Various vitamin D molecules (calciferols) exist, the two of principal importance being vitamin D3 and Vitamin D2. The major source of vitamin D is dermal synthesis of Vitamin D3, cholecalciferol, when exposed to ultraviolet light. Vitamin D3 also occurs in food and can be taken as a supplementary vitamin. In the non-hydroxylated form vitamin D3 is metabolically inactive. The first step towards activation takes place in the liver and is hydroxylation at position 25, this is followed by hydroxylation at position 1, which primarily takes place in the kidneys and is mediated by the enzyme 1α-hydroxylase. The activated vitamin D; 1,25-dihydroxy-vitamin D3 (=1,25-OH vitamin D3) is also called calcitriol [5].
Vitamin D2, ergocalciferol, (produced by some fungi) is of minor importance in humans if not consumed as a vitamin supplement. Figure 2 shows the synthesis of active vitamin D.
Both monohydroxylated vitamin D and dihydroxylated vitamin D bind to the vitamin D receptor (VDR) in the small intestines, kidneys and bones, but calcitriol binds with a much stronger affinity than the other metabolites [6]. Stimulation of the VDRs increases intestinal absorption and renal reabsorption of calcium and promotes mineralization of bone [7].
Most cases of TIH are caused by either HHM or osteolytic bone metastasis. In this patient, alkaline phosphatase was elevated but the patient was found to be without bone metastasis. HHM was dismissed by a negative blood test for PTHrP, and hyperparathyrodism from ectopic PTH production, a rare cause of hypercalcemia in cancer, was dismissed by decreased plasma PTH. In some cancers including multiple myeloma, breast cancer, prostate cancer, and renal carcinoma hypercalcemia may be induced by production of osteoclast-activating factors such as tumor necrosis factor alpha, interleukine 6, and receptor activator of nuclear factor-κB ligand (RANKL) [8, 9]. In our case, however, both the PET-CT and the absence of monoclonal protein in the blood ruled out these cancers.
Analysis of vitamin D subtypes revealed normal levels of both 25-OH Vitamin D2 and 25-OH Vitamin D3, whereas 1,25 OH Vitamin D3 (calcitriol) was elevated. Reasons for a picture with elevated calcitriol, normal 25-OH vitamin D, and minimally lowered PTH could be treatment with calcitriol (sometimes used in the treatment of parathyroid or kidney disease) or endogenous production of calcitriol. The patient, however, was not treated with calcitriol.
Extra-renal 1α-hydroxylase activity and autocrine/paracrine secretion of calcitriol have been detected in normal tissue (skin, breast, immune system, bone, and intestines) although activity of the enzyme is not sufficient to elevate calcitriol in the blood [6, 10].
Recently, most types of cancer tissue have been found to express autocrine/paracrine 1α-hydroxylase activity but it is not clear whether the aberrant regulation of the vitamin D system is a consequence of the malignant transformation or contributes to tumour development [11].
It is well-known that hypercalcemia caused by extra-renal 1α-hydroxylase activity may occur in patients suffering from lymphoma [12] and in patients with benign granulomatous diseases such as sarcoidosis [13]. Based on the clinical picture and laboratory investigations our patient was judged free from these diseases.
Elevated calcitriol as a stand-alone biochemical cause of hypercalcemia has only been reported in a few patients with solid cancers (other than lymphomas) [14–17]. Evans et al. analysed the expression of 1α-hydroxylase in tissue from 12 patients with dysgerminomas. They concluded that the enzyme was expressed by both tumour cells and macrophages associated with the tumour; the localised produced calcitriol eventually spilled over into the circulation causing hypercalcemia. The authors speculated if the high expression of 1α-hydroxylase in the tumour is part of the immune response [15].
In the present case, the fact that the hypercalcemia did not respond to treatment with inhibition of osteoclast activity by intravenous zoledronic acid, also indicates a non-bone related mechanism of TIH. In general glucocorticoid therapy is expected to lower the calcium levels within three to five days and it has previously been shown that glucocorticoids are specifically effective when treating calcitriol-induced hypercalcemia [18]. Hence, the insufficient response to oral glucocorticoid therapy five days after initiation is a surprising finding which could be caused by an insufficient oral dose of glucocorticoid. The conclusive treatment of the hypercalcemia appeared to be the tyrosine kinase inhibitor imatinib, which has previously proved effective in other cases of TIH in GIST [3, 19, 20]. One could speculate whether treatment with tyrosine kinase inhibitors is generally effective in critical TIH and should be tried when the standard treatment of hypercalcemia fails.
Regarding GIST, we have found only four reports on hypercalcemia. In two of the cases, the reason for hypercalcemia was not sought [19, 21], in one case hypercalcemia was found to be PTHrP-mediated [20], and in the last case hypercalcemia was found to be calcitriol-mediated (not secondary to elevated PTH or PTHrP) [3].
In our case, elevated calcitriol was the only identified reason for the hypercalcemia. We believe that GIST tumour cells or tumour-associated cells possessed 1α-hydroxylase activity causing elevated p-calcitriol and p-ionized calcium.
