Hypercalcaemia

• Hypercalcaemia means too much calcium in the blood: an albumin-adjusted (corrected) serum calcium above 2.6 mmol/L, or a raised ionised (free) calcium on an assay that reports it directly.
• The commonest causes are primary hyperparathyroidism in outpatients and malignancy in hospital inpatients, often through parathyroid hormone-related peptide (PTHrP), bone metastases, myeloma or lymphoma.
• Calcium above 3.5 mmol/L is a medical emergency, with confusion, vomiting, kidney injury and a shortened QT interval that can provoke dangerous arrhythmias.
• The first step in almost every case is the same: restore the patient to a normal fluid volume with isotonic (0.9%) saline through a drip, then choose a specific drug for the cause. ^[2]
• The parathyroid hormone (PTH) level is the fork in the road: detectable or high PTH points to the parathyroid glands; a suppressed PTH points to everything else.

By the end of this page you should be able to:

1. Define hypercalcaemia in corrected and ionised terms, and correct a total calcium for albumin.
2. Explain normal calcium control by PTH and vitamin D, and why high calcium suppresses PTH.
3. List the causes in order of likelihood, and sort them by whether PTH is high, normal or suppressed.
4. Connect each symptom and sign to its mechanism (nephrogenic diabetes insipidus, bone resorption, short QT, gut effects).
5. Plan the investigations of hypercalcaemia, including the urine calcium to creatinine clearance ratio that separates primary hyperparathyroidism from familial hypocalciuric hypercalcaemia.
6. Manage severe hypercalcaemia step by step, with correct drug, dose, route and renal cautions, and outline when primary hyperparathyroidism is treated with parathyroid surgery.
7. Adjust the approach for a granulomatous disease, a vitamin D-mediated cause, and a low-resource setting.

Hypercalcaemia is one of the commonest electrolyte disorders a junior doctor meets: it accounts for roughly 0.6% of all acute medical admissions and has a prevalence of up to 1 in 1,000 in the general population.^[1] It is usually found by accident on a blood test, and the patient often feels well. Two causes dominate: primary hyperparathyroidism (PHPT), an overactive parathyroid gland, is the commonest outpatient cause and tends to be mild and chronic; malignancy-associated hypercalcaemia is the commonest inpatient cause, rises faster and can be severe.^[5] Many other causes exist and are missed unless you think of them. Every case starts with the same two questions: how high is the calcium, and what is the PTH doing? ^[4]

Most laboratories measure total calcium. About half of circulating calcium is bound to albumin and anions, and the other half is free and active (ionised). When albumin is low, total calcium looks normal or low even when the active fraction is high; when albumin is high (or a paraprotein is present), the opposite occurs. That is why every result must be corrected for albumin:

Adjusted calcium (mmol/L) = total calcium (mmol/L) + [(40 − albumin (g/L)) × 0.02]^[1][4]

So an albumin of 34 g/L instead of 40 g/L adds 0.12 mmol/L to the total calcium value. If ionised calcium can be measured directly, correction is not needed, and measurement of ionised calcium is preferable in patients with paraproteins (for example myeloma), which interfere with total calcium assays.^{[4] [1]}

A commonly used classification of hypercalcaemia of malignancy is: mild when serum calcium is below 3.0 mmol/L, moderate 3.0 to 3.5 mmol/L, and severe above 3.5 mmol/L.^[2] These bands come from studies of hypercalcaemia of malignancy, and a patient can be very unwell with a smaller rise if it has been rapid. In practice, treat the patient, not only the number. ^[1]

• Hypercalcaemia as a whole: up to 1 in 1,000 people in the general population, and about 0.6% of acute medical admissions.^[1]
• Primary hyperparathyroidism: occurs in roughly 1 in 500 to 1 in 1,000 people, is most frequent in the sixth decade, and is more common in women. It accounts for about 50 to 60% of outpatient hypercalcaemia.^[5]
• Malignancy-associated hypercalcaemia: occurs in 20 to 30% of cancers overall, up to 20% of all carcinoma patients at some point, and makes up most inpatient hypercalcaemia.^[5][1]
• One series of head and neck cancer patients and others notwithstanding, the general message is that severity and tempo differ: primary hyperparathyroidism is usually found on a routine screen, whereas malignancy is found in someone who is ill.

The practical split is PTH-dependent (a problem with the parathyroid glands) versus PTH-independent (everything else, which suppresses PTH). Primary hyperparathyroidism and malignancy together explain about 90% of cases.^[4]

Parathyroid (PTH high or inappropriately normal)

• Primary hyperparathyroidism: about 80 to 85% a single benign adenoma, under 1% parathyroid carcinoma, the rest multiple adenomata or four-gland hyperplasia.^[1]
• Tertiary hyperparathyroidism: long-standing secondary hyperparathyroidism (usually chronic kidney disease) that has become autonomous.
• Familial hypocalciuric hypercalcaemia (FHH): an autosomal dominant calcium-sensing receptor defect; lifelong, usually asymptomatic, with normal or mildly raised PTH and low urine calcium.^[1][5]
• Lithium therapy, which changes the calcium set point and can mimic or cause PHPT.^[1]

Malignancy (PTH suppressed)

• Humoral hypercalcaemia of malignancy through PTHrP (about 80% of malignancy-related cases): breast, lung, kidney, squamous and other solid cancers.^[1][2]
• Local osteolytic disease: extensive skeletal metastases and myeloma releasing cytokines that drive osteoclasts (about 20% of malignancy-related cases).^[2][5]
• Calcitriol-mediated disease: lymphomas and ovarian dysgerminomas expressing 1-alpha hydroxylase, which activates vitamin D.^[5]
• Very rare ectopic PTH secretion by a tumour.

Vitamin D and granulomatous (PTH suppressed)

• Excess vitamin D intake in any form, or topical calcipotriol.
• Granulomatous disease (sarcoidosis, tuberculosis, fungal infections, HIV/AIDS, Wegener granulomatosis and others) expressing 1-alpha hydroxylase and activating vitamin D.^[5]
• Hypercalcaemia may be the presenting feature of sarcoidosis.

Drugs (mostly PTH suppressed, lithium is an exception)

• Thiazide diuretics, by reducing urine calcium excretion.^[5]
• Lithium (see above).
• Poorly monitored alfacalcidol or calcitriol therapy.^[1]
• Excessive vitamin A (over 50,000 international units daily) and retinoic acid-containing regimens.^[5]
• Milk-alkali syndrome (large amounts of milk or calcium carbonate, usually with an antacid) with metabolic alkalosis and renal impairment.^[5]

Other endocrine and metabolic (PTH suppressed or variable)

• Thyrotoxicosis (mild hypercalcaemia in 15 to 20% of patients through accelerated bone resorption).^[5]
• Immobilisation, by increasing bone resorption, sometimes combined with Paget disease of bone.^[5]
• Untreated Addison disease, and pheochromocytoma.^[1]
• Acute kidney injury resolving after rhabdomyolysis, or secondary hyperparathyroidism after a kidney transplant.^[5]

Normal calcium is held in a narrow range (as corrected calcium) by three organs and two hormones. Parathyroid hormone (PTH), released when calcium falls, releases calcium from bone, reabsorbs it in the kidney and stimulates conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D, which increases gut absorption. Calcitonin has only a minor clinical role.

In hypercalcaemia the problem is one of three things: too much bone breakdown, too much absorption from the gut, or too little kidney excretion. PTH is usually suppressed by negative feedback. If PTH is detectable in the face of high calcium it is inappropriate: the parathyroid gland is running autonomously (PHPT) or the calcium signal is misread (FHH). That is why a random PTH is the single most useful test.

Symptoms arise from the high calcium itself: the kidney concentrates urine poorly (nephrogenic diabetes insipidus), causing polyuria, nocturia and thirst; cell membranes depolarise less easily, causing weakness, constipation and nausea; the cardiac action potential shortens, giving a shortened QT interval; bone turnover can be high. Prolonged high calcium also deposits in tissue: renal stones, nephrocalcinosis, valvular and vascular calcification.

Most patients are found incidentally and feel well. When symptoms appear they are classically grouped as moans, bones, stones and groans^[1]:

• Moans: low mood, anxiety, irritability, memory difficulty, apathy, insomnia and, at high levels, lethargy, confusion, stupor or coma.
• Bones: diffuse aches, proximal weakness, pathological fracture, and the rare but classic bone lesions of prolonged PHPT (resorption of distal clavicles, subperiosteal erosions, brown tumours). Most patients now have mild disease and these are rare.
• Stones: renal colic; nephrolithiasis or nephrocalcinosis in a proportion of those with chronic hypercalcaemia (polyuria and polydipsia affect about 20%).^[5]
• Groans: constipation, nausea, vomiting, anorexia, abdominal pain, severe and recurrent peptic ulcer disease, and acute pancreatitis (hypercalcaemia stimulates gastric acid and pancreatic enzyme secretion).^[5]
• Polyuria and polydipsia from nephrogenic diabetes insipidus; fatigue; weight loss with malignancy.
• Palpitations may occur, but QT shortening rarely produces arrhythmias on its own.

Severity rises with the level and the speed of rise: a chronic 2.8 mmol/L may cause only non-specific symptoms, whereas a rapid rise to the same level can be dramatic.

Physical findings are scant. Look for:

• Band keratopathy (a horizontal calcium band across the cornea in the exposed area, visible on slit-lamp) — rare.
• Findings of the underlying cause: a thyroid mass, lymph nodes, lung signs of sarcoidosis, stigmata of myeloma.
• Hypertension, arthralgia or pseudogout.
• Mild hypercalcaemia can shorten the QT interval on the ECG but does not usually trigger arrhythmias by itself. Cardiac arrest is a feature of hypercalcaemic crisis rather than of modest chronic elevation.

The differential is organised by the PTH result, which is the single most useful discriminator.

• PTH high or inappropriately normal: primary hyperparathyroidism, tertiary hyperparathyroidism, FHH, lithium effect.
• PTH suppressed: malignancy, granulomatous disease and vitamin D excess, thyrotoxicosis, milk-alkali syndrome, thiazides, immobilisation, adrenal insufficiency and the rest.

Two cautions. First, a result at the bottom of the reference range (roughly 1.6 to 6.9 pmol/L) is close to the detection limit of some assays, and may not be "appropriately suppressed": repeat it, discuss with the laboratory and investigate further if you are unsure.^[1] Second, PHPT and FHH can have indistinguishable serum biochemistry; the only reliable separator is urinary calcium, specifically the calcium to creatinine clearance ratio, which is under 0.01 in FHH and over 0.01 in PHPT.^[1] That distinction matters, because FHH does not need surgery. NICE guidance also lists three practical ways to measure urine calcium excretion: 24-hour urine calcium, random renal calcium to creatinine ratio, or random calcium to creatinine clearance ratio.^[3]

Clinical clues help before the results return: PHPT tends to be chronic, mild and asymptomatic, found on screening; malignancy is usually more abrupt, more severe and found in a patient with known or suspected cancer.^[4]

1. Repeat the corrected calcium at least once before concluding; if it is 2.6 mmol/L or higher on two separate occasions, PTH is measured.^[3]
2. PTH (random sample, with a concurrent corrected calcium).^[3]
3. Phosphate (often low in PHPT, variable in malignancy).
4. 25-hydroxyvitamin D, to detect toxicity and deficiency (deficiency is common in PHPT and should be corrected, carefully).^[1][3]
5. Urine calcium (24-hour excretion or calcium to creatinine ratio) if FHH is a possibility, especially with a family history or presentation under 45 years.^[3]
6. 1,25-dihydroxyvitamin D, only when the origin is unclear and increased conversion of 25-hydroxyvitamin D is suspected (for example granulomatous disease or lymphoma); there is no other routine clinical use for it.^[4]
7. Tests for malignancy when PTH is suppressed: erythrocyte sedimentation rate, immunoglobulins, serum and urine protein electrophoresis, serum free light chains, chest X-ray, liver function tests, bone scan, abdominal ultrasound, guided by symptoms and signs.^[1]
8. Tests for sarcoidosis if clinically suspected: chest X-ray, serum angiotensin-converting enzyme, 1,25-dihydroxyvitamin D and biopsy of appropriate tissue.^[1]
9. Other targeted tests: thyroid function for thyrotoxicosis, cortisol or ACTH stimulation for adrenal insufficiency, plasma metanephrines if hypertension suggests a pheochromocytoma, vitamin A level, serum and urine electrophoresis for myeloma.^[5]
10. Clinical thyroid, renal and bone assessment in PHPT: DXA scan of the lumbar spine, distal radius and hip; renal ultrasound; eGFR or creatinine; symptom and comorbidity review.^[3]
11. Genetic testing where PHPT presents before 45, is familial or multi-gland, or where an inherited endocrinopathy (MEN1, MEN2, MEN4, hyperparathyroidism-jaw tumour) is possible: up to 10% of PHPT presenting below 45 has an underlying genetic predisposition (nine potentially causative genes are recognised).^[1]
12. Parathyroid localisation (ultrasound, sestamibi, SPECT-CT with sensitivity up to 88%) only when surgery is planned; it does not confirm PHPT, it only finds the target gland.^[1]

The first intervention in every significantly hypercalcaemic patient is to restore them to euvolaemia. IV 0.9% saline at rates up to 500 mL/h may be required; fluid rates and the patient's cardiac and renal status govern how fast you can go.^[1][4] Three to six litres over 24 to 48 hours can lower calcium by 1 to 3 mg/dL.^[5] Less than 30% of patients become normocalcaemic with fluids alone, so fluids are the bridge, not the answer.^[4] Monitor intake and output, daily weight and for volume overload; if overload develops, stop the saline and use a loop diuretic. ^[2]

Important details:

• Loop diuretics (furosemide) are not routine treatment for hypercalcaemia and may worsen it if given before adequate hydration. They are best reserved for volume overload after hydration. Their direct calciuretic effect is expected only at doses above 100 mg per hour. Evidence that combining furosemide with saline lowers calcium is lacking.^[4][5]
• Check the PTH before giving bisphosphonates: bisphosphonates can alter serum PTH and give misleading results.^[4]
• Correct hypokalaemia, hypomagnesaemia and hypophosphataemia as they develop.
• Life-threatening hypercalcaemia is an indication for haemodialysis against a low-calcium (or calcium-free) bath, especially with renal or cardiac failure where hydration is impossible.^[4][5]
• Early or semi-urgent parathyroidectomy can be needed in severe PHPT, or in PHPT during the second trimester of pregnancy.^[4]

• Zoledronic acid is the bisphosphonate of choice. Standard dose: 4 mg IV infusion over 15 to 30 minutes, repeatable after 7 days if required and every 3 to 4 weeks thereafter. Renal function matters: many guidelines reduce the dose to 3 mg over 30 minutes at a creatinine clearance (CrCl) of 30 to 60 mL/min and avoid it below 30 mL/min, while the UK label allows the standard dose for tumour-induced hypercalcaemia until creatinine reaches about 400 micromol/L, so follow the local label.^[2] Zoledronic acid may have a lower relapse rate than other bisphosphonates.^{[4] [5]}
• Pamidronate is an alternative: 90 mg IV over 2 hours (60 mg over 4 hours if CrCl 30 to 60 mL/min; contraindicated if below 30 mL/min).^[2][5]
• Salmon calcitonin acts fast: 4 to 8 units/kg subcutaneously, repeated every 6 to 12 hours depending on the label or guideline (a fixed-dose schedule is also used) for 2 to 3 days, which can lower calcium by 0.25 to 0.5 mmol/L within hours; tachyphylaxis develops after 48 to 72 hours.^[2][5] Useful in severe disease, and when fluids cannot be given rapidly.
• Denosumab is a monoclonal antibody against RANK ligand: 120 mg subcutaneously, repeated after 1, 2 and 4 weeks and then monthly. It is suggested as first-line treatment ahead of IV bisphosphonates by the Endocrine Society for hypercalcaemia of malignancy, and normalised calcium in 67% of patients whose disease was refractory to bisphosphonates.^[2] It can be used in stage 4 to 5 chronic kidney disease (with a higher hypocalcaemia risk) and subcutaneously in the community. It is licensed for bisphosphonate-refractory hypercalcaemia but is off-label as first-line therapy, which patients should be told.^[2]
• Glucocorticoids for calcitriol-mediated disease (granulomatous disease and calcitriol-secreting lymphoma): prednisone 20 to 40 mg daily, reducing calcitriol production from activated mononuclear cells within about three days^[5], or a short course such as prednisolone 60 mg daily for 10 days, or hydrocortisone 200 to 400 mg daily for 3 to 5 days.^[2] If calcium remains inadequately controlled after glucocorticoids, add an IV bisphosphonate or denosumab.^[2]
• Cinacalcet (a calcimimetic acting on the calcium-sensing receptor) for parathyroid carcinoma or refractory primary hyperparathyroidism: start 30 mg twice daily, titrating to 90 mg three or four times daily; limited by nausea and vomiting.^[2][5]
• Dialysis is reserved for severe hypercalcaemia with renal or cardiac failure, as above.

Parathyroidectomy is the only curative treatment. All symptomatic patients should be considered for surgery.^[4] For asymptomatic disease, criteria differ between guideline groups, so state both rather than pretending one is universal:

• Fourth International Workshop (widely used): adjusted calcium more than 0.25 mmol/L above the upper limit of the reference range; age under 50; eGFR below 60 mL/min/1.73 m²; T-score below −2.5 at any DXA site (or previous fragility fracture); nephrolithiasis or nephrocalcinosis on imaging; 24-hour urine calcium above 10 mmol/day with an increased biochemical stone risk. Meeting one criterion is enough.^[1]
• NICE NG132: symptoms of hypercalcaemia (thirst, frequent or excessive urination, constipation); end-organ disease (renal stones, fragility fractures or osteoporosis); or an albumin-adjusted calcium of 2.85 mmol/L or higher.^[3]

Where surgery is not suitable or is declined, cinacalcet can be used (NICE: 2.85 mmol/L or higher with symptoms, or 3.0 mmol/L or higher with or without symptoms). Oral bisphosphonates may improve bone density but do not correct calcium or PTH in PHPT, and hypercalcaemia should not be managed long term with IV bisphosphonates. Conservative management is acceptable for many: vitamin D repletion carried out cautiously, annual calcium, annual eGFR, periodic DXA (every 2 to 3 years) and renal imaging, watch for progression. Oral bisphosphonates may be considered to reduce fracture risk where appropriate.^[3][1]

• After successful parathyroid surgery: annual corrected calcium.^[3]
• Without successful surgery: annual corrected calcium and eGFR, with DXA every 2 to 3 years and renal tract imaging when stones are suspected.^[3]
• With cinacalcet: monitor per the summary of product characteristics.

• Kidney: nephrolithiasis, nephrocalcinosis, polyuria and polydipsia, renal impairment, type 1 renal tubular acidosis promoting stones.
• Bone: osteoporosis, fragility fracture, osteitis fibrosa cystica (now rare).
• Gastrointestinal: nausea, vomiting, constipation, peptic ulcer disease, acute pancreatitis.
• Cardiovascular: shortened QT interval (rarely arrhythmic without crisis), hypertension, valvular and vascular calcification, sensitivity to digoxin.
• Neuromuscular: weakness, cognitive and psychiatric disturbance, confusion and coma in crisis.
• Oncology: hypercalcaemia of malignancy carries a poor short-term prognosis (median survival around 52 days in those with solid malignancies in one report), so treating the cancer alongside the calcium is essential.^[2]

• Hypercalcaemia found on screening in a middle-aged woman is usually PHPT and, if managed well, carries an excellent prognosis.
• Conservative follow-up of mild PHPT for more than 10 to 15 years is reasonably safe, although up to a third of cases eventually show overt features of the disease.^[1]
• Malignancy-associated hypercalcaemia has a poor outlook that has improved with modern oncology treatment; controlling the calcium is only the first step.
• Hypercalcaemia of malignancy recurs commonly; rebound after calcitonin is a particular trap.

• Pregnancy. Offer parathyroidectomy to women with PHPT who are considering pregnancy. During pregnancy, manage PHPT in a multidisciplinary team (obstetrician, endocrinologist, surgeon, anaesthetist, midwife); do not use cinacalcet or bisphosphonates in pregnancy.^[3]
• Children and young adults. PHPT is uncommon; early presentation suggests a familial endocrinopathy and should prompt genetic testing and family assessment. FHH is usually identified in this group.
• Older adults and those with heart or kidney disease. Hydrate more cautiously, avoid volume overload, and be vigilant with bisphosphonates and renal function.
• Parathyroid carcinoma. Rare but important: surgery is definitive; cinacalcet and antiresorptive therapy help control recurrent disease.

• If a laboratory can only measure total calcium, correct it with the albumin formula by hand, and use ionised calcium if available. Do not interpret a normal total calcium as normal when albumin is low.
• IV 0.9% saline is the first and often the only available treatment; if hydration must be limited, use a slow, carefully monitored infusion.
• Zoledronic acid is cheapest and most potent, but if creatinine clearance is under 30 mL/min, or if drug availability differs, use pamidronate dosing or consult on local formulary. Oral bisphosphonates do not help acute hypercalcaemia. Denosumab, calcitonin and cinacalcet are often unavailable or unaffordable; know your local costs.
• Granulomatous or lymphoma-related disease usually responds to a short course of oral prednisolone where testing for calcitriol is unavailable; the clinical picture and a chest X-ray may be all you have.
• An experienced parathyroid surgeon may not be local; refer early rather than pursuing repeated imaging.
• Renal ultrasound and basic DXA are more useful than advanced localisation when surgery is finally arranged.

Primary hyperparathyroidism; hypercalcaemia of malignancy; multiple myeloma; sarcoidosis; chronic kidney disease; vitamin D deficiency and excess; thyrotoxicosis; renal stones and nephrocalcinosis; parathyroid carcinoma.