Hypercalcemia

How calcium is controlled

The body holds about 1 kg of calcium, 99% of it in bones. Blood calcium is kept in a narrow range because it controls nerve signals, muscle contraction and heart rhythm. Three systems regulate it:

• Parathyroid hormone (PTH) from four rice-sized glands behind the thyroid raises calcium by releasing it from bone, reducing its loss in urine, and activating vitamin D.
• Active vitamin D (calcitriol) increases calcium absorption from the gut.
• The kidneys fine-tune how much is excreted.

Hypercalcemia occurs when calcium enters the blood from bone or gut faster than the kidneys can remove it.

Causes

PTH-driven (PTH high or inappropriately normal)

• Primary hyperparathyroidism: about 85% of cases are due to a single benign parathyroid adenoma, around 15% to enlargement of all four glands, and under 1% to parathyroid cancer. It affects about 1 in 100 adults over 60, mostly women.
• Tertiary hyperparathyroidism: after years of kidney failure, the glands become autonomous.
• Familial hypocalciuric hypercalcemia (FHH): an inherited, benign condition with low urine calcium that does not need surgery.
• Lithium treatment, which resets the parathyroid threshold.
• Inherited syndromes such as multiple endocrine neoplasia (MEN1 and MEN2A).

Non-PTH-driven (PTH low)

• Hypercalcemia of malignancy: occurs in up to 20 to 30% of people with cancer at some point. Mechanisms include a PTH-related protein (PTHrP) released by squamous cell lung, head and neck, kidney, bladder and breast cancers, bone destruction from metastases or multiple myeloma, and excess vitamin D production by some lymphomas.
• Vitamin D excess: high-dose supplements, or granulomatous diseases such as sarcoidosis and tuberculosis.
• Medicines: thiazide diuretics (which reduce urinary calcium loss), vitamin A and retinoids, theophylline, and excess calcium with antacids (milk-alkali syndrome).
• Immobilization, especially in adolescents and people with Paget's disease of bone.
• Hyperthyroidism, adrenal insufficiency and pheochromocytoma.

Symptoms

Mild hypercalcemia is frequently symptom-free. As levels rise:

• thirst, frequent urination and dehydration
• constipation, nausea, loss of appetite and abdominal pain
• fatigue, weakness, aches and low mood
• poor concentration and memory
• kidney stones
• bone pain and fractures
• confusion, drowsiness and coma at very high levels
• a short QT interval and arrhythmias on the ECG

For a practical guide to what a high result means and what to do next, see high blood calcium symptoms.

Diagnosis

1. Confirm the result: repeat total calcium with albumin, or measure ionized calcium.
2. Measure intact PTH: - High or normal PTH with high calcium points to primary hyperparathyroidism. - Low PTH points to cancer, vitamin D excess, or another non-parathyroid cause.
3. 24-hour urine calcium or the calcium-to-creatinine clearance ratio: very low values suggest FHH.
4. Further tests when PTH is low: PTHrP, 25-hydroxy and 1,25-dihydroxy vitamin D, serum and urine protein electrophoresis and free light chains (myeloma), chest X-ray or CT, and thyroid function.
5. When hyperparathyroidism is confirmed: bone density scan (DXA) including the forearm, kidney imaging for stones, kidney function, and imaging to locate the adenoma (neck ultrasound, sestamibi scan or 4D CT) before surgery.

Treatment

Severe or symptomatic hypercalcemia

This is usually managed in hospital:

• IV saline: the first step, to correct dehydration and help the kidneys excrete calcium.
• Calcitonin: lowers calcium within hours but its effect fades within 2 days. Used as a bridge.
• IV bisphosphonates (zoledronic acid or pamidronate): block bone breakdown. Calcium falls over 2 to 4 days and stays down for weeks.
• Denosumab: an alternative when kidney function is poor or bisphosphonates fail.
• Steroids: for vitamin D-driven causes such as sarcoidosis and some lymphomas.
• Dialysis: for very severe cases with kidney failure.
• Stop thiazides, lithium if possible, and calcium or vitamin D supplements.

Primary hyperparathyroidism

Parathyroidectomy is the only cure, with success rates around 95% in experienced hands, usually through a small neck incision. International guidelines recommend surgery for:

• calcium more than 1 mg/dL (0.25 mmol/L) above the upper limit of normal
• osteoporosis, a vertebral fracture, or kidney stones
• reduced kidney function or high urinary calcium
• age under 50
• symptoms

Surgery can also be offered to people outside these criteria who prefer it. People who do not have surgery are monitored with yearly calcium and kidney function and bone density every 1 to 2 years. Cinacalcet lowers calcium in those who cannot have surgery, and bisphosphonates protect bone.

Hypercalcemia of malignancy

Treatment combines fluids and bisphosphonates or denosumab with treatment of the cancer itself. Its appearance often signals advanced disease, so it is an important point to discuss treatment goals.

Self-care for mild hypercalcemia

• Drink 6 to 8 glasses of fluid a day unless told otherwise.
• Keep dietary calcium normal, about 1,000 to 1,200 mg a day. Restricting calcium can worsen bone loss.
• Keep vitamin D in the normal range, but avoid high-dose supplements.
• Stay physically active.
• Avoid thiazide diuretics and excess calcium-containing antacids.

Complications

• Kidney stones and calcium deposits in the kidneys (nephrocalcinosis)
• Chronic kidney disease
• Osteoporosis and fractures
• Pancreatitis and peptic ulcers
• Heart rhythm disturbances
• Hypercalcemic crisis: very high calcium causing dehydration, kidney failure, confusion and coma

Outlook

Primary hyperparathyroidism is cured in most people by surgery, after which bone density often improves and the kidney stone risk falls. Mild untreated cases can remain stable for years with monitoring. The outlook for hypercalcemia of malignancy depends on the cancer, but correcting the calcium relieves symptoms quickly.

Frequently asked questions

What is the most common cause of hypercalcemia?

Primary hyperparathyroidism is the most common cause in the general population, usually from a single benign parathyroid adenoma. Cancer is the most common cause in hospitalized patients. Together they cause about 90% of cases.

How is hypercalcemia treated?

It depends on the severity and cause. Severe cases need IV fluids, calcitonin and bisphosphonates or denosumab in hospital. Primary hyperparathyroidism is cured by removing the overactive gland. Medicines, supplements and underlying diseases are addressed where relevant.

What is hypercalcemia of malignancy?

It is high calcium caused by cancer, either through a PTH-like hormone (PTHrP) made by the tumor, destruction of bone by cancer spread or myeloma, or excess vitamin D from lymphoma. It usually develops quickly and causes noticeable symptoms.

Is hypercalcemia dangerous?

Mild hypercalcemia is not immediately dangerous but can damage bones and kidneys over years. Severe hypercalcemia can cause dehydration, kidney failure, heart rhythm problems, confusion and coma, and needs emergency treatment.

Can hypercalcemia be cured?

Often, yes. Parathyroid surgery cures most primary hyperparathyroidism. Stopping a causative medicine or supplement corrects drug-related cases. Hypercalcemia from cancer or sarcoidosis is controlled by treating the underlying disease.