Hypervitaminosis D

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Hypervitaminosis D
Classification and external resources

Cholecalciferol (shown above) and ergocalciferol are the two major forms of Vitamin D.
ICD-10E67.3
ICD-9278.4
DiseasesDB13939
MedlinePlus001594
 
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Hypervitaminosis D
Classification and external resources

Cholecalciferol (shown above) and ergocalciferol are the two major forms of Vitamin D.
ICD-10E67.3
ICD-9278.4
DiseasesDB13939
MedlinePlus001594

Hypervitaminosis D is a state of vitamin D toxicity.

The recommended daily allowance is 15 µg/d (600 IU per day). Overdose has been observed at 1,925 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).[1] Foods contain low levels, and have not been known to cause overdose.

Contents

Symptoms and presentation

Symptoms of vitamin D poisoning include:

An excess of vitamin D causes abnormally high blood concentrations of calcium (hypercalcemia), which can cause overcalcification of the bones, soft tissues, heart and kidneys. It can also damage the kidney and produce kidney stones[citation needed]. In addition, hypertension can result [2]. 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.

Long term effects of supplementary oral intake

Vitamin D toxicity is unlikely except when certain medical conditions are present, such as primary hyperparathyroidism, sarcoidosis, tuberculosis, and lymphoma.[3][4] 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.[5] According to some sources, endogenous production with full body exposure to sunlight is approximately 250 µg (10,000 IU) per day.[6] According to Holick, "the skin has a large capacity to produce cholecalciferol"; 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 µg/d (10,000 and 25,000 IU per day) vitamin D."[5]

Using the dose-response of a whole body exposure to one erythemal dose of ultraviolet radiation as a reference, Heaney et al. suggest 250 µg/d (10,000 IU) in healthy adults be adopted as the upper safe limit.[7]

Supplements and skin synthesis have a different effect on serum 25(OH)D concentrations;[8] 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 ounces (1 kg) to provide 10,000 IU.[9] It has been argued[10] 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[11] 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[12] for 1000 generations.[13] 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.[14]

Cardiovascular disease

There is a certain amount of evidence to suggest that dietary vitamin D may be carried by lipoprotein particles[15] into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages.[16] These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Dietary vitamin D may be causing vascular[17] calcification. Calcifediol (25-hydroxy-vitamin D) is implicated in the etiology of atherosclerosis, especially in non-Caucasians.[18][19][20]

1,25-Dihydroxycholecalciferol(active serum vitamin D) levels are inversely correlated with coronary calcification[21] Moreover one-alpha-hydroxy-cholecalciferol, an active vitamin D analog[22] therapy seems to protect patients from developing vascular calcification.[23] African Americans have higher active serum vitamin D levels.[24][25][26] There are racial differences in the association of coronary calcified plaque[27] 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.[19]

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".[28] 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".[20] 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.[29][30][31][32]

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.[14] 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,[33] does not raise 25(OH)D levels to the levels typically found in Europeans,[34][35][36]

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[37] Another study by the Toronto group[38] 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.[39] 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)[34] 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 cancer, those with the highest serum 25(OH)D concentrations have a significantly increased risk of the precursor lesion.[11] Inuit have relatively high rates of esophageal cancer and there are ethnic differences in the metabolism of vitamin D between Caucasians and Inuit.[37][40]

In South Asians Harinarayan (2009)[41] 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.[19] 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".[42][43] A study of French Canadians[44] 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.[45] Oral vitamin D intake,[46] is lower in Europe than both North America and Scandinavia.[8] Whether the toxicity of oral intake of vitamin D is due to that route being unnatural as suggested by Fraser[8][18] is not known, but there is a certain amount of evidence to suggest that dietary vitamin D may be carried by lipoprotein particles[15] into cells of the artery wall and atherosclerotic plaque, where it may be converted to active form by monocyte-macrophages.[16] These findings raise questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk. Dietary vitamin D may be causing vascular[17] calcification.

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 homeostasis of vitamin D increase mortality.[16] Overall, excess or deficiency in the calcipherol system appear to cause abnormal functioning and premature aging.[47][48][49]

See also

References

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