Hypervitaminosis D

Hypervitaminosis D
Classification and external resources
Cholecalciferol (shown above) and ergocalciferol are the two major forms of Vitamin D.
ICD-10	E67.3
ICD-9	278.4
DiseasesDB	13939
MedlinePlus	001594

Hypervitaminosis D is a state of vitamin D toxicity. The normal range for blood concentration is 30.0 to 74.0 nanograms per milliliter (ng/mL).^[1]

Symptoms and presentation

Symptoms of vitamin D toxicity include:

• Dehydration
• Vomiting
• Decreased appetite
• Irritability
• Constipation
• Fatigue
• Muscle weakness
• Metastatic calcification of the soft tissues^[2]

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.^[3] 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.^{[citation needed]}

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.

A loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose.^[4] Another name for a single high-dose oral vitamin D(3) is stoss therapy.^[5] A single oral dose of 600,000 IU of cholecalciferol rapidly increases levels of calcifediol, or 25-deoxy-cholecalciferol [25(OH)D], and reduces levels of parathyroid hormone (PTH) in young people with vitamin D deficiency.^[6]

A cholecalciferol loading dose guideline for vitamin D-deficient adults has been developed.^[7]

Recommended supplement limits

The U.S Institute of Medicine has established a Tolerable Upper Level of Intake (UL) to protect against vitamin D toxicity. These levels in microgram (mcg or µg) and International Units (IU) for male and female are:
(Conversion : 1 µg = 40 IU and 0.025 µg = 1 IU.^[8])

• 0–6 months: 25 µg (1000 IU)
• 7–12 months: 38 µg (1500 IU)
• 1–3 years: 63 µg (2500 IU)
• 4–8 years:75 µg (3000 IU)
• 9+ years:100 µg (4000 IU)
• Pregnant and Lactating: 100 µg (4000 IU)

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).^[9] Foods contain low levels, and have not been known to cause overdose.

Suggested tolerable upper intake level (UL)

Based on risk assessment, a safe upper intake level of 250 µg (10,000 IU) per day in healthy adult has been suggested.^[10][11]

Long term effects of supplementary oral intake

Excessive exposure to sunlight poses no risk in vitamin D toxicity through overproduction of vitamin D precursor, cholecalciferol, regulating vitamin D production. During ultraviolet exposure, the concentration of vitamin D precursors produced in the skin reach an equilibrium, and any further vitamin D that is produced is degraded.^[12] This process is less efficient with increased melanin pigmentation in the skin. Endogenous production with full body exposure to sunlight is comparable to taking an oral dose between 250 µg and 625 µg (10,000 IU and 25,000 IU) per day.^[12]

Vitamin D oral supplementation and skin synthesis have a different effect on the transport form of vitamin D, plasma calcifediol concentrations. Endogenously synthesized vitamin D₃ travels mainly with vitamin D-binding protein, which slows hepatic delivery of vitamin D and the availability in the plasma.^[13]

Orally administered vitamin D produces rapid hepatic delivery of vitamin D and increases plasma calcifediol.^[13] One of the richest food sources of vitamin D — wild salmon — would require 35 ounces (1 kg) to provide 10,000 IU.^[14] 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.^[15] 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.^[16]

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.^[17][18] 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.^[19]

Current theories of the mechanism behind vitamin D toxicity propose that:

• Intake of vitamin D raises calcitriol concentrations in the plasma and cell
• Intake of vitamin D raises plasma calcifediol concentrations which exceed the binding capacity of the DBP, and free calcifediol enters the cell
• Intake of vitamin D raises the concentration of vitamin D metabolites which exceed DBP binding capacity and free calcitriol enters the cell

All of which affect gene transcription and overwhelm the vitamin D signal transduction process, leading to vitamin D toxicity.^[20]

Cardiovascular disease

Whether the toxicity of oral intake of vitamin D is due to it being unnatural is not known.^[21] However, evidence suggests 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.^[13][22][23] This raises questions regarding the effects of vitamin D intake on atherosclerotic calcification and cardiovascular risk as it may be causing vascular calcification.^[24] Calcifediol is implicated in the etiology of atherosclerosis, especially in non-Caucasians.^[21][25][26]

The levels of the active form of vitamin D, calcitriol, are inversely correlated with coronary calcification^[27] Moreover, the active vitamin D analog, alfacalcidol, seems to protect patients from developing vascular calcification.^[28][29] Serum vitamin D has been found to correlate with calcified atherosclerotic plaque in African Americans as they have higher active serum vitamin D levels compared to Euro-Americans.^{[26][30][31][32]} Higher levels of calcidiol positively correlate with aorta and carotid calcified atherosclerotic plaque in African Americans but not with coronary plaque, whereas individuals of European descent have an opposite, negative association.^[26] 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.^[33]

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.^[25]

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.^[19] Despite abundant sunshine in India, vitamin D status in Indians are low and suggests a public health need to fortify Indian foods with vitamin D. 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, does not raise 25(OH)D levels to the levels typically found in Europeans.^{[34][35][36][37]}

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.^{[38][39][40][41]}

Ethnic differences

Possible ethnic differences in physiological pathways for ingested vitamin D, such as the Inuit, 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.^[42] The Inuit have relatively high rates of esophageal cancer and there are ethnic differences in the metabolism of vitamin D between Caucasians and Inuit.^[42][43] A Toronto study of young Canadians of diverse ancestry applied a standard of serum 25(OH)D levels that was significantly higher than official recommendations.^[44][45] These levels were described to be 75 nmol/L as "optimal", between 75 nmol/L and 50 nmol/L as "insufficient" and < 50 nmol/L as "deficient". 22% of individuals of European ancestry had 25(OH)D levels less than the 40 nmol/L cutoff, comparable to the values observed in previous studies (40nmol/L is 15 ng/mL). 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. Vitamin D deficiency is highly prevalent in China and occurred in more than 40% of adolescent girls in winter.^[35] In a Chinese population at particular risk for esophageal cancer and with the high serum 25(OH)D concentrations have a significantly increased risk of the precursor lesion.^[16]

Studies on the South Asians population uniformly point to low 25(OH)D levels, despite abundant sunshine.^[46] Rural men around Delhi average 44nmol/L. Healthy Indians 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 above 222.5 nmol/l and considered extremely high.^[25] Measuring melanin content to assess skin pigmentation showed an inverse relationship with serum 25(OH)D.^[44] 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. 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.^[47][48] Oral vitamin D intake is lower in Europe than both North America and Scandinavia.^[13][49]

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.^[22] Overall, excess or deficiency in the calcipherol system appear to cause abnormal functioning and premature aging.^[50][51][52]

See also

• Vitamin poisoning

References