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Terra A Cederroth, Gary L Horowitz, Nicole V Tolan, Clinical Laboratory Investigation of a Patient with Extreme Hypercalcemia, Clinical Chemistry, Volume 63, Issue 2, 1 February 2017, Pages 459–462, https://doi.org/10.1373/clinchem.2016.261024
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CASE DESCRIPTION
A critical value for total calcium was reported on a 68-year-old female patient who was admitted to the emergency department 15 h prior. The patient's laboratory results were significant for a serum total calcium of 16.8 (8.4–10.3) mg/dL, which was verified by replicate analysis, and her free calcium concentration of 2.25 (1.12–1.32) mmol/L. The patient's serum phosphate was low at 0.5 (2.7–4.5) mg/dL, and her parathyroid hormone (PTH)2 was also suppressed at 6 (15–65) pg/mL. A review of the patient's medical records revealed a past medical history significant for hypertension, hyperlipidemia, and non–insulin-dependent diabetes mellitus. Her medication list included aspirin (81 mg daily), pravastatin (80 mg daily), and verapamil (120 mg daily).
Discussion
Calcium exists in 3 states: approximately 50% ionized, 40% protein-bound (primarily albumin), and the remaining 10% complexed with anions, such as sulfate or phosphate. The concentration of calcium distributed among these forms is dependent on the total calcium, the albumin concentration, and the plasma pH. The biologically active form, the free ionized fraction, is tightly regulated by the calcium-regulating hormones: PTH and 1,25-dihydroxyvitamin D (1). PTH directly increases calcium reabsorption in the distal nephron of the kidney through TRPV5 (transient receptor potential vanilloid 5) and also increases the expression of various calcium transport proteins. In response to increased PTH, 1α-hydroxylase in the kidney begins to convert the major reservoir of vitamin D, 25-hydroxyvitamin D, to the biologically active form, 1,25-dihydroxyvitamin D. The 1,25-dihydroxyvitamin D then stimulates calcium absorption in the small intestines through the VDR-RXR (vitamin D receptor-retinoic acid x-receptor complex) to enhance the expression of the epithelial calcium channels. Further, it is also recognized by its receptor in osteoblasts, increasing the expression of the RANKL (receptor activator of nuclear factor-kB ligand), which then induces proosteoclasts to develop to mature osteoclasts and induce bone resorption. Once adequate circulating free calcium is achieved, negative feedback to the parathyroid glands then reduces PTH synthesis. Calcitonin, secreted by the parafollicular cells of the thyroid gland, also acts on calcium concentrations to balance, and oppose, the effects of PTH.
