Hypercalcemia / Hypocalcemia

Serum calcium exists in three forms: ionized (free, physiologically active — approximately 45%), protein-bound (primarily to albumin — approximately 40%), and complexed to anions (phosphate, citrate, bicarbonate — approximately 15%). Only ionized calcium is biologically active and regulated by PTH and vitamin D.

Total serum calcium measures all three forms together. Because approximately 40% is protein-bound to albumin, total calcium is significantly affected by albumin levels. In hypoalbuminemia, total calcium is falsely low — the ionized calcium may be normal. In hyperalbuminemia (rare, seen with dehydration or multiple myeloma with high protein), total calcium may be falsely elevated.

The corrected calcium formula: corrected calcium = measured total calcium + 0.8 × (4.0 − albumin in g/dL). This correction is an approximation — it is reasonably accurate when albumin is mildly to moderately low, but less reliable when albumin is very low (below 2 g/dL) or when acid-base disturbances are present. When in doubt, measure ionized calcium directly — it is not affected by albumin and is the definitive measure of physiologically active calcium.

Acid-base status affects ionized calcium independently of total calcium. Alkalosis increases calcium binding to albumin, reducing ionized calcium — this is why hyperventilation can cause tetany (respiratory alkalosis lowers ionized calcium). Acidosis decreases calcium binding, increasing ionized calcium. This is clinically important in patients with acid-base disturbances: total calcium and corrected calcium may not accurately reflect ionized calcium.

Primary hyperparathyroidism and malignancy account for approximately 90% of all hypercalcemia. The PTH level is the single most important test for distinguishing between them.

Primary hyperparathyroidism is the most common cause of hypercalcemia in outpatients. It is usually caused by a single parathyroid adenoma (80–85%), less commonly by parathyroid hyperplasia (15%), and rarely by parathyroid carcinoma (less than 1%). PTH is elevated or inappropriately normal (PTH should be suppressed when calcium is high — a "normal" PTH in the setting of hypercalcemia is abnormal). Most cases are asymptomatic and discovered incidentally on routine labs. Symptomatic primary hyperparathyroidism presents with the classic "bones, stones, groans, and psychic moans" — bone pain, nephrolithiasis, constipation/nausea, and neuropsychiatric symptoms.

Malignancy-associated hypercalcemia is the most common cause in hospitalized patients. It occurs through three mechanisms: PTHrP secretion (humoral hypercalcemia of malignancy — most common, associated with squamous cell carcinoma, renal cell carcinoma, breast cancer, bladder cancer), osteolytic metastases (bone destruction releasing calcium — breast cancer, multiple myeloma, lymphoma), and 1,25-OH vitamin D production by lymphoma cells. PTH is suppressed in malignancy-associated hypercalcemia — this is the key distinguishing feature from primary hyperparathyroidism.

Other causes of hypercalcemia include: granulomatous diseases (sarcoidosis, tuberculosis, histoplasmosis — macrophages produce 1,25-OH vitamin D; PTH is suppressed), vitamin D toxicity, thiazide diuretics (reduce renal calcium excretion), lithium (raises the PTH set point), immobilization (increased bone resorption), and milk-alkali syndrome (calcium carbonate supplementation with alkalosis).

The urgency of treatment depends on the severity of hypercalcemia and the presence of symptoms. Mild hypercalcemia (calcium below 12 mg/dL) without symptoms can often be managed with hydration and treatment of the underlying cause. Moderate hypercalcemia (12–14 mg/dL) requires more active management. Severe hypercalcemia (above 14 mg/dL) or any symptomatic hypercalcemia requires urgent treatment.

IV normal saline is the first-line treatment for acute symptomatic hypercalcemia. Volume expansion increases renal calcium excretion. Patients with hypercalcemia are typically volume-depleted (calcium causes nephrogenic diabetes insipidus and nausea/vomiting), and aggressive hydration (1–2 L/hour initially, then adjusted) is the cornerstone of acute management.

Bisphosphonates (zoledronic acid, pamidronate) are the most effective agents for reducing calcium in malignancy-associated hypercalcemia. They inhibit osteoclast-mediated bone resorption. The effect is delayed by 2–4 days and lasts 2–4 weeks. Zoledronic acid is more potent and longer-acting than pamidronate. Renal function must be checked before administration — bisphosphonates are nephrotoxic and require dose adjustment or avoidance in renal impairment.

Denosumab (RANKL inhibitor) is an alternative for malignancy-associated hypercalcemia, particularly when bisphosphonates are contraindicated due to renal impairment. Calcitonin provides rapid but short-lived calcium reduction (2–4 mg/dL within hours) and is useful as a bridge while waiting for bisphosphonate effect. Corticosteroids are effective for granulomatous disease and lymphoma (which produce 1,25-OH vitamin D) but not for primary hyperparathyroidism or most solid tumor hypercalcemia.

Hypocalcemia results from hypoparathyroidism, vitamin D deficiency, hypomagnesemia, or conditions that sequester calcium (pancreatitis, rhabdomyolysis, tumor lysis syndrome). The clinical presentation reflects neuromuscular irritability from reduced ionized calcium.

Symptoms of hypocalcemia range from mild (perioral numbness, paresthesias of the hands and feet, muscle cramps) to severe (tetany, laryngospasm, bronchospasm, seizures, cardiac arrhythmias). Chvostek's sign (facial muscle twitch with tapping over the facial nerve anterior to the ear) and Trousseau's sign (carpal spasm with blood pressure cuff inflated above systolic for 3 minutes) are clinical indicators of latent tetany from hypocalcemia.

Hypoparathyroidism is the most common cause of acute hypocalcemia in the postoperative setting. It occurs after thyroidectomy (inadvertent removal or devascularization of the parathyroid glands) or parathyroidectomy. Symptoms typically develop within 24–48 hours of surgery. Transient hypoparathyroidism is common after thyroidectomy; permanent hypoparathyroidism occurs in approximately 1–2% of total thyroidectomies.

Vitamin D deficiency is the most common cause of chronic hypocalcemia worldwide. It impairs intestinal calcium absorption, leading to secondary hyperparathyroidism (elevated PTH attempting to maintain calcium by increasing bone resorption and renal calcium reabsorption). The pattern: low or low-normal calcium, elevated PTH, low 25-OH vitamin D, low phosphate (PTH promotes renal phosphate excretion). Severe vitamin D deficiency causes osteomalacia (adults) or rickets (children).

Acute symptomatic hypocalcemia (tetany, laryngospasm, seizures, or cardiac arrhythmias) requires immediate IV calcium. Calcium gluconate (1–2 g IV over 10–20 minutes) is preferred over calcium chloride in peripheral IV lines because calcium chloride is more caustic and causes tissue necrosis with extravasation. Calcium chloride is appropriate for central line administration or in cardiac arrest.

After the acute bolus, a continuous calcium infusion is typically needed to maintain calcium while the underlying cause is addressed. Oral calcium supplementation and active vitamin D (calcitriol) are started as soon as the patient can take oral medications.

Chronic hypocalcemia from hypoparathyroidism is managed with oral calcium supplements and active vitamin D (calcitriol or alfacalcidol). PTH replacement (recombinant PTH 1-84, teriparatide) is available for patients with hypoparathyroidism who are difficult to control with calcium and vitamin D alone.

Hypomagnesemia causes refractory hypocalcemia by impairing PTH secretion and causing PTH resistance. Magnesium must be repleted before calcium repletion will be effective. This is a critical point: a patient with hypocalcemia that is not responding to calcium supplementation should have magnesium checked and repleted if low.

Bisphosphonates and denosumab can cause severe hypocalcemia — particularly in patients with vitamin D deficiency or renal impairment. Calcium and vitamin D should be supplemented before and during treatment with these agents. Patients receiving IV bisphosphonates for malignancy should have calcium and vitamin D levels checked before each infusion.