Vitamin D is stored in the human body as calcidiol (25-hydroxy-vitamin D) which has a large volume of distribution and a half-life of about 20 to 29 days. Serum levels of calcidiol (25-hydroxy-vitamin D) are typically used to diagnose vitamin D overdose. In healthy individuals, calcidiol levels are normally between 32 to 70 ng/mL (80 to 175 nmol/L), but these levels may be as much as 15-fold greater in cases of vitamin D toxicity. Serum levels of bioactive vitamin D hormone (1,25(OH2)D) are usually normal in cases of vitamin D overdose., but this is viewed by some researchers as outdated and overly restrictive.
A 2007 risk assessment was made by two employees of the dietary supplement trade association Council for Responsible Nutrition, and their two colleagues, who declared that they had no personal or financial conflicts of interest. They suggested that 250 micrograms/day (10,000 IU) in healthy adults should be adopted as the tolerable upper limit. In rats an oral LD50 of 619 mg/kg is noted. All known cases of vitamin D toxicity with hypercalcemia have involved intake of over 1,000 micrograms/day (40,000 IU) if taken in an attempt to increase the levels of vitamin D. Most officially-recorded historical cases of vitamin D overdose have occurred due to manufacturing and industrial accidents. In the United States, overdose exposure of vitamin D was reported by 284 individuals in 2004 (a randomly selected year), leading to 1 death.
Some symptoms of vitamin D toxicity are a result of hypercalcemia (an elevated level of calcium in the blood) caused by increased intestinal calcium absorption. Vitamin D toxicity is known to be a cause of high blood pressure. Gastrointestinal symptoms of vitamin D toxicity can include anorexia, nausea, and vomiting. These symptoms are often followed by polyuria (excessive production of urine), polydipsia (increased thirst), weakness, nervousness, pruritus (itch), and eventually renal failure. Other signals of kidney disease including elevated protein levels in the urine, urinary casts, and a build up of wastes in the blood stream can also develop. Another study showed elevated risk of ischemic heart disease when 25D was above 89 ng/mL. Vitamin D toxicity is treated by discontinuing vitamin D supplementation, and restricting calcium intake. If the toxicity is severe blood calcium levels can be further reduced with corticosteroids or bisphosphonates. In some cases kidney damage may be irreversible. According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day.
VDR ligands have been shown to increase the activity of natural killer cells, and enhance the phagocytic activity of macrophages. Vitamin D deficiency tends to increase the risk of infections, such as influenza and tuberculosis. In a 1997 study, Ethiopian children with rickets were 13 times more likely to get pneumonia than children without rickets.
Effects of VDR-ligands, such as vitamin D hormone, on T-cells include suppression of T cell activation and induction of regulatory T cells, as well as effects on cytokine secretion patterns. VDR-ligands have also been shown to affect maturation, differentiation, and migration of dendritic cells, and inhibits DC-dependent T cell activation, resulting in an overall state of immunosuppression.
These immunoregulatory properties indicate that ligands with the potential to activate the VDR, including supplementation with calcitriol (as well as a number of synthetic modulators), may have therapeutic clinical applications in the treatment of inflammatory diseases (rheumatoid arthritis, psoriatic arthritis), dermatological conditions (psoriasis, actinic keratosis), osteoporosis, cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), and autoimmune diseases (systemic lupus erythematosus, type I diabetes); central nervous systems diseases (multiple sclerosis); and in preventing organ transplant rejection. Further research conducted in 2009 indicates that vitamin D is required to activate a histocompatibility gene (HLA-DRB1*1501) necessary for differentiating between self and foreign proteins in a subgroup of individuals genetically predisposed to MS. Suggestions that pregnant women take vitamin D during their pregnancy, especially during winter months, is beginning to show merit to lessen the likelihood of the child developing MS later in life.
The vitamin D hormone, calcitriol, has been found to induce death of cancer cells ''in vitro'' and ''in vivo''. The anti-cancer activity of vitamin D is thought to result from its role as a nuclear transcription factor that regulates cell growth, differentiation, apoptosis and a wide range of cellular mechanisms central to the development of cancer. These effects may be mediated through vitamin D receptors expressed in cancer cells. A scientific review undertaken by the National Cancer Institute found that vitamin D was beneficial in preventing colorectal cancer, which showed an inverse relationship with blood levels of 80 nmol/L or higher associated with a 72% risk reduction. However, the same study found no link between baseline vitamin D status and overall cancer ''mortality''.
A 2006 study using data on over 4 million cancer patients from 13 different countries showed a marked difference in cancer risk between countries classified as sunny and countries classified as less–sunny for a number of different cancers. Research has also suggested that cancer patients who have surgery or treatment in the summer — and therefore make more endogenous vitamin D — have a better chance of surviving their cancer than those who undergo treatment in the winter when they are exposed to less sunlight. Another 2006 study found that taking the U.S. RDA of vitamin D (400 IU per day) cut the risk of pancreatic cancer by 43% in a sample of more than 120,000 people from two long-term health surveys. A randomized intervention study involving 1,200 women, published in June 2007, reports that vitamin D supplementation (1,100 international units (IU)/day) resulted in a 60% reduction in cancer incidence, during a four-year clinical trial, rising to a 77% reduction for cancers diagnosed ''after'' the first year (and therefore excluding those cancers more likely to have originated prior to the vitamin D intervention). Research has also indicated beneficial effects of high levels of calcitriol on patients with advanced prostate cancer.
Low levels of vitamin D in serum have also been correlated with breast cancer disease progression and bone metastases, Polymorphisms of the vitamin D receptor (VDR) gene have been associated with an increased risk of breast cancer. Impairment of the VDR-mediated gene expression is thought to alter mammary gland development or function and may predispose cells to malignant transformation. Women with homozygous FOK1 mutations in the VDR gene had an increased risk of breast cancer compared with the women who did not. FOK1 mutation has also been associated with decreasing bone mineral density which in turn may be associated with an increase in the risk of breast cancer.
The Canadian Cancer Society was the first to recommend, in 2007, that all of its adult citizens begin taking 1,000(IU) per day of vitamin D. The country's northern latitude was a factor in the decision, as was the growing body of evidence showing the vitamin's effectiveness in lowering instances of cancer.
Research indicates that vitamin D may play a role in preventing or reversing coronary disease. Vitamin D deficiency is associated with an increase in high blood pressure and cardiovascular risk. Numerous observational studies show this link, but no randomized trial has proven the impact of vitamin D supplementation. The precise mechanism for cardiovascular regulation is still under investigation; possibilities include blood pressure regulation through the renin-angiotensin system, parathyroid hormone levels, direct impact on heart muscle function, inflammation, and vascular calcification.
When researchers monitored the vitamin D levels, blood pressure and other cardiovascular risk factors of 1739 people, of an average age of 59 years for 5 years, they found that those people with low levels of vitamin D had a 62% higher risk of a cardiovascular event than those with normal vitamin D levels. Low levels of vitamin D have also been implicated in hypertension, elevated VLDL triglycerides, and impaired insulin metabolism.
A report from the National Health and Nutrition Examination Survey (NHANES) involving nearly 5,000 participants found that low levels of vitamin D were associated with an increased risk of peripheral artery disease (PAD). The incidence of PAD was 80% higher in participants with the lowest vitamin D levels (<17.8 ng/mL). Heart attacks peak in winter and decline in summer in temperate but not tropical latitudes.
The issue of vitamin D in heart health has not yet been settled. Exercise may account for some of the benefit attributed to vitamin D, since vitamin D levels are generally higher in physically active persons. Moreover, there may be an upper limit after which cardiac benefits decline. One study found an elevated risk of ischaemic heart disease in Southern India in individuals whose vitamin D levels were above 89 ng/mL. The study evaluated whether low serum vitamin D levels were associated with all-cause mortality, cancer, and cardiovascular disease (CVD) mortality among 13,331 diverse American adults who were 20 years or older. Vitamin D levels of these participants were collected over a 6-year period (from 1988 through 1994), and individuals were passively followed for mortality through the year 2000.
Among many factors that may be responsible for vitamin D's apparent beneficial effect on all-cause mortality is its effect on telomeres and its potential effect on slowing aging. Shortening of leukocyte telomeres is a marker of aging. Leukocyte telomere length (LTL) predicts the development of aging-related disease, and length of these telomeres decreases with each cell division and with increased inflammation (more common in the elderly). Research indicates that vitamin D is a potent inhibitor of the proinflammatory response and slows the turnover of leukocytes.
Higher vitamin D levels were also associated with longer leukocyte telomere length, indicating that vitamin D sufficiency may play a role in preventing age-related diseases.
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