Hypervitaminosis D
Encyclopedia
Hypervitaminosis D is a state of vitamin D
toxicity.
The recommended daily allowance
is 400 IU per day. Overdose has been observed at 1925 µg/d (77,000 IU per day). Acute overdose requires between 15,000 µg/d (600,000 IU per day) and 42,000 µg/d (1,680,000 IU per day) over a period of several days to months, with a safe intake level being 250 µg/d (10,000 IU per day). Foods contain low levels, and have not been known to cause overdose.
An excess of vitamin D causes abnormally high blood
concentrations of calcium
(hypercalcemia), which can cause overcalcification of the bone
s, soft tissue
s, heart
and kidneys. It can also damage the kidney and produce kidney stones. In addition, hypertension
can result. Ongoing research indicates antagonism with oil soluble menatetrenone
, MK-4, an internally transported natural form of vitamin K2, which is associated with bone formation and calcium retention in the bones.
Note: Hypervitaminosis D symptoms appear several months after excessive doses of vitamin D are administered. In almost every case, a low calcium diet combined with corticosteroid drugs will allow for a full recovery within a month.
, sarcoidosis
, tuberculosis
, and lymphoma
. This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium
, and any further vitamin D that is produced is degraded. According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day. According to Holick
, "the skin has a large capacity to produce cholecalciferol
"; his experiments indicate that,
Using the dose-response of a whole body exposure to one erythemal dose of ultraviolet radiation as a reference, Heaney et al suggest 250 micrograms/day (10,000 IU) in healthy adults be adopted as the upper safe limit.
Supplements and skin synthesis have a different effect on on serum 25(OH)D concentrations; endogenously synthesized vitamin D3 travels in plasma almost exclusively on vitamin D-binding protein (VDBP), providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol observed after depot, parenteral administration of vitamin D.
Yet the orally administered route vitamin D produces swift hepatic delivery of vitamin D, and transient, but nonetheless abrupt, increases in plasma 25-hydroxycholecalciferol. One of the richest food sources of vitamin D — wild salmon — would require 35 ounce (0.992233305 kg) a day to provide 10,000IU. It has been argued that ingestion of vitamin D in large amounts was achieved in the process of grooming by furry human ancestors and that from UV-exposed human skin secretions early humans ingested vitamin D by licking the skin, however this putative ingestion of vitamin D by early humans is not quantified. A study found 34% of its sample of healthy western Canadians to be under 40nmol/L at some point and 97% to be under 80nmol/L at least once.
It has been questioned whether to ascribe a state of sub-optimal vitamin D status when the annual variation in ultraviolet
will naturally produce a period of falling levels, and such a seasonal decline has been a part of Europeans' adaptive environment for 1000 generations. Still more contentious is recommending supplementation when those supposedly in need of it are labeled healthy and serious doubts exist as to the long term effect of attaining and maintaining serum 25(OH)D of at least 80nmol/L by supplementation.
. Calcifediol (25-hydroxy-vitamin D) is implicated in the etiology of atherosclerosis, especially in non-Caucasians.
1,25-Dihydroxycholecalciferol(active serum vitamin D) levels are inversely correlated with coronary calcification moreover one-alpha-hydroxy-cholecalciferol, an active vitamin D analog therapy seems to protect patients from developing vascular calcification. African Americans have higher active serum vitamin D levels. There are racial differences in the association of coronary calcified plaque in that there is less calcified atherosclerotic plaque in the coronary arteries of African-Americans than in whites.
A case control study on a population in southern India found that more than 50% of patients with ischaemic heart disease
had serum levels of vitamin D higher than 222.5 nmol/L, but the study did not evaluate causation.
Freedman et al. (2010) have found that serum vitamin D correlates in African Americans, but not in Euro-Americans, with calcified atheroscleratic plaque. Pharmacokinetics of vitamin D toxicity states - "Early assumptions that 1,25(OH)2D3 might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D3 at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1,25(OH)2D from vitamin D binding". Freedman et al. (2010) states - "Higher levels of 25-hydroxyvitamin D seem to be positively correlated with aorta and carotid CP in African Americans but not with coronary CP. These results contradict what is observed in individuals of European descent". Recommendations stemming for a single standard for optimal serum 25(OH)D concentrations ignores the differing genetically mediated determinates of serum 25(OH)D and may result in ethnic minorities in Western countries having the results of studies done with subjects not representative of ethnic diversity applied to them. Vitamin D levels vary for genetically mediated reasons as well as environmental ones.
Among descent groups with heavy sun exposure during their evolution, taking supplemental vitamin D to attain the 25(OH)D level associated with optimal health in studies done with mainly European populations may have deleterious outcomes. A review of vitamin D status in India concluded that studies uniformly point to low 25(OH)D levels in Indians despite abundant sunshine, and suggested a public health need to fortify Indian foods with vitamin D might exist. However the levels found in India are consistent with many other studies of tropical populations which have found that even an extreme amount of sun exposure, such as incured by rural Indians, does not raise 25(OH)D levels to the levels typically found in Europeans,
, those with the highest serum 25(OH)D concentrations have a significantly increased risk of the precursor lesion. Inuit
have relatively high rates of esophageal cancer and there are ethnic differences in the metabolism of vitamin D between Caucasians and Inuit.
In South Asians Harinarayan (2009) found "All studies uniformly point to low 25(OH)D levels in the populations studies despite abundant sunshine in our country". For example rural men around Delhi average 44nmol/L. Healthy Indians living at the latitude they are presumably best adapted to seem have low 25(OH)D levels which are not very different from healthy South Asians living in Canada. South Indian patients with ischemic heart disease have serum 25-hydroxyvitamin D3 levels which are extremely high — above 222.5 nmol/l. The Toronto group conclude -"skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D". The uniform occurrence of very low serum 25(OH)D in Indians living in India and Chinese in China does not support the hypothesis that the low levels seen in the more pigmented are due to lack of synthesis from the sun at higher latitudes, the leader of the study has urged dark-skinned immigrants to take vitamin D supplements nonetheless; "I see no risk, no downside, there's only a potential benefit". A study of French Canadians found that a significant minority did not maximize ingested serum 25(OH)D for genetic reasons; vitamin D-binding protein polymorphisms explained as much of the variation in circulating 25(OH)D as did total ingestion of vitamin D. Oral vitamin D intake, is lower in Europe than both North America and Scandinavia. Whether the toxicity of oral intake of vitamin D is due to that route being unnatural as suggested by Fraser is not known, but there is a certain amount of evidence to suggest that dietary vitamin D may be carried by lipoprotein particles into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages. These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Dietary vitamin D may be causing vascular calcification
.
of vitamin D increase mortality. Overall, excess or deficiency in the calcipherol system appear to cause abnormal functioning and premature aging.
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
toxicity.
The recommended daily allowance
Reference Daily Intake
The Reference Daily Intake or Recommended Daily Intake is the daily intake level of a nutrient that is considered to be sufficient to meet the requirements of 97–98% of healthy individuals in every demographic in the United States .The RDI is used to determine the Daily Value of foods,...
is 400 IU per day. Overdose has been observed at 1925 µg/d (77,000 IU per day). Acute overdose requires between 15,000 µg/d (600,000 IU per day) and 42,000 µg/d (1,680,000 IU per day) over a period of several days to months, with a safe intake level being 250 µg/d (10,000 IU per day). Foods contain low levels, and have not been known to cause overdose.
Symptoms and presentation
Symptoms of vitamin D poisoning include:- DehydrationDehydrationIn physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
- VomitingVomitingVomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
- Decreased appetiteAppetiteThe appetite is the desire to eat food, felt as hunger. Appetite exists in all higher life-forms, and serves to regulate adequate energy intake to maintain metabolic needs. It is regulated by a close interplay between the digestive tract, adipose tissue and the brain. Decreased desire to eat is...
(anorexiaAnorexia (symptom)Anorexia is the decreased sensation of appetite...
) - IrritabilityIrritabilityIrritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
- ConstipationConstipationConstipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
- Fatigue
- Muscle weaknessMuscle weaknessMuscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
An excess of vitamin D causes abnormally high blood
Blood
Blood is a specialized bodily fluid in animals that delivers necessary substances such as nutrients and oxygen to the cells and transports metabolic waste products away from those same cells....
concentrations of calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
(hypercalcemia), which can cause overcalcification of the bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
s, soft tissue
Soft tissue
In anatomy, the term soft tissue refers to tissues that connect, support, or surround other structures and organs of the body, not being bone. Soft tissue includes tendons, ligaments, fascia, skin, fibrous tissues, fat, and synovial membranes , and muscles, nerves and blood vessels .It is sometimes...
s, heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
and kidneys. It can also damage the kidney and produce kidney stones. In addition, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
can result. Ongoing research indicates antagonism with oil soluble menatetrenone
Menatetrenone
Menatetrenone , also known as MK4, is a menaquinone compound used as a hemostatic agent and as adjunctive therapy for the pain of osteoporosis. It is marketed for the latter indication in Japan by Eisai Co., under the trade name Glakay....
, MK-4, an internally transported natural form of vitamin K2, which is associated with bone formation and calcium retention in the bones.
Note: Hypervitaminosis D symptoms appear several months after excessive doses of vitamin D are administered. In almost every case, a low calcium diet combined with corticosteroid drugs will allow for a full recovery within a month.
Long term effects of supplementary oral intake
Vitamin D toxicity is unlikely except when certain medical conditions are present, such as primary hyperparathyroidismPrimary hyperparathyroidism
Primary hyperparathyroidism causes hypercalcemia through the excessive secretion of parathyroid hormone , usually by an adenoma of the parathyroid glands.-Epidemiology:...
, sarcoidosis
Sarcoidosis
Sarcoidosis , also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells form as nodules in multiple organs. The cause of sarcoidosis is unknown...
, tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...
, and lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
. This is because within about 20 minutes of ultraviolet exposure in light skinned individuals (3–6 times longer for pigmented skin) the concentration of vitamin D precursors produced in the skin reach an equilibrium
Chemical equilibrium
In a chemical reaction, chemical equilibrium is the state in which the concentrations of the reactants and products have not yet changed with time. It occurs only in reversible reactions, and not in irreversible reactions. Usually, this state results when the forward reaction proceeds at the same...
, and any further vitamin D that is produced is degraded. According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day. According to Holick
Michael Holick
Michael Holick is an American dermatologist, a professor of medicine, physiology and biophysics at Boston University who is known for recommending exposure to sunlight 2 to 3 times per week for photosynthesis of Vitamin D. He was asked to resign from his position in dermatology at Boston...
, "the skin has a large capacity to produce cholecalciferol
Cholecalciferol
Cholecalciferol is a form of vitamin D, also called vitamin D3 or calciol.It is structurally similar to steroids such as testosterone, cholesterol, and cortisol .-Forms:Vitamin D3 has several forms:...
"; his experiments indicate that,
"[W]hole-body exposure to one minimal erythemal dose of simulated solar ultraviolet radiation is comparable with taking an oral dose of between 250 and 625 micrograms (10 000 and 25 000 IU) vitamin D."
Using the dose-response of a whole body exposure to one erythemal dose of ultraviolet radiation as a reference, Heaney et al suggest 250 micrograms/day (10,000 IU) in healthy adults be adopted as the upper safe limit.
Supplements and skin synthesis have a different effect on on serum 25(OH)D concentrations; endogenously synthesized vitamin D3 travels in plasma almost exclusively on vitamin D-binding protein (VDBP), providing for a slower hepatic delivery of the vitamin D and the more sustained increase in plasma 25-hydroxycholecalciferol observed after depot, parenteral administration of vitamin D.
Yet the orally administered route vitamin D produces swift hepatic delivery of vitamin D, and transient, but nonetheless abrupt, increases in plasma 25-hydroxycholecalciferol. One of the richest food sources of vitamin D — wild salmon — would require 35 ounce (0.992233305 kg) a day to provide 10,000IU. It has been argued that ingestion of vitamin D in large amounts was achieved in the process of grooming by furry human ancestors and that from UV-exposed human skin secretions early humans ingested vitamin D by licking the skin, however this putative ingestion of vitamin D by early humans is not quantified. A study found 34% of its sample of healthy western Canadians to be under 40nmol/L at some point and 97% to be under 80nmol/L at least once.
It has been questioned whether to ascribe a state of sub-optimal vitamin D status when the annual variation in ultraviolet
Ultraviolet
Ultraviolet light is electromagnetic radiation with a wavelength shorter than that of visible light, but longer than X-rays, in the range 10 nm to 400 nm, and energies from 3 eV to 124 eV...
will naturally produce a period of falling levels, and such a seasonal decline has been a part of Europeans' adaptive environment for 1000 generations. Still more contentious is recommending supplementation when those supposedly in need of it are labeled healthy and serious doubts exist as to the long term effect of attaining and maintaining serum 25(OH)D of at least 80nmol/L by supplementation.
Cardiovascular disease
There is a certain amount of evidence to suggest that dietary vitamin D may be carried by lipoprotein particles into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages. These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Dietary vitamin D may be causing vascular calcificationCalcification
Calcification is the process in which calcium salts build up in soft tissue, causing it to harden. Calcifications may be classified on whether there is mineral balance or not, and the location of the calcification.-Causes:...
. Calcifediol (25-hydroxy-vitamin D) is implicated in the etiology of atherosclerosis, especially in non-Caucasians.
1,25-Dihydroxycholecalciferol(active serum vitamin D) levels are inversely correlated with coronary calcification moreover one-alpha-hydroxy-cholecalciferol, an active vitamin D analog therapy seems to protect patients from developing vascular calcification. African Americans have higher active serum vitamin D levels. There are racial differences in the association of coronary calcified plaque in that there is less calcified atherosclerotic plaque in the coronary arteries of African-Americans than in whites.
A case control study on a population in southern India found that more than 50% of patients with ischaemic heart disease
Ischaemic heart disease
Ischaemic or ischemic heart disease , or myocardial ischaemia, is a disease characterized by ischaemia of the heart muscle, usually due to coronary artery disease...
had serum levels of vitamin D higher than 222.5 nmol/L, but the study did not evaluate causation.
Freedman et al. (2010) have found that serum vitamin D correlates in African Americans, but not in Euro-Americans, with calcified atheroscleratic plaque. Pharmacokinetics of vitamin D toxicity states - "Early assumptions that 1,25(OH)2D3 might cause hypercalcemia in vitamin D toxicity have been replaced by the theories that 25(OH)D3 at pharmacologic concentrations can overcome vitamin D receptor affinity disadvantages to directly stimulate transcription or that total vitamin D metabolite concentrations displace 1,25(OH)2D from vitamin D binding". Freedman et al. (2010) states - "Higher levels of 25-hydroxyvitamin D seem to be positively correlated with aorta and carotid CP in African Americans but not with coronary CP. These results contradict what is observed in individuals of European descent". Recommendations stemming for a single standard for optimal serum 25(OH)D concentrations ignores the differing genetically mediated determinates of serum 25(OH)D and may result in ethnic minorities in Western countries having the results of studies done with subjects not representative of ethnic diversity applied to them. Vitamin D levels vary for genetically mediated reasons as well as environmental ones.
Among descent groups with heavy sun exposure during their evolution, taking supplemental vitamin D to attain the 25(OH)D level associated with optimal health in studies done with mainly European populations may have deleterious outcomes. A review of vitamin D status in India concluded that studies uniformly point to low 25(OH)D levels in Indians despite abundant sunshine, and suggested a public health need to fortify Indian foods with vitamin D might exist. However the levels found in India are consistent with many other studies of tropical populations which have found that even an extreme amount of sun exposure, such as incured by rural Indians, does not raise 25(OH)D levels to the levels typically found in Europeans,
Ethnic differences
Possible ethnic differences in physiological pathways for ingested vitamin D, such as Inuit have, may confound across the board recommendations for vitamin D levels. Inuit compensate for lower production of vitamin D by converting more of this vitamin to its most active form Another study by the Toronto group did have 'young Canadian adults of diverse ancestry' but applied a standard of serum 25(OH)D levels that was significantly higher than official recommendations. 75 nmol/L as "optimal", between 75 nmol/L and 50 nmol/L as "insufficient" and < 50 nmol/L as "deficient". The results were ' 22% of individuals of European ancestry had 25(OH)D levels less than the 40 nmol/L cutoff, which is comparable to the values observed in previous studies. 78% of individuals of East Asian ancestry and 77% of individuals of South Asian ancestry had 25(OH)D concentrations lower than 40 nmol/L. The East Asians in the Toronto sample had low 25(OH)D levels when compared to whites. Lipps (2010) in a world wide review says 'vitamin D deficiency (serum 25(OH)D<25nmol/l) is highly prevalent in China: "A survey in Beijing indicated that Vitamin D-deficiency (plasma 25(OH)D concentration <12.5 nmol/l) occurred in more than 40% of adolescent girls in winter." In a Chinese population at particular risk for esophageal cancerEsophageal cancer
Esophageal cancer is malignancy of the esophagus. There are various subtypes, primarily squamous cell cancer and adenocarcinoma . Squamous cell cancer arises from the cells that line the upper part of the esophagus...
, those with the highest serum 25(OH)D concentrations have a significantly increased risk of the precursor lesion. Inuit
Inuit
The Inuit are a group of culturally similar indigenous peoples inhabiting the Arctic regions of Canada , Denmark , Russia and the United States . Inuit means “the people” in the Inuktitut language...
have relatively high rates of esophageal cancer and there are ethnic differences in the metabolism of vitamin D between Caucasians and Inuit.
In South Asians Harinarayan (2009) found "All studies uniformly point to low 25(OH)D levels in the populations studies despite abundant sunshine in our country". For example rural men around Delhi average 44nmol/L. Healthy Indians living at the latitude they are presumably best adapted to seem have low 25(OH)D levels which are not very different from healthy South Asians living in Canada. South Indian patients with ischemic heart disease have serum 25-hydroxyvitamin D3 levels which are extremely high — above 222.5 nmol/l. The Toronto group conclude -"skin pigmentation, assessed by measuring skin melanin content, showed an inverse relationship with serum 25(OH)D". The uniform occurrence of very low serum 25(OH)D in Indians living in India and Chinese in China does not support the hypothesis that the low levels seen in the more pigmented are due to lack of synthesis from the sun at higher latitudes, the leader of the study has urged dark-skinned immigrants to take vitamin D supplements nonetheless; "I see no risk, no downside, there's only a potential benefit". A study of French Canadians found that a significant minority did not maximize ingested serum 25(OH)D for genetic reasons; vitamin D-binding protein polymorphisms explained as much of the variation in circulating 25(OH)D as did total ingestion of vitamin D. Oral vitamin D intake, is lower in Europe than both North America and Scandinavia. Whether the toxicity of oral intake of vitamin D is due to that route being unnatural as suggested by Fraser is not known, but there is a certain amount of evidence to suggest that dietary vitamin D may be carried by lipoprotein particles into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages. These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Dietary vitamin D may be causing vascular calcification
Calcification
Calcification is the process in which calcium salts build up in soft tissue, causing it to harden. Calcifications may be classified on whether there is mineral balance or not, and the location of the calcification.-Causes:...
.
Premature aging
Complex regulatory mechanisms control metabolism, recent epidemiologic evidence suggests that there is a narrow range of vitamin D levels in which vascular function is optimized. Levels above or below this natural homeostasisHuman homeostasis
Human homeostasis is derived from the Greek, homeo or "same", and stasis or "stable" and means remaining stable or remaining the same.The human body manages a multitude of highly complex interactions to maintain balance or return systems to functioning within a normal range...
of vitamin D increase mortality. Overall, excess or deficiency in the calcipherol system appear to cause abnormal functioning and premature aging.