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Review
. 2016 Oct;37(5):521-547.
doi: 10.1210/er.2016-1070. Epub 2016 Sep 2.

Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

Peter J Tebben  1 , Ravinder J Singh  1 , Rajiv Kumar  1
Affiliations
Review

Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

Peter J Tebben et al. Endocr Rev. 2016 Oct.

Abstract

Hypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

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Figures

Figure 1.
Figure 1.
A, The formation and metabolism of vitamin D3. B, Docking studies may explain ligand specificity of cytochrome P450s for vitamin D3 and its metabolites. Top panel, Crystal structure of the Cyp2R1 bound to vitamin D3 (cyan) (PDB ID 3c6g) (100). Middle panel, Homology model of Cyp24A1 (-9.2 kcal/mol) bound to substrate 25(OH)D3 (cyan). Bottom panel, Homology model of Cyp27B1 (-9.4 kcal/mol) bound to 25(OH)D3 (cyan). The heme, heme iron, and bound oxygen (yellow) positions in these cytochrome P450 cavities are shown as spheres at right. The amino acids nearby or in the positions of all three ligands are shown for comparison. Residue names and numbers are provided only if one or more enzyme atoms fall within a 4 Å distance of a ligand atom. The homology models shown were based on the closed ligand cavity conformation observed for the crystal structure of Cyp11A1 (PDB ID 3na0). (All protein structural figures and modeling are courtesy of Dr. James R. Thompson.) C, Physiological changes in response to decreases in serum calcium concentrations.
Figure 2.
Figure 2.
Integrated model of active Ca2+ reabsorption in the intestine and distal part of the nephron. Apical entry of Ca2+ is facilitated by Transient Receptor Potential Cation Channel Subfamily V Members 5,6 (TRPV 5,6)/Epithelial calcium channel (EcaC); Ca2+ then binds to calbindin-D28K, and this complex diffuses through the cytosol to the basolateral membrane, where Ca2+ is extruded by a Na+/Ca2+ exchanger and a plasma membrane Ca2+-ATPase. The individually controlled steps in the activation process of the rate-limiting Ca2+ entry channel include 1α,25(OH)2D3-mediated transcriptional and translational activation, shuttling to the apical membrane, and subsequent activation of apically located channels by ambient Ca2+ concentration, direct phosphorylation, and/or accessory proteins. (Modified from Kumar and Vallon; Ref. .)
Figure 3.
Figure 3.
5,6-trans-25(OH)D3 is produced from 25(OH)D3 in animal models administered large amounts of vitamin D3. Because of the presence of a C-1 hydroxyl group, 5,6-trans-25(OH)D3 binds to the vitamin D receptor with higher affinity than 25(OH)D3.
Figure 4.
Figure 4.
Association between 25(OH)D/24,25(OH)2D in healthy individuals (●) and patients with CYP24A1 mutations (▴). The inset shows that although the 25(OH)D/24,25(OH)2D ratio at 25(OH)D <20 ng/mL is higher, it still distinguishes between unaffected and affected individuals (93). Modified Figure 4B from: Kumar R, Vallon V. Reduced renal calcium excretion in the absence of sclerostin expression: evidence for a novel calcium–regulating bone kidney axis. J Am Soc Nephrol. 2014 Oct;25(10):2159–68. doi: 10.1681/ASN.2014020166. Epub 2014 May 29. Review. PubMed PMID: 24876121; PubMed Central PMCID: PMC4178449.
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