This patient most likely has hypercalcemia due to increased 1,25-dihydroxyvitamin D levels. She has an elevated calcium level with a low parathyroid hormone level, indicating non-parathyroid hormone (PTH)–mediated hypercalcemia. The differential diagnosis of non–PTH-mediated hypercalcemia includes cancer-related hypercalcemia caused by osteolytic lesions of bone, humorally mediated by tumor-secreted parathyroid hormone-related protein (PTHrP), or granulomatous diseases, such as sarcoidosis. In granulomatous diseases, the hydroxylase in disease-associated macrophages actively converts 25-hydroxyvitamin D to the highly active 1,25-dihydroxyvitamin D metabolite. The increased levels of active vitamin D lead to increased absorption of calcium in the gut, promotion of increased bone resorption of calcium, and decreased calcium and phosphate excretion by the kidney.
Elevated serum calcium can be due to a mutation in the G-coupled protein calcium–sensing receptor (CASR) gene. These receptors are in the parathyroid glands and the kidneys. The sensor mutation results in a shift upward in the “normal” range of calcium that the receptor recognizes, resulting in a mildly elevated serum calcium level (usually <11.0 mg/dL [2.7 mmol/L]) and high normal or mildly elevated PTH level, unlike this patient whose PTH level was low.
25-Hydroxyvitamin D is the major circulating form of vitamin D and is minimally metabolically active relative to 1,25-dihydroxyvitamin D. Levels in this patient are likely to be low due to excessive conversion to the 1,25-dihydroxyvitamin D form, and would not identify the likely mechanism of hypercalcemia in this patient.
Hydrochlorothiazide, a thiazide diuretic, reduces blood volume by acting on the kidneys to reduce sodium (Na+) reabsorption in the distal convoluted tubule. Thiazides increase the reabsorption of calcium in the distal convoluted tubule by their action on a Na+-Cl− calcium co-transporter. However, any increase in calcium caused by thiazides is mild and rarely reduces the PTH level below the lower range of normal.