What is Vitamin D?
Vitamin D is a steroid hormone - NOT a vitamin. It is regulated through G protein activation, like the other steroid and thyroid hormones. Thyroid hormones control Vitamin D metabolism.
"Like the receptors for other steroid hormones and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA. In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription."
The vitamin D receptor binds several forms of cholecalciferol. Its affinity for 1,25-dihydroxycholecalciferol (also called Calcitriol, Vitamin D, Dihydroxy Vitamin D, 1,25-dihydroxy-vitamin D3) is roughly 1000 times that for 25-hydroxycholecalciferol (25-D3 or “calcidiol”), which explains their relative biological potencies.
“The story of vitamin D begins when a vitamin D precursor is eaten. The precursor we get from plants is called “ergosterol” and the precursor we get from eating animal tissues is called “7-dehydrocholesterol.” These substances are absorbed into the body when they are eaten and transported to the skin for modification by sunlight radiation (hence the popular terminology of vitamin D as the “sunshine vitamin”). The animal origin substance is converted to what is called “vitamin D3” or “cholecalciferol” while the plant substance becomes “vitamin D2” or “ergocalciferol.” From here we will follow the animal origin hormone as it is the most metabolically active.
“The next stop is the liver for modification (a hydroxyl group is added to the 25th carbon of the vitamin D3 molecule) thus forming 25-hydroxycholecalciferol. After this 25-hydroxycholecalciferol (often abbreviated 25-D3 or “calcidiol”) circulates to the kidney for its final activation. Another hydroxyl group is added in the final activation to form 1,25 dihydroxylcholecalciferol, aka calcitriol.” (Courtesy Vet Info Sheet for ROCALTROL)
Excessive exposure to sunlight does not lead to overproduction of vitamin D. Vitamin D toxicity is inevitably the result of overdosing on vitamin D supplements.
To assess vitamin D deficiency, serum levels of 25-OH vitamin D3 are usually tested. Unfortunately this is done without any consideration for thyroid status, although it has been known for more than 30 years that thyroid hormones control Vitamin D metabolism.
Some studies have shown that Vitamin D3 and fluoride have synergistic effects on bone aluminum accumulation (Ittel et al, 1993), reducing the aluminum deposited in some bone tissue, but not changing parameters of bone-disease.
Reduction of aluminum deposits in bone does not mean less aluminum is absorbed, but is more a sign of “redistribution”. Increased Al levels are seen in plasma of hemodialized patients at doses of D3 as low as 240 IU per week (6 micrograms) (Demontis et al, 1986).
Like fluoride, Vit D may cause increased absorbtion of lead, cadmium, aluminum, and cobalt; and radioactive isotopes such as strontium and cesium (Moon 1997; 1994; Babarykin, 1994).
Like fluoride, Vitamin D has been used as rodenticide.
Although some animal studies report benefits of Vitamin D supplementation in fluoride poisoning (Guna Sherlin & Verma RJ, 2000; 2001) caution is advised. While it may benefit those suffering from T3 toxicosis or hyperthyroidism as a result of fluoride-induced disturbances in deiodination activity, it may worsen some conditions in those having Low T3 (hypothyroidism).
In children with skeletal fluorosis - as in hypothyroidism - elevated levels of 1,25-Dihydroxy-Vitamin D3 have been observed (Pettifor et al, 1989).
Hypothyroid children have higher serum levels of both calcium and 1,25-dihydroxy-vitamin D3, while having lower levels of osteocalcin (Lauffer et al, 1993; Verrotti et al, 1998), while the opposite is reported in hyperthyroidism (Saggese et al, 1990). These levels normalize after thyroid status is corrected (Verrotti et al, 1998; Saggeese et al, 1990).
In hypothyroid patients treated with Levothyroxine, Vitamin D significantly raised TSH secretion (Gasinska et al, 1993). In hypothyroid newborns, 70% of those given Vitamin D together with Levothyroxine suffered from hypercalcemia, compared to 21% on L-T4 only.
SEE ALSO: Vitamin D & Thyroid Status
Vitamin D may be Harmful in Rheumatic Disease
References & Research Material
Aburto A, Edwards HM Jr, Britton WM - “The influence of vitamin A on the utilization and amelioration of toxicity of cholecalciferol, 25-hydroxycholecalciferol, and 1,25 dihydroxycholecalciferol in young broiler chickens” Poult Sci 77(4):585-93 (1998)
Adams JS, Lee G - "Gains in bone mineral density with resolution of vitamin D intoxication" Ann Intern Med 127:203-206 (1997)
- "The cases of 3 women and 1 man, ages 53-73 yr, with osteoporosis who were diagnosed with vitamin D intoxication associated with the mobilization of skeletal calcium resulting from the daily use of 3-8 nonprescription dietary supplements daily, including animal extract preparations, with some containing unadvertised high levels of Vitamin D, including cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), and in whom resolution of vitamin D intoxication was associated with a rebound in bone mineral density is presented. Concomitant therapy included estrogens conjugated (n=1) and levothyroxine sodium and estrogens conjugated (n=1). The 4 patients had hypercalciuria and elevated serum levels of 25-hydroxyvitamin D. Each of the patients was taking 1000 mg of supplemental calcium and a multivitamin preparation daily and the additional dietary supplements. The supplemental therapy was stopped. Serial measurement of serum levels of 25-hydroxyvitamin D, ratio of fasting urinary calcium to creatinine, and bone mineral density were performed during a mean 3.2 yr follow-up period. Serum levels of 25-hydroxyvitamin D and the ratio of urinary calcium to creatinine normalized, and there was a mean annual increase in bone mineral density of 1.9%. When dietary calcium supplements only were restarted, laboratory test values remained in the normal range."
Andersen L, Richards A, Care AD, Andersen HM, Kragstrup J, Fejerskov O - “Parathyroid glands, calcium, and vitamin D in experimental fluorosis in pigs” Calcif Tissue Int 38(4):222-6 (1986)
Babarykin DA, Bauman VK - “The metabolism of heavy metals depends on the vitamin-D status of the body” Fiziol Zh Im I M Sechenova 80(7):88-98 (1994)
“The results obtained demonstrated that vitamin D3 caused accumulation of those metals in tissues and their toxicity in organisms. When increasing the vitamin dose from 200 to 500 IU on 1 kg of ration that tendency was being heightened.”
Colussi G, Rombola G, De Ferrari ME, Minola E, Minetti L - “Vitamin D treatment: a hidden risk factor for aluminum bone toxicity?” Nephron 47(1):78-80 (1987)
Davies M, Adams PH - "Continuing risk of vitamin D intoxication" Lancet 2:621-623 (1978)
- "Eight cases of vitamin D poisoning are described, of which 2 involved the ingestion of ergocalciferol. In 6 patients this therapy was unnecessary and in the remaining 2 patients inadequate supervision of the treatment resulted in overdosage. In 5 cases the history of vitamin D therapy was either unknown or not appreciated by the referring clinician so that 3 surgical procedures of dubious value were performed on 2 patients. These results suggest that large doses of vitamin D should only be used when strictly indicated and on the understanding that close biochemical and clinical supervision is necessary."
Demontis R, Leflon A, Fournier A, Tahiri Y, Herve M, Moriniere P, Abdull-Massih Z, Atik H, Belbrik S, Renaud H - “1 alpha(OH) vitamin D3 increases plasma aluminum in hemodialized patients taking AI(OH)3” Clin Nephrol 26(3):146-9 (1986)
Gasinska T, Kierat A, Kochanska-Dziurowicz A, Izbicka M - "TSH secretion stimulated by thyroliberin in patients with hypothyroidism receiving 1,25-hydroxyvitamin D3" Endokrynol Pol 44(1):47-55(1993) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8050389
Guna Sherlin DM, Verma RJ - "Vitamin D ameliorates fluoride-induced embryotoxicity in pregnant rats" Neurotoxicol Teratol 23(2):197-201 (2001) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11348838
Guna Sherlin DM, Verma RJ - "Amelioration of fluoride-induced hypocalcaemia by vitamins" Hum Exp Toxicol 19(11):632-4 (2000) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11211241
Ittel TH, Gladziwa U, Sieberth HG - "Synergistic effect of 1,25-vitamin D3 and fluoride on bone aluminum accumulation" Bone 14(3):427-32 (1993)
Ittel TH, Hofstadter F, Gladziwa U, Sieberth HG - “Reduced deposition of aluminium in trabecular bone of uraemic rats treated with dihydroxylated vitamin D metabolites” Nephrol Dial Transplant 4(11):957-65 (1989)
Ittel TH, Gruber E, Heinrichs A, Handt S, Hofstadter F, Sieberth HG - “Effect of fluoride on aluminum-induced bone disease in rats with renal failure” Kidney Int 41(5):1340-8 (1992)
Jacobus CH, Holick MF, Shaq Q, Chen TC, Holm TA, Kolodny JM, Fuleihan G EH, Seely EW - "Hypervitaminosis D associated with drinking milk" NEJM 326 (18):1173-1177(1992)
- "Vitamin D has been added to milk in the United States since the 1930s to prevent rickets. We report the unusual occurrence of eight cases of vitamin D intoxication that appear to have been caused by excessive vitamin D fortification of dairy milk. Methods: Medical records were reviewed and a dietary questionnaire was sent to eight patients who had unexplained hypervitaminosis D. Vitamin D analyses with high-performance liquid chromatography were performed on samples of the patients' serum, the dairy milk they drank, and the vitamin D concentrate added to the milk. Results: All eight patients drank milk produced by a local dairy in amounts ranging from 1/2 to 3 cups (118 to 710 ml) daily. All had elevated serum 25-hydroxyvitamin D concentrations (mean (| SD), 731| 434 nmol per liter (293 | 174 ng per milliliter)). Six of the eight patients had elevated serum vitamin D3 concentrations. Of the eight patients, seven had hypercalcemia and one had hypercalciuria."
Jin X, Meng X, Zhou X, Liu H, Yang X - “Effects of combined treatment with flouride and 1,25-dihydroxyvitamin D3 on the histomorphometry and biomechanical properties of bone in ovariectomized rats” Zhongguo Yi Xue Ke Xue Yuan Xue Bao 21(4):241-6 (1999)
Kashio Y, Iwasaki J, Chihara K, Kaji H, Kita T, Okimura Y, Fujita T - "Pituitary 1,25-dihydroxyvitamin D3 receptors in hyperthyroid- and hypothyroid-rats" Biochem Biophys Res Commun 131(1):122-8 (1985) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2994643
Kassem M, Mosekilde L, Eriksen EF - “1,25-dihydroxyvitamin D3 potentiates fluoride-stimulated collagen type I production in cultures of human bone marrow stromal osteoblast-like cells” J Bone Miner Res 8(12):1453-8 (1993)
Kawakami-Tani T, Fukawa E, Tanaka H, Abe Y, Makino I - “Effect of 1 alpha-hydroxyvitamin D3 on serum levels of thyroid hormones in hyperthyroid patients with untreated Graves' disease” Metabolism 46(10):1184-8 (1997)
Langdahl BL, Loft AG, Eriksen EF, Mosekilde L, Charles P - “Bone mass, bone turnover, calcium homeostasis, and body composition in surgically and radioiodine-treated former hyperthyroid patients” Thyroid 6(3):169-75 (1996)
Leger J, Tau C, Garabedian M, Farriaux JP, Czernichow P - "Prophylaxis of vitamin D deficiency in hypothyroidism in the newborn infant" Arch Fr Pediatr 46(8):567-71 (1989)
Lindblom P, Valdemarsson S, Lindergard B, Westerdahl J, Bergenfelz A - “Decreased levels of ionized calcium one year after hemithyroidectomy: importance of reduced thyroid hormones” Horm Res 55(2):81-7 (2001)
Lindemann G - “Experimental chronic fluorosis in young rats receiving supplementary doses of vitamin D” Acta Odontol Scand 23(6):575-92 (1965)
Laufer J, Noff D, Orda S, Sack J - "Effect of short-term hyperthyroxinemia on vitamin D metabolism in congenital hypothyroidism" Horm Metab Res 25(7):386-8 (1993) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8406326
Leger J, Tau C, Garabedian M, Farriaux JP, Czernichow P - "Prophylaxis of vitamin D deficiency in hypothyroidism in the newborn infant" Arch Fr Pediatr 46(8):567-71 (1989) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=2604508
Lindblom P, Valdemarsson S, Lindergard B, Westerdahl J, Bergenfelz A - "Decreased levels of ionized calcium one year after hemithyroidectomy: importance of reduced thyroid hormones" Horm Res 55(2):81-7 (2001)
- "We conclude that the reduction in ionized calcium 1 year after hemithyroidectomy was not due to PTH deficiency. Instead our results suggest that the reduced effects of thyroid hormones on bone and kidney function is essential."
Mano H, Ozawa T, Takeyama K, Yoshizawa Y, Kojima R, Kato S, Masushige S - "Thyroid hormone affects the gene expression of retinoid X receptors in the adult rat" Biochem Biophys Res Commun 191(3):943-9 (1993)
"These results suggest that thyroid hormone might affect the signal transduction of retinoid, vitamin D and thyroid hormone by changing RXR levels."
Mathias RS, Amin U, Mathews CH, Denbesten P - "Increased fluoride content in the femur growth plate and cortical bone of uremic rats" Pediatr Nephrol 14(10-11):935-9 (2000) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10975302
Maxwell JD, Ang L, Brooke OG, Brown IR - "Vitamin D supplements enhance weight gain and nutritional status in pregnant Asians" Br J Obstet Gynaecol 88(10):987-91 (1981) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=6793058
Misselwitz J, Hesse V, Markestad T - "Nephrocalcinosis, hypercalciuria and elevated serum levels of 1,25-dihydroxyvitamin D in children. Possible link to vitamin D toxicity" Acta Paediatr Scand 79(6-7):637-43 (1990)
Moon JC - "A brief history of vitamin D toxicity" J Appl Nutr 49
- “The margin between the prophylactic dose of vitamin D and the toxic dose is very narrow. The problem of preventing rickets by adding vitamin D to food without producing toxic effects has not been solved. Significant evidence from animal experiments and humans poisoned by excess vitamin D suggest that current usage of vitamin D in North America contributes to atherosclerosis, renal calculi, and toxic metal accumulations. Addition of vitamin D to foods and supplements is not adequately controlled, resulting in large differences between label-stated and measured content of vitamin D in fortified foods. Vitamin D is very unstable both to light and to heat. Attempts to stabilize it have resulted in some stabilized forms that are hundreds of times more toxic than unstabilized forms, and call attention to the need for caution in use of these newer forms of vitamin D."
Moon J - "The role of vitamin D in toxic metal absorption: A review" J Am Col Nutr 13 (6): 559-564 (1994)
"Vitamin D increases intestinal calcium and phosphate absorption. Not so well known, however, is that vitamin D stimulates the co-absorption of other essential minerals like magnesium, iron, and zinc; toxic metals including lead, cadmium, aluminum, and cobalt; and radioactive isotopes such as strontium and cesium. Vitamin D may contribute to the pathologies induced by toxic metals by increasing their absorption and retention. Reciprocally, lead, cadmium, aluminum, and strontium interfere with normal vitamin D metabolism by blocking renal synthesis of 1,25-dihydroxyvitamin D. This is the first review of the role of the vitamin D endocrine system in metal toxicology."
Morita R, Yamamoto I, Takada M, Ohnaka Y, Yuu I - "Hypervitaminosis D" Nippon Rinsho 51(4):984-8 (1993) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=8483281
Paterson CR - " Vitamin D poisoning: survey of causes in 21 patients with hypercalcemia" Lancet 1:1164-1165 (1980)
- "Hypercalcemia developed in 21 patients due to vitamin D2 (ergocalciferol,I) poisoning; 2 were poisoned twice and 2 were poisoned 3 times. All patients had taken mg doses of I, which for 5 patients was inappropriate. For the other 16 patients (mainly with hypoparathyroidism) mg doses of I were appropriate; the patients were poisoned either early in therapy, trying to correct the plasma calcium too quickly, or, later, because of failure to follow up patients properly. Two patients died as a result of their intoxication. Constant vigilance is essential when patients are taking large doses of I."
Pettifor JM, Bikle DD, Cavaleros M, Zachen D, Kamdar MC, Ross FP - "Serum levels of free 1,25-dihydroxyvitamin D in vitamin D toxicity" Ann Intern Med 122(7):511-3 (1995)
Pettifor JM, Schnitzler CM, Ross FP, Moodley GP - “Endemic skeletal fluorosis in children: hypocalcemia and the presence of renal resistance to parathyroid hormone” Bone Miner 7(3):275-88 (1989)
“Furthermore in a separate study of nine children with skeletal symptoms due to endemic fluorosis, hypocalcemia was found in six. 1,25-Dihydroxyvitamin D levels were elevated in the seven children in whom it was measured.”
Raghuramulu N, Krishnamachari KA VR, Rao B SN - “Serum 25-hydroxy vitamin D3 in endemic genu valgum and fluorosis” Fluoride 30(3):147-152 (1997)
“Vitamin D nutritional status was assessed by determining serum 25-hydroxy vitamin D3 (25-OH-D3) levels in subjects suffering from endemic fluorosis and endemic genu valgum. Appropriate age and sex matched controls from the endemic and nonendemic areas were also studied for comparison. No evidence of vitamin D deficiency was found in any of the groups studied. On the other hand, serum 25-OH-D3 levels were significantly elevated in genu valgum subjects. Thus, the results indicate that vitamin D deficiency may not be one of the factors responsible for bone manifestations seen in endemic fluorosis and endemic genu valgum.”
Saggese G, Bertelloni S, Baroncelli GI - “Bone mineralization and calciotropic hormones in children with hyperthyroidism. Effects of methimazole therapy” J Endocrinol Invest 13(7):587-92 (1990)
“Our study provides further evidence that in hyperthyroidism an altered mineral homeostasis is present with a reversible disturbance in vitamin D metabolism. We found that the return to euthyroidism was associated with a normalization of mineral homeostasis and with a recovery of bone mineralization.”
Schwartzman MS, Franck WA - "Vitamin D toxicity complicating the treatment of senile, postmenopausal, and glucocorticoid-induced osteoporosis. Four case reports and a critical commentary on the use of vitamin D in these disorders" Am J Med 82(2):224-30 (1987) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3812514
Tau C, Garabedian M, Farriaux JP, Czernichow P, Pomarede R, Balsan S - "Hypercalcemia in infants with congenital hypothyroidism and its relation to vitamin D and thyroid hormones" Pediatr 109(5):808-14 (1986) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=3490559
Tiwari S, Gupta SK, Kumar K, Trivedi R, Godbole MM - “Simultaneous Exposure of Excess Fluoride and Calcium Deficiency Alters VDR, CaR, and Calbindin D 9 k mRNA Levels in Rat Duodenal Mucosa” Calcif Tissue Int 75(4):313-320 (2004)
Vazquez G, Boland R, De Boland AR - “Modulation by 1,25(OH)2-vitamin D3 of the adenylyl cyclase/cyclic AMP pathway in rat and chick myoblasts” Biochimica et Biophysica Acta 1269 (1) 91-97 (1995)
“Fluoride and GTPgammaS mimicked 1,25(OH)2D3-stimulation of calcium influx while GDPbetaS suppressed the effect of the hormone.”
Verrotti A, Greco R, Altobelli E, Morgese G, Chiarelli F - "Bone metabolism in children with congenital hypothyroidism--a longitudinal study" J Pediatr Endocrinol Metab 11(6):699-705 (1998) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9829223
- “Before the beginning of therapy, the hypothyroid patients showed higher values of calcium (2.78 +/- 0.04 vs 2.65 +/- 0.07 mmol/l; p < 0.05) and of 1,25-dihydroxy-vitamin D (159.7 +/- 31.6 vs 90.5+/- 33.1 ng/l; p < 0.01”
Vieth R - "Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety" Am J Clin Nutr 69(5):842-56 (1999) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10232622
Vukicevic S, Krempien B, Stavljenic A - “Effects of 1 alpha,25- and 24R,25-dihydroxyvitamin D3 on aluminum-induced rickets in growing uremic rats” J Bone Miner Res 2(6):533-45 (1987)
“Moreover, calcitriol produced hyperosteoidosis and osteosclerosis in the same rats.”
Gupta SK, Gupta RC, Seth AK, Gupta A - “Reversal of fluorosis in children” Acta Paediatr Jpn 38(5):513-9 (1996)
Gupta SK, Gupta RC, Seth AK - Reversal of clinical and dental fluorosis” Indian Pediatr 31(4):439-43 (1994)
Vitamin D & Thyroid Status
“An interesting finding was the fact that when an animal maintained on a diet containing vitamin D received fluoride injections, fluorosis (mottled enamel) did not occur. However, when animals maintained on a vitamin D free diet received fluoride injections, fluorosis was plainly evident. This might explain why some children when drinking fluoridated water from the same water supply are affected with fluorosis and others not.” [HREX TIF#:d5392007]