Very rarely will Vitamin D cause Hypercalcemia – a simple diagnostic - April 2021

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Differential diagnosis of vitamin D-related hypercalcemia using serum vitamin D metabolite profiling

J Bone Miner Res. 2021 Apr 15. doi: 10.1002/jbmr.4306
Martin Kaufmann 1 2, Karl-Peter Schlingmann 3, Linor Berezin 1, Arnaud Molin 4, Jesse Sheftel 1, Melanie Vig 1, John C Gallagher 5, Akiko Nagata 6, Shadi Sedghi Masoud 6, Ryota Sakamoto 6, Kazuo Nagasawa 6, Motonari Uesugi 7, Marie Laure Kottler 4, Martin Konrad 3, Glenville Jones 1

Genetic causes of vitamin D-related hypercalcemia are known to involve mutation of 25-hydroxyvitamin D-24-hydroxylase CYP24A1 or the sodium phosphate co-transporter SLC34A1; which result in excessive 1,25-(OH)2 D hormonal action.
However, at least 20% of idiopathic hypercalcemia (IH) cases remain unresolved. In this case-control study, we used precision vitamin D metabolite profiling based on LC-MS/MS of an expanded range of vitamin D metabolites - to screen German and French cohorts of hypercalcemia patients, to identify patients with altered vitamin D metabolism where involvement of CYP24A1 or SLC34A1 mutation had been ruled out, and possessed normal 25-OH-D3 :24,25-(OH)2 D3 ratios. Profiles were compared to those of hypercalcemia patients with hypervitaminosis D, Williams-Beuren syndrome (WBS), CYP24A1 mutation, and normal subjects with a range of 25-OH-D levels. We observed that certain IH and WBS patients exhibited a unique profile comprising 8-10-fold higher serum 23,25,26-(OH)3 D3 and 25-OH-D3 -26,23-lactone than normals; as well as very low serum 1,25-(OH)2 D3 (2-5 pg/mL) and elevated 1,24,25-(OH)3 D3 , which we interpret implies hypersensitive expression of vitamin D-dependent genes, including CYP24A1, as a general underlying mechanism of hypercalcemia in these patients. As serum 25-OH-D3 and 24,25-(OH)2 D3 remained normal, we excluded the possibility that the aberrant profile was caused by hypervitaminosis D, but instead points to an underlying genetic cause that parallels the effect of Williams Syndrome Transcription Factor deficiency in WBS. Furthermore, we observed normalization of serum calcium and vitamin D metabolite profiles at follow up of an IH patient where 25-OH-D was reduced to 9 ng/mL, suggesting that symptomatic IH may depend on vitamin D nutritional status. Other hypercalcemic patients with complex conditions exhibited distinct vitamin D metabolite profiles. Our work points to the importance of serum vitamin D metabolite profiling in the differential diagnosis of vitamin D-related hypercalcemia that can rationalize expensive genetic testing, and assist healthcare providers in selecting appropriate treatment.
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• Must balance co-factors when increasing vitamin D 500 Ca, 500 Mg - which has the following concept graph

• More than 800 mg of Calcium increases Cardiovascular events by 85 %– Nov 2011

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