same amount of sunlight exposure than individuals with lighter skin color. Age: Older people are less efficient at making D3 and less likely to go outside in the sun. Religion or culture: People (especially women) whose beliefs require them to cover most of their skin and/or face usually do not receive adequate sunlight for their skin to make vitamin d. Avoidance of the sun and use of sunscreen: Fears of skin cancer and skin aging mean people spend less time in the sun than in the past, although only 10 minutes of direct summer sun is necessary to make an adequate daily dose of vitamin D.

In addition, a poor intake of vitamin D through the diet may also contribute; however, studies have shown less than 10% of the vitamin D in our body is obtained through diet, so it is not considered a major contributing factor.

Other factors that increase the risk of vitamin D deficiency include:

Chronic liver disease Chronic kidney disease Eating disorders (eg, anorexia nervosa) Medical conditions that affect absorption of vitamin D from the diet (such as Celiac disease or pancreatic insufficiency) Prolonged, exclusive breastfeeding or being born to a vitamin D deficient mother Obesity (stores of vitamin D get locked up in adipose tissue) Taking medications that affect vitamin D synthesis or degradation (such as carbamazepine, efavirenz, phenobarbital, phenytoin, primidone, rifampin).

Symptoms of vitamin D deficiency are initially vague, and most people do not realize they are deficient unless their doctor orders a blood test to test for vitamin D deficiency. Any symptoms reflect the fact that vitamin D impacts on your bone health, mood and immune system and may include:

Bone or back pain Constant fatigue or tiredness Frequent infections (such as colds or flu) Hair loss Low mood or depression Muscle pain Osteoporosis (bone density scans show bone loss) Poor oral health Skin wounds that take a long time to heal.

If the deficiency continues unresolved, then more noticeable symptoms may occur, such as bone fractures, rickets, or osteomalacia.

Low blood levels of vitamin D have also been associated with:

An impairment in memory and thinking skills in older adults Cancer (particularly colon cancer) Cardiovascular disease, and an increased risk of dying from a stroke or a heart attack Kidney disease Severe asthma in children.

Research also suggests vitamin D may help prevent or be helpful in the management of several other conditions such as diabetes, high blood pressure, and multiple sclerosis.

Rickets is a bone condition characterized by the softening and weakening of bones in children. It is caused by a prolonged lack of vitamin D which affects the absorption of other minerals necessary for good bone health, such as calcium and phosphate. A softening of the bones in adults is called osteomalacia.

Rickets most commonly occurs in children aged between six months and 36 months. Although rare in the U.S., it is common in other parts of the world, such as regions of Asia where vegetarianism coupled with low daylight hours are prevalent.

Risk factors include being born to a vitamin D deficient mother, exclusive breastfeeding, poor nutrition, a lack of sun exposure, and malabsorption syndromes that prevent nutrient absorption. Children who are dark skinned and living in cloudy northern cities or those with cultural or religious beliefs that limit exposure to the sun are also more likely to develop the condition.

Symptoms of rickets in infants include:

A delay in the closure of the bones of the skull Bead-like nodules where the bones of the rib cage join to cartilage (rachitic rosary) Bowed legs and knock-knees from the ends of the long bones becoming enlarged Chest deformity due to the pull on the diaphragm on the ribs Delays in crawling, sitting, or walking Poor growth Poor sleep Restlessness Skull thinning or swelling Tooth decay and poor tooth development.

In very severe cases, bone fractures, convulsions, muscle spasms, and mental retardation can also occur.

Rickets may also occur in nursing mothers who have a diet deficient in vitamin D. Symptoms may include muscle and bone aches and pains and joint swelling, tiredness, and hair loss.

Treatment includes vitamin D supplementation which is usually continued long-term, even once symptoms have resolved. In severe cases, intravenous calcium may also be given. Sometimes surgery may be required to correct bone and muscle distortions.

Most people know that vitamin D is good for calcium absorption and bone health, but vitamin D is also important for many other vital bodily processes.

A lack of vitamin D has been associated with:

An impairment in memory and thinking skills in older adults Bone, back, or muscle pain Cancer (particularly colon cancer) Cardiovascular disease, and an increased risk of dying from a stroke or a heart attack Constant fatigue and tiredness Frequent infections (such as colds and flu) Hair loss Kidney disease Low mood or depression Osteomalacia Osteoporosis Poor dental health Rickets Severe asthma in children Skin wounds that take a long time to heal.

Research also suggests low vitamin D may be a factor in several other conditions such as diabetes, high blood pressure, and multiple sclerosis.

Most experts are against routine screening for vitamin D deficiency. This is because:

Vitamin D testing is considerably more expensive than supplements No clear cut-off point for deficiency has been agreed upon Routine screening can lead to overtreatment of perceived vitamin D deficiency.

Most experts recommend that babies, children, and adults who are at high risk of vitamin D deficiency should be prescribed supplements without testing for deficiency, even if they don’t have any symptoms.

Testing may be appropriate in people who are suspected of having severe vitamin D deficiency.  In these cases, blood levels of calcium, phosphate, and alkaline phosphatase; kidney function; and other tests should be investigated as well.

Vitamin D testing is appropriate for people with:

low calcium or phosphate levels or an unexplained increase in serum alkaline phosphatase atypical osteoporosis unexplained limb pain near a joint in older people unusual fractures, unexplained bone pain, or other symptoms suggesting metabolic bone disease.

Some people may need a referral to a specialist if it is discovered that they have a metabolic bone disease rather than a simple vitamin D deficiency.

There is some controversy about whether people should take vitamin D as an oral supplement or just improve their level of sun exposure, while still staying sun safe.

An estimated 90% of vitamin D in our bodies is made when our skin is exposed to sunlight, which means our diet only contributes a small amount. However, there are certain groups of people, such as babies, young children, people with mental or physical disabilities, people with malabsorption syndromes, the elderly, and people who cover their skin for religious or cultural reasons that are at high risk of becoming vitamin D deficient.

The recommended daily intake of vitamin D is:

Aged birth to 1 year: 400 IU Aged 1-70 years: 600 IU Aged >70 years: 800 IU

The safe upper limit of vitamin D is 4,000 IU/day for adults. But even though dosages above this amount are not recommended, doctors may still prescribe them for people who are vitamin D deficient. The upper limit for children is 1000IU for infants up to 6 months; 2,500IU for toddlers up to 3 years; 3,000IU for children aged 4-8 years, and 4,000IU for those aged 9 years and older. Blood levels should be monitored when someone is taking high doses of vitamin D.

The Endocrine Society is an expert organization that recommends slightly higher daily intakes of vitamin D, and higher safe upper limits. This organization specifically deals with people at higher risk of deficiency, such as transplant recipients, chronic conditions that can cause malabsorption, or those taking medications that may threaten their bone health.

Guidelines do not currently differentiate between supplementation with different forms of vitamin D (such as D2 or D3).

Vitamin D toxicity is rare, but it can happen if you take too many supplements. You cannot get vitamin D toxicity from the sun or by eating foods that contain vitamin D.

Vitamin D toxicity is said to occur at blood levels above 150 ng/ml (375 nmol/L) of 25(OH)D. because vitamin D is a fat-soluble vitamin, it may take several weeks for levels to come down, even after you stop taking supplements.

Vitamin D levels are linked with calcium absorption, so early symptoms of vitamin D toxicity are caused by too much calcium in the blood (hypercalcemia) and include nausea, vomiting, constipation/diarrhea, weakness, or frequent urination. If levels are left too high for too long, bone pain, headaches, drowsiness, itching and calcium stones in the kidneys may occur. Very high levels may also lead to low levels of vitamin K2 in the blood, which can, ironically, cause bone loss of calcium. There are reports that excessive levels of vitamin D have caused kidney failure.

Vitamin D toxicity can be treated by stopping vitamin D supplements and restricting dietary calcium. Fluids and other medications, such as bisphosphonates may also be prescribed.

Research has shown that taking 40,000-60,000 IU of vitamin D per day for several months can lead to toxicity. But this is significantly more than the recommended safe upper dosage of vitamin D, which is 4,000 IU/day for adults. The Recommended Dietary Allowance (RDA) for most adults is 600 IU of vitamin D a day.

Always talk to your doctor before taking vitamin and mineral supplements.

Vitamin D3 has historically been made from lanolin extracted from sheep wool, but recently, a vegan/vegetarian form has become available. This version is extracted from lichen (a type of plant usually found on rocks, walls, or trees) and it is called Vitashine. This product is also sugar, wheat, gluten, and dairy-free.

Vitamin D2 supplements, made by irradiating mushrooms, are also vegan/vegetarian-friendly.

Studies have shown that D3 increases blood levels of vitamin D more significantly than D2.

Only a few foods contain vitamin D. Vitamin D can be found in foods and supplements as either D2 or D3.

Food sources of vitamin D2 include:

Mushrooms Fortified foods containing D2 (eg, breakfast cereal, infant formula, margarine, orange juice, milk)

Sources of vitamin D3 include:

Butter Cheese Egg yolk Liver Oily fish (eg, mackerel, salmon, tuna) and fish oil Fortified foods containing D3 (eg, breakfast cereal, infant formula, margarines, orange juice, milk)

Since D2 is cheaper to produce, it’s the most common form in fortified foods.

Vitamin D was first added to milk in the U.S. in the late 1930s. Up until then, rickets was a common disease and rampant among poor children living in polluted and industrialized cities in the United States.

Rickets is a bone disease that causes bone and growth deformities, typically in young children. It was first recognized as a medical condition in 1650. Although cod liver oil had been used as a treatment for other ailments for some time, it wasn’t prescribed for rickets until 1824. A landmark study in 1922 that showed that malnourished children with rickets could be cured by the addition of whole milk or cod-liver oil in their diet, paved the way for researchers to isolate active vitamin D in the 1930s.

Originally, the addition of vitamin D to milk was accomplished by irradiating milk or by feeding cows irradiated yeast. But in the 1940s this practice was replaced by the simpler and more effective method of adding vitamin D concentrate to milk, which continues today.