HypercalcemiaEdit

Hypercalcemia is a metabolic disturbance defined by an elevated level of calcium in the blood. It can range from mild, with subtle symptoms, to severe, life-threatening states that require urgent evaluation and intervention. In clinical practice, the condition is most often caused by abnormal parathyroid activity or malignancy, with other, less common etiologies including excessive vitamin D, granulomatous diseases, certain medications, and prolonged immobilization. Identifying the underlying driver is essential, because treatment that targets the root cause is the best path to a durable correction of the calcium excess as well as prevention of organ injury.

Calcium homeostasis is a tightly regulated system in which the endocrine axis involving parathyroid hormone, vitamin D, and calcitonin coordinates intestinal absorption, renal excretion, and bone remodeling. When this balance is disrupted, extracellular calcium can rise, producing symptoms and potential complications. Understanding the regulatory network helps guide diagnostic workup and treatment decisions.

Pathophysiology

Hypercalcemia arises from increased bone resorption, increased intestinal calcium absorption, decreased renal excretion, or a combination of these. PTH plays a central role in most cases, either driving calcium release from bone or increasing renal reabsorption. When PTH is suppressed, other mechanisms such as cancer-related factors or vitamin D–mediated processes take on a dominant role. In some conditions, abnormal calcium handling reflects genetic variants that alter renal calcium sensing or bone metabolism.

Causes

Hypercalcemia can be categorized by whether it is driven by parathyroid hormone (PTH) or by other mechanisms.

PTH-dependent causes

Primary hyperparathyroidism, most commonly due to a parathyroid adenoma or hyperplasia, which elevates PTH and calcium.
Familial hypocalciuric hypercalcemia, a genetic disorder that shifts the set point for calcium sensing in the parathyroids and kidneys.

PTH-independent causes

Hypercalcemia of malignancy, either from secretion of PTH-related peptide (PTHrP) or from osteolytic metastases that release calcium from bone.
Vitamin D–mediated hypercalcemia, including vitamin D intoxication and granulomatous diseases such as sarcoidosis or certain infections that activate macrophages to produce active vitamin D.
Medication-related hypercalcemia, notably thiazide diuretics and certain other drugs such as lithium.
Immobilization, especially in the context of high bone turnover and limited physical activity.
Milk-alkali syndrome, resulting from excessive intake of calcium and absorbable alkali.
Less common causes include endocrinologic disorders, severe dehydration, and genetic disorders affecting bone or kidney handling of calcium.

Clinical features

Symptoms reflect the multisystem effects of elevated calcium and may include fatigue, malaise, polyuria, polydipsia, constipation, anorexia, and nausea. Neuropsychiatric symptoms range from mild confusion to obtundation or coma in severe cases. Cardiac manifestations can include shortened QT interval and arrhythmias. Gynecologic, renal, and musculoskeletal complaints may also occur, and long-standing hypercalcemia risks nephrolithiasis and nephrocalcinosis.

Diagnosis

Diagnosis starts with confirming elevated total serum calcium and then assessing albumin-corrected calcium or, when accurate assessment is needed, ionized calcium. The key step is measuring intact parathyroid hormone (PTH) to distinguish PTH-dependent from PTH-independent etiologies. A high or inappropriately normal PTH suggests a PTH-dependent cause, while a suppressed PTH points toward PTH-independent mechanisms such as malignancy or vitamin D–mediated processes.

Further laboratory evaluation typically includes: - Serum phosphate, which can aid in differentiating causes (for example, phosphate may be low in primary hyperparathyroidism and high or normal in other contexts). - 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels to assess vitamin D–mediated disease. - PTH-related peptide (PTHrP) measurement when malignancy is suspected. - Urine calcium excretion, to help distinguish familial forms from acquired conditions. - Renal function tests to assess kidney involvement. Imaging and targeted testing may follow, such as neck imaging for suspected parathyroid adenoma or bone imaging when malignancy is a concern.

Management

Acute management aims to restore intravascular volume and rapidly reduce calcium while addressing the underlying cause.

Hydration with normal saline is a foundational first step to correct volume depletion and promote calcium excretion.
Calcitonin can provide a quick but modest decrease in calcium, useful for rapid short-term control.
Bisphosphonates (for example, zoledronic acid or pamidronate) are the mainstay for sustained reduction of bone resorption, though their onset is slower than calcitonin.
Denosumab may be used in patients with bisphosphonate-refractory hypercalcemia or when there is significant renal insufficiency.
Treat underlying causes: surgical removal of a parathyroid adenoma for primary hyperparathyroidism; oncologic management for hypercalcemia of malignancy; reducing vitamin D intake or stopping offending medications when appropriate.

Longer-term management depends on the etiology: - For primary hyperparathyroidism, surgical cure is often definitive. - For familial hypocalciuric hypercalcemia, management is typically conservative, with monitoring, since surgery is not routinely beneficial. - In hypercalcemia of malignancy, prognosis depends on the cancer course and overall treatment goals.

Prognosis

The outlook for hypercalcemia depends heavily on the underlying cause and the rapidity of diagnosis and treatment. Mild cases with prompt correction and management of the primary disorder typically carry a favorable prognosis, whereas severe hypercalcemia due to aggressive malignancy or delayed treatment carries higher risk of organ dysfunction and mortality. Ongoing surveillance for recurrence or progression of the underlying condition is standard.

Epidemiology

Hypercalcemia is more common in older adults and tends to reflect the prevalence of the causes mentioned above, particularly primary hyperparathyroidism in outpatient settings and malignancy in inpatient contexts. The exact distribution of etiologies varies by population, access to healthcare, and local disease patterns.