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Endocr Rev. 2016 Oct; 37(5): 521–547.

Published online 2016 Sep 2. doi: 10.1210/er.2016-1070

PMCID: PMC5045493

PMID: 27588937

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

Peter J. Tebben, Ravinder J. Singh, and Rajiv Kumar

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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.

1. Introduction

2. Vitamin D-Associated Hypercalcemia

   1. Vitamin D metabolism

   2. Preval‎ence and clinical manifestations of vitamin D-mediated hypercalcemia

   3. Hypercalcemia associated with excessive ingestion of vitamin D and active vitamin D metabolites/analogs

   4. Hypercalcemia associated with granulomatous disease.

   5. Hypercalcemia associated with CYP24A1 mutations

3. Summary and Conclusions

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I. Introduction

Hypercalcemia is encountered in 0.2 to 4% of community-dwelling subjects and hospital patients (1,–8). The incidence of hypercalcemia is dependent upon whether serum calcium measurements are performed in free-living subjects in a community (1), in a hospital population (2,–4), or in patients seen in an emergency department (5, 6, 8). Causes of hypercalcemia are listed in Table 1. Cancer-associated hypercalcemia and primary hyperparathyroidism are the most frequent causes of hypercalcemia. Their relative frequency depends upon whether the diagnosis of hypercalcemia is made in a hospital setting (where cancer-associated hypercalcemia is most frequent) or within the context of an outpatient practice (where the diagnosis of primary hyperparathyroidism predominates) (9).

Table 1.

Causes of Hypercalcemia

PTH-Mediated

    Primary hyperparathyroidism

    Tertiary hyperparathyroidism

    Post-transplant hyperparathyroidism

    Familial hypocalciuric hypercalcemia/severe neonatal hyperparathyroidism

    Humoral hypercalcemia of malignancy—PTH-mediated

Non-PTH-Mediated

    Endocrine

        Hypothyroidism

        Hypoadrenalism/Addison's syndrome

        VIPoma

        Pheochromocytoma

        Pregnancy/lactation-associated (PTHrP-mediated)

    Malignancy

        Humoral hypercalcemia of malignancy

            PTH-related peptide

            1,25-dihydroxyvitamin D

        Lytic bone lesions

    Drug-related

        Thiazide diuretics

        Vitamin D or vitamin D analogs

        Vitamin K

        Calcium

        Aluminum

        Beryllium

        Theophylline

        Vitamin A intoxication

    Vitamin D-mediated

        Excessive cholecalciferol or ergocalciferol indigestion

        Ingestion or administration of excessive calcitriol (or other 1α-hydroxylated vitamin D analogs)

        Ectopic 1,25-dihydroxyvitamin D production

            Granulomatous disease

                Sarcoidosis

                Tuberculosis

                Fungal diseases

                Leprosy

                Other granulomatous lesions

            Lymphoma

        Inactivating mutations of the CYP24A1 gene in children and adults

    Miscellaneous conditions

        Post-acute renal failure

        William's syndrome

        Paget's disease

        Immobilization

        Jansen's metaphyseal chondrodysplasia

        Hypophosphatasia

        Milk-alkali syndrome

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From a diagnostic and therapeutic perspective, it is useful to think of hypercalcemia as a PTH-dependent or PTH-independent process. Increases in PTH concentrations in association with hypercalcemia indicate the presence of primary (10,–14), tertiary (15,–28), and post-transplant hyperparathyroidism (3, 21, 25, 26, 28,–38) or severe neonatal hyperparathyroidism (associated with homozygous mutations of the calcium-sensing receptor) (39,–42), whereas hypercalcemia in association with a low or suppressed PTH concentration indicates the presence of PTH-independent mechanisms causing hypercalcemia. In the latter category, cancer-associated hypercalcemia is predominant. In vitamin D-associated hypercalcemia, PTH concentrations are appropriately reduced.

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II. Vitamin D-Associated Hypercalcemia

A review of vitamin D metabolism will assist in the understanding of mechanisms associated with vitamin D-mediated hypercalcemia and the utility of measurements of vitamin D metabolites when a diagnosis of vitamin-associated hypercalcemia is made.

A. Vitamin D metabolism

The major physiological role of vitamin D through the activity of its active metabolite 1α,25-dihydroxyvitamin D [1α,25(OH)2D] is the maintenance of normal calcium and phosphorus balance (43,–46). 1α,25(OH)2D also mediates several other biological effects such as the modulation of immune function (47, 48), muscle function (49,–51), and cell growth and differentiation (52,–54). A brief review of the metabolism, regulation, and mechanism of action of vitamin D follows. For more detailed information, readers are referred to prior reviews in Endocrine Reviews (49, 50, 54,–64) and other journals (48, 65, 67,–69).

Figure 1A summarizes the salient biochemical transformations that occur during the formation and metabolism of vitamin D metabolites. The endogenous form of vitamin D, vitamin D3 (cholecalciferol), is formed in the skin as a result of photolysis of the precursor sterol, 7-dehydrocholesterol (70,–78). Under the influence of ultraviolet light (optimal wave lengths for photolysis, 295–300 nm), the B-ring of the sterol is cleaved, giving rise to previtamin D3, which undergoes thermal equilibration to vitamin D3 (76,–78). Vitamin D3, bound to vitamin D-binding protein, to which it preferentially binds relative to its precursor, previtamin D3, exits the skin and enters the circulation (77). Similar biochemical transformations occur with the plant sterol, ergosterol, which upon photolysis gives rise to vitamin D2, or ergocalciferol (79). Although there are interspecies differences in the biological activity of vitamin D3 vs vitamin D2 (for example, vitamin D2 is much less active in birds than mammals) (80), the major metabolic transformations of vitamin D3 and vitamin D2 are similar. For the purposes of this review, we will use the term “vitamin D3” throughout. Unless specified, the reader may assume that the similar metabolic transformations occur in the case of vitamin D3 and vitamin D2. The term “vitamin D” will be used to refer to both vitamin D2 and vitamin D3 metabolites.

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.

Vitamin D3 is metabolized in the liver microsomes and mitochondria to 25-hydroxyvitamin D3 [25(OH)D3] by the vitamin D3-25-hydroxylase (81,–92). The vitamin D3-25-hydroxylase is only partially inhibited by its product, and hence, increasing amounts of administered vitamin D3 are associated with increases in the amount of product, namely, 25(OH)D3, and hence, increasing concentrations of vitamin D3 in the serum are associated with proportional increases in serum 25(OH)D3. 25(OH)D3 (both free and bound to vitamin D-binding protein) is the major circulating vitamin D3 metabolite (43, 68, 69, 74, 94–95), and measurements of this vitamin D metabolite are widely used as an index of nutritional vitamin D status (96,–99). The CYP2R1 is the cytochrome P450 of the microsomal vitamin D3-25 hydroxylase, a mutant form of which was identified in a human subject with low circulating concentrations of 25-hydroxyvitamin D [25(OH)D] and classic symptoms of vitamin D deficiency (90). In the patient studied, homozygous mutations in exon 2 of the CYP2R1 gene on chromosome 11p15.2 resulted in the substitution of a proline for an evolutionarily conserved leucine at amino acid 99 in the CYP2R1 protein and reduced vitamin D3-25 hydroxylase activity. Other vitamin D3-25 hydroxylases are also likely to play a role in the transformation of vitamin D3 to 25(OH)D3 because Cyp2r1−/− mice have only a partial (∼50%) reduction in serum 25(OH)D3 concentrations and lack overt rickets and hypocalcemia (92). The structure of the Cyp2A1 cytochrome P450 bound to its ligand, vitamin D3, has been solved by x-ray crystallography (100). Vitamin D3 is bound in an elongated conformation with the aliphatic side-chain pointing toward the heme group (Figure 1B, top panel). The active site is lined by conserved, mostly hydrophobic residues.

The further metabolism of 25(OH)D3 is dependent upon the calcium and phosphorus requirements of the individual. In states of calcium demand, 25(OH)D3 is metabolized by the 25-hydroxyvitamin D3-1α-hydroxylase to the biologically active vitamin D metabolite, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], in the kidney by PTH-dependent processes (Figure 1C) (43, 65, 74, 101,–112). Changes in PTH alter multiple processes including renal calcium reabsorption (directly and indirectly through changes in sclerostin expression‎) (111,–114), 25(OH)D 1α-hydroxylase activity, and bone resorption mechanisms (43, 65, 74, 101,–112). In states of calcium sufficiency, the synthesis of 1α,25(OH)2D3 is reduced, and the synthesis of 24R,25-dihydroxyvitamin D3 (24R,25(OH)2D3) (115,–117), an inert vitamin D metabolite, is increased. The synthesis of 24R,25(OH)2D3 is mediated by the 25(OH)D3-24-hydroxylase that is present in several target tissues of 1α,25(OH)2D3 including the intestine and the kidney (115, 118,–120). This enzyme is induced by 1α,25(OH)2D3 (118, 121). Serum phosphate concentrations also regulate the synthesis of 1α,25(OH)2D3 by PTH-independent mechanisms (122). Thus, in states of phosphorous demand, 25(OH)D3 is metabolized to 1α,25(OH)2D3, and the synthesis of 24R,25(OH)2D3 is reduced (69, 103, 123,–126). The converse occurs in hyperphosphatemic states. Numerous factors other than calcium and phosphorus alter the activity of the 25(OH)D-1α-hydroxylase, and the reader is referred to reviews on this matter (104, 127,–131). As noted in Figure 1A, 1α,25(OH)2D3 and 24R,25(OH)2D3 are metabolized to 1α,24R,25(OH)3D3 by the 24 and 1α-hydroxylases.

The 25(OH)D3-24-hydroxylase is a mitochondrial, multicomponent enzyme with a terminal cytochrome P450, the CYP24A1, which uses molecular oxygen to hydroxylate 25(OH)D3 at C-24 on the side chain of the sterol (132). The Cyp24A1/CYP24A1 gene has been cloned from rats (133,–136) and humans (137, 138). As we will discuss in later sections, deletions or mutations in the mouse and human CYP24A1 gene are responsible for hypercalcemia as a result of elevated 1α,25(OH)2D3 concentrations (69, 139,–147). Shown in Figure 1B, middle panel, is a model of the Cyp24A1 protein bound to 25(OH)D3. Note the proximity of the side chain to oxygen and heme groups. Models of the Cyp24A1 and Cyp27B1 were generated by threading Cyp24A1 and Cyp27B1 amino acid sequences onto the backbone polypeptide positions to form three cytochrome p450 structures: rat 24-hydroxylase (Cyp24A1; PDB ID 3k9v), human cholesterol side-chain cleavage enzyme (Cyp11A1; PDB ID 3na0), and human 11-β-hydroxylase (Cyp11B1; PDB ID 4fdh) (148,–154). The 25(OH)D3-1α-hydroxylase is a mitochondrial, multicomponent enzyme with a terminal cytochrome P450 (155,–158), CYP27B1, which uses molecular oxygen to hydroxylate 25(OH)D3 at C-1 on the A ring of the sterol (159,–162). Mutations of the CYP27B1 gene are responsible for vitamin D dependency rickets, type 1 (163,–166), and deletion of the Cyp27B1 gene in mice confers a rachitic phenotype (167). Shown in Figure 1B, lower panel, is a model of the Cyp27B1 cytochrome P450 protein bound to 25(OH)D3. Note the proximity of the A ring to oxygen and heme groups. The enzyme is also responsible for the conversion of 24R,25(OH)2D3 to the metabolite, 1α, 24R, 25-trihydroxyviatamin D3. Besides metabolism to 1α,24,25(OH)3D3, 1α,25(OH)2D3 is also metabolized to polar steroids (glucuronides and sulfates) in the liver and excreted in bile [about 30–40% of an administered dose of 1α,25(OH)2D3] (55, 104, 168,–172); to calcitroic acid that is excreted in the bile as a polar metabolite (about 20–25% of an administered dose of 1α,25(OH)2D3) (173,–176); and to 1α,25R(OH)2D3-26,23S-lactone (177,–179).

The bioactivity of vitamin D3 is dependent on the formation of 1α,25(OH)2D3. Pharmacological amounts of precursors such as vitamin D3 itself or intermediary metabolites such as 25(OH)D3 are required to elicit a biological response in anephric animals and patients (109, 180, 181). In such individuals, 1α,25(OH)2D3 readily increases intestinal calcium transport (105, 106) and mobilizes calcium from bone (181). The actions of 1α,25(OH)2D3 require the presence of the vitamin D receptor, a steroid hormone receptor that binds 1α,25(OH)2D3 with high affinity and binds other vitamin D metabolites with lower affinities (182,–185). After binding of the ligand, 1α,25(OH)2D3, to the ligand-binding domain of the receptor, a conformational change in the receptor is associated with the recruitment of other steroid hormone receptors such as the RXRα and various coactivator (or corepressor) proteins to the transcription start site of genes regulated by 1α,25(OH)2D3 (186,–194). The vitamin D receptor binds DNA binding elements of varied nucleotide structures within vitamin D-regulated genes via its amino-terminal DNA binding domain (195,–199). Numerous calcium-regulating genes are induced or repressed in vitamin D-responsive target tissues such as the intestine, kidney, and bone (45, 51, 200,–205).

Absorption of dietary calcium by the intestine is essential for the maintenance of normal calcium homeostasis (206) and is a major factor contributing to hypercalcemia in patients with vitamin D intoxication. The efficiency of calcium absorption increases or decreases inversely with the amount of dietary calcium, and adaptations to changes in calcium intake are dependent upon vitamin D and its active metabolite, 1α,25(OH)2D3 (206, 207). Calcium is absorbed by the intestine (predominantly in the duodenum and proximal small intestine) by two mechanisms, a passive paracellular mechanism, and an active transcellular one (206, 208, 209). Active calcium absorption initially involves the movement of calcium across the apical border of the intestinal cell into the cell down a concentration gradient (the interior of the intestinal cell has a calcium concentration in the high nanomolar range) and an electrical gradient (the interior of the cell is electronegative relative to the lumen). It does not require the expenditure of energy (210, 211). The extrusion of calcium out of the intestinal cell at the basolateral membrane is against an electrical and concentration gradient and requires the expenditure of energy (210, 211). Essential to the process of active calcium transport are several vitamin D dependent proteins, each with a specific function. These include the epithelial calcium channel, calbindin D9K andD28K, and the plasma membrane calcium pump (212). In the duodenal enterocyte, apically situated TRPV 5/6 cation channels mediate the increase in calcium uptake from the lumen into the cell (213); intracellular calcium binding proteins such as calbindin D9K and D28K facilitate the movement of calcium across the cell (209, 210); and the basal-lateral plasma membrane calcium pump (214,–216) and the sodium-calcium exchanger (217) assist in the extrusion of calcium from within the cell into the extracellular fluid (Figure 2). The sodium gradient for the activity of the sodium-calcium exchanger is maintained by the Na-K ATPase. Intestinal transcellular calcium transport is regulated by vitamin D through its active metabolite, 1α,25(OH)2D3, which increases the expression‎ of TRPV 6 channels (218), the intracellular concentrations of calbindin D9K and D28K (210, 219,–221), and the expression‎ of the plasma membrane pump, isoform 1 (222, 223) (Figure 2). The requirement of various intestinal calcium transporter proteins in transcellular calcium transport in vivo has been examined in knockout mice. Deletions of TrpV6 and calbindin D9K genes are not associated with alterations in intestinal calcium transport in vivo in the basal state and after the administration of 1α,25(OH)2D3 (224, 225), although one report suggests that basal calcium transport on an adequate calcium diet is normal in TrpV6 knockout mice but adaptations to a low-calcium diet are impaired (226). We recently showed that deletion of the Pmca1 in the intestine is associated with reduced growth and bone mineralization and a failure to up-regulate calcium absorption in response to 1α,25(OH)2D3, thereby establishing the essential role of the pump in transcellular calcium transport (227).

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. 112.)

1α,25(OH)2D3, PTH, and the phosphatonin, fibroblast growth factor-23 (FGF-23), regulate and maintain normal phosphorus concentrations (212, 228, 229). Changes in serum phosphate concentrations are associated with changes in 1α,25(OH)2D3 concentrations. A decrease in serum phosphate concentration is associated with an increase in ionized calcium, a decrease in PTH secretion, and a subsequent decrease in renal phosphate excretion. An increase in renal 25(OH)D 1α-hydroxylase activity, increased 1α,25(OH)2D3 synthesis, and increased phosphorus absorption in the intestine and reabsorption in the kidney occur (122, 126, 230,–237). In the intestine and kidney, 1α,25(OH)2D3 regulates the expression‎ of the sodium-phosphate cotransporters IIb, and IIA and IIc, respectively, thereby regulating the efficiency of inorganic phosphate absorption in enterocytes and proximal tubule cells (212, 238,–240).

B. Preval‎ence and clinical manifestations of vitamin D-mediated hypercalcemia

Although relatively uncommon in comparison to cancer-associated hypercalcemia and primary hyperparathyroidism, the true preval‎ence of vitamin D-mediated hypercalcemia is unknown. With the increase in vitamin D supplementation in the general population and with new information becoming available on the preval‎ence of CYP24A1 mutations (139,–147) in the general population (241), it is likely that the preval‎ence of vitamin D-mediated hypercalcemia will increase. Table 2 summarizes the causes and mechanisms associated with the development of vitamin D-associated hypercalcemia.

Table 2.

Vitamin D-Associated Hypercalcemia

Exogenous Vitamin D Toxicity

    Administration of excessive amounts of vitamin D3 or vitamin D2

    Administration of excessive amounts of 25(OH)D3

    Administration of excessive amounts of 1α,25(OH)2D3, other 1α- hydroxylated vitamin D analogs such as 1α(OH)D3, paricalcitol, and doxercalciferol in the context of chronic renal failure, end-stage renal disease, and hemodialysis therapy

Excessive Production of Vitamin D Metabolites

    Congenital disorders: excessive production of 25(OH)D and 1,25(OH)2D3, eg, in Williams-Beuren syndrome with mutations of the Williams Syndrome Transcription Factor

    Granulomatous disease: excessive production of 1,25(OH)2D3: sarcoidosis, tuberculosis, leprosy, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, candidiasis, cat-scratch disease, Pneumocystis jiroveci or P. carinii pneumonia, Mycobacterium avium complex, Wegener's granulomatosis, Crohn's disease, infantile sc fat necrosis, giant cell polymyositis, berylliosis, silicone-induced granuloma, paraffin-induced granulomatosis, talc granuloma.

    Lymphomas and malignant lymphoproliferative disease: excessive production of 1,25(OH)2D3: lymphoma, non-Hodgkin lymphoma, lymphomatoid, granulomatosis, inflammatory myofibroblastic tumor, dysgerminoma

Mutations in Enzymes Associated With Vitamin D Metabolite Degradation

    Mutations of the CYP24A1 gene: reduced degradation of 1,25(OH)2D3: infantile and adult hypercalcemia

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C. Hypercalcemia associated with excessive ingestion of vitamin D and active vitamin D metabolites/analogs

1. Vitamin D intake and hypercalcemia

The upper tolerable limit, defined as the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects to almost all individuals in the general population, for vitamin D3 is 1000 IU/d in infants ages 0–6 months, 1500 IU/d in infants ages 6–12 months; 2500 IU/d in children ages 1–5 years; 3000 IU/d in children ages 4–8 years, and 4000 IU/d in adolescents and adults (97, 99). The short-term ingestion of up to 10 000 IU/d of vitamin D3 is associated with the maintenance of 25(OH)D serum concentrations below 50 ng/mL (125 nmol/L) (240), a concentration below which toxicity has not been observed. In a study of 40 patients with metastatic breast tumors, daily doses of 10 000 IU vitamin D3 for 4 months were not associated with hypercalcemia although small increases in serum calcium and decreases in PTH were observed (243). Ingestion of amounts of vitamin D3 or vitamin D2 higher than 10 000 IU/d in an adult (and lower amounts in children) should raise the suspicion of vitamin D intoxication, especially in the context of hypercalciuria and/or hypercalcemia because the serum 25(OH)D concentration rises steeply at intakes >10,000 IU/d. The duration of ingestion of vitamin D, the starting 25(OH)D concentration before the ingestion of vitamin D3, and the underlying reason for therapy are important in considering the contribution of vitamin D ingestion to changes in 25(OH)D concentrations (see Ref. 242 for a summary of multiple studies). Generally, vitamin D-associated hypercalcemia occurs only when extremely large doses of vitamin D (often several hundred-fold the recommended intake) are ingested (244,–257).

2. Diagnosis of hypervitaminosis D

The clinical symptoms of vitamin D toxicity are the result of hypercalcemia and hypercalciuria and are similar to those of hypercalcemia due to any other cause. Symptoms include neuropsychiatric manifestations such as lethargy, confusion, irritability, depression, hallucinations, and in extreme cases, stupor, and coma; gastrointestinal symptoms such as anorexia, nausea, vomiting, and constipation; cardiovascular manifestations such as ectopy; and renal symptoms such as polyuria and renal colic from the passage of renal stones.

Reports suggest that the administration of vitamin D3 in large amounts is associated with an increased risk of falls and fractures (258,–261). For example, in a 1-year, double-blind, randomized clinical trial conducted in Switzerland among community-dwelling men and women 70 years of age and older, groups of subjects receiving monthly treatment with 60 000 IU of vitamin D3, and 24 000 IU of vitamin D3 plus 300 μg of calcifediol [25(OH)D3], had a higher incidence of falls than a the group receiving 24 000 IU of vitamin D3 (261). In another study, in which older women received a single annual oral dose of 500 000 IU of vitamin D3, the relative risk of falling in the vitamin D group vs the placebo group was 1.31 in the first 3 months after dosing and 1.13 during the following 9 months (258). Thus, among older community-dwelling women, annual oral administration of high-dose cholecalciferol resulted in an increased risk of falls and fractures.

Laboratory findings other than hypercalcemia include hyperphosphatemia and suppressed serum PTH concentrations. The presence of hyperphosphatemia is a clue to the presence of hypervitaminosis D. It occurs as a result of an increase in intestinal and renal phosphate absorption. In contrast, patients with primary hyperparathyroidism have hypercalcemia and hypophosphatemia on account of PTH-mediated losses of phosphate in the urine. Hypercalciuria is frequently present. Urinary calcium excretion is generally elevated before the development of hypercalcemia in patients with hypervitaminosis D. Urine osmolality may be low on account of a renal concentrating defect that occurs as a result of resistance to the effects of antidiuretic hormone and resultant nephrogenic diabetes insipidus. Three mechanisms have been proposed to mediate the diabetes insipidus associated with hypercalcemia. Activation of the calcium-sensing receptor in the thick ascending limb with attendant inhibition of sodium chloride reabsorption and countercurrent multiplication results in a dilute urine (262). In addition, the sensing of the increased Ca2+ concentrations in the urine in the terminal collecting duct by calcium-sensing receptors facing the urinary space is believed to reduce antidiuretic hormone-stimulated water reabsorption from urine to medullary interstitial fluid (262). Decreased aquaporin-2 expression‎ and apical plasma membrane delivery in kidney collecting ducts also contributes to the polyuria seen with hypercalcemia (263). Elevated serum creatinine and blood urea nitrogen, and nephrocalcinosis on radiographic examination of the kidneys are frequently present. Electrocardiogram findings include a shortened QTc, ST segment coving, T wave broadening, and first degree heart block.

Although vitamin D (vitamin D3 and vitamin D2) can be measured in serum and plasma and quantitated by various methods such as ultraviolet spectroscopy and competitive protein binding, its measurement is technically difficult, and few reports have appeared on its use in the measurement of vitamin D in patients with hypervitaminosis D (264, 265). Measurements of serum 25(OH)D, which can be performed by a variety of methods—including competitive protein binding assay (266,–268), RIA (269,–272), HPLC/ultraviolet spectroscopy (273, 274), automated, antibody-, and microparticle-based, chemiluminescent immunoassay (275), and liquid chromatography mass spectrometry (272, 276,–279)—are widely used in the assessment of vitamin D status. Various epimers contribute to the total 25(OH)D measurement and appear to be most prominent in infants and very young patients in whom C-3 epimers of 25(OH)D can account for a significant proportion of 25(OH)D measured by liquid chromatography-tandem mass spectrometry unless measures are taken to separate metabolites by chromatography (279). In hypervitaminosis D [25(OH)D3 >64–439 ng/mL], the mean relative contribution of 3-epi-25(OH)D3 was <4%, and concentrations ranged from 2–28.6 ng/mL (280). Serum levels of the C-3 epimer correlate with serum 25(OH)D3 concentrations. In subjects with 25(OH)D3 concentrations indicative of hypervitaminosis D, the presence and concentrations of the C-3 epimer were unrelated to age, serum markers of renal and liver function, acute-phase reactants, and the presence of hypercalcemia. Subjects with significant PTH suppression (<14 pg/mL) showed higher concentrations of 3-epi-25(OH)D3.

It is challenging to assign an absolute serum vitamin D concentration over which toxicity is always present. Some patients can have 25(OH)D concentrations well over 80 ng/mL without hypercalcemia or hypercalciuria. However, in general, serum total 25(OH)D concentrations >80 ng/mL (200 nmol/L) are necessary to result in vitamin D toxicity, with concentrations typically severalfold higher than 80 ng/mL in those who present with symptomatic hypercalcemia (244,–257). In most cases, serum 1α,25(OH)2D3 concentrations are normal. The vitamin D concentration at which an individual develops hypercalcemia or hypercalciuria is likely influenced by the amount of dietary calcium intake. As a result, serum and urine calcium concentrations may be quite variable, despite concentrations of serum 25(OH)D that might be regarded as elevated. A report by Adams and Lee (281) suggested that concentrations of 25(OH)D as low as 50 ng/mL (125 nmol/L) were associated with hypercalciuria. In addition, results of the Women's Health Initiative found that modest vitamin D and calcium supplementation resulted in a higher risk of nephrolithiasis compared to placebo (282). Although 25(OH)D concentrations of approximately 50 ng/mL (125 nmol/L) may increase urinary calcium excretion and the risk of nephrolithiasis, it should be remembered that normal individuals exposed to sunlight for short or long periods of time can have 25(OH)D serum concentrations as high as 65 ng/mL (163 nmol/L) without ill effects or hypercalcemia (248, 266, 283,–295). Concentrations of 25(OH)D >80 ng/mL in the presence of hypercalcemia and the clinical setting of excessive vitamin D ingestion should raise the suspicion of vitamin D intoxication.

In serum, 25(OH)D is tightly bound to vitamin D binding protein (VDBP) (296,–298), and only a small percentage of total serum 25(OH)D is free or unbound (95, 299,–301). The role of VDBP in determining the amount of bioavailable 25(OH)D has recently been investigated by Powe et al (302), who reported that community-dwelling black Americans, as compared with whites, had low levels of total 25(OH)D and vitamin D-binding protein but similar concentrations of estimated bioavailable 25(OH)D. Subsequent studies using mass spectrometry or a polyclonal antiserum against VDBP (instead of an anti-VDBP monoclonal antibody) to measure VDBP failed to validate the previous report and concluded that total 25(OH)D was an appropriate measure of vitamin D nutritional status (303,–306). There is a paucity of information about the role of VDBP in human vitamin D toxicity. The biological role of VDBP was explored in mice in which the VDBP gene had been deleted (307). On vitamin D-replete diets, DBP−/− mice had low levels of total serum vitamin D metabolites but were otherwise normal. When maintained on vitamin D-deficient diets, the DBP−/−, but not DBP+/+, mice developed secondary hyperparathyroidism and the accompanying bone changes associated with vitamin D deficiency. After an overload of vitamin D, DBP−/− mice were unexpectedly less susceptible to hypercalcemia and its toxic effects.

3. Mechanism of hypercalcemia in hypervitaminosis D

Hypercalcemia occurs as a result of increased calcium absorption from the intestine and increased bone mobilization. The 25(OH)D3 or 25(OH)D2 which are present in increased amounts bind to the vitamin D receptor in sufficient amounts to induce processes that enhance intestinal calcium absorption and enhance bone mobilization (81, 82, 83, 308, 309, 311). In in vitro radioligand binding assays with the vitamin D receptor, the B50 (B50 value is defined as the concentration of material necessary to cause 50% displacement of the radiolabel from the protein) of 1α,25(OH)2D3 is approximately 1.62 × 10−10 m, whereas, the B50 of 25(OH)D for the vitamin D receptor is approximately 1.38 × 10−7 m. These concentrations of 25(OH)D may be present in vitamin D target tissues in hypervitaminosis D. A second possible mechanism is the endogenous production of 5,6-trans-25(OH)D3, which has a 1α hydroxyl group and which binds to the vitamin D receptor with increased affinity (312) (Figure 3). We have shown that 5,6-trans-25(OH)D3 is present in the serum of rats administered large doses of vitamin D3 (312). Because of the presence of a 1α hydroxyl group, binding of 5,6-trans-25(OH)D3 to the vitamin D receptor is increased—6.9 × 10−8 m for 5,6-trans-25(OH)D3, 1.95 × 10−7 m for 25(OH)D3, and 2.2 × 10−10 m for 1α,25(OH)D3 (312). It should be noted, however, that although we have isolated 5,6-trans-25(OH)D3 from the serum of rats dosed with vitamin D3, it is not known whether this metabolite is present in the serum of humans with hypervitaminosis D.

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.

4. Hypercalcemia associated with the administration of 1α-hydroxylated vitamin D metabolites and analogs

Several 1α-hydroxylated vitamin D compounds are available for the treatment of secondary hyperparathyroidism seen in the context of chronic renal failure and end-stage renal disease and in various forms of inherited rickets. 1α,25(OH)2D3 (calcitriol), 1α,(OH)D3 (alfacalcidol), doxercalciferol (Hectrol), paricalcitol (Zemplar), and 22-oxacalcitriol are examples of such drugs that are available in the United States and Europe. Other drugs, such as dihydrotachysterol (313, 314) and 5,6-trans-25(OH)D3 (312), also have hydroxyl groups in the 1α configuration in the A-ring of the sterol. All are capable of causing hypercalcemia when administered in excess. Some drugs, such as paricalcitol, are believed to be less hypercalcemic than others, such as calcitriol (315,–322). Table 3 shows the relative potencies of various vitamin D analogs in chronic renal failure and the duration of toxicity.

Table 3.

Usual Daily Dose Requirement for the Treatment of Secondary Hyperparathyroidism and Duration of Toxicity of Vitamin D Analogs in Chronic Renal Failure

AnalogPotency Relative to Vitamin D3Daily Dose, μgDuration of Toxicity, d

Vitamin D3	1	750–10 000	17–30
Dihydrotachysterol	10	200–1000	17–30
25(OH)D3	50	50–200	15–30
1α(OH)D3	5000	0.5–2.0	5–15
1α,25(OH)2D3	5000	0.25–2.0	2–7

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Data are from Ref. 310.

5. Treatment of hypercalcemia associated with hypervitaminosis D

Treatment of hypercalcemia associated with hypervitaminosis D includes withholding the vitamin D preparation. In individuals with no previous renal dysfunction, the administration of isotonic fluids with or without a loop diuretic such as furosemide and the administration of glucocorticoids are usually effective in reducing serum calcium concentrations. In patients with chronic renal failure receiving 1α-hydroxylated vitamin D analogs, withholding the drug may be sufficient. If sufficient renal function is still present, administration of isotonic fluids and a loop diuretic will be of value. Glucocorticoids, which act by inhibiting intestinal calcium absorption through the inhibition of enterocyte basolateral membrane calcium extrusion and inhibition of intestinal cell RNA polymerase activity (323,–325), will also help in this circumstance. Patients on hemodialysis will need to have the offending drug withheld and, if hypercalcemia persists, may require dialysis against a low calcium hemodialysis bath (2 mEq/L calcium).

D. Hypercalcemia associated with granulomatous disease

As noted in Tables 1 and ​and2,2, granulomatous disease is associated with hypercalcemia.

1. Sarcoidosis

Hypercalcemia in sarcoidosis has been described since the 1930s (326, 327). Up to 10% of patients with sarcoidosis have hypercalcemia of varying degrees (328, 329). The association of sunlight exposure with hypercalcemia raised the possibility that abnormal vitamin D metabolism might play a role in the pathogenesis of hypercalcemia (330). Hypercalciuria responsive to cortisone and sodium phytate therapy suggested abnormal intestinal calcium metabolism and hypervitaminosis D (331, 332). Bell and Bartter (333) suggested the presence of increased sensitivity of bone to vitamin D in patients with sarcoidosis. The finding of increased serum 1α,25(OH)2D3 concentrations in patients with sarcoidosis explained many of the prior findings (334, 335). Investigators demonstrated the presence of elevated serum concentrations of 1α,25(OH)2D3 in an anephric subject and patients with end-stage renal disease, thus establishing that the kidney was not the source of the elevated serum concentrations of 1α,25(OH)2D3 (336, 337). The earlier observations of Bell and Bartter (338) that hypercalcemia in sarcoidosis persisted after the occurrence of concomitant nephritis are consistent with the presence of a nonrenal source of 1α,25(OH)2D3 production (338).

Mason et al (339) described the metabolic conversion of 25(OH)D3 to 1,25(OH)2D3 by sarcoid lymph node homogenates but not by normal lymph nodes. Adams et al (340,–343) showed that pulmonary alveolar macrophages derived from patients with sarcoidosis metabolized 25(OH)D3 to 1α,25(OH)2D3. The 25(OH)D3-1α-hydroxylase present in sarcoid-associated pulmonary alveolar macrophages (PAMs) has properties distinct from that of the native renal enzyme. PAM 25(OH)D3-1α-hydroxylase is stimulated by γ-interferon and is not inhibited by 1,25(OH)2D3 or calcium (340, 344,–347). The enzyme is not stimulated by PTH (343), and 1,25(OH)2D3 does not induce 25(OH)D3-24-hydroxylase activity in PAMs (340).

The symptoms and signs of hypercalcemia in the context of sarcoidosis are similar to those found in hypercalcemia due to excessive exogenous vitamin D intake. Laboratory findings are similar except for the presence of increases in serum angiotensin-converting enzyme concentrations that are also found in other granulomatous diseases such as leprosy also found in other granulomatous diseases, and generally correlate with disease activity in sarcoidosis (328, 348,–355). Serum 25(OH)D concentrations are normal, whereas 1α,25(OH)2D concentrations are elevated (334, 335, 337, 341, 345, 356). Treatment regimens are similar to those used for the treatment of hypercalcemia. Glucocorticoids are effective in suppressing the activity of the PAM 25(OH)D3-1α-hydroxylase (340) and reducing hypercalcemia, as well as reducing other manifestations of sarcoid activity (357, 358). Ketoconazole, an inhibitor of 25(OH)D3-1α-hydroxylase activity, has also been effectively used to treat the hypercalcemia of sarcoidosis (135, 359,–365).

2. Tuberculosis

Hypercalcemia occurs in patients with tuberculosis. The preval‎ence is quite variable in patients with the disease, varying from approximately 2.3% in some studies (366) to 10–48% in other studies (367,–371). The precise reason for the variability is uncertain, although vitamin D and calcium intake may play a role. It should be kept in mind that rifampin and isoniazid, drugs used in the treatment of tuberculosis, may alter concentrations of serum 25(OH)D and 1,25(OH)2D and thereby reduce the degree of hypercalcemia (372,–376). Rifampin induces several enzymes (Cyp3A4, Cyp24A1, and uridine 5′-diphospho-glucuronyltransferases) that degrade 25(OH)D (373,–376) and, by reducing substrate, reduce 1,25(OH)2D concentrations. In contrast, isoniazid inhibits 1,25(OH)2D synthesis (371). As in sarcoidosis, pulmonary alveolar macrophages and lymphocytes, as well as macrophages isolated from pleural fluid, express the 25(OH)D3-1α-hydroxylase (377,–381). The pleural fluid:serum 1,25(OH)2D3 gradient is approximately 2:1, suggesting 1,25(OH)2D3 production by cells in the pleural cavity (381). Toll-like receptor activation of human macrophages up-regulates expression‎ of the vitamin D receptor and the 25(OH)D3-1α-hydroxylase genes (382), the latter increasing 1,25(OH)2D3 synthesis. Additionally, pleural fluid contains substances such as γ-interferon that potentiate 25(OH)D3-1α-hydroxylase expression‎ (380). 1,25(OH)2D3 potentiates macrophage killing of Mycobacterium tuberculosis bacteria through the generation of antimicrobial peptides, the cathelicidins (382, 383).

The symptoms and signs of hypercalcemia in the context of tuberculosis are similar to those found in hypercalcemia due to excessive exogenous vitamin D intake. Laboratory findings include suppressed PTH, elevated 1α,25(OH)2D, and usually normal 25(OH)D concentrations. Treatment regimens are similar to those used for the treatment of hypercalcemia. Patients with tuberculosis frequently receive vitamin D supplements, which should be eliminated. Ketoconazole, an inhibitor of 25(OH)D3-1α-hydroxylase activity, has also been effectively used to treat the hypercalcemia of tuberculosis (365, 384).

3. Leprosy, fungal diseases, and other granulomatous disorders

Hypercalcemia has been reported in association with infections such as leprosy (385,–389), Mycobacterium avium complex (390,–395), Bacille Calmette Guérin administration (396, 397), a variety of fungal infections (see Table 2) (398,–411), cat-scratch disease (412), and Pneumocystis pneumonia (244, 413,–417). A number of noninfectious granulomatous conditions are also associated with hypercalcemia, including Wegener's granulomatosis (418), Crohn's disease (419,–421), infantile subcutaneous fat necrosis (422, 423), giant cell polymyositis (424), berylliosis (365, 425), silicone-induced granuloma (426,–428), paraffin-associated granulomas (429, 430), and talc granuloma (431). The mechanism for the hypercalcemia in these disorders is the ectopic production of 1α,25(OH)2D3.

4. Lymphomas

Hodgkin, non-Hodgkin, and adult T-cell leukemia/lymphoma are associated with hypercalcemia (432,–435). Hypercalcemia occurs in approximately 13% of non-Hodgkin lymphomas and 5% of Hodgkin lymphomas (432,–435). Lymphoma patients with hypercalcemia tend to have more extensive disease and reduced survival (436). Increased serum levels of 1α,25(OH)2D3 have been implicated in the pathogenesis of hypercalcemia in virtually all cases of Hodgkin lymphoma and in 30–40% non-Hodgkin lymphoma (434). It is likely that the production of 1α,25(OH)2D3 occurs at extrarenal sites inasmuch as patients with lymphoma have had elevated 1α,25(OH)2D3 despite the presence of renal failure (437). The production of 1α,25(OH)2D3 in vitro in lymph node homogenates supports the concept of extrarenal production of the hormone (438).

Adult T-cell leukemia/lymphoma is associated with hypercalcemia in 50–70% of patients with this disease, but the mechanism of hypercalcemia is independent of vitamin D and is often associated with the expression‎ of PTHrP (439, 440) or other cytokines (441,–443). The human T lymphotropic virus (HTLV) that is often associated with adult T-cell leukemia/lymphoma elaborates a protein (HTLV-1 transactivator protein, tax) that binds to and activates the PTHrP promoter (444,–450). IL-2-mediated stimulation of the PTHrP promoter has been reported in HTLV-1 infected cells (451). Osteoclastogenesis and activity may be influenced by increased expression‎ of Wnt5 and Dkk1 and inhibition of expression‎ of osteoprotegerin by HTLV-1 transfected cells (452,–454).

E. Hypercalcemia associated with CYP24A1 mutations

1. Inactivating CYP24A1 mutations and hypercalcemia

Idiopathic infantile hypercalcemia (IIH) is characterized by hypercalcemia, hypercalciuria, nephrocalcinosis, and failure to thrive. The role of vitamin D in IIH was considered in the United Kingdom in the 1950s when over 200 children were diagnosed with this condition (112, 65). At that time, infants routinely received up to 4000 IU of vitamin D per day between fortified milk powder, infant cereal, and supplementation with cod liver oil (65). As a result, a reduction in vitamin D intake for infants was recommended. In the 1960s, the Committee on Nutrition of the American Academy of Pediatrics also provided guidance on vitamin D fortification for infant formula, suggesting a limit of 400 IU per day in an effort to prevent rickets while avoiding possible toxicity (67, 68).

In 2011, Schlingmann et al (136) described 10 patients with IIH due to loss of function mutations in the CYP24A1 gene. The majority of the patients were symptomatic at the time of diagnosis with failure to thrive, dehydration, hypotonia, and lethargy. All experienced hypercalciuria and/or nephrocalcinosis. Several of the patients were receiving only modest doses of vitamin D daily (500 IU/d), whereas others had received high doses less frequently (600 000 IU/dose).

In 2012, we described the presence of a similar syndrome in adults (140). Since these original reports, numerous groups have collectively described the clinical and biochemical phenotype of over 100 patients with mono- or biallelic mutations in the CYP24A1 gene (49, 50, 55, 56, 60,–64, 141, 147, 455,–459).

2. The syndrome of hypercalcemia, hypercalciuria, nephrocalcinosis, and nephrolithiasis due to CYP24A1 mutations

The clinical manifestations of this disease depend largely on the age at diagnosis. As noted above, infants present with weight loss or failure to thrive, vomiting, dehydration, lethargy, and hypotonia (50, 62, 139, 140, 146, 456, 457). Some infants and children have been asymptomatic at diagnosis and were discovered only after eval‎uation due to positive family history (63, 139, 140). In some cases, this was attributed to avoidance of vitamin D supplementation in a younger child due to hypercalcemia experienced by the older sibling. Adults with CYP24A1 mutations most frequently present with renal manifestations such as nephrolithiasis and/or nephrocalcinosis and may experience polyuria. The degree of hypercalcemia (and symptoms) can vary from mild and intermittent to severe but in general is less pronounced compared to those who manifest disease during infancy. As with other causes of vitamin D-mediated hypercalcemia, adults may develop neuropsychiatric symptoms such as lethargy, confusion, and irritability. Gastrointestinal symptoms can include abdominal pain, nausea, vomiting, and constipation. Additional features described in adults with CYP24A1 mutations include hypertension (56, 63, 142, 144, 458) and pancreatitis (56). Exposure to ultraviolet radiation due to seasonal changes or tanning bed use has been implicated as a factor altering disease severity in some patients (49, 55, 62). It should be noted that pregnancy is a time when this condition may initially manifest or progress as a result of increased 1α,25(OH)2D production. Worsening hypercalcemia during pregnancy or shortly after delivery has been described in several recent reports (56, 141, 146). It has long been recognized that calcitriol concentrations are elevated during normal pregnancy (129, 460), which will lead to exacerbation of hypercalcemia and hypercalciuria in women lacking an adequate calcitriol disposal pathway due to CYP24A1 mutations. A review of the changes in mineral and bone metabolism during pregnancy has been recently published and details the changes in calcium, PTH, and vitamin D concentrations during gestation (131).

The effect of this condition on bone health and bone density is not clear. The few reports that included bone mineral density assessment have yielded conflicting results ranging from low, to normal, to clearly elevated bone mineral density (49, 140, 142, 145, 455). Infants with IIH are frequently treated with a low-calcium diet, which conceivably could lead to low bone density over time. Alternatively, a lifetime of suppressed PTH due to intestinal calcium hyperabsorption and hypercalcemia may produce an elevated bone density such as that seen in patients with acquired hypoparathyroidism. More data are needed to understand the effect of the underlying disease and its treatment on bone health.

Distinguishing laboratory findings include variable degrees of hypercalcemia, low PTH, and an inappropriate 1,25(OH)2D concentration (upper normal or elevated). Infants who are symptomatic nearly universally have moderate to severe hypercalcemia sometimes exceeding 20 mg/dL. Most adults have serum calcium concentrations in the 10–15 mg/dL range. Because the underlying mechanism is an inadequate disposal pathway for active vitamin D and not excessive substrate, 25(OH)D concentrations can be low, normal, or elevated. A family history of hypercalcemia or a personal history of overzealous vitamin D supplementation would be helpful but is not always readily apparent. The biochemical profile of hypercalcemia, low PTH, and elevated 1,25(OH)2D is indistinguishable from patients with endogenous overproduction of 1,25(OH)2D due to granulomatous disease and lymphoma described above.

Low serum concentrations of 24,25(OH)2D have proved useful in identifying patients with CYP24A1 mutations (93). We recently developed and validated a liquid chromatography-tandem mass spectrometry assay for the measurement of serum 24,25(OH)2D (93). The limits of detection for 24,25(OH)2D3 and 24,25(OH)2D2 were 0.03 ng/mL (0.2 nmol/L) and 0.1 ng/mL (0.23 nmol/L), respectively; the corresponding limits of quantification were 0.1 ng/mL (0.2 nmol/L) and 0.5 ng/mL (1.2 nmol/L). On the basis of the limits of quantification and the highest calibrators used, the analytical measurement range for undiluted samples was set at 0.1–25 ng/mL (0.2–60 nmol/L) for 24,25(OH)2D3 and 0.5–25 ng/mL (1.2–58.3 nmol/L) for 24,25(OH)2D2. Across this range, intra-assay imprecision was 3.1–6.2% for 24,25(OH)2D3 and 11.7–14.8% for 24,25(OH)2D2. The corresponding interassay values were 4.5–8.3% and 3.0–10.1%. Recovery of exogenous 24,25(OH)2D3 and 24,25(OH)2D2 spiked into samples was 94–100% and 90–94%, respectively. 24,25(OH)2D3 showed very low cross-reactivity (0.6%) with the spiked 25(OH)D, and 24,25(OH)2D2 showed 4% cross-reactivity. We observed <5% signal suppression for both 24,25(OH)2D2 and 24,25(OH)2D3. 25(OH)D/24,25(OH)2D ratios of 7–35 were observed in healthy subjects. In these individuals, serum 24,25(OH)2D3 concentrations correlated with 25(OH)D3 concentrations of 7–60 ng/mL (17.5–150 nmol/L): 24,25(OH)2D3 = 0.10 × 25(OH)D3 − 0.32; r2 = 0.75; n = 91 (Figure 4). It should be noted that in the presence of vitamin D excess or deficiency when substrate, namely 25(OH)D, concentrations are high or low, 24,25(OH)2D increases or decreases, but the 25(OH)D/24,25(OH)2D ratio does not change significantly. In patients with Cyp24A1 mutations, 24,25(OH)2D is low as a result of reduced 24-hydroxylase activity, despite the presence of adequate amounts of substrate. As a result, the ratio of 25(OH)D to 24,25(OH)2D measured on a simultaneous sample is elevated. Hence, the assessment of the 25(OH)D/24,25(OH)2D ratio is necessary for the interpretation of 24,25(OH)2D concentrations and the assessment 24-hydroxylase activity. A 25(OH)D/24,25(OH)2D ratio of 7–35 was observed in healthy subjects, whereas in patients with CYP24A1 mutations, 25(OH)D/24, 25(OH)2D was significantly increased (99–467; P < .001) (Figure 4). A 25(OH)D/24,25(OH)2D ratio >99 identified patients who were candidates for CYP24A1 genetic testing (Table 4). Nearly all patients described to date with biallelic disease have a 25(OH)D/24,25(OH)2D ratio >80 (60, 140,–144, 458). Unaffected patients and most heterozygotes have a ratio <30.

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.

Table 4.

Serum 25(OH)D, 1,25(OH)2D, PTH, and 25(OH)D/24,25(OH)2D Ratio in Patients With Genetically Confirmed Cyp24A1 Mutations

Patient No.25(OH)D, ng/mL1,25(OH)2D, pg/mLPTH, pg/mL25(OH)D/24, 25(OH)2D

1	47	79	24	336
2	70	70	14	467
3	50	123	8.1	250
4	37	101	13	103
5	47	104	22	124
6	37	66	<1	132
7	29.7	82	11	149
8	49	86	9	189
9–11	39–59	83–160	3–10	130–230
12	71	79–121	3	112
13	38			99
14	32.5			113
Reference interval	20–80	22–65	15–65	7–35

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Data are from Ref. 93.

3. Biallelic vs monoallelic disease

Patients with biallelic disease (homozygous or compound heterozygous mutations) consistently demonstrate the clinical and biochemical phenotype described above. It is less clear whether individuals with monoallelic gene changes are asymptomatic carriers or manifest an attenuated condition. We have described two kindreds with some, but not all, monoallelic members having symptomatic disease including IIH (calcium as high as 16 mg/dL), hypercalcemia, hypercalciuria, nephrolithiasis, and/or nephrocalcinosis (60, 140). Other groups have described asymptomatic family members with monoallelic disease who have normal biochemical findings including a normal 25(OH)D/24,25(OH)2D ratio (53, 143). Cools et al (455) recently described heterozygous members of a family and reviewed the available literature regarding the biochemical and clinical phenotype of patients with monoallelic mutations in CYP24A1. It should be noted that not all monoallelic patients reported in the literature have been fully phenotyped, leaving much to be learned about this population. In those with available data, however, five of 28 were hypercalcemic (calcium >10.6 mg/dL), seven of 22 had 1,25(OH)2D concentrations >80 pg/mL, nine of 26 had a low PTH (<15 pg/mL), three of 15 had an elevated 25(OH)D:24,25(OH)2D ratio, and eight of 40 had nephrolithiasis and/or nephrocalcinosis. These findings suggest that patients with monoallelic mutations can become symptomatic. It is likely that environment (calcium and vitamin D intake) and other genetic factors affect disease expressivity in this group.

4. Treatment of hypercalcemia and hypercalciuria due to inactivating CYP24A1 mutations

Initial treatment of severe, symptomatic hypercalcemia caused by CYP24A1 mutations is the same as any other cause of hypercalcemia and should begin with intravenous isotonic saline. A loop diuretic can be added once the patient is adequately hydrated. Intravenous bisphosphonates, calcitonin, and glucocorticoids have been used in the acute setting with variable results (49, 50, 55, 56, 63, 139, 141, 142, 144,–146). It is difficult to attribute improvement in hypercalcemia to any single treatment when multiple therapies are provided in the acute setting. However, based on available reports, bisphosphonate therapy appears to be more effective, and glucocorticoids have a limited, if any, role in the acute (or chronic) management of these patients.

Acute management of hypercalcemia during pregnancy is more problematic because some of the available medications are contraindicated. In this population, focusing efforts on calcium restriction and hydration seems prudent. The effects of hypercalcemia are not limited to the mother because intrauterine hypercalcemia can lead to fetal/neonatal PTH suppression with resulting severe and sometimes prolonged hypoparathyroidism and hypocalcemia after birth (61, 66, 88, 131). Infants born to mothers with hypercalcemia should be monitored closely for hypocalcemia, especially if maternal hypercalcemia was moderate to severe.

Long-term management is focused on eliminating or minimizing symptoms of hypercalcemia and reducing hypercalciuria (and thus nephrocalcinosis/nephrolithiasis). Because the underlying mechanism of disease is intestinal calcium hyperabsorption, a low-calcium and vitamin D diet is the cornerstone of therapy. Although this is sufficient for some patients, others will remain hypercalcemic with ongoing active renal stone disease. A variety of long-term strategies have been described including glucocorticoids, loop and thiazide diuretics, phosphate supplementation, proton pump inhibitors, and antifungals such as ketoconazole and fluconazole. Glucocorticoids have not consistently been shown to be effective and would not be a desirable long-term solution due to a multitude of toxicities associated with glucocorticoid exposure (49, 141, 146, 457). Thiazide diuretics may reduce urine calcium without exacerbating hypercalcemia in some patients (49) but have been implicated for producing significant hypercalcemia in others (144). Normalization of serum calcium with reductions in urine calcium have been described in several patients treated with the azole drugs, ketoconazole or fluconazole, acting to inhibit 25(OH)D-1-hydroxylase (55, 140, 141, 143,–145). Toxicity and off-target P450 enzyme blockade from azole drugs will limit their long-term use in many patients. It is interesting that patients do not sufficiently down-regulate 25(OH)D-1-hydroxylase activity sufficiently despite the suppression of PTH and elevation in serum calcium concentrations. This would suggest that 25(OH)D-1-hydroxylase is to some degree constitutively active. A selective, titratable inhibitor of 25(OH)D-1-hydroxylase would be optimal but is not currently available.

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III. Summary and Conclusions

Vitamin D-mediated hypercalcemia occurs as a result of diverse mechanisms including excessive ingestion of vitamin D and its metabolites, ectopic enzyme overexpression‎, and mutations of inactivating enzymes. Diagnosis of vitamin D-mediated hypercalcemia is usually based on the presence of hypercalcemia, elevated concentrations of various vitamin D metabolites in the presence of a suppressed concentration of PTH. A few select biochemical tests will allow the diagnosis to be established. Treatment with various drugs or by withholding vitamin D and/or calcium is usually successful in treating vitamin D-mediated hypercalcemia.

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Acknowledgments

This work was supported by National Institutes of Health Grant U01DK066013 (RK) and a grant from the Fred C. and Katherine B. Andersen Foundation (RK).

Disclosure Summary: The authors have nothing to declare.

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Footnotes

Abbreviations:

HTLVhuman T lymphotropic virusIIHidiopathic infantile hypercalcemia1,25(OH)2D1,25-dihydroxyvitamin D25(OH)D25-hydroxyvitamin DPAMpulmonary alveolar macrophageVDBPvitamin D binding protein.

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Reference

1. Christensson T, Hellström K, Wengle B, Alveryd A, Wikland B. Preval‎ence of hypercalcaemia in a health screening in Stockholm. Acta Med Scand. 1976;200:131–137. [PubMed] [Google Scholar]

2. Dent DM, Miller JL, Klaff L, Barron J. The incidence and causes of hypercalcaemia. Postgrad Med J. 1987;63:745–750. [PMC free article] [PubMed] [Google Scholar]

3. Fisken RA, Heath DA, Bold AM. Hypercalcaemia–a hospital survey. Q J Med. 1980;49:405–418. [PubMed] [Google Scholar]

4. Frølich A. Preval‎ence of hypercalcaemia in normal and in hospital populations. Dan Med Bull. 1998;45:436–439. [PubMed] [Google Scholar]

5. Lee CT, Yang CC, Lam KK, Kung CT, Tsai CJ, Chen HC. Hypercalcemia in the emergency department. Am J Med Sci. 2006;331:119–123. [PubMed] [Google Scholar]

6. Lindner G, Felber R, Schwarz C, et al. Hypercalcemia in the ED: preval‎ence, etiology, and outcome. Am J Emerg Med. 2013;31:657–660. [PubMed] [Google Scholar]

7. Newman EM, Bouvet M, Borgehi S, Herold DA, Deftos LJ. Causes of hypercalcemia in a population of military veterans in the United States. Endocr Pract. 2006;12:535–541. [PubMed] [Google Scholar]

8. Royer AM, Maclellan RA, Stanley JD, Willingham TB, Giles WH. Hypercalcemia in the emergency department: a missed opportunity. Am Surg. 2014;80:732–735. [PubMed] [Google Scholar]

9. Lafferty FW. Differential diagnosis of hypercalcemia. J Bone Miner Res. 1991;6(suppl 2):S51–S59; discussion S61. [PubMed] [Google Scholar]

10. Griebeler ML, Kearns AE, Ryu E, Hathcock MA, Melton LJ, 3rd, Wermers RA. Secular trends in the incidence of primary hyperparathyroidism over five decades (1965–2010). Bone. 2015;73:1–7. [PMC free article] [PubMed] [Google Scholar]

11. Wermers RA, Khosla S, Atkinson EJ, et al. Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993–2001: an update on the changing epidemiology of the disease. J Bone Miner Res. 2006;21:171–177. [PubMed] [Google Scholar]

12. Wermers RA, Khosla S, Atkinson EJ, Hodgson SF, O'Fallon WM, Melton LJ., 3rd The rise and fall of primary hyperparathyroidism: a population-based study in Rochester, Minnesota, 1965–1992. Ann Intern Med. 1997;126:433–440. [PubMed] [Google Scholar]

13. Heath H., 3rd Primary hyperparathyroidism. Lancet. 1980;2:204. [PubMed] [Google Scholar]

14. Heath H, 3rd, Hodgson SF, Kennedy MA. Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community. N Engl J Med. 1980;302:189–193. [PubMed] [Google Scholar]

15. Carpenter TO, Mitnick MA, Ellison A, Smith C, Insogna KL. Nocturnal hyperparathyroidism: a frequent feature of X-linked hypophosphatemia. J Clin Endocrinol Metab. 1994;78:1378–1383. [PubMed] [Google Scholar]

16. Firth RG, Grant CS, Riggs BL. Development of hypercalcemic hyperparathyroidism after long-term phosphate supplementation in hypophosphatemic osteomalacia. Report of two cases. Am J Med. 1985;78:669–673. [PubMed] [Google Scholar]

17. Ludwig GD, Kyle CG, de Blanco M. “Tertiary” hyperparathyroidism induced by osteomalacia resulting from phosphorus depletion. Am J Med. 1967;43:136–140. [PubMed] [Google Scholar]

18. Milas M, Weber CJ. Near-total parathyroidectomy is beneficial for patients with secondary and tertiary hyperparathyroidism. Surgery. 2004;136:1252–1260. [PubMed] [Google Scholar]

19. Olefsky J, Kempson R, Jones H, Reaven G. “Tertiary” hyperparathyroidism and apparent “cure” of vitamin-D-resistant rickets after removal of an ossifying mesenchymal tumor of the pharynx. N Engl J Med. 1972;286:740–745. [PubMed] [Google Scholar]

20. Savio RM, Gosnell JE, Posen S, Reeve TS, Delbridge LW. Parathyroidectomy for tertiary hyperparathyroidism associated with X-linked dominant hypophosphatemic rickets. Arch Surg. 2004;139:218–222. [PubMed] [Google Scholar]

21. Schlosser K, Zielke A, Rothmund M. Medical and surgical treatment for secondary and tertiary hyperparathyroidism. Scand J Surg. 2004;93:288–297. [PubMed] [Google Scholar]

22. Seshadri MS, Qurttom MA, Sivanandan R, Shihab-al-Mohannadi, Samiaman Tertiary hyperparathyroidism in nutritional osteomalacia. Postgrad Med J. 1994;70:595–596. [PMC free article] [PubMed] [Google Scholar]

23. Abboud B, Salameh J, Chelala D, Moussalli A, Mallat S. Tertiary hyperparathyroidism in patients on hemodialysis for chronic renal failure: subtotal parathyroidectomy or conservative treatment? J Med Liban. 2003;51:192–197. [PubMed] [Google Scholar]

24. Greenberg A, Piraino BM, Bruns FJ. Hypercalcemia in patients with advanced chronic renal failure not yet requiring dialysis. Am J Nephrol. 1989;9:205–210. [PubMed] [Google Scholar]

25. Kerby JD, Rue LW, Blair H, Hudson S, Sellers MT, Diethelm AG. Operative treatment of tertiary hyperparathyroidism: a single-center experience. Ann Surg. 1998;227:878–886. [PMC free article] [PubMed] [Google Scholar]

26. Moazam F, Orak JK, Fennell RS, 3rd, Richard GA, Talbert JL. Total parathyroidectomy and autotransplantation for tertiary hyperparathyroidism in children with chronic renal failure. J Pediatr Surg. 1984;19:389–393. [PubMed] [Google Scholar]

27. Reid DJ. Surgical treatment of secondary and tertiary hyperparathyroidism. Br J Clin Pract. 1989;43:68–70. [PubMed] [Google Scholar]

28. Zachariou Z, Buhr H, von Herbay A, Klaus G. Preoperative diagnostics and surgical management of tertiary hyperparathyroidism after chronic renal failure in a child. Eur J Pediatr Surg. 1995;5:288–291. [PubMed] [Google Scholar]

29. Bigos ST, Neer RM, Goar WT. Hypercalcemia of seven years' duration after kidney transplantation. Am J Surg. 1976;132:83–89. [PubMed] [Google Scholar]

30. Leonard N, Brown JH. Persistent and symptomatic post-transplant hyperparathyroidism: a dramatic response to cinacalcet. Nephrol Dial Transplant. 2006;21:1736. [PubMed] [Google Scholar]

31. McCarron DA, Krutzik S, Barry JM, Muther RS, Bennett WM. Post-transplant hyperparathyroidism: retained control by serum Ca++. Proc Eur Dial Transplant Assoc. 1979;16:677–678. [PubMed] [Google Scholar]

32. McCarron DA, Lenfesty B, Thier A, et al. Total parathyroidectomy for post-transplantation hyperparathyroidism. Proc Clin Dial Transplant Forum. 1980;10:51–55. [PubMed] [Google Scholar]

33. Muirhead N, Zaltman JS, Gill JS, et al. Hypercalcemia in renal transplant patients: preval‎ence and management in Canadian transplant practice. Clin Transplant. 2014;28:161–165. [PubMed] [Google Scholar]

34. Pletka PG, Strom TB, Hampers CL, et al. Secondary hyperparathyroidism in human kidney transplant recipients. Nephron. 1976;17:371–381. [PubMed] [Google Scholar]

35. Schmid T, Müller P, Spelsberg F. Parathyroidectomy after renal transplantation: a retrospective analysis of long-term outcome. Nephrol Dial Transplant. 1997;12:2393–2396. [PubMed] [Google Scholar]

36. Taweesedt PT, Disthabanchong S. Mineral and bone disorder after kidney transplantation. World J Transplant. 2015;5:231–242. [PMC free article] [PubMed] [Google Scholar]

37. Uchida K, Tominaga Y, Tanaka Y, Takagi H. Renal transplantation and secondary hyperparathyroidism. Semin Surg Oncol. 1997;13:97–103. [PubMed] [Google Scholar]

38. Yamamoto T, Tominaga Y, Okada M, et al. Characteristics of persistent hyperparathyroidism after renal transplantation. World J Surg. 2016;40:600–606. [PubMed] [Google Scholar]

39. Johnson JA, Kumar R. Vitamin D and renal calcium transport. Curr Opin Nephrol Hypertens. 1994;3:424–429. [PubMed] [Google Scholar]

40. Kumar R. Calcium transport in epithelial cells of the intestine and kidney. J Cell Biochem. 1995;57:392–398. [PubMed] [Google Scholar]

41. Friedman PA, Gesek FA. Cellular calcium transport in renal epithelia: measurement, mechanisms, and regulation. Physiol Rev. 1995;75:429–471. [PubMed] [Google Scholar]

42. Borke JL, Penniston JT, Kumar R. Recent advances in calcium transport by the kidney. Semin Nephrol. 1990;10:15–23. [PubMed] [Google Scholar]

43. Deluca HF. Historical overview of Vitamin D. In: Feldman D, Pike JW, Adams JS, eds. Vitamin D. Vol 1 3rd ed Boston, MA: Elsevier; 2011:3–12. [Google Scholar]

44. DeLuca HF. Evolution of our understanding of vitamin D. Nutr Rev. 2008;66:S73–S87. [PubMed] [Google Scholar]

45. Haussler MR, Whitfield GK, Kaneko I, et al. Molecular mechanisms of vitamin D action. Calcif Tissue Int. 2013;92:77–98. [PubMed] [Google Scholar]

46. Mizwicki MT, Norman AW. The vitamin D sterol-vitamin D receptor ensemble model offers unique insights into both genomic and rapid-response signaling. Sci Signal. 2009;2:re4. [PubMed] [Google Scholar]

47. Griffin MD, Kumar R. Multiple potential clinical benefits for 1α,25-dihydroxyvitamin D3 analogs in kidney transplant recipients. J Steroid Biochem Mol Biol. 2005;97:213–218. [PubMed] [Google Scholar]

48. Griffin MD, Xing N, Kumar R. Vitamin D and its analogs as regulators of immune activation and antigen presentation. Annu Rev Nutr. 2003;23:117–145. [PubMed] [Google Scholar]

49. Girgis CM, Clifton-Bligh RJ, Hamrick MW, Holick MF, Gunton JE. The roles of vitamin D in skeletal muscle: form, function, and metabolism. Endocr Rev. 2013;34:33–83. [PubMed] [Google Scholar]

50. Boland R. Role of vitamin D in skeletal muscle function. Endocr Rev. 1986;7:434–448. [PubMed] [Google Scholar]

51. Ryan ZC, Craig TA, Folmes CD, et al. 1α,25-Dihydroxyvitamin D3 regulates mitochondrial oxygen consumption and dynamics in human skeletal muscle cells. J Biol Chem. 2016;291:1514–1528. [PMC free article] [PubMed] [Google Scholar]

52. Gurlek A, Kumar R. Regulation of osteoblast growth by interactions between transforming growth factor-β and 1α,25-dihydroxyvitamin D3. Crit Rev Eukaryot Gene Expr. 2001;11:299–317. [PubMed] [Google Scholar]

53. Gurlek A, Pittelkow MR, Kumar R. Modulation of growth factor/cytokine synthesis and signaling by 1α,25-dihydroxyvitamin D(3): implications in cell growth and differentiation. Endocr Rev. 2002;23:763–786. [PubMed] [Google Scholar]

54. Bikle DD, Pillai S. Vitamin D, calcium, and epidermal differentiation. Endocr Rev. 1993;14:3–19. [PubMed] [Google Scholar]

55. Kumar R. The metabolism of 1,25-dihydroxyvitamin D3. Endocr Rev. 1980;1:258–267. [PubMed] [Google Scholar]

56. Gray TK, Lowe W, Lester GE. Vitamin D and pregnancy: the maternal-fetal metabolism of vitamin D. Endocr Rev. 1981;2:264–274. [PubMed] [Google Scholar]

57. Norman AW, Roth J, Orci L. The vitamin D endocrine system: steroid metabolism, hormone receptors, and biological response (calcium binding proteins). Endocr Rev. 1982;3:331–366. [PubMed] [Google Scholar]

58. Brommage R, DeLuca HF. Evidence that 1,25-dihydroxyvitamin D3 is the physiologically active metabolite of vitamin D3. Endocr Rev. 1985;6:491–511. [PubMed] [Google Scholar]

59. Christakos S, Gabrielides C, Rhoten WB. Vitamin D-dependent calcium binding proteins: chemistry, distribution, functional considerations, and molecular biology. Endocr Rev. 1989;10:3–26. [PubMed] [Google Scholar]

60. Malloy PJ, Pike JW, Feldman D. The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets. Endocr Rev. 1999;20:156–188. [PubMed] [Google Scholar]

61. McDonnell CM, Zacharin MR. Maternal primary hyperparathyroidism: discordant outcomes in a twin pregnancy. J Paediatr Child Health. 2006;42:70–71. [PubMed] [Google Scholar]

62. Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 2005;26:662–687. [PubMed] [Google Scholar]

63. Bouillon R, Carmeliet G, Verlinden L, et al. Vitamin D and human health: lessons from vitamin D receptor null mice. Endocr Rev. 2008;29:726–776. [PMC free article] [PubMed] [Google Scholar]

64. Rosen CJ, Adams JS, Bikle DD, et al. The nonskeletal effects of vitamin D: an Endocrine Society scientific statement. Endocr Rev. 2012;33:456–492. [PMC free article] [PubMed] [Google Scholar]

65. Kumar R. Vitamin D metabolism and mechanisms of calcium transport. J Am Soc Nephrol. 1990;1:30–42. [PubMed] [Google Scholar]

66. Norman J, Politz D, Politz L. Hyperparathyroidism during pregnancy and the effect of rising calcium on pregnancy loss: a call for earlier intervention. Clin Endocrinol (Oxf). 2009;71:104–109. [PubMed] [Google Scholar]

67. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96:365–408. [PMC free article] [PubMed] [Google Scholar]

68. DeLuca HF, Schnoes HK. Metabolism and mechanism of action of vitamin D. Annu Rev Biochem. 1976;45:631–666. [PubMed] [Google Scholar]

69. DeLuca HF, Schnoes HK. Vitamin D: recent advances. Annu Rev Biochem. 1983;52:411–439. [PubMed] [Google Scholar]

70. McCollum EV, Simmonds N, Becker JE, Shipley PG. Studies on experimental rickets. XXI. An experimental demonstration of the existence of a vitamin which promotes calcium deposition. J Biol Chem. 1922;53:293–312. [PubMed] [Google Scholar]

71. Windaus A, Schenck F, von Weder F. Uber das antirachitsch wirksame bestrahlungs-produkt aus 7-dehydro-cholesterin. Hoppe-Seylers Z Physiol Chem. 1936;241:100–103. [Google Scholar]

72. Steenbock H, Black A. Fat-soluble vitamins. XVII. The induction of gross-promoting and calcifying properties in a ration by exposure to ultraviolet light. J Biol Chem. 1924;61:405–422. [Google Scholar]

73. Hess AF, Weinstock M. Anti-rachitic properties imparted to lettuce and to growing wheat by ultraviolet irradiation. Proc Soc Exper Biol Med. 1924;22:5–6. [Google Scholar]

74. DeLuca HF. The metabolism, physiology and function of vitamin D. In: Kumar R, ed. Vitamin D. Boston/The Hague/Dordrecht/ Lancaster: Martinus Nijhoff Publishing; 1984. [Google Scholar]

75. Esvelt RP, Schnoes HK, DeLuca HF. Vitamin D3 from rat skins irradiated in vitro with ultraviolet light. Arch Biochem Biophys. 1978;188:282–286. [PubMed] [Google Scholar]

76. Holick MF, Clark MB. The photobiogenesis and metabolism of vitamin D. Fed Proc. 1978;37:2567–2574. [PubMed] [Google Scholar]

77. Holick MF, MacLaughlin JA, Clark MB, et al. Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science. 1980;210:203–205. [PubMed] [Google Scholar]

78. Holick MF, Richtand NM, McNeill SC, et al. Isolation and identification of previtamin D3 from the skin of rats exposed to ultraviolet irradiation. Biochemistry. 1979;18:1003–1008. [PubMed] [Google Scholar]

79. Green J. Studies on the analysis of vitamins D. 4. Studies on the irradiation of ergosterol and 7-dehydrocholesterol and the analysis of the products for calciferol, vitamin D3, and component sterols. Biochem J. 1951;49:232–243. [PMC free article] [PubMed] [Google Scholar]

80. Rambeck WA, Weiser H, Zucker H. Biological activity of 1 α,25-dihydroxyergocalciferol in rachitic chicks and in rats. Int J Vitam Nutr Res. 1984;54:135–139. [PubMed] [Google Scholar]

81. Blunt JW, DeLuca HF, Schnoes HK. 25-hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry. 1968;7:3317–3322. [PubMed] [Google Scholar]

82. Suda T, DeLuca HF, Schnoes H, Blunt JW. 25-hydroxyergocalciferol: a biologically active metabolite of vitamin D2. Biochem Biophys Res Commun. 1969;35:182–185. [PubMed] [Google Scholar]

83. Suda T, DeLuca HF, Schnoes HK, Blunt JW. The isolation and identification of 25-hydroxyergocalciferol. Biochemistry. 1969;8:3515–3520. [PubMed] [Google Scholar]

84. Ponchon G, DeLuca HF. The role of the liver in the metabolism of vitamin D. J Clin Invest. 1969;48:1273–1279. [PMC free article] [PubMed] [Google Scholar]

85. Ponchon G, Kennan AL, DeLuca HF. “Activation” of vitamin D by the liver. J Clin Invest. 1969;48:2032–2037. [PMC free article] [PubMed] [Google Scholar]

86. Bhattacharyya MH, DeLuca HF. The regulation of rat liver calciferol-25-hydroxylase. J Biol Chem. 1973;248:2969–2973. [PubMed] [Google Scholar]

87. Bhattacharyya MH, DeLuca HF. Subcellular location of rat liver calciferol-25-hydroxylase. Arch Biochem Biophys. 1974;160:58–62. [PubMed] [Google Scholar]

88. Kelly TR. Primary hyperparathyroidism during pregnancy. Surgery. 1991;110:1028–1033; discussion 1033–1044. [PubMed] [Google Scholar]

89. Madhok TC, DeLuca HF. Characteristics of the rat liver microsomal enzyme system converting cholecalciferol into 25-hydroxycholecalciferol. Evidence for the participation of cytochrome p-450. Biochem J. 1979;184:491–499. [PMC free article] [PubMed] [Google Scholar]

90. Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci USA. 2004;101:7711–7715. [PMC free article] [PubMed] [Google Scholar]

91. Zhu J, DeLuca HF. Vitamin D 25-hydroxylase - Four decades of searching, are we there yet? Arch Biochem Biophys. 2012;523:30–36. [PubMed] [Google Scholar]

92. Zhu JG, Ochalek JT, Kaufmann M, Jones G, Deluca HF. CYP2R1 is a major, but not exclusive, contributor to 25-hydroxyvitamin D production in vivo. Proc Natl Acad Sci USA. 2013;110:15650–15655. [PMC free article] [PubMed] [Google Scholar]

93. Drezner MK, Neelon FA, Haussler M, McPherson HT, Lebovitz HE. 1,25-Dihydroxycholecalciferol deficiency: the probable cause of hypocalcemia and metabolic bone disease in pseudohypoparathyroidism. J Clin Endocrinol Metab. 1976;42:621–628. [PubMed] [Google Scholar]

94. Haddad JG., Jr Transport of vitamin D metabolites. Clin Orthop Relat Res. 1979;142:249–261. [PubMed] [Google Scholar]

95. Schwartz JB, Lai J, Lizaola B, et al. Variability in free 25(OH) vitamin D levels in clinical populations. J Steroid Biochem Mol Biol. 2014;144:156–158. [PMC free article] [PubMed] [Google Scholar]

96. Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep). 2009;183:1–420. [PMC free article] [PubMed] [Google Scholar]

97. Rosen CJ, Gallagher JC. The 2011 IOM report on vitamin D and calcium requirements for North America: clinical implications for providers treating patients with low bone mineral density. J Clin Densitom. 2011;14:79–84. [PubMed] [Google Scholar]

98. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Eval‎uation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96:1911–1930. [PubMed] [Google Scholar]

99. Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Dietary reference intakes for calcium and vitamin D. The National Academies Collection: Reports funded by National Institutes of Health. Washington, DC: National Academies Press; 2011. [Google Scholar]

100. Strushkevich N, Usanov SA, Plotnikov AN, Jones G, Park HW. Structural analysis of CYP2R1 in complex with vitamin D3. J Mol Biol. 2008;380:95–106. [PubMed] [Google Scholar]

101. Bilezikian JP, Canfield RE, Jacobs TP, et al. Response of 1α,25-dihydroxyvitamin D3 to hypocalcemia in human subjects. N Engl J Med. 1978;299:437–441. [PubMed] [Google Scholar]

102. Boyle IT, Gray RW, DeLuca HF. Regulation by calcium of in vivo synthesis of 1,25-dihydroxycholecalciferol and 21,25-dihydroxycholecalciferol. Proc Natl Acad Sci USA. 1971;68:2131–2134. [PMC free article] [PubMed] [Google Scholar]

103. DeLuca HF. Regulation of vitamin D metabolism in the kidney. Adv Exp Med Biol. 1977;81:195–209. [PubMed] [Google Scholar]

104. Kumar R. Metabolism of 1,25-dihydroxyvitamin D3. Physiol Rev. 1984;64:478–504. [PubMed] [Google Scholar]

105. Holick MF, Schnoes HK, DeLuca HF. Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3 metabolically active in the intestine. Proc Natl Acad Sci USA. 1971;68:803–804. [PMC free article] [PubMed] [Google Scholar]

106. Holick MF, Schnoes HK, DeLuca HF, Suda T, Cousins RJ. Isolation and identification of 1,25-dihydroxycholecalciferol. A metabolite of vitamin D active in intestine. Biochemistry. 1971;10:2799–2804. [PubMed] [Google Scholar]

107. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biological active vitamin D metabolite. Nature. 1970;228:764–766. [PubMed] [Google Scholar]

108. Garabedian M, Holick MF, Deluca HF, Boyle IT. Control of 25-hydroxycholecalciferol metabolism by parathyroid glands. Proc Natl Acad Sci USA. 1972;69:1673–1676. [PMC free article] [PubMed] [Google Scholar]

109. Reeve L, Tanaka Y, DeLuca HF. Studies on the site of 1,25-dihydroxyvitamin D3 synthesis in vivo. J Biol Chem. 1983;258:3615–3617. [PubMed] [Google Scholar]

110. Shultz TD, Fox J, Heath H, 3rd, Kumar R. Do tissues other than the kidney produce 1,25-dihydroxyvitamin D3 in vivo? A reexamination. Proc Natl Acad Sci USA. 1983;80:1746–1750. [PMC free article] [PubMed] [Google Scholar]

111. Ryan ZC, Ketha H, McNulty MS, et al. Sclerostin alters serum vitamin D metabolite and fibroblast growth factor 23 concentrations and the urinary excretion of calcium. Proc Natl Acad Sci USA. 2013;110:6199–6204. [PMC free article] [PubMed] [Google Scholar]

112. 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;25:2159–2168. [PMC free article] [PubMed] [Google Scholar]

113. Berndt TJ, Thompson JR, Kumar R. The regulation of calcium, magnesium, and phosphate excretion by the kidney. In: Skorecki K, Chertow GM, Mardsen PA, Taal MW, Yu AS, Wasser WG, eds. Brenner and Rector's The Kidney. Vol 1 Philadelphia, PA: Elsevier; 2106:185–203. [Google Scholar]

114. Bellido T. Downregulation of SOST/sclerostin by PTH: a novel mechanism of hormonal control of bone formation mediated by osteocytes. J Musculoskelet Neuronal Interact. 2006;6:358–359. [PubMed] [Google Scholar]

115. Holick MF, Schnoes HK, DeLuca HF, Gray RW, Boyle IT, Suda T. Isolation and identification of 24,25-dihydroxycholecalciferol, a metabolite of vitamin D made in the kidney. Biochemistry. 1972;11:4251–4255. [PubMed] [Google Scholar]

116. Lam HY, Schnoes HK, DeLuca HF, Chen TC. 24,25-Dihydroxyvitamin D3. Synthesis and biological activity. Biochemistry. 1973;12:4851–4855. [PubMed] [Google Scholar]

117. Tanaka Y, DeLuca HF, Ikekawa N, Morisaki M, Koizumi N. Determination of stereochemical configuration of the 24-hydroxyl group of 24,25-dihydroxyvitamin D3 and its biological importance. Arch Biochem Biophys. 1975;170:620–626. [PubMed] [Google Scholar]

118. Kumar R, Schnoes HK, DeLuca HF. Rat intestinal 25-hydroxyvitamin D3- and 1α,25-dihydroxyvitamin D3–24-hydroxylase. J Biol Chem. 1978;253:3804–3809. [PubMed] [Google Scholar]

119. Kumar R, Schaefer J, Grande JP, Roche PC. Immunolocalization of calcitriol receptor, 24-hydroxylase cytochrome P-450, and calbindin D28k in human kidney. Am J Physiol. 1994;266:F477–F485. [PubMed] [Google Scholar]

120. Yang W, Friedman PA, Kumar R, et al. Expression‎ of 25(OH)D3 24-hydroxylase in distal nephron: coordinate regulation by 1,25(OH)2D3 and cAMP or PTH. Am J Physiol. 1999;276:E793–E805. [PubMed] [Google Scholar]

121. Tanaka Y, Castillo L, DeLuca HF. The 24-hydroxylation of 1,25-dihydroxyvitamin D3. J Biol Chem. 1977;252:1421–1424. [PubMed] [Google Scholar]

122. Tanaka Y, Deluca HF. The control of 25-hydroxyvitamin D metabolism by inorganic phosphorus. Arch Biochem Biophys. 1973;154:566–574. [PubMed] [Google Scholar]

123. Baxter LA, DeLuca HF. Stimulation of 25-hydroxyvitamin D3–1α-hydroxylase by phosphate depletion. J Biol Chem. 1976;251:3158–3161. [PubMed] [Google Scholar]

124. Ribovich ML, DeLuca HF. 1,25-Dihydroxyvitamin D3 metabolism. The effect of dietary calcium and phosphorus. Arch Biochem Biophys. 1978;188:164–171. [PubMed] [Google Scholar]

125. Dominguez JH, Gray RW, Lemann J., Jr Dietary phosphate deprivation in women and men: effects on mineral and acid balances, parathyroid hormone and the metabolism of 25-OH-vitamin D. J Clin Endocrinol Metab. 1976;43:1056–1068. [PubMed] [Google Scholar]

126. Gray RW, Wilz DR, Caldas AE, Lemann J., Jr The importance of phosphate in regulating plasma 1,25-(OH)2-vitamin D levels in humans: studies in healthy subjects in calcium-stone formers and in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 1977;45:299–306. [PubMed] [Google Scholar]

127. Kumar R. The metabolism of dihydroxylated vitamin D metabolites. In: Kumar R, ed. Vitamin D: Basic and Clinical Aspects. Boston, MA: Martinus Nirjhoff; 1984:69–90. [Google Scholar]

128. Kumar R. The metabolism and mechanism of action of 1,25-dihydroxyvitamin D3. Kidney Int. 1986;30:793–803. [PubMed] [Google Scholar]

129. Kumar R, Cohen WR, Epstein FH. Vitamin D and calcium hormones in pregnancy. N Engl J Med. 1980;302:1143–1145. [PubMed] [Google Scholar]

130. Kumar R. Vitamin D and calcium transport. Kidney Int. 1991;40:1177–1189. [PubMed] [Google Scholar]

131. Kovacs CS. Maternal mineral and bone metabolism during pregnancy, lactation, and post-weaning recovery. Physiol Rev. 2016;96:449–547. [PubMed] [Google Scholar]

132. Madhok TC, Schnoes HK, DeLuca HF. Mechanism of 25-hydroxyvitamin D3 24-hydroxylation: incorporation of oxygen-18 into the 24 position of 25-hydroxyvitamin D3. Biochemistry. 1977;16:2142–2145. [PubMed] [Google Scholar]

133. Ohyama Y, Noshiro M, Eggertsen G, et al. Structural characterization of the gene encoding rat 25-hydroxyvitamin D3 24-hydroxylase. Biochemistry. 1993;32:76–82. [PubMed] [Google Scholar]

134. Ohyama Y, Noshiro M, Okuda K. Cloning and expression‎ of cDNA encoding 25-hydroxyvitamin D3 24-hydroxylase. FEBS Lett. 1991;278:195–198. [PubMed] [Google Scholar]

135. Ohyama Y, Okuda K. Isolation and characterization of a cytochrome P-450 from rat kidney mitochondria that catalyzes the 24-hydroxylation of 25-hydroxyvitamin D3. J Biol Chem. 1991;266:8690–8695. [PubMed] [Google Scholar]

136. Ohyama Y, Ozono K, Uchida M, et al. Identification of a vitamin D-responsive element in the 5′-flanking region of the rat 25-hydroxyvitamin D3 24-hydroxylase gene. J Biol Chem. 1994;269:10545–10550. [PubMed] [Google Scholar]

137. Chen KS, DeLuca HF. Cloning of the human 1 α,25-dihydroxyvitamin D-3 24-hydroxylase gene promoter and identification of two vitamin D-responsive elements. Biochim Biophys Acta. 1995;1263:1–9. [PubMed] [Google Scholar]

138. Chen KS, Prahl JM, DeLuca HF. Isolation and expression‎ of human 1,25-dihydroxyvitamin D3 24-hydroxylase cDNA. Proc Natl Acad Sci USA. 1993;90:4543–4547. [PMC free article] [PubMed] [Google Scholar]

139. Schlingmann KP, Kaufmann M, Weber S, Irwin A, et al. Mutations in CYP24A1 and idiopathic infantile hypercalcemia. N Engl J Med. 2011;365:410–421. [PubMed] [Google Scholar]

140. Tebben PJ, Milliner DS, Horst RL, et al. Hypercalcemia, hypercalciuria, and elevated calcitriol concentrations with autosomal dominant transmission due to CYP24A1 mutations: effects of ketoconazole therapy. J Clin Endocrinol Metab. 2012;97:E423–E427. [PMC free article] [PubMed] [Google Scholar]

141. Dinour D, Beckerman P, Ganon L, Tordjman K, Eisenstein Z, Holtzman EJ. Loss-of-function mutations of CYP24A1, the vitamin D 24-hydroxylase gene, cause long-standing hypercalciuric nephrolithiasis and nephrocalcinosis. J Urol. 2013;190:552–557. [PubMed] [Google Scholar]

142. Meusburger E, Mündlein A, Zitt E, Obermayer-Pietsch B, Kotzot D, Lhotta K. Medullary nephrocalcinosis in an adult patient with idiopathic infantile hypercalcaemia and a novel CYP24A1 mutation. Clin Kidney J. 2013;6:211–215. [PMC free article] [PubMed] [Google Scholar]

143. Nesterova G, Malicdan MC, Yasuda K, et al. 1,25-(OH)2D-24 Hydroxylase (CYP24A1) deficiency as a cause of nephrolithiasis. Clin J Am Soc Nephrol. 2013;8:649–657. [PMC free article] [PubMed] [Google Scholar]

144. Jacobs TP, Kaufman M, Jones G, et al. A lifetime of hypercalcemia and hypercalciuria, finally explained. J Clin Endocrinol Metab. 2014;99:708–712. [PMC free article] [PubMed] [Google Scholar]

145. Colussi G, Ganon L, Penco S, et al. Chronic hypercalcaemia from inactivating mutations of vitamin D 24-hydroxylase (CYP24A1): implications for mineral metabolism changes in chronic renal failure. Nephrol Dial Transplant. 2014;29:636–643. [PubMed] [Google Scholar]

146. Dinour D, Davidovits M, Aviner S, et al. Maternal and infantile hypercalcemia caused by vitamin-D-hydroxylase mutations and vitamin D intake. Pediatr Nephrol. 2015;30:145–152. [PubMed] [Google Scholar]

147. Marks BE, Doyle DA. Idiopathic infantile hypercalcemia: case report and review of the literature. J Pediatr Endocrinol Metab. 2016;29:127–132. [PubMed] [Google Scholar]

148. Annalora AJ, Goodin DB, Hong WX, Zhang Q, Johnson EF, Stout CD. Crystal structure of CYP24A1, a mitochondrial cytochrome P450 involved in vitamin D metabolism. J Mol Biol. 2010;396:441–451. [PMC free article] [PubMed] [Google Scholar]

149. Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10:845–858. [PMC free article] [PubMed] [Google Scholar]

150. Kelley LA, Sternberg MJ. Protein structure prediction on the Web: a case study using the Phyre server. Nat Protoc. 2009;4:363–371. [PubMed] [Google Scholar]

151. Rhieu SY, Annalora AJ, Gathungu RM, Vouros P, Uskokovic MR, Schuster I, Palmore GT, Reddy GS. A new insight into the role of rat cytochrome P450 24A1 in metabolism of selective analogs of 1α,25-dihydroxyvitamin D3. Arch Biochem Biophys. 2011;509:33–43. [PMC free article] [PubMed] [Google Scholar]

152. Strushkevich N, Gilep AA, Shen L, et al. Structural insights into aldosterone synthase substrate specificity and targeted inhibition. Mol Endocrinol. 2013;27:315–324. [PMC free article] [PubMed] [Google Scholar]

153. Strushkevich N, MacKenzie F, Cherkesova T, Grabovec I, Usanov S, Park HW. Structural basis for pregnenolone biosynthesis by the mitochondrial monooxygenase system. Proc Natl Acad Sci USA. 2011;108:10139–10143. [PMC free article] [PubMed] [Google Scholar]

154. Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31:455–461. [PMC free article] [PubMed] [Google Scholar]

155. Ghazarian JG, DeLuca HF. 25-Hydroxycholecalciferol-1-hydroxylase: a specific requirement for NADPH and a hemoprotein component in chick kidney mitochondria. Arch Biochem Biophys. 1974;160:63–72. [PubMed] [Google Scholar]

156. Ghazarian JG, Jefcoate CR, Knutson JC, Orme-Johnson WH, DeLuca HF. Mitochondrial cytochrome p450. A component of chick kidney 25-hydrocholecalciferol-1α-hydroxylase. J Biol Chem. 1974;249:3026–3033. [PubMed] [Google Scholar]

157. Ghazarian JG, Schnoes HK, DeLuca HF. Mechanism of 25-hydroxycholecalciferol 1-hydroxylation. Incorporation of oxygen-18 into the 1 position of 25-hydroxycholecalciferol. Biochemistry. 1973;12:2555–2558. [PubMed] [Google Scholar]

158. Gray RW, Omdahl JL, Ghazarian JG, DeLuca HF. 25-Hydroxycholecalciferol-1-hydroxylase. Subcellular location and properties. J Biol Chem. 1972;247:7528–7532. [PubMed] [Google Scholar]

159. Monkawa T, Yoshida T, Wakino S, et al. Molecular cloning of cDNA and genomic DNA for human 25-hydroxyvitamin D3 1 α-hydroxylase. Biochem Biophys Res Commun. 1997;239:527–533. [PubMed] [Google Scholar]

160. St-Arnaud R, Messerlian S, Moir JM, Omdahl JL, Glorieux FH. The 25-hydroxyvitamin D 1-α-hydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. J Bone Miner Res. 1997;12:1552–1559. [PubMed] [Google Scholar]

161. Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S. 25-Hydroxyvitamin D3 1α-hydroxylase and vitamin D synthesis. Science. 1997;277:1827–1830. [PubMed] [Google Scholar]

162. Fu GK, Lin D, Zhang MY, et al. Cloning of human 25-hydroxyvitamin D-1 α-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol Endocrinol. 1997;11:1961–1970. [PubMed] [Google Scholar]

163. Wang JT, Lin CJ, Burridge SM, et al. Genetics of vitamin D 1α-hydroxylase deficiency in 17 families. Am J Hum Genet. 1998;63:1694–1702. [PMC free article] [PubMed] [Google Scholar]

164. Wang X, Zhang MY, Miller WL, Portale AA. Novel gene mutations in patients with 1α-hydroxylase deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab. 2002;87:2424–2430. [PubMed] [Google Scholar]

165. Kitanaka S, Takeyama K, Murayama A, Kato S. The molecular basis of vitamin D-dependent rickets type I. Endocr J. 2001;48:427–432. [PubMed] [Google Scholar]

166. Sawada N, Sakaki T, Kitanaka S, Kato S, Inouye K. Structure-function analysis of CYP27B1 and CYP27A1. Studies on mutants from patients with vitamin D-dependent rickets type I (VDDR-I) and cerebrotendinous xanthomatosis (CTX). Eur J Biochem. 2001;268:6607–6615. [PubMed] [Google Scholar]

167. Dardenne O, Prud'homme J, Arabian A, Glorieux FH, St-Arnaud R. Targeted inactivation of the 25-hydroxyvitamin D(3)-1(α)-hydroxylase gene (CYP27B1) creates an animal model of pseudovitamin D-deficiency rickets. Endocrinology. 2001;142:3135–3141. [PubMed] [Google Scholar]

168. Kumar R, Nagubandi S, Londowski JM. Production of a polar metabolite of 1,25-dihydroxyvitamin D3 in a rat liver perfusion system. Dig Dis Sci. 1981;26:242–246. [PubMed] [Google Scholar]

169. Kumar R, Nagubandi S, Mattox VR, Londowski JM. Enterohepatic physiology of 1,25-dihydroxyvitamin D3. J Clin Invest. 1980;65:277–284. [PMC free article] [PubMed] [Google Scholar]

170. Litwiller RD, Mattox VR, Jardine I, Kumar R. Evidence for a monoglucuronide of 1,25-dihydroxyvitamin D3 in rat bile. J Biol Chem. 1982;257:7491–7494. [PubMed] [Google Scholar]

171. Nagubandi S, Kumar R, Londowski JM, Corradino RA, Tietz PS. Role of vitamin D glucosiduronate in calcium homeostasis. J Clin Invest. 1980;66:1274–1280. [PMC free article] [PubMed] [Google Scholar]

172. Wiesner RH, Kumar R, Seeman E, Go VL. Enterohepatic physiology of 1,25-dihydroxyvitamin D3 metabolites in normal man. J Lab Clin Med. 1980;96:1094–1100. [PubMed] [Google Scholar]

173. Harnden D, Kumar R, Holick MF, Deluca HF. Side chain metabolism of 25-hydroxy-[26,27–14C] vitamin D3 and 1,25-dihydroxy-[26,27–14C] vitamin D3 in vivo. Science. 1976;193:493–494. [PubMed] [Google Scholar]

174. Kumar R, DeLuca HF. Side chain oxidation of 25-hydroxy-[26,27–14C]vitamin D3 and 1,25-dihydroxy-[26,27–14C]vitamin D3 in vivo by chickens. Biochem Biophys Res Commun. 1976;69:197–200. [PubMed] [Google Scholar]

175. Kumar R, Harnden D, DeLuca HF. Metabolism of 1,25-dihydroxyvitamin D3: evidence for side-chain oxidation. Biochemistry. 1976;15:2420–2423. [PubMed] [Google Scholar]

176. Esvelt RP, Schnoes HK, DeLuca HF. Isolation and characterization of 1 α-hydroxy-23-carboxytetranorvitamin D: a major metabolite of 1,25-dihydroxyvitamin D3. Biochemistry. 1979;18:3977–3983. [PubMed] [Google Scholar]

177. Horst RL, Wovkulich PM, Baggiolini EG, Uskoković MR, Engstrom GW, Napoli JL. (23S)-1,23,25-Trihydroxyvitamin D3: its biologic activity and role in 1 α,25-dihydroxyvitamin D3 26,23-lactone biosynthesis. Biochemistry. 1984;23:3973–3979. [PubMed] [Google Scholar]

178. Wilhelm F, Mayer E, Norman AW. Biological activity assessment of the 26,23-lactones of 1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 and their binding properties to chick intestinal receptor and plasma vitamin D binding protein. Arch Biochem Biophys. 1984;233:322–329. [PubMed] [Google Scholar]

179. Ishizuka S, Oshida J, Tsuruta H, Norman AW. The stereochemical configuration of the natural 1 α,25-dihydroxyvitamin D3–26,23-lactone. Arch Biochem Biophys. 1985;242:82–89. [PubMed] [Google Scholar]

180. DeLuca HF. The kidney as an endocrine organ involved in the function of vitamin D. Am J Med. 1975;58:39–47. [PubMed] [Google Scholar]

181. Holick MF, Garabedian M, DeLuca HF. 1,25-Dihydroxycholecalciferol: metabolite of vitamin D3 active on bone in anephric rats. Science. 1972;176:1146–1147. [PubMed] [Google Scholar]

182. Baker AR, McDonnell DP, Hughes M, et al. Cloning and expression‎ of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci USA. 1988;85:3294–3298. [PMC free article] [PubMed] [Google Scholar]

183. Jehan F, DeLuca HF. Cloning and characterization of the mouse vitamin D receptor promoter. Proc Natl Acad Sci USA. 1997;94:10138–10143. [PMC free article] [PubMed] [Google Scholar]

184. Lu Z, Hanson K, DeLuca HF. Cloning and origin of the two forms of chicken vitamin D receptor. Arch Biochem Biophys. 1997;339:99–106. [PubMed] [Google Scholar]

185. Brumbaugh PF, Haussler MR. 1α,25-dihydroxyvitamin D3 receptor: competitive binding of vitamin D analogs. Life Sci. 1973;13:1737–1746. [PubMed] [Google Scholar]

186. Rachez C, Lemon BD, Suldan Z, et al. Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature. 1999;398:824–828. [PubMed] [Google Scholar]

187. Ciesielski F, Rochel N, Moras D. Adaptability of the vitamin D nuclear receptor to the synthetic ligand Gemini: remodelling the LBP with one side chain rotation. J Steroid Biochem Mol Biol. 2007;103:235–242. [PubMed] [Google Scholar]

188. Hourai S, Rodrigues LC, Antony P, et al. Structure-based design of a superagonist ligand for the vitamin D nuclear receptor. Chem Biol. 2008;15:383–392. [PubMed] [Google Scholar]

189. Rochel N, Hourai S, Pérez-García X, Rumbo A, Mourino A, Moras D. Crystal structure of the vitamin D nuclear receptor ligand binding domain in complex with a locked side chain analog of calcitriol. Arch Biochem Biophys. 2007;460:172–176. [PubMed] [Google Scholar]

190. Rochel N, Wurtz JM, Mitschler A, Klaholz B, Moras D. The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. Mol Cell. 2000;5:173–179. [PubMed] [Google Scholar]

191. Molnár F, Peräkylä M, Carlberg C. Vitamin D receptor agonists specifically modulate the volume of the ligand-binding pocket. J Biol Chem. 2006;281:10516–10526. [PubMed] [Google Scholar]

192. Väisänen S, Ryhänen S, Saarela JT, Peräkylä M, Andersin T, Mäenpää PH. Structurally and functionally important amino acids of the agonistic conformation of the human vitamin D receptor. Mol Pharmacol. 2002;62:788–794. [PubMed] [Google Scholar]

193. Yamada S, Shimizu M, Yamamoto K. Structure-function relationships of vitamin D including ligand recognition by the vitamin D receptor. Med Res Rev. 2003;23:89–115. [PubMed] [Google Scholar]

194. Yamamoto K, Masuno H, Choi M, et al. Three-dimensional modeling of and ligand docking to vitamin D receptor ligand binding domain. Proc Natl Acad Sci USA. 2000;97:1467–1472. [PMC free article] [PubMed] [Google Scholar]

195. Shaffer PL, Gewirth DT. Structural basis of VDR-DNA interactions on direct repeat response elements. EMBO J. 2002;21:2242–2252. [PMC free article] [PubMed] [Google Scholar]

196. Umesono K, Giguere V, Glass CK, Rosenfeld MG, Evans RM. Retinoic acid and thyroid hormone induce gene expression‎ through a common responsive element. Nature. 1988;336:262–265. [PubMed] [Google Scholar]

197. Carlberg C, Bendik I, Wyss A, et al. Two nuclear signalling pathways for vitamin D. Nature. 1993;361:657–660. [PubMed] [Google Scholar]

198. Carlberg C, Polly P. Gene regulation by vitamin D3. Crit Rev Eukaryot Gene Expr. 1998;8:19–42. [PubMed] [Google Scholar]

199. Schräder M, Bendik I, Becker-André M, Carlberg C. Interaction between retinoic acid and vitamin D signaling pathways. J Biol Chem. 1993;268:17830–17836. [PubMed] [Google Scholar]

200. Darwish H, DeLuca HF. Vitamin D-regulated gene expression‎. Crit Rev Eukaryot Gene Expr. 1993;3:89–116. [PubMed] [Google Scholar]

201. Haussler MR, Jurutka PW, Mizwicki M, Norman AW. Vitamin D receptor (VDR)-mediated actions of 1α,25(OH) vitamin D: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab. 2011;25:543–559. [PubMed] [Google Scholar]

202. Jurutka PW, Whitfield GK, Hsieh JC, Thompson PD, Haussler CA, Haussler MR. Molecular nature of the vitamin D receptor and its role in regulation of gene expression‎. Rev Endocr Metab Disord. 2001;2:203–216. [PubMed] [Google Scholar]

203. Lowe KE, Maiyar AC, Norman AW. Vitamin D-mediated gene expression‎. Crit Rev Eukaryot Gene Expr. 1992;2:65–109. [PubMed] [Google Scholar]

204. Craig TA, Zhang Y, Magis AT, et al. Detection of 1α,25-dihydroxyvitamin D-regulated miRNAs in zebrafish by whole transcriptome sequencing. Zebrafish. 2014;11:207–218. [PMC free article] [PubMed] [Google Scholar]

205. Craig TA, Zhang Y, McNulty MS, et al. Research resource: whole transcriptome RNA sequencing detects multiple 1α,25-dihydroxyvitamin D(3)-sensitive metabolic pathways in developing zebrafish. Mol Endocrinol. 2012;26:1630–1642. [PMC free article] [PubMed] [Google Scholar]

206. Tebben PJ, Kumar R. The hormonal regulation of calcium metabolism. In: Alpern RJ, Moe OW, Caplan M, eds. Seldin and Giebisch's The Kidney, Physiology and Pathophysiology. Vol 2 New York, NY: Academic Press; 2013:2273–2330. [Google Scholar]

207. DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr. 2004;80:1689S–1696S. [PubMed] [Google Scholar]

208. Wasserman RH, Corradino RA, Fullmer CS, Taylor AN. Some aspects of vitamin D action; calcium absorption and the vitamin D-dependent calcium-binding protein. Vitam Horm. 1974;32:299–324. [PubMed] [Google Scholar]

209. Wasserman RH, Fullmer CS. Vitamin D and intestinal calcium transport: facts, speculations and hypotheses. J Nutr. 1995;125:1971S–1979S. [PubMed] [Google Scholar]

210. Wasserman RH, Smith CA, Brindak ME, et al. Vitamin D and mineral deficiencies increase the plasma membrane calcium pump of chicken intestine. Gastroenterology. 1992;102:886–894. [PubMed] [Google Scholar]

211. Wasserman RH, Chandler JS, Meyer SA, et al. Intestinal calcium transport and calcium extrusion processes at the basolateral membrane. J Nutr. 1992;122:662–671. [PubMed] [Google Scholar]

212. Berndt T, Thompson JR, Kumar R. The regulation of calcium, magnesium, and phosphate excretion by the kidney. In: Skorecki K, Chertow G, Marsden P, Taal M, Yu A, eds. Brenner and Rector's The Kidney. Vol 1 10th ed Atlanta, GA: Elsevier; 2015:185–203. [Google Scholar]

213. Dimke H, Hoenderop JG, Bindels RJ. Molecular basis of epithelial Ca2+ and Mg2+ transport: insights from the TRP channel family. J Physiol. 2011;589:1535–1542. [PMC free article] [PubMed] [Google Scholar]

214. Brini M, Calì T, Ottolini D, Carafoli E. The plasma membrane calcium pump in health and disease. FEBS J. 2013;280:5385–5397. [PubMed] [Google Scholar]

215. Brini M, Carafoli E. Calcium pumps in health and disease. Physiol Rev. 2009;89:1341–1378. [PubMed] [Google Scholar]

216. Borke JL, Caride A, Verma AK, Penniston JT, Kumar R. Cellular and segmental distribution of Ca2(+)-pump epitopes in rat intestine. Pflugers Arch. 1990;417:120–122. [PubMed] [Google Scholar]

217. Philipson KD, Nicoll DA. Sodium-calcium exchange: a molecular perspective. Annu Rev Physiol. 2000;62:111–133. [PubMed] [Google Scholar]

218. Meyer MB, Zella LA, Nerenz RD, Pike JW. Characterizing early events associated with the activation of target genes by 1,25-dihydroxyvitamin D3 in mouse kidney and intestine in vivo. J Biol Chem. 2007;282:22344–22352. [PubMed] [Google Scholar]

219. Taylor AN, Wasserman RH. Vitamin D-induced calcium-binding protein: comparative aspects in kidney and intestine. Am J Physiol. 1972;223:110–114. [PubMed] [Google Scholar]

220. Wasserman RH, Brindak ME, Meyer SA, Fullmer CS. Evidence for multiple effects of vitamin D3 on calcium absorption: response of rachitic chicks, with or without partial vitamin D3 repletion, to 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA. 1982;79:7939–7943. [PMC free article] [PubMed] [Google Scholar]

221. Wasserman RH, Taylor AN. Vitamin d3-induced calcium-binding protein in chick intestinal mucosa. Science. 1966;152:791–793. [PubMed] [Google Scholar]

222. Cai Q, Chandler JS, Wasserman RH, Kumar R, Penniston JT. Vitamin D and adaptation to dietary calcium and phosphate deficiencies increase intestinal plasma membrane calcium pump gene expression‎. Proc Natl Acad Sci USA. 1993;90:1345–1349. [PMC free article] [PubMed] [Google Scholar]

223. Lee SM, Riley EM, Meyer MB, et al. 1,25-Dihydroxyvitamin D3 controls a cohort of vitamin D receptor target genes in the proximal intestine that is enriched for calcium-regulating components. J Biol Chem. 2015;290:18199–18215. [PMC free article] [PubMed] [Google Scholar]

224. Benn BS, Ajibade D, Porta A, et al. Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9k. Endocrinology. 2008;149:3196–3205. [PMC free article] [PubMed] [Google Scholar]

225. Kutuzova GD, Sundersingh F, Vaughan J, et al. TRPV6 is not required for 1α,25-dihydroxyvitamin D3-induced intestinal calcium absorption in vivo. Proc Natl Acad Sci USA. 2008;105:19655–19659. [PMC free article] [PubMed] [Google Scholar]

226. Lieben L, Benn BS, Ajibade D, et al. Trpv6 mediates intestinal calcium absorption during calcium restriction and contributes to bone homeostasis. Bone. 2010;47:301–308. [PMC free article] [PubMed] [Google Scholar]

227. Ryan ZC, Craig TA, Filoteo AG, et al. Deletion of the intestinal plasma membrane calcium pump, isoform 1, Atp2b1, in mice is associated with decreased bone mineral density and impaired responsiveness to 1, 25-dihydroxyvitamin D3. Biochem Biophys Res Commun. 2015;467:152–156. [PMC free article] [PubMed] [Google Scholar]

228. Popovtzer MM, Knochel JP, Kumar R. Disorders of calcium phosphorus, vitamin D, and parathyroid hormone activity. In: Schrier RW, ed. Renal and Electrolyte Disorders. 5th ed Philadelphia, PA: Little, Lippincott-Raven; 1997:241–319. [Google Scholar]

229. Berndt TJ, Kumar R. Clinical disturbances or phosphate homeostasis. In: Alpern RJ, Caplan MJ, Moe OW, eds. The Kidney: Physiology and Pathophysiology. Vol 2 5th ed New York, NY: Elsevier-Academic Press; 2013:2369–2391. [Google Scholar]

230. Steele TH, Engle JE, Tanaka Y, Lorenc RS, Dudgeon KL, DeLuca HF. Phosphatemic action of 1,25-dihydroxyvitamin D3. Am J Physiol. 1975;229:489–495. [PubMed] [Google Scholar]

231. Tanaka Y, Frank H, DeLuca HF. Intestinal calcium transport: stimulation by low phosphorus diets. Science. 1973;181:564–566. [PubMed] [Google Scholar]

232. Gray RW. Control of plasma 1,25-(OH)2-vitamin D concentrations by calcium and phosphorus in the rat: effects of hypophysectomy. Calcif Tissue Int. 1981;33:485–488. [PubMed] [Google Scholar]

233. Gray RW. Effects of age and sex on the regulation of plasma 1,25-(OH)2-D by phosphorus in the rat. Calcif Tissue Int. 1981;33:477–484. [PubMed] [Google Scholar]

234. Gray RW, Garthwaite TL. Activation of renal 1,25-dihydroxyvitamin D3 synthesis by phosphate deprivation: evidence for a role for growth hormone. Endocrinology. 1985;116:189–193. [PubMed] [Google Scholar]

235. Gray RW, Garthwaite TL, Phillips LS. Growth hormone and triiodothyronine permit an increase in plasma 1,25(OH)2D concentrations in response to dietary phosphate deprivation in hypophysectomized rats. Calcif Tissue Int. 1983;35:100–106. [PubMed] [Google Scholar]

236. Gray RW, Haasch ML, Brown CE. Regulation of plasma 1,25-(OH)2-D3 by phosphate: evidence against a role for total or acid-soluble renal phosphate content. Calcif Tissue Int. 1983;35:773–777. [PubMed] [Google Scholar]

237. Gray RW, Napoli JL. Dietary phosphate deprivation increases 1,25-dihyroxyvitamin D3 synthesis in rat kidney in vitro. J Biol Chem. 1983;258:1152–1155. [PubMed] [Google Scholar]

238. Kido S, Kaneko I, Tatsumi S, Segawa H, Miyamoto K. Vitamin D and type II sodium-dependent phosphate cotransporters. Contrib Nephrol. 2013;180:86–97. [PubMed] [Google Scholar]

239. Taketani Y, Segawa H, Chikamori M, et al. Regulation of type II renal Na+-dependent inorganic phosphate transporters by 1,25-dihydroxyvitamin D3. Identification of a vitamin D-responsive element in the human NAPi-3 gene. J Biol Chem. 1998;273:14575–14581. [PubMed] [Google Scholar]

240. Wagner CA, Hernando N, Forster IC, Biber J. The SLC34 family of sodium-dependent phosphate transporters. Pflugers Arch. 2014;466:139–153. [PubMed] [Google Scholar]

241. Cusano NE, Thys-Jacobs S, Bilezikian JP. Hypercalcemia due to vitamin D toxicity. In: Feldman D, Pike JW, Adams D, eds. Vitamin D. Vol 2 3rd ed Waltham, MA: Academic Press; 2011:1381–1381. [Google Scholar]

242. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842–856. [PubMed] [Google Scholar]

243. Amir E, Simmons CE, Freedman OC, et al. A phase 2 trial exploring the effects of high-dose (10,000 IU/day) vitamin D(3) in breast cancer patients with bone metastases. Cancer. 2010;116:284–291. [PubMed] [Google Scholar]

244. Lowe H, Cusano NE, Binkley N, Blaner WS, Bilezikian JP. Vitamin D toxicity due to a commonly available “over the counter” remedy from the Dominican Republic. J Clin Endocrinol Metab. 2011;96:291–295. [PubMed] [Google Scholar]

245. 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. 1995;122:511–513. [PubMed] [Google Scholar]

246. Kaur P, Mishra SK, Mithal A. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Clin Endocrinol (Oxf). 2015;83:327–331. [PubMed] [Google Scholar]

247. Mason RS, Lissner D, Grunstein HS, Posen S. A simplified assay for dihydroxylated vitamin D metabolites in human serum: application to hyper- and hypovitaminosis D. Clin Chem. 1980;26:444–450. [PubMed] [Google Scholar]

248. Haddock L, Corcino J, Vasquez MD. 25(OH)D serum levels in normal Puerto Rican population and in subjects with tropical sprue and parathyroid disease. Puerto Rico Health Sci J. 1982;1:85–91. [Google Scholar]

249. Gertner JM, Domenech M. 25-Hydroxyvitamin D levels in patients treated with high-dosage ergo- and cholecalciferol. J Clin Pathol. 1977;30:144–150. [PMC free article] [PubMed] [Google Scholar]

250. Hughes MR, Baylink DJ, Jones PG, Haussler MR. Radioligand receptor assay for 25-hydroxyvitamin D2/D3 and 1 α, 25-dihydroxyvitamin D2/D3. J Clin Invest. 1976;58:61–70. [PMC free article] [PubMed] [Google Scholar]

251. Counts SJ, Baylink DJ, Shen FH, Sherrard DJ, Hickman RO. Vitamin D intoxication in an anephric child. Ann Intern Med. 1975;82:196–200. [PubMed] [Google Scholar]

252. Streck WF, Waterhouse C, Haddad JG. Glucocorticoid effects in vitamin D intoxication. Arch Intern Med. 1979;139:974–977. [PubMed] [Google Scholar]

253. Davies M, Adams PH. The continuing risk of vitamin-D intoxication. Lancet. 1978;2:621–623. [PubMed] [Google Scholar]

254. Mawer EB, Hann JT, Berry JL, Davies M. Vitamin D metabolism in patients intoxicated with ergocalciferol. Clin Sci (Lond). 1985;68:135–141. [PubMed] [Google Scholar]

255. Allen SH, Shah JH. Calcinosis and metastatic calcification due to vitamin D intoxication. A case report and review. Horm Res. 1992;37:68–77. [PubMed] [Google Scholar]

256. Rizzoli R, Stoermann C, Ammann P, Bonjour JP. Hypercalcemia and hyperosteolysis in vitamin D intoxication: effects of clodronate therapy. Bone. 1994;15:193–198. [PubMed] [Google Scholar]

257. Jacobus CH, Holick MF, Shao Q, et al. Hypervitaminosis D associated with drinking milk. N Engl J Med. 1992;326:1173–1177. [PubMed] [Google Scholar]

258. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815–1822. [PubMed] [Google Scholar]

259. Sanders KM, Seibel MJ. Therapy: new findings on vitamin D3 supplementation and falls - when more is perhaps not better. Nat Rev Endocrinol. 2016;12:190–191. [PubMed] [Google Scholar]

260. Sanders KM, Nicholson GC, Ebeling PR. Is high dose vitamin D harmful? Calcif Tissue Int. 2013;92:191–206. [PubMed] [Google Scholar]

261. Bischoff-Ferrari HA, Dawson-Hughes B, Orav EJ, et al. Monthly high-dose vitamin D treatment for the prevention of functional decline: a randomized clinical trial. JAMA Intern Med. 2016;176:175–183. [PubMed] [Google Scholar]

262. Hebert SC, Brown EM, Harris HW. Role of the Ca(2+)-sensing receptor in divalent mineral ion homeostasis. J Exp Biol. 1997;200:295–302. [PubMed] [Google Scholar]

263. Earm JH, Christensen BM, Frøkiaer J, et al. Decreased aquaporin-2 expression‎ and apical plasma membrane delivery in kidney collecting ducts of polyuric hypercalcemic rats. J Am Soc Nephrol. 1998;9:2181–2193. [PubMed] [Google Scholar]

264. Weisman Y, Vargas A, Duckett G, Reiter E, Root AW. Synthesis of 1,25-dihydroxyvitamin D in the nephrectomized pregnant rat. Endocrinology. 1978;103:1992–1996. [PubMed] [Google Scholar]

265. Tanaka Y, Halloran B, Schnoes HK, DeLuca HF. In vitro production of 1,25-dihydroxyvitamin D3 by rat placental tissue. Proc Natl Acad Sci USA. 1979;76:5033–5035. [PMC free article] [PubMed] [Google Scholar]

266. Haddad JG, Chyu KJ. Competitive protein-binding radioassay for 25-hydroxycholecalciferol. J Clin Endocrinol Metab. 1971;33:992–995. [PubMed] [Google Scholar]

267. Brunette MG, Chan M, Ferriere C, Roberts KD. Site of 1,25(OH)2 vitamin D3 synthesis in the kidney. Nature. 1978;276:287–289. [PubMed] [Google Scholar]

268. Golconda MS, Larson TS, Kolb LG, Kumar R. 1,25-Dihydroxyvitamin D-mediated hypercalcemia in a renal transplant recipient. Mayo Clin Proc. 1996;71:32–36. [PubMed] [Google Scholar]

269. Yoon PS, DeLuca HF. Purification and properties of chick renal mitochondrial ferredoxin. Biochemistry. 1980;19:2165–2171. [PubMed] [Google Scholar]

270. Henry HL. Regulation of the hydroxylation of 25-hydroxyvitamin D3 in vivo and in primary cultures of chick kidney cells. J Biol Chem. 1979;254:2722–2729. [PubMed] [Google Scholar]

271. Trechsel U, Bonjour JP, Fleisch H. Regulation of the metabolism of 25-hydroxyvitamin D3 in primary cultures of chick kidney cells. J Clin Invest. 1979;64:206–217. [PMC free article] [PubMed] [Google Scholar]

272. Gray R, Boyle I, DeLuca HF. Vitamin D metabolism: the role of kidney tissue. Science. 1971;172:1232–1234. [PubMed] [Google Scholar]

273. Yoon PS, Rawlings J, Orme-Johnson WH, DeLuca HF. Renal mitochondrial ferredoxin active in 25-hydroxyvitamin D3 1 α-hydroxylase. Characterization of the iron- sulfur cluster using interprotein cluster transfer and electron paramagnetic resonance spectroscopy. Biochemistry. 1980;19:2172–2176. [PubMed] [Google Scholar]

274. Okamoto Y, DeLuca HF. Separation of two forms of chick 1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 24-hydroxylase. Proc Soc Exp Biol Med. 1994;205:52–55. [PubMed] [Google Scholar]

275. Burgos-Trinidad M, Ismail R, Ettinger RA, Prahl JM, DeLuca HF. Immunopurified 25-hydroxyvitamin D 1 α-hydroxylase and 1,25-dihydroxyvitamin D 24-hydroxylase are closely related but distinct enzymes. J Biol Chem. 1992;267:3498–3505. [PubMed] [Google Scholar]

276. Adams ND, Garthwaite TL, Gray RW, Hagen TC, Lemann J., Jr The interrelationships among prolactin, 1,25-dihydroxyvitamin D, and parathyroid hormone in humans. J Clin Endocrinol Metab. 1979;49:628–630. [PubMed] [Google Scholar]

277. Adams ND, Gray RW, Lemann J., Jr The calciuria of increased fixed acid production in humans: evidence against a role for parathyroid hormone and 1,25(OH)2-vitamin D. Calcif Tissue Int. 1979;28:233–238. [PubMed] [Google Scholar]

278. Adams ND, Gray RW, Lemann J., Jr The effects of oral CaCO3 loading and dietary calcium deprivation on plasma 1,25-dihydroxyvitamin D concentrations in healthy adults. J Clin Endocrinol Metab. 1979;48:1008–1016. [PubMed] [Google Scholar]

279. Singh RJ, Taylor RL, Reddy GS, Grebe SK. C-3 epimers can account for a significant proportion of total circulating 25-hydroxyvitamin D in infants, complicating accurate measurement and interpretation of vitamin D status. J Clin Endocrinol Metab. 2006;91:3055–3061. [PubMed] [Google Scholar]

280. Carré M, Ayigbedé O, Miravet L, Rasmussen H. The effect of Prednisolone upon the metabolism and action of 25-hydroxy-and 1,25-dihydroxyvitamin D3. Proc Natl Acad Sci USA. 1974;71:2996–3000. [PMC free article] [PubMed] [Google Scholar]

281. Adams JS, Lee G. Gains in bone mineral density with resolution of vitamin D intoxication. Ann Intern Med. 1997;127:203–206. [PubMed] [Google Scholar]

282. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669–683. [PubMed] [Google Scholar]

283. Better OS, Shabtai M, Kedar S, Melamud A, Berenheim J, Chaimovitz C. Increased incidence of nephrolithiasis (N) in lifeguards (LG) in Israel. Adv Exp Med Biol. 1980;128:467–472. [PubMed] [Google Scholar]

284. Snell AP, MacLennan WJ, Hamilton JC. Ultra-violet irradiation and 25-hydroxy-vitamin D levels in sick old people. Age Ageing. 1978;7:225–228. [PubMed] [Google Scholar]

285. Davie MW, Lawson DE, Emberson C, Barnes JL, Roberts GE, Barnes ND. Vitamin D from skin: contribution to vitamin D status compared with oral vitamin D in normal and anticonvulsant-treated subjects. Clin Sci (Lond). 1982;63:461–472. [PubMed] [Google Scholar]

286. Davies M, Mawer EB. The effects of simulated solar exposure upon serum vitamin D and 25-hydroxyvitamin D3 and healthy controls and patients with metabolic bone disease. In: Norman AW, Bouillon R, Thomassett M, eds. Vitamin D: Chemistry, Biology, and Clinical Applications of the Steroid Hormone. Riverside, CA: University of California; 1997. [Google Scholar]

287. Chel VG, Ooms ME, Popp-Snijders C, et al. Ultraviolet irradiation corrects vitamin D deficiency and suppresses secondary hyperparathyroidism in the elderly. J Bone Miner Res. 1998;13:1238–1242. [PubMed] [Google Scholar]

288. Reid IR, Schooler BA, Hannan SF, Ibbertson HK. The acute biochemical effects of four proprietary calcium preparations. Aust N Z J Med. 1986;16:193–197. [PubMed] [Google Scholar]

289. Falkenbach A. Primary prevention of osteopenia [in German]. Schweiz Med Wochenschr. 1992;122:1728–1735. [PubMed] [Google Scholar]

290. Matsuoka LY, Wortsman J, Hollis BW. Suntanning and cutaneous synthesis of vitamin D3. J Lab Clin Med. 1990;116:87–90. [PubMed] [Google Scholar]

291. Mawer EB, Berry JL, Sommer-Tsilenis E, Beykirch W, Kuhlwein A, Rohde BT. Ultraviolet irradiation increases serum 1,25-dihydroxyvitamin D in vitamin-D-replete adults. Miner Electrolyte Metab. 1984;10:117–121. [PubMed] [Google Scholar]

292. Stamp TC, Haddad JG, Twigg CA. Comparison of oral 25-hydroxycholecalciferol, vitamin D, and ultraviolet light as determinants of circulating 25-hydroxyvitamin D. Lancet. 1977;1:1341–1343. [PubMed] [Google Scholar]

293. Dent CE, Round JM, Rowe DJ, Stamp TC. Effect of chapattis and ultraviolet irradiation on nutritional rickets in an Indian immigrant. Lancet. 1973;1:1282–1284. [PubMed] [Google Scholar]

294. Varghese M, Rodman JS, Williams JJ, et al. The effect of ultraviolet B radiation treatments on calcium excretion and vitamin D metabolites in kidney stone formers. Clin Nephrol. 1989;31:225–231. [PubMed] [Google Scholar]

295. Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet. 1998;352:709–710. [PubMed] [Google Scholar]

296. Haddad JG., Jr Vitamin D binding proteins. Adv Nutr Res. 1982;4:35–58. [PubMed] [Google Scholar]

297. Haddad JG, Matsuoka LY, Hollis BW, Hu YZ, Wortsman J. Human plasma transport of vitamin D after its endogenous synthesis. J Clin Invest. 1993;91:2552–2555. [PMC free article] [PubMed] [Google Scholar]

298. Haddad JG, Birge SJ. Widespread, specific binding of 25-hydroxycholecalciferol in rat tissues. J Biol Chem. 1975;250:299–303. [PubMed] [Google Scholar]

299. Bikle DD, Gee E, Halloran B, Kowalski MA, Ryzen E, Haddad JG. Assessment of the free fraction of 25-hydroxyvitamin D in serum and its regulation by albumin and the vitamin D-binding protein. J Clin Endocrinol Metab. 1986;63:954–959. [PubMed] [Google Scholar]

300. Schwartz JB, Lai J, Lizaola B, et al. A comparison of measured and calculated free 25(OH) vitamin D levels in clinical populations. J Clin Endocrinol Metab. 2014;99:1631–1637. [PMC free article] [PubMed] [Google Scholar]

301. Lai JC, Bikle DD, Lizaola B, Hayssen H, Terrault NA, Schwartz JB. Total 25(OH) vitamin D, free 25(OH) vitamin D and markers of bone turnover in cirrhotics with and without synthetic dysfunction. Liver Int. 2015;35:2294–2300. [PMC free article] [PubMed] [Google Scholar]

302. Powe CE, Evans MK, Wenger J, et al. Vitamin D-binding protein and vitamin D status of black Americans and white Americans. N Engl J Med. 2013;369:1991–2000. [PMC free article] [PubMed] [Google Scholar]

303. Henderson CM, Lutsey PL, Misialek JR, et al. Measurement by a novel LC-MS/MS methodology reveals similar serum concentrations of vitamin D-binding protein in blacks and whites. Clin Chem. 2016;62:179–187. [PMC free article] [PubMed] [Google Scholar]

304. Aloia J, Mikhail M, Dhaliwal R, et al. Free 25(OH)D and the vitamin D paradox in African Americans. J Clin Endocrinol Metab. 2015;100:3356–3363. [PMC free article] [PubMed] [Google Scholar]

305. Nielson CM, Jones KS, Chun RF, et al. Free 25-hydroxyvitamin D: impact of vitamin D binding protein assays on racial-genotypic associations. J Clin Endocrinol Metab. 2016;101:2226–2234. [PMC free article] [PubMed] [Google Scholar]

306. Nielson CM, Jones KS, Bouillon R, et al. Role of assay type in determining free 25-hydroxyvitamin D levels in diverse populations. N Engl J Med. 2016;374:1695–1696. [PMC free article] [PubMed] [Google Scholar]

307. Safadi FF, Thornton P, Magiera H, et al. Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J Clin Invest. 1999;103:239–251. [PMC free article] [PubMed] [Google Scholar]

308. Blunt JW, DeLuca HF. The synthesis of 25-hydroxycholecalciferol. A biologically active metabolite of vitamin D3. Biochemistry. 1969;8:671–675. [PubMed] [Google Scholar]

309. Blunt JW, Tanaka Y, DeLuca HF. The biological activity of 25-hydroxycholecalciferol, a metabolite of vitamin D3. Proc Natl Acad Sci USA. 1968;61:717–718. [PMC free article] [PubMed] [Google Scholar]

310. Johnson WJ. The Use of Vitamin D Analogues Renal Failure, William J. Johnson, and, pages 611–664, 1984). In: Kumar R, ed. Vitamin D: Basic and Clinical Aspects. Dortrecht: Martinus Nijhoff Publishers; 1984:641–664. [Google Scholar]

311. Trummel CL, Raisz LG, Blunt JW, Deluca HF. 25-Hydroxycholecalciferol: stimulation of bone resorption in tissue culture. Science. 1969;163:1450–1451. [PubMed] [Google Scholar]

312. Kumar R, Nagubandi S, Jardine I, Londowski JM, Bollman S. The isolation and identification of 5,6-trans-25-hydroxyvitamin D3 from the plasma of rats dosed with vitamin D3. Evidence for a novel mechanism in the metabolism of vitamin D3. J Biol Chem. 1981;256:9389–9392. [PubMed] [Google Scholar]

313. Albright F, Bloomberg E, Drake T, Sulkowitch HW. A comparison of the effects of A.T. 10 (dihydrotachysterol) and vitamin D on calcium and phosphorus metabolism in hypoparathyroidism. J Clin Invest. 1938;17:317–329. [PMC free article] [PubMed] [Google Scholar]

314. Kuhlback B, Gordin R, Lamberg BA. Hypercalcaemia and renal failure following long-term treatment with dihydrotachysterol (AT 10). Acta Med Scand. 1959;163:257–263. [PubMed] [Google Scholar]

315. Brown AJ, Finch J, Takahashi F, Slatopolsky E. Calcemic activity of 19-Nor-1,25(OH)(2)D(2) decreases with duration of treatment. J Am Soc Nephrol. 2000;11:2088–2094. [PubMed] [Google Scholar]

316. Finch JL, Brown AJ, Slatopolsky E. Differential effects of 1,25-dihydroxy-vitamin D3 and 19-nor-1,25-dihydroxy-vitamin D2 on calcium and phosphorus resorption in bone. J Am Soc Nephrol. 1999;10:980–985. [PubMed] [Google Scholar]

317. Slatopolsky E, Finch J, Ritter C, Takahashi F. Effects of 19-nor-1,25(OH)2D2, a new analogue of calcitriol, on secondary hyperparathyroidism in uremic rats. Am J Kidney Dis. 1998;32:S40–S47. [PubMed] [Google Scholar]

318. Takahashi F, Finch JL, Denda M, Dusso AS, Brown AJ, Slatopolsky E. A new analog of 1,25-(OH)2D3, 19-NOR-1,25-(OH)2D2, suppresses serum PTH and parathyroid gland growth in uremic rats without elevation of intestinal vitamin D receptor content. Am J Kidney Dis. 1997;30:105–112. [PubMed] [Google Scholar]

319. Goldenberg MM. Paricalcitol, a new agent for the management of secondary hyperparathyroidism in patients undergoing chronic renal dialysis. Clin Ther. 1999;21:432–441. [PubMed] [Google Scholar]

320. Martin KJ, González EA. Vitamin D analogues for the management of secondary hyperparathyroidism. Am J Kidney Dis. 2001;38:S34–40. [PubMed] [Google Scholar]

321. Martin KJ, González EA, Gellens ME, Hamm LL, Abboud H, Lindberg J. Therapy of secondary hyperparathyroidism with 19-nor-1α,25-dihydroxyvitamin D2. Am J Kidney Dis. 1998;32:S61–66. [PubMed] [Google Scholar]

322. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D. Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int. 2003;63:1483–1490. [PubMed] [Google Scholar]

323. Shultz TD, Bollman S, Kumar R. Decreased intestinal calcium absorption in vivo and normal brush border membrane vesicle calcium uptake in cortisol-treated chickens: evidence for dissociation of calcium absorption from brush border vesicle uptake. Proc Natl Acad Sci USA. 1982;79:3542–3546. [PMC free article] [PubMed] [Google Scholar]

324. Shultz TD, Kumar R. Effect of cortisol on [3H] 1,25-dihydroxyvitamin D3 uptake and 1,25-dihydroxyvitamin D3-induced DNA-dependent RNA polymerase activity in chick intestinal cells. Calcif Tissue Int. 1987;40:224–230. [PubMed] [Google Scholar]

325. Kumar R. Glucocorticoid-induced osteoporosis. Curr Opin Nephrol Hypertens. 2001;10:589–595. [PubMed] [Google Scholar]

326. Harrell GT, Fisher S. Blood chemical changes in Boeck's sarcoid with particular reference to protein, calcium and phosphate values. J Clin Invest. 1939;18:687–693. [PMC free article] [PubMed] [Google Scholar]

327. Longcope WT, Pierson JW. Boeck's sarcoid (sarcoidosis). Bull Johns Hopkins Hosp. 1937;60:223. [Google Scholar]

328. Studdy PR, Bird R, Neville E, James DG. Biochemical findings in sarcoidosis. J Clin Pathol. 1980;33:528–533. [PMC free article] [PubMed] [Google Scholar]

329. Rizzato G. Clinical impact of bone and calcium metabolism changes in sarcoidosis. Thorax. 1998;53:425–429. [PMC free article] [PubMed] [Google Scholar]

330. Taylor RL, Lynch HJ, Jr, Wysor WG., Jr Seasonal influence of sunlight on the hypercalcemia of sarcoidosis. Am J Med. 1963;34:221–227. [PubMed] [Google Scholar]

331. Henneman PH, Dempsey EF, L. CE, Albright F. The cause of hypercalcuria in sarcoid and its treatment with cortisone and sodium phytate. J Clin Invest. 1956;35:1229–1242. [PMC free article] [PubMed] [Google Scholar]

332. Anderson J, Harper C, Dent CE, Philpot GR. Effect of cortisone on calcium metabolism in sarcoidosis with hypercalcaemia; possibly antagonistic actions of cortisone and vitamin D. Lancet. 1954;267:720–724. [PubMed] [Google Scholar]

333. Bell NH, Bartter FC. Studies of 47-Ca metabolism in sarcoidosis: evidence for increased sensitivity of bone to vitamin D. Acta Endocrinol (Copenh). 1967;54:173–180. [PubMed] [Google Scholar]

334. Papapoulos SE, Clemens TL, Fraher LJ, Lewin IG, Sandler LM, O'Riordan JL. 1, 25-Dihydroxycholecalciferol in the pathogenesis of the hypercalcaemia of sarcoidosis. Lancet. 1979;1:627–630. [PubMed] [Google Scholar]

335. Bell NH, Stern PH, Pantzer E, Sinha TK, DeLuca HF. Evidence that increased circulating 1 α, 25-dihydroxyvitamin D is the probable cause for abnormal calcium metabolism in sarcoidosis. J Clin Invest. 1979;64:218–225. [PMC free article] [PubMed] [Google Scholar]

336. Barbour GL, Coburn JW, Slatopolsky E, Norman AW, Horst RL. Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D. N Engl J Med. 1981;305:440–443. [PubMed] [Google Scholar]

337. Maesaka JK, Batuman V, Pablo NC, Shakamuri S. Elevated 1,25-dihydroxyvitamin D levels: occurrence with sarcoidosis with end-stage renal disease. Arch Intern Med. 1982;142:1206–1207. [PubMed] [Google Scholar]

338. Bell NH, Bartter FC. Transient reversal of hyperabsorption of calcium and of abnormal sensitivity to vitamin D in a patient with sarcoidosis during episode of nephritis. Ann Intern Med. 1964;61:702–710. [PubMed] [Google Scholar]

339. Mason RS, Frankel T, Chan YL, Lissner D, Posen S. Vitamin D conversion by sarcoid lymph node homogenate. Ann Intern Med. 1984;100:59–61. [PubMed] [Google Scholar]

340. Adams JS, Gacad MA. Characterization of 1 α-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med. 1985;161:755–765. [PMC free article] [PubMed] [Google Scholar]

341. Adams JS, Gacad MA, Singer FR, Sharma OP. Production of 1,25-dihydroxyvitamin D3 by pulmonary alveolar macrophages from patients with sarcoidosis. Ann NY Acad Sci. 1986;465:587–594. [PubMed] [Google Scholar]

342. Adams JS, Sharma OP, Gacad MA, Singer FR. Metabolism of 25-hydroxyvitamin D3 by cultured pulmonary alveolar macrophages in sarcoidosis. J Clin Invest. 1983;72:1856–1860. [PMC free article] [PubMed] [Google Scholar]

343. Adams JS, Singer FR, Gacad MA, et al. Isolation and structural identification of 1,25-dihydroxyvitamin D3 produced by cultured alveolar macrophages in sarcoidosis. J Clin Endocrinol Metab. 1985;60:960–966. [PubMed] [Google Scholar]

344. Adams JS, Gacad MA, Diz MM, Nadler JL. A role for endogenous arachidonate metabolites in the regulated expression‎ of the 25-hydroxyvitamin D-1-hydroxylation reaction in cultured alveolar macrophages from patients with sarcoidosis. J Clin Endocrinol Metab. 1990;70:595–600. [PubMed] [Google Scholar]

345. Basile JN, Liel Y, Shary J, Bell NH. Increased calcium intake does not suppress circulating 1,25-dihydroxyvitamin D in normocalcemic patients with sarcoidosis. J Clin Invest. 1993;91:1396–1398. [PMC free article] [PubMed] [Google Scholar]

346. Monkawa T, Yoshida T, Hayashi M, Saruta T. Identification of 25-hydroxyvitamin D3 1α-hydroxylase gene expression‎ in macrophages. Kidney Int. 2000;58:559–568. [PubMed] [Google Scholar]

347. Vidal M, Ramana CV, Dusso AS. Stat1-vitamin D receptor interactions antagonize 1,25-dihydroxyvitamin D transcriptional activity and enhance stat1-mediated transcription. Mol Cell Biol. 2002;22:2777–2787. [PMC free article] [PubMed] [Google Scholar]

348. Lieberman J. Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis. Am J Med. 1975;59:365–372. [PubMed] [Google Scholar]

349. Ashutosh K, Keighley JF. Diagnostic value of serum angiotensin converting enzyme activity in lung diseases. Thorax. 1976;31:552–557. [PMC free article] [PubMed] [Google Scholar]

350. Friedland J, Silverstein E. Similarity in some properties of serum angiotensin converting enzyme from sarcoidosis patients and normal subjects. Biochem Med. 1976;15:178–185. [PubMed] [Google Scholar]

351. Lieberman J. The specificity and nature of serum-angiotensin-converting enzyme (serum ACE) elevations in sarcoidosis. Ann NY Acad Sci. 1976;278:488–497. [PubMed] [Google Scholar]

352. Silverstein E, Friedland J, Lyons HA, Gourin A. Elevation of angiotensin-converting enzyme in granulomatous lymph nodes and serum in sarcoidosis: clinical and possible pathogenic significance. Ann NY Acad Sci. 1976;278:498–513. [PubMed] [Google Scholar]

353. Lieberman J, Rea TH. Serum angiotensin-converting enzyme in leprosy and coccidioidomycosis. Ann Intern Med. 1977;87:423–425. [PubMed] [Google Scholar]

354. Davies SF, Rohrbach MS, Thelen V, et al. Elevated serum angiotensin-converting enzyme (SACE) activity in acute pulmonary histoplasmosis. Chest. 1984;85:307–310. [PubMed] [Google Scholar]

355. Adams JS, Gacad MA, Anders A, Endres DB, Sharma OP. Biochemical indicators of disordered vitamin D and calcium homeostasis in sarcoidosis. Sarcoidosis. 1986;3:1–6. [PubMed] [Google Scholar]

356. Insogna KL, Dreyer BE, Mitnick M, Ellison AF, Broadus AE. Enhanced production rate of 1,25-dihydroxyvitamin D in sarcoidosis. J Clin Endocrinol Metab. 1988;66:72–75. [PubMed] [Google Scholar]

357. Johns CJ, Michele TM. The clinical management of sarcoidosis. A 50-year experience at the Johns Hopkins Hospital. Medicine (Baltimore). 1999;78:65–111. [PubMed] [Google Scholar]

358. Paramothayan S, Jones PW. Corticosteroid therapy in pulmonary sarcoidosis: a systematic review. JAMA. 2002;287:1301–1307. [PubMed] [Google Scholar]

359. Glass AR, Eil C. Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D. J Clin Endocrinol Metab. 1986;63:766–769. [PubMed] [Google Scholar]

360. Glass AR, Eil C. Ketoconazole-induced reduction in serum 1,25-dihydroxyvitamin D and total serum calcium in hypercalcemic patients. J Clin Endocrinol Metab. 1988;66:934–938. [PubMed] [Google Scholar]

361. Adams JS, Sharma OP, Diz MM, Endres DB. Ketoconazole decreases the serum 1,25-dihydroxyvitamin D and calcium concentration in sarcoidosis-associated hypercalcemia. J Clin Endocrinol Metab. 1990;70:1090–1095. [PubMed] [Google Scholar]

362. Glass AR, Cerletty JM, Elliott W, Lemann J, Jr, Gray RW, Eil C. Ketoconazole reduces elevated serum levels of 1,25-dihydroxyvitamin D in hypercalcemic sarcoidosis. J Endocrinol Invest. 1990;13:407–413. [PubMed] [Google Scholar]

363. Bia MJ, Insogna K. Treatment of sarcoidosis-associated hypercalcemia with ketoconazole. Am J Kidney Dis. 1991;18:702–705. [PubMed] [Google Scholar]

364. Conron M, Beynon HL. Ketoconazole for the treatment of refractory hypercalcemic sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2000;17:277–280. [PubMed] [Google Scholar]

365. Sharma OP. Hypercalcemia in granulomatous disorders: a clinical review. Curr Opin Pulm Med. 2000;6:442–447. [PubMed] [Google Scholar]

366. Tan TT, Lee BC, Khalid BA. Low incidence of hypercalcaemia in tuberculosis in Malaysia. J Trop Med Hyg. 1993;96:349–351. [PubMed] [Google Scholar]

367. Sharma SC. Serum calcium in pulmonary tuberculosis. Postgrad Med J. 1981;57:694–696. [PMC free article] [PubMed] [Google Scholar]

368. Chan TY, Chan CH, Shek CC. The preval‎ence of hypercalcaemia in pulmonary and miliary tuberculosis–a longitudinal study. Singapore Med J. 1994;35:613–615. [PubMed] [Google Scholar]

369. Abbasi AA, Chemplavil JK, Farah S, Muller BF, Arnstein AR. Hypercalcemia in active pulmonary tuberculosis. Ann Intern Med. 1979;90:324–328. [PubMed] [Google Scholar]

370. Lind L, Ljunghall S. Hypercalcemia in pulmonary tuberculosis. Ups J Med Sci. 1990;95:157–160. [PubMed] [Google Scholar]

371. Roussos A, Lagogianni I, Gonis A, et al. Hypercalcaemia in Greek patients with tuberculosis before the initiation of anti-tuberculosis treatment. Respir Med. 2001;95:187–190. [PubMed] [Google Scholar]

372. Brodie MJ, Boobis AR, Hillyard CJ, Abeyasekera G, MacIntyre I, Park BK. Effect of isoniazid on vitamin D metabolism and hepatic monooxygenase activity. Clin Pharmacol Ther. 1981;30:363–367. [PubMed] [Google Scholar]

373. Pascussi JM, Robert A, Nguyen M, et al. Possible involvement of pregnane X receptor-enhanced CYP24 expression‎ in drug-induced osteomalacia. J Clin Invest. 2005;115:177–186. [PMC free article] [PubMed] [Google Scholar]

374. Wang Z, Lin YS, Dickmann LJ, et al. Enhancement of hepatic 4-hydroxylation of 25-hydroxyvitamin D3 through CYP3A4 induction in vitro and in vivo: implications for drug-induced osteomalacia. J Bone Miner Res. 2013;28:1101–1116. [PMC free article] [PubMed] [Google Scholar]

375. Wang Z, Lin YS, Zheng XE, et al. An inducible cytochrome P450 3A4-dependent vitamin D catabolic pathway. Mol Pharmacol. 2012;81:498–509. [PMC free article] [PubMed] [Google Scholar]

376. Wang Z, Wong T, Hashizume T, et al. Human UGT1A4 and UGT1A3 conjugate 25-hydroxyvitamin D3: metabolite structure, kinetics, inducibility, and interindividual variability. Endocrinology. 2014;155:2052–2063. [PMC free article] [PubMed] [Google Scholar]

377. Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ. 1,25(OH)2D2 Production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest. 1990;85:1588–1593. [PMC free article] [PubMed] [Google Scholar]

378. Cadranel JL, Garabédian M, Milleron B, et al. Vitamin D metabolism by alveolar immune cells in tuberculosis: correlation with calcium metabolism and clinical manifestations. Eur Respir J. 1994;7:1103–1110. [PubMed] [Google Scholar]

379. Adams JS, Hewison M. Extrarenal expression‎ of the 25-hydroxyvitamin D-1-hydroxylase. Arch Biochem Biophys. 2012;523:95–102. [PMC free article] [PubMed] [Google Scholar]

380. Adams JS, Modlin RL, Diz MM, Barnes PF. Potentiation of the macrophage 25-hydroxyvitamin D-1-hydroxylation reaction by human tuberculous pleural effusion fluid. J Clin Endocrinol Metab. 1989;69:457–460. [PubMed] [Google Scholar]

381. Barnes PF, Modlin RL, Bikle DD, Adams JS. Transpleural gradient of 1,25-dihydroxyvitamin D in tuberculous pleuritis. J Clin Invest. 1989;83:1527–1532. [PMC free article] [PubMed] [Google Scholar]

382. Liu PT, Stenger S, Li H, et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311:1770–1773. [PubMed] [Google Scholar]

383. Martineau AR, Wilkinson KA, Newton SM, et al. IFN-γ- and TNF-independent vitamin D-inducible human suppression of mycobacteria: the role of cathelicidin LL-37. J Immunol. 2007;178:7190–7198. [PubMed] [Google Scholar]

384. Saggese G, Bertelloni S, Baroncelli GI, Di Nero G. Ketoconazole decreases the serum ionized calcium and 1,25-dihydroxyvitamin D levels in tuberculosis-associated hypercalcemia. Am J Dis Child. 1993;147:270–273. [PubMed] [Google Scholar]

385. Ryzen E, Singer FR. Hypercalcemia in leprosy. Arch Intern Med. 1985;145:1305–1306. [PubMed] [Google Scholar]

386. Hoffman VN, Korzeniowski OM. Leprosy, hypercalcemia, and elevated serum calcitriol levels. Ann Intern Med. 1986;105:890–891. [PubMed] [Google Scholar]

387. Fraser AG, Croxson MS, Ellis-Pegler RB. Hypercalcaemia and elevated 1,25-dihydroxy-vitamin D3 levels in a patient with multibacillary leprosy and a type I leprosy reaction. N Z Med J. 1987;100:86. [PubMed] [Google Scholar]

388. Ryzen E, Rea TH, Singer FR. Hypercalcemia and abnormal 1,25-dihydroxyvitamin D concentrations in leprosy. Am J Med. 1988;84:325–329. [PubMed] [Google Scholar]

389. Couri CE, Foss NT, Dos Santos CS, de Paula FJ. Hypercalcemia secondary to leprosy. Am J Med Sci. 2004;328:357–359. [PubMed] [Google Scholar]

390. Delahunt JW, Romeril KE. Hypercalcemia in a patient with the acquired immunodeficiency syndrome and Mycobacterium avium intracellulare infection. J Acquir Immune Defic Syndr. 1994;7:871–872. [PubMed] [Google Scholar]

391. Newell A, Nelson MR. Hypercalcaemia in a patient with AIDS and Mycobacterium avium intracellulare infection. Int J STD AIDS. 1997;8:405. [PubMed] [Google Scholar]

392. Playford EG, Bansal AS, Looke DF, Whitby M, Hogan PG. Hypercalcaemia and elevated 1,25(OH)(2)D(3) levels associated with disseminated Mycobacterium avium infection in AIDS. J Infect. 2001;42:157–158. [PubMed] [Google Scholar]

393. Choudhary M, Rose F. Posterior reversible encephalopathic syndrome due to severe hypercalcemia in AIDS. Scand J Infect Dis. 2005;37:524–526. [PubMed] [Google Scholar]

394. Lavae-Mokhtari M, Mohammad-Khani S, Schmidt RE, Stoll M. Acute renal failure and hypercalcemia in an AIDS patient on tenofovir and low-dose vitamin D therapy with immune reconstitution inflammatory syndrome[in German]. Med Klin (Munich). 2009;104:810–813. [PubMed] [Google Scholar]

395. Shrayyef MZ, DePapp Z, Cave WT, Wittlin SD. Hypercalcemia in two patients with sarcoidosis and Mycobacterium avium intracellulare not mediated by elevated vitamin D metabolites. Am J Med Sci. 2011;342:336–340. [PubMed] [Google Scholar]

396. Schattner A, Gilad A, Cohen J. Systemic granulomatosis and hypercalcaemia following intravesical bacillus Calmette-Guérin immunotherapy. J Intern Med. 2002;251:272–277. [PubMed] [Google Scholar]

397. Kojmane W, Chaouki S, Souilmi FZ, et al. Hypercalcemia complicating BCG lymphadenitis: case report [in French]. Arch Pediatr. 2015;22:276–278. [PubMed] [Google Scholar]

398. Murray JJ, Heim CR. Hypercalcemia in disseminated histoplasmosis. Aggravation by vitamin D. Am J Med. 1985;78:881–884. [PubMed] [Google Scholar]

399. Liu JW, Huang TC, Lu YC, et al. Acute disseminated histoplasmosis complicated with hypercalcaemia. J Infect. 1999;39:88–90. [PubMed] [Google Scholar]

400. Gupta V, Singhal V, Singh MK, Xess I, Ramam M. Disseminated histoplasmosis with hypercalcemia. J Am Acad Dermatol. 2013;69:e250–e251. [PubMed] [Google Scholar]

401. Khasawneh FA, Ahmed S, Halloush RA. Progressive disseminated histoplasmosis presenting with cachexia and hypercalcemia. Int J Gen Med. 2013;6:79–83. [PMC free article] [PubMed] [Google Scholar]

402. Kantarjian HM, Saad MF, Estey EH, Sellin RV, Samaan NA. Hypercalcemia in disseminated candidiasis. Am J Med. 1983;74:721–724. [PubMed] [Google Scholar]

403. Lee JC, Catanzaro A, Parthemore JG, Roach B, Deftos LJ. Hypercalcemia in disseminated coccidioidomycosis. N Engl J Med. 1977;297:431–433. [PubMed] [Google Scholar]

404. Rosen MJ. Hypercalcemia in coccidioidomycosis. N Engl J Med. 1977;297:1355. [PubMed] [Google Scholar]

405. Walter RM, Jr, Lawrence RM. Total ionized serum calcium and parathyroid hormone levels in patients with disseminated coccidioidomycosis. Am J Med Sci. 1981;281:97–99. [PubMed] [Google Scholar]

406. Parker MS, Dokoh S, Woolfenden JM, Buchsbaum HW. Hypercalcemia in coccidioidomycosis. Am J Med. 1984;76:341–344. [PubMed] [Google Scholar]

407. Westphal SA. Disseminated coccidioidomycosis associated with hypercalcemia. Mayo Clin Proc. 1998;73:893–894. [PubMed] [Google Scholar]

408. Ali MY, Gopal KV, Llerena LA, Taylor HC. Hypercalcemia associated with infection by Cryptococcus neoformans and Coccidioides immitis. Am J Med Sci. 1999;318:419–423. [PubMed] [Google Scholar]

409. Caldwell JW, Arsura EL, Kilgore WB, Reddy CM, Johnson RH. Hypercalcemia in patients with disseminated coccidioidomycosis. Am J Med Sci. 2004;327:15–18. [PubMed] [Google Scholar]

410. Silva LC, Ferrari TC. Hypercalcaemia and paracoccidioidomycosis. Trans R Soc Trop Med Hyg. 1998;92:187. [PubMed] [Google Scholar]

411. Almeida RM, Cezana L, Tsukumo DM, de Carvalho-Filho MA, Saad MJ. Hypercalcemia in a patient with disseminated paracoccidioidomycosis: a case report. J Med Case Rep. 2008;2:262. [PMC free article] [PubMed] [Google Scholar]

412. Bosch X. Hypercalcemia due to endogenous overproduction of active vitamin D in identical twins with cat-scratch disease. JAMA. 1998;279:532–534. [PubMed] [Google Scholar]

413. Ahmed B, Jaspan JB. Case report: hypercalcemia in a patient with AIDS and Pneumocystis carinii pneumonia. Am J Med Sci. 1993;306:313–316. [PubMed] [Google Scholar]

414. Bency R, Roger SD, Elder GJ. Hypercalcaemia as a prodromal feature of indolent Pneumocystis jivorecii after renal transplantation. Nephrol Dial Transplant. 2011;26:1740–1742. [PubMed] [Google Scholar]

415. Chen WC, Chang SC, Wu TH, Yang WC, Tarng DC. Hypercalcemia in a renal transplant recipient suffering with Pneumocystis carinii pneumonia. Am J Kidney Dis. 2002;39:E8. [PubMed] [Google Scholar]

416. Hung YM. Pneumocystis carinii pneumonia with hypercalcemia and suppressed parathyroid hormone levels in a renal transplant patient. Transplantation. 2006;81:639. [PubMed] [Google Scholar]

417. Mills AK, Wright SJ, Taylor KM, McCormack JG. Hypercalcaemia caused by Pneumocystis carinii pneumonia while in leukaemic remission. Aust N Z J Med. 1999;29:102–103. [PubMed] [Google Scholar]

418. Shaker JL, Redlin KC, Warren GV, Findling JW. Case report: hypercalcemia with inappropriate 1,25-dihydroxyvitamin D in Wegener's granulomatosis. Am J Med Sci. 1994;308:115–118. [PubMed] [Google Scholar]

419. Bosch X. Hypercalcemia due to endogenous overproduction of 1,25-dihydroxyvitamin D in Crohn's disease. Gastroenterology. 1998;114:1061–1065. [PubMed] [Google Scholar]

420. Tuohy KA, Steinman TI. Hypercalcemia due to excess 1,25-dihydroxyvitamin D in Crohn's disease. Am J Kidney Dis. 2005;45:e3–e6. [PubMed] [Google Scholar]

421. Zemrak F, McNeil L, Peden N. Rennies, Crohn's disease and severe hypercalcaemia. BMJ Case Rep. 2010;2010. [PMC free article] [PubMed] [Google Scholar]

422. Wilkerson JA. Idiopathic infantile hypercalcemia, with subcutaneous fat necrosis. Am J Clin Pathol. 1964;41:390–401. [PubMed] [Google Scholar]

423. Veldhuis JD, Kulin HE, Demers LM, Lambert PW. Infantile hypercalcemia with subcutaneous fat necrosis: endocrine studies. J Pediatr. 1979;95:460–462. [PubMed] [Google Scholar]

424. Kallas M, Green F, Hewison M, White C, Kline G. Rare causes of calcitriol-mediated hypercalcemia: a case report and literature review. J Clin Endocrinol Metab. 2010;95:3111–3117. [PubMed] [Google Scholar]

425. Rossman MD. Chronic beryllium disease: diagnosis and management. Environ Health Perspect. 1996;104(suppl 5):945–947. [PMC free article] [PubMed] [Google Scholar]

426. Kozeny GA, Barbato AL, Bansal VK, Vertuno LL, Hano JE. Hypercalcemia associated with silicone-induced granulomas. N Engl J Med. 1984;311:1103–1105. [PubMed] [Google Scholar]

427. Altmann P, Dodd S, Williams A, Marsh F, Cunningham J. Silicone-induced hypercalcaemia in haemodialysis patients. Nephrol Dial Transplant. 1987;2:26–29. [PubMed] [Google Scholar]

428. Agrawal N, Altiner S, Mezitis NH, Helbig S. Silicone-induced granuloma after injection for cosmetic purposes: a rare entity of calcitriol-mediated hypercalcemia. Case Rep Med. 2013;2013:807292. [PMC free article] [PubMed] [Google Scholar]

429. Albitar S, Genin R, Fen-Chong M, et al. Multisystem granulomatous injuries 28 years after paraffin injections. Nephrol Dial Transplant. 1997;12:1974–1976. [PubMed] [Google Scholar]

430. Gyldenløve M, Rørvig S, Skov L, Hansen D. Severe hypercalcaemia, nephrocalcinosis, and multiple paraffinomas caused by paraffin oil injections in a young bodybuilder. Lancet. 2014;383:2098. [PubMed] [Google Scholar]

431. Woywodt A, Schneider W, Goebel U, Luft FC. Hypercalcemia due to talc granulomatosis. Chest. 2000;117:1195–1196. [PubMed] [Google Scholar]

432. Sargent JT, Smith OP. Haematological emergencies managing hypercalcaemia in adults and children with haematological disorders. Br J Haematol. 2010;149:465–477. [PubMed] [Google Scholar]

433. Burt ME, Brennan MF. Incidence of hypercalcemia and malignant neoplasm. Arch Surg. 1980;115:704–707. [PubMed] [Google Scholar]

434. Seymour JF, Gagel RF. Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin's disease and non-Hodgkin's lymphomas. Blood. 1993;82:1383–1394. [PubMed] [Google Scholar]

435. Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA, Cabanillas F. Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma. Ann Intern Med. 1994;121:633–640. [PubMed] [Google Scholar]

436. Majumdar G. Incidence and prognostic significance of hypercalcaemia in B-cell non-Hodgkin's lymphoma. J Clin Pathol. 2002;55:637–638. [PMC free article] [PubMed] [Google Scholar]

437. Breslau NA, McGuire JL, Zerwekh JE, Frenkel EP, Pak CY. Hypercalcemia associated with increased serum calcitriol levels in three patients with lymphoma. Ann Intern Med. 1984;100:1–6. [PubMed] [Google Scholar]

438. Mudde AH, van den Berg H, Boshuis PG, et al. Ectopic production of 1,25-dihydroxyvitamin D by B-cell lymphoma as a cause of hypercalcemia. Cancer. 1987;59:1543–1546. [PubMed] [Google Scholar]

439. Kiyokawa T, Yamaguchi K, Takeya M, et al. Hypercalcemia and osteoclast proliferation in adult T-cell leukemia. Cancer. 1987;59:1187–1191. [PubMed] [Google Scholar]

440. Matutes E. Adult T-cell leukaemia/lymphoma. J Clin Pathol. 2007;60:1373–1377. [PMC free article] [PubMed] [Google Scholar]

441. Chiba K, Hashino S, Izumiyama K, et al. Multiple osteolytic bone lesions with high serum levels of interleukin-6 and CCL chemokines in a patient with adult T cell leukemia. Int J Lab Hematol. 2009;31:368–371. [PubMed] [Google Scholar]

442. Nosaka K, Miyamoto T, Sakai T, Mitsuya H, Suda T, Matsuoka M. Mechanism of hypercalcemia in adult T-cell leukemia: overexpression‎ of receptor activator of nuclear factor κB ligand on adult T-cell leukemia cells. Blood. 2002;99:634–640. [PubMed] [Google Scholar]

443. Okada Y, Tsukada J, Nakano K, Tonai S, Mine S, Tanaka Y. Macrophage inflammatory protein-1α induces hypercalcemia in adult T-cell leukemia. J Bone Miner Res. 2004;19:1105–1111. [PubMed] [Google Scholar]

444. Ejima E, Rosenblatt JD, Massari M, et al. Cell-type-specific transactivation of the parathyroid hormone-related protein gene promoter by the human T-cell leukemia virus type I (HTLV-I) tax and HTLV-II tax proteins. Blood. 1993;81:1017–1024. [PubMed] [Google Scholar]

445. Honda S, Yamaguchi K, Miyake Y, et al. Production of parathyroid hormone-related protein in adult T-cell leukemia cells. Jpn J Cancer Res. 1988;79:1264–1268. [PMC free article] [PubMed] [Google Scholar]

446. Imamura H, Koreeda Y, Okadome T, et al. Urinary excretion of parathyroid hormone-related protein as a predictor of hypercalcemia in patients with adult T-cell leukemia. Jpn J Clin Oncol. 1992;22:325–330. [PubMed] [Google Scholar]

447. Peter SA, Cervantes JF. Hypercalcemia associated with adult T-cell leukemia/lymphoma (ATL). J Natl Med Assoc. 1995;87:746–748. [PMC free article] [PubMed] [Google Scholar]

448. Prager D, Rosenblatt JD, Ejima E. Hypercalcemia, parathyroid hormone-related protein expression‎ and human T-cell leukemia virus infection. Leuk Lymphoma. 1994;14:395–400. [PubMed] [Google Scholar]

449. Ruddle NH, Li CB, Horne WC, et al. Mice transgenic for HTLV-I LTR-tax exhibit tax expression‎ in bone, skeletal alterations, and high bone turnover. Virology. 1993;197:196–204. [PubMed] [Google Scholar]

450. Watanabe T, Yamaguchi K, Takatsuki K, Osame M, Yoshida M. Constitutive expression‎ of parathyroid hormone-related protein gene in human T cell leukemia virus type 1 (HTLV-1) carriers and adult T cell leukemia patients that can be trans-activated by HTLV-1 tax gene. J Exp Med. 1990;172:759–765. [PMC free article] [PubMed] [Google Scholar]

451. Ikeda K, Okazaki R, Inoue D, Ohno H, Ogata E, Matsumoto T. Interleukin-2 increases production and secretion of parathyroid hormone-related peptide by human T cell leukemia virus type I-infected T cells: possible role in hypercalcemia associated with adult T cell leukemia. Endocrinology. 1993;132:2551–2556. [PubMed] [Google Scholar]

452. Bellon M, Ko NL, Lee MJ, et al. Adult T-cell leukemia cells overexpress Wnt5a and promote osteoclast differentiation. Blood. 2013;121:5045–5054. [PMC free article] [PubMed] [Google Scholar]

453. Polakowski N, Gregory H, Mesnard JM, Lemasson I. Expression‎ of a protein involved in bone resorption, Dkk1, is activated by HTLV-1 bZIP factor through its activation domain. Retrovirology. 2010;7:61. [PMC free article] [PubMed] [Google Scholar]

454. Shu ST, Martin CK, Thudi NK, Dirksen WP, Rosol TJ. Osteolytic bone resorption in adult T-cell leukemia/lymphoma. Leuk Lymphoma. 2010;51:702–714. [PMC free article] [PubMed] [Google Scholar]

455. Cools M, Goemaere S, Baetens D, et al. Calcium and bone homeostasis in heterozygous carriers of CYP24A1 mutations: a cross-sectional study. Bone. 2015;81:89–96. [PubMed] [Google Scholar]

456. Dauber A, Nguyen TT, Sochett E, et al. Genetic defect in CYP24A1, the vitamin D 24-hydroxylase gene, in a patient with severe infantile hypercalcemia. J Clin Endocrinol Metab. 2012;97:E268–E274. [PMC free article] [PubMed] [Google Scholar]

457. Fencl F, Bláhová K, Schlingmann KP, Konrad M, Seeman T. Severe hypercalcemic crisis in an infant with idiopathic infantile hypercalcemia caused by mutation in CYP24A1 gene. Eur J Pediatr. 2013;172:45–49. [PubMed] [Google Scholar]

458. Shah AD, Hsiao EC, O'Donnell B, et al. Maternal hypercalcemia due to failure of 1,25-dihydroxyvitamin-D3 catabolism in a patient with CYP24A1 mutations. J Clin Endocrinol Metab. 2015;100:2832–2836. [PMC free article] [PubMed] [Google Scholar]

459. Tray KA, Laut J, Saidi A. Idiopathic infantile hypercalcemia, presenting in adulthood–no longer idiopathic nor infantile: two case reports and review. Conn Med. 2015;79:593–597. [PubMed] [Google Scholar]

460. Kumar R, Cohen WR, Silva P, Epstein FH. Elevated 1,25-dihydroxyvitamin D plasma levels in normal human pregnancy and lactation. J Clin Invest. 1979;63:342–344. [PMC free article] [PubMed] [Google Scholar]