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[Severe hypercalcemia due to vitamin D intoxication] Chambellan-Tison C, Horen B, Plat-Wilson G, Moulin P, Claudet I. Arch Pediatr. 2007 Nov;14(11):1328-32. Epub 2007 Oct 10. French. PMID: 17931839

Hypercalcemia due to Hypervitaminosis D: Report of Seven Patients. Joshi R. J Trop Pediatr. 2009 Apr 1. [Epub ahead of print] PMID: 19339514

Vitamin D and intervention trials in prostate cancer: from theory to therapy. Schwartz GG. Ann Epidemiol. 2009 Feb;19(2):96-102. Epub 2008 Jul 10. PMID: 18619854 doi:10.1016/j.annepidem.2008.03.007 This suggests that whereas vitamin D (e.g., cholecalciferol) might prevent prostate cancer, existing prostate tumors likely would require treatment with 1,25(OH)(2)D and/or its analogs. The major obstacle to the use of 1,25(OH)(2)D in patients therapeutically is the risk of hypercalcemia. Several maneuvers to reduce this risk, including pulse dosing and the use of less calcemic 1,25(OH)(2)D analogs, have been explored in Phase I-III clinical trials. Once merely a promise, vitamin D-based therapies for prostate cancer may soon be medical practice.

"From 1955 to 1990, all infants in East Germany received 600,000 IU of Vitamin D every three months for a total of 3,600,000 IU at age 18 months. With the 400 IU/day recommendation of the American Pediatric Association in mind, I ran across this amazing paper while surfing Medline for Vitamin D. According to this paper, all infants in the German Democratic Republic (East Germany) received dangerously high doses of Vitamin D every three months in their doctors office. The policy was in place for 35 years. The first 600,000 IU dose was given at three months and then every three months until the child was 18 months of age. This works out to an average of 6,000 IU per day (actually, for several technical reasons it is not equivalent) for 18 months. The authors collected blood before the dose and then 2 weeks after the quarterly dose to obtain 25(OH)D, 1,25(OH)D, and calcium levels on a total of 43 infants. Before the first dose, at 3 months of age, the average infant was extremely deficient (median 25(OH)D of 7 ng/ml). Two weeks after the first dose the average 25(OH)D level was 120 ng/ml, the second dose 170 ng/ml, the third dose, 180 ng/ml, the fourth dose, 144 ng/ml, the fifth dose, 110 ng/ml and after the sixth and final dose, 3.6 million total units, at age 18 months, the children had mean levels of 100 ng/ml. That is, by the 15 and 18 month doses, the children were beginning to effectively handle these massive doses. The highest level recorded in any of the 43 infants was 408 ng/ml at age 9 months, two weeks after the third 600,000 IU dose. Thirty-four percent of the infants had at least one episode of hypercalcemia but only 3 had an elevated serum 1,25(OH)D. The authors reported that all the infants appeared healthy, even the infant with a level of 408 ng/ml, that is, no clinical toxicity was noted in any of these infants."

Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration. Aloia JF, Patel M, Dimaano R, Li-Ng M, Talwar SA, Mikhail M, Pollack S, Yeh JK. Am J Clin Nutr. 2008 Jun;87(6):1952-8. PMID: 18541590 The mean daily dose was 86 microg (3440 IU). The use of computer simulations to obtain the most participants within the range of 75-220 nmol/L predicted an optimal daily dose of 115 microg/d (4600 IU). No hypercalcemia or hypercalciuria was observed. CONCLUSIONS: Determination of the intake required to attain serum 25(OH)D concentrations >75 nmol/L must consider the wide variability in the dose-response curve and basal 25(OH)D concentrations. Projection of the dose-response curves observed in this convenience sample onto the population of the third National Health and Nutrition Examination Survey suggests a dose of 95 microg/d (3800 IU) for those above a 25(OH)D threshold of 55 nmol/L and a dose of 125 microg/d (5000 IU) for those below that threshold.

Vitamin D supplementation. Eveleigh B. Can Fam Physician. 2007 Sep;53(9):1435; author reply 1435. PMID: 17872869 My concern regarding vitamin D2 is that it is a synthetic analogue and might interact with the vitamin D receptor differently in various cell systems. It has been reported that vitamin D3 might improve glycemic control.7 Vitamin D2 has been reported to cause worsening of glycemic control in people of East Indian descent.8 Is this because of vitamin D receptor polymorphism, or because of enhanced 24-hydroxylase enzyme activation, or is it due to how vitamin D2 interacts with the receptor? Until this has been sorted out, I feel safest using vitamin D3. There are about 2000 synthetic analogues of vitamin D. The search is on for one that can cross the blood-brain barrier to treat certain types of brain cancers without causing hypercalcemia.9 But then again, what other effects would this compound have? There are still so many unknowns

Serum levels of free 1,25-dihydroxyvitamin D in vitamin D toxicity. Pettifor JM, Bikle DD, Cavaleros M, Zachen D, Kamdar MC, Ross FP. Ann Intern Med. 1995 Apr 1;122(7):511-3. PMID: 7872586 CONCLUSIONS: Although the patients had normal or near-normal total 1,25-(OH)2D values, most patients had elevated free 1,25-(OH)2D levels. These findings suggest that elevated free 1,25-(OH)2D levels might play a role in the pathogenesis of hypercalcemia in vitamin D toxicity.

Despite inadequacies in information concerning the minimum prophylactic requirement of vitamin D for all age groups beyond infancy, there is no doubt that a total intake of 400 I.U. per day is adequate to prevent vitamin D deficiency in substantially all normal children from birth through adolescence. Evidence derived from the study of idiopathic hypercalcemia suggests that certain infants excessively sensitive to the toxic action of vitamin D may, on rare occasions, be adversely affected by daily intakes of 3,000 to 4,000 I.U. and sometimes considerably less. Because of the prevalent practice of food fortification in the United States and Canada, there is now a definite possibility that the individual, even the young infant, may ingest considerably more than the recommended vitamin D allowance, and intakes of 2,000 to 3,500 I.U. per day are possible, particularly beyond infancy. Although there has been no specific evidence that intakes of this order produce deleterious effects beyond infancy, it is pointed out that the long-term consequences of this new nutritional situation on older children or adults are entirely unknown.

Vitamin D is safe when used in physiological doses (those used by Nature). Physiological doses are 3,000-5,000 IU/day, from all sources (sun, diet and supplements). Should hypercalcemia occur with such doses, it is due to vitamin D hypersensitivity syndrome, not vitamin D toxicity. Vitamin D hypersensitivity syndromes include conditions such as primary hyperparathyroidism, occult cancers (especially lymphoma) or granulomatous disease (especially sarcoidosis). In such cases, treatment of vitamin D deficiency should be done under the care of a knowledgeable physician. A serum 25(OH)D, serum 1,25(OH)D, PTH and SMA will lead the clinician in the right direction.

Safety of vitamin D3 in adults with multiple sclerosis. Kimball SM, Ursell MR, O'Connor P, Vieth R. Am J Clin Nutr. 2007 Sep;86(3):645-51. PMID: 17823429 Conclusions: Patients' serum 25(OH)D concentrations reached twice the top of the physiologic range without eliciting hypercalcemia or hypercalciuria. The data support the feasibility of pharmacologic doses of vitamin D3 for clinical research, and they provide objective evidence that vitamin D intake beyond the current upper limit is safe by a large margin.

Evidence from clinical trials shows, with a wide margin of confidence, that a prolonged intake of 10,000IU/d of vitamin D3 poses no risk of adverse effects for adults, even if this is added to a rather high physiologic background level of vitamin D. Vitamin D and cancer mini-symposium: the risk of additional vitamin D. Vieth R.\nAnn Epidemiol. 2009 Jul;19(7):441-5. Epub 2009 Apr 11. PMID: 19364661 doi:10.1016/j.annepidem.2009.01.009

Vitamin D and Cancer Mini-Symposium: The Risk of Additional Vitamin D. Vieth R. Ann Epidemiol. 2009 Apr 11. [Epub ahead of print] PMID: 19364661 doi:10.1016/j.annepidem.2009.01.009   

Vieth R. \nCritique of the considerations for establishing the tolerable upper intake level for vitamin D: critical need for revision upwards.\nJ Nutr. 2006 Apr;136(4):1117-22.\nPMID: 16549491 [PubMed - indexed for MEDLINE]

Benefit-risk assessment of vitamin D supplementation. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC. Osteoporos Int. 2009 Dec 3. [Epub ahead of print] PMID: 19957164 Conclusion Our analysis suggests that mean serum 25(OH)D levels of about 75 to 110 nmol/l provide optimal benefits for all investigated endpoints without increasing health risks. These levels can be best obtained with oral doses in the range of 1,800 to 4,000 IU vitamin D per day; further work is needed, including subject and environment factors, to better define the doses that will achieve optimal blood levels in the large majority of the population.