The parathyroid glands typically lie adjacent to the thyroid gland, although they are occasionally located in the superior mediastinum.¹ Parathyroid glands regulate serum calcium in response to abnormal levels. When the extracellular calcium-sensing receptor (CASR) on parathyroid cells detects low serum calcium levels, one or more of the parathyroid glands release parathyroid hormone (PTH), an 84–amino acid peptide.¹ PTH stimulates osteoclasts to resorb bone and mobilize calcium into the blood, reduces renal calcium clearance, and stimulates intestinal calcium absorption through synthesis of 1,25-dihydroxyvitamin D (Figure 1).² Conversely, high calcium levels drive PTH suppression, with hypermagnesemia and 1,25-dihydroxyvitamin D also inhibiting the production and release of PTH. Parathyroid disorders can be primary or secondary.

Initial Approach to Calcium Abnormalities

Parathyroid disorders are most often identified incidentally by abnormalities in serum calcium levels when screening for renal or bone disease or other conditions.^1,3 Once a calcium abnormality has been identified, the evaluation should include a systematic search for signs and symptoms associated with abnormal calcium levels (Table 1).^1,2,4–6 A history should include dietary intake of calcium and phosphorus, medications that increase serum calcium levels (Table 2^1,2,4–6), supplements that contain calcium, and family history of endocrine disorders. A patient history of conditions such as fractures, pancreatitis, and nephrolithiasis may indicate or contribute to abnormal calcium levels.

Initial laboratory testing (Figure 2^1,2,4–6 and Figure 3^7–11) can be used to identify potential etiologies of parathyroid disorders that affect calcium levels. Primary hyperparathyroidism and malignancy are the most common causes of hypercalcemia.⁴ Additional causes are listed in Table 2.^1,2,4–6 Humoral hypercalcemia of malignancy, a paraneoplastic syndrome mediated by PTH-related peptide, should be considered in patients with low PTH levels, rapid onset of symptoms, and other signs and symptoms of malignancy (e.g., weight loss, fatigue, loss of appetite, night sweats). It is most often associated with squamous cell carcinoma and solid tumors of the lung, breast, esophagus, skin, cervix, and kidney.⁴ Vitamin D deficiency is the most common cause of hypocalcemia.⁵

Severe symptomatic hypercalcemia (serum calcium level greater than 14 mg per dL [3.50 mmol per L]) should be managed acutely with intravenous fluids, bisphosphonates, calcitonin, denosumab, or dialysis.⁶ Severe symptomatic hypocalcemia, which can present acutely with carpopedal spasm, tetany, seizures, and a prolonged QT interval, should be managed with intravenous calcium gluconate while the cause is being determined.¹²

Hyperparathyroidism

PRIMARY

Primary hyperparathyroidism is a common condition and the most common cause of hyperparathyroidism and mild hypercalcemia.^1,13 In primary hyperparathyroidism, calcium levels are usually elevated without appropriate suppression of PTH levels, which can be normal or high.¹³ However, in normocalcemic cases, calcium levels can be normal with elevated PTH levels, which may be encountered incidentally when screening for bone and renal disorders. In nations with readily accessible laboratory services, primary hyperparathyroidism is most often identified in asymptomatic individuals as an incidental finding of hypercalcemia on routine laboratory testing.