Hypercalcemia

Hypercalcemia is defined as a total corrected serum calcium over 2.6mmol/L or ionized calcium over 1.35mmol/L. The first step in the evaluation of a patient with hypercalcemia is to verify with repeat measurement (total calcium corrected for albumin) that there is a true increase in the serum calcium concentration. The next step is to measure parathyroid hormone (PTH). PTH is a polypeptide secreted by the parathyroid gland in response to low calcium levels detected in the blood. PTH facilitates the synthesis of active vitamin D and calcitriol (1,25-dihydroxycholecalciferol) in the kidneys, and also regulates calcium and phosphate. PTH effects are present in the bones, kidneys, and small intestines. As serum calcium levels drop, the secretion of PTH by the parathyroid gland increases. If serum calcium is elevated, as in hypercalcemia, the parathyroid glands should stop the release of PTH. 

Therefore, in hypercalcemia, we would expect PTH to be lower than its normal range of 10 to 65 ng/L. If serum PTH is found to be elevated in the context of hypercalcemia, this indicates that the problem is PTH-dependent, and we should investigate the parathyroid gland for hyperparathyroidism. The next step is to get a 24-hour urinary calcium excretion. If this 24-hour level is high, you can diagnose your patient with a primary hyperparathyroidism. If this 24-hour urine calcium is low, you can diagnose your patient with familial hypocalciuric hypercalcemia (FHH). Its also important to check if your patient is taking lithium, as this can cause hyperparathyroidism as well. 

If PTH is normal or low in the context of hypercalcemia, this is considered a PTH-independent cause of hypercalcemia, and nonparathyroid causes of hypercalcemia such as thyrotoxicosis and malignancy must be considered. In the presence of low serum PTH concentrations (<20 pg/mL), vitamin D metabolites and Parathyroid hormone related protein (PTHrP) should be measured (25(OH)D, 1,25-dihydroxyvitamin D, PTHrP). An elevated serum concentration of 25(OH)D is indicative of vitamin D intoxication due to the ingestion of either vitamin D or calcidiol itself. Increased levels of 1,25-dihydroxyvitamin D may be induced by direct intake of this metabolite, extrarenal production in granulomatous diseases or lymphoma, or increased renal production that can be induced by primary hyperparathyroidism but not by PTHrP. If both of these are not elevated, but PTHrP is, we need to evaluated for malignancy. Specifically, we would be concerned for multiple myeloma (a hematological malignancy of plasma cells). Presentation of multiple myeloma includes hypercalcemia, renal failure, anemia, and bone pain. To evaluate for multiple myeloma, you should order a CBC (to look for normocytic anemia), serum protein electrophoresis (to look for monoclonal expansion), serum free light chains, bone marrow biopsy, and urinalysis. 

Other investigations that should be ordered for hypercalcemia include vitamin D, phosphorus, albumin, and urinalysis. If bone pain is a presenting symptom, an MRI of the area inducing pain may be warranted.

The treatment of hypercalcemia is as follows: 1) discontinue oral calcium supplements, 2) hydration with intravenous normal saline, 3) consider furosemide, and 4) give bisphosphonates (Pamidronate 60-90 mg IV or zoledronate 4mg IV). For refractory patients, you can consider calcitonin. 

References:

1. Diagnostic approach to hypercalcemia - UptoDate

2. Treatment of hypercalcemia - UptoDate

3. Physiology, Parathyroid Hormone - NCBI

-KM