Hypercalcemia and Primary Hyperparathyroidism

Hypercalcaemia is an elevation of serum calcium above the normal range. Its two most common causes are primary hyperparathyroidism, in which one or more parathyroid glands secrete excess parathyroid hormone autonomously, and malignancy. Together these account for the great majority of cases and illustrate how the calcium-regulating axis can fail.

Definition

Hypercalcaemia is a serum calcium concentration above the reference range; primary hyperparathyroidism is a disorder in which autonomous overproduction of parathyroid hormone, usually by a parathyroid adenoma, raises serum calcium and is the commonest cause of hypercalcaemia in ambulatory populations.

Scope

This entry describes hypercalcaemia and its leading cause, primary hyperparathyroidism: the disorders of the calcium axis that raise serum calcium, the distinction between parathyroid-hormone-driven and malignancy-related mechanisms, and the spectrum of clinical presentation. It is a reference account and does not provide diagnostic algorithms, surgical indications, or treatment instructions for individual patients.

Core questions

• What are the main causes of a high serum calcium?
• How does primary hyperparathyroidism disturb the calcium axis?
• How is parathyroid-hormone-driven hypercalcaemia distinguished from malignancy-related hypercalcaemia?
• What is the clinical spectrum of primary hyperparathyroidism?

Key concepts

• Serum calcium elevation
• Parathyroid adenoma
• Autonomous parathyroid hormone secretion
• Parathyroid-hormone-related protein (PTHrP)
• Humoral hypercalcaemia of malignancy
• Asymptomatic primary hyperparathyroidism
• Calcium-sensing receptor set point

Mechanisms

Normally, a rise in calcium suppresses parathyroid hormone secretion through the calcium-sensing receptor. In primary hyperparathyroidism this feedback is disrupted, most often by a benign parathyroid adenoma that secretes parathyroid hormone autonomously; the hormone raises serum calcium by increasing bone resorption, renal calcium reabsorption, and active vitamin D production, so calcium and parathyroid hormone are inappropriately high together. In malignancy-related hypercalcaemia the mechanism is usually humoral, driven by tumour secretion of parathyroid-hormone-related protein, which mimics parathyroid hormone at its receptor while the patient's own parathyroid hormone is appropriately suppressed; local osteolysis from bone metastases is another route. Measuring parathyroid hormone therefore separates the parathyroid-driven causes from the parathyroid-independent ones.

Clinical relevance

Hypercalcaemia ranges from an incidental biochemical finding to a medical emergency, and primary hyperparathyroidism is now often detected while asymptomatic. This entry frames the pathophysiology and causes for reference; it explains how the disorders are categorised and is not a guide to investigating or treating high calcium in any individual, which requires clinical assessment under current guidelines.

Epidemiology

Primary hyperparathyroidism is among the most common endocrine disorders and a leading cause of hypercalcaemia in outpatients, frequently presenting in a mild, asymptomatic form detected on routine biochemistry; malignancy is the predominant cause of hypercalcaemia among hospitalised patients (Walker & Silverberg, 2017; Stewart, 2005).

Evidence & guidelines

International workshop guidance addresses the evaluation and management of asymptomatic primary hyperparathyroidism (Bilezikian et al., 2014), and authoritative reviews describe the disorder and the mechanisms of malignancy-associated hypercalcaemia (Walker & Silverberg, 2017; Stewart, 2005). Specific operative and monitoring criteria are set by these sources and not reproduced here.

History

Primary hyperparathyroidism was historically a symptomatic disease of stones, bones, and overt skeletal disease. The widespread adoption of automated serum calcium measurement transformed its presentation, so that most cases are now identified incidentally and often asymptomatic, prompting successive international workshops to define how such patients should be evaluated. The identification of parathyroid-hormone-related protein clarified the mechanism of malignancy-related hypercalcaemia.

Debates

When should asymptomatic primary hyperparathyroidism be treated surgically versus monitored?

Because many patients are now detected without classic symptoms, the indications for parathyroidectomy versus observation are defined by consensus criteria that have been revised across successive international workshops and remain an area of ongoing refinement.

Key figures

• John Bilezikian
• Shonni Silverberg
• Andrew Stewart
• Marcella Walker

Seminal works

• walker-2017
• bilezikian-2014
• stewart-2005

Frequently asked questions

What are the two most common causes of a high serum calcium?

Primary hyperparathyroidism and malignancy account for most cases; primary hyperparathyroidism predominates in ambulatory patients, while malignancy is the leading cause in hospitalised patients.

How does measuring parathyroid hormone help distinguish the causes?

In primary hyperparathyroidism calcium and parathyroid hormone are both inappropriately high, whereas in malignancy-related hypercalcaemia the patient's own parathyroid hormone is suppressed because a tumour-derived protein is driving the calcium up instead.