Hypercalcaemia

Hypercalcaemia is an albumin corrected serum calcium over 2.60 mmol/L (or ionised calcium over 1.30 mmol/L). Most cases found in outpatients are mild and due to primary hyperparathyroidism. Most cases in hospital are due to malignancy, are more severe and carry a worse prognosis. Severe hypercalcaemia is an emergency because of dehydration, kidney injury, arrhythmia and altered consciousness.

Clinical relevance. Primary hyperparathyroidism affects about 1% of adults and 2% of postmenopausal women. Hypercalcaemia complicates up to 30% of cancers, most often breast, lung, myeloma, renal, and head and neck cancers.

Physiology. Calcium is regulated by parathyroid hormone (PTH), vitamin D and calcitonin acting on bone, kidney and gut. About half of serum calcium is ionised and active. High calcium causes nephrogenic diabetes insipidus (polyuria and volume depletion), which reduces calcium excretion and worsens the hypercalcaemia.

Classification by severity (corrected calcium).

• Mild: 2.60 to 3.00 mmol/L.
• Moderate: 3.01 to 3.50 mmol/L.
• Severe: over 3.50 mmol/L (hypercalcaemic crisis if symptomatic).

Classification by mechanism.

• PTH dependent: primary hyperparathyroidism (adenoma 85%, hyperplasia, carcinoma), tertiary hyperparathyroidism, familial hypocalciuric hypercalcaemia, lithium effect, multiple endocrine neoplasia.
• PTH independent: malignancy (humoral hypercalcaemia from PTH related peptide, local osteolysis, 1,25 dihydroxyvitamin D production by lymphoma, ectopic PTH), vitamin D excess, granulomatous disease, increased bone turnover (thyrotoxicosis, immobilisation), drugs (thiazides, lithium, vitamin A), milk alkali syndrome, adrenal insufficiency, and kidney failure related.

Key distinctions. A high PTH (or a normal PTH with a high calcium) means primary hyperparathyroidism or familial hypocalciuric hypercalcaemia. A suppressed PTH means non-parathyroid causes, most often malignancy.

History.

• Symptoms: polyuria, thirst, constipation, nausea, vomiting, abdominal pain, anorexia, weight loss, fatigue, muscle weakness, bone pain, fractures, low mood, confusion, drowsiness, and psychosis.
• Kidney stones, peptic ulcer, pancreatitis, hypertension, and family history of hypercalcaemia, kidney stones or endocrine tumours (multiple endocrine neoplasia, parathyroid disease).
• Drugs: calcium and vitamin D supplements, thiazides, lithium, vitamin A and retinoids, antacids (calcium carbonate), teriparatide, and theophylline toxicity.
• Cancer history and symptoms (breast lump, haemoptysis, haematuria, bone pain), sarcoid or tuberculosis symptoms, immobility, and thyroid symptoms.
• Dietary intake of dairy and antacids.

Examination.

• Volume status (dehydration, postural hypotension), mental state, muscle strength, proximal myopathy.
• Band keratopathy (eye), calcification, neck mass, breast, lymph nodes, and signs of malignancy, sarcoidosis, thyrotoxicosis, or adrenal insufficiency.
• Abdominal tenderness (pancreatitis), renal angle tenderness, and bone tenderness.
• Blood pressure, pulse, and ECG.

Red flags.

• Corrected calcium over 3.5 mmol/L, or over 3.0 mmol/L with symptoms.
• Reduced consciousness, confusion, psychosis, or coma.
• Acute kidney injury, severe dehydration, vomiting, or oliguria.
• ECG changes: short QT interval, arrhythmia, bradycardia, or heart block, especially with digoxin.
• Acute pancreatitis.
• Known or suspected cancer, weight loss, or bone pain.
• Pregnancy or children.
• Parathyroid crisis (calcium over 3.75 mmol/L with acute illness).

Special groups. Older adults are more susceptible to confusion and kidney injury. Pregnancy: hypercalcaemia raises risk of miscarriage, pre-eclampsia and neonatal hypocalcaemia. Children with hypercalcaemia need genetic and endocrine evaluation. Patients on digoxin develop toxicity at lower digoxin levels.

PTH dependent hypercalcaemia. Primary hyperparathyroidism (single adenoma, multiglandular hyperplasia, parathyroid carcinoma), familial hypocalciuric hypercalcaemia, multiple endocrine neoplasia types 1, 2A and 4, tertiary hyperparathyroidism in chronic kidney disease or after transplant, and lithium induced hyperparathyroidism.

Malignancy associated hypercalcaemia. Solid tumours with PTH related peptide (squamous cell carcinoma of lung, head and neck, oesophagus, cervix, renal cell carcinoma, bladder, ovary, breast), osteolytic bone metastases (breast, myeloma, lung), lymphoma producing 1,25 dihydroxyvitamin D, ectopic PTH production (rare).

Vitamin D mediated. Vitamin D intoxication, calcitriol and calcifediol excess, sarcoidosis, tuberculosis, fungal infections, berylliosis, lymphomas, granulomatous disease, and Williams syndrome.

Other endocrine and metabolic. Hyperthyroidism, adrenal insufficiency, phaeochromocytoma, VIPoma, acromegaly, and immobilisation (especially in young people with high bone turnover or Paget disease).

Drugs and nutritional. Thiazide diuretics, lithium, calcium carbonate with vitamin D (milk alkali syndrome), vitamin A, teriparatide, theophylline, aluminium, and total parenteral nutrition.

Kidney and other. Acute kidney injury recovery phase after rhabdomyolysis, chronic kidney disease with aluminium bone disease, and spurious (tourniquet use, dehydration, high albumin, and uncorrected paraproteinaemia).

Step 1. Confirm hypercalcaemia: repeat the calcium with albumin and, if in doubt, an ionised calcium. Corrected calcium equals measured calcium plus 0.02 multiplied by (40 minus albumin in g/L). Check ECG.

Step 2. Immediate tests: urea, creatinine, electrolytes (potassium, magnesium), phosphate, alkaline phosphatase, liver tests, glucose, full blood count, urinalysis, and ECG. Intact PTH on the same sample.

Step 3. Use the PTH to separate causes.

• PTH high, or normal with calcium high, and phosphate low or low normal, with a high urine calcium: primary hyperparathyroidism. Confirm with a 24 hour urinary calcium and creatinine clearance (calcium to creatinine clearance ratio under 0.01 suggests familial hypocalciuric hypercalcaemia), vitamin D, and a family history.
• PTH low (suppressed, under 2 pmol/L): non-parathyroid. Request PTH related peptide, 25 hydroxyvitamin D, 1,25 dihydroxyvitamin D, serum protein electrophoresis and free light chains, TSH, cortisol, angiotensin converting enzyme, chest radiograph, and urine Bence Jones protein.
• Phosphate is low in PTH dependent and PTH related peptide hypercalcaemia, and high in vitamin D intoxication, granulomatous disease and kidney failure.

Step 4. Imaging as indicated: chest radiograph, ultrasound or sestamibi scan and 4D CT for parathyroid localisation (only after biochemical diagnosis), bone densitometry and kidney imaging for stones and calcification, skeletal survey or whole body CT for myeloma and metastases, and CT chest, abdomen and pelvis for occult cancer.

Interpretation. Calcium over 3.5 mmol/L with PTH suppressed in an inpatient suggests malignancy, and survival is often under 3 months. Familial hypocalciuric hypercalcaemia is benign and needs no surgery.

Limitations. Albumin correction is unreliable in critical illness, so ionised calcium is preferred. PTH can be inappropriately normal in primary hyperparathyroidism. PTH related peptide assays are not widely available.

Principles. Rehydrate, lower the calcium with antiresorptive therapy for moderate to severe or symptomatic hypercalcaemia (corrected calcium over 3.0 mmol/L, or over 2.8 mmol/L with symptoms), stop calcium raising drugs, and treat the underlying cause. Mild asymptomatic hypercalcaemia (under 3.0 mmol/L) is managed by oral hydration and treatment of the cause.

Rehydration.

• Isotonic saline 0.9% 1 to 2 litres IV over the first 2 to 4 hours, then 200 to 300 mL/hour or about 3 to 4 litres in 24 hours, adjusted to keep urine output at 100 to 150 mL/hour. Monitor volume status, sodium, potassium and magnesium (replace as needed), and watch for fluid overload in heart failure and kidney failure.
• Loop diuretics only after rehydration and for fluid overload: furosemide 20 to 40 mg IV (monitor volume status, electrolytes and creatinine). Routine loop diuretics are not advised.
• Oral fluids 2 to 3 litres daily in mild disease.

Bisphosphonates (for corrected calcium over 3.0 mmol/L or symptomatic).

• Zoledronic acid 4 mg IV in 100 mL isotonic saline or 5% glucose over at least 15 minutes, as a single dose (repeat after 7 days if calcium has not fallen; maximum 4 mg for each dose; reduce the dose or avoid with CrCl under 30 to 35 mL/min; monitor creatinine, calcium, phosphate and magnesium, and jaw health; check dental status). Onset 2 to 4 days, maximum effect at 4 to 7 days, lasting 2 to 4 weeks.
• Pamidronate 60 to 90 mg IV in 500 mL isotonic saline or 5% glucose over 2 to 4 hours (30 mg if calcium is under 3.0 mmol/L; 60 mg if CrCl is under 30 mL/min; maximum 90 mg for each dose), repeated after 7 days if needed. Monitor creatinine and electrolytes.
• Adverse effects: fever and flu like symptoms in 24 to 48 hours (treat with paracetamol 1 g orally every 6 hours; maximum 4 g daily), hypocalcaemia, hypophosphataemia, hypomagnesaemia, kidney injury, osteonecrosis of the jaw (rare), and atypical femoral fracture with long term use.

Calcitonin (for rapid short term lowering in severe hypercalcaemia). Calcitonin salmon 4 units/kg subcutaneously or intramuscularly every 12 hours (increase to 8 units/kg every 6 to 12 hours if needed, maximum 8 units/kg every 6 hours) for up to 48 hours. Effect is within 2 to 4 hours, with an average fall of 0.3 to 0.5 mmol/L, and tachyphylaxis within 48 hours. Monitor for nausea, flushing and allergic reactions (skin test where required).

Denosumab (kidney failure, refractory disease, or bisphosphonate intolerance). Denosumab 120 mg subcutaneously (repeat on days 8 and 15 for refractory hypercalcaemia, then every 4 weeks), with calcium and vitamin D supplements and monitoring for hypocalcaemia (which is severe in kidney failure), osteonecrosis of the jaw and atypical femoral fracture. Onset within 4 to 10 days.

Glucocorticoids (lymphoma, myeloma, vitamin D toxicity, sarcoidosis, granulomatous disease). Prednisolone 40 to 60 mg orally once daily (or hydrocortisone 200 to 400 mg IV daily in divided doses) for 3 to 10 days, then reduce to the lowest effective dose; onset in 2 to 5 days. Monitor glucose, blood pressure and infection. Not effective in hyperparathyroidism and most solid tumours.

Dialysis. Haemodialysis with a low or zero calcium dialysate for severe hypercalcaemia with kidney failure or heart failure, or when other measures fail.

Cinacalcet. 30 mg orally twice daily, increased every 2 to 4 weeks to a maximum of 90 mg four times daily, for hypercalcaemia in parathyroid carcinoma and in primary hyperparathyroidism that cannot be treated surgically (monitor calcium within 1 week of each change, nausea, QT interval and hypocalcaemia).

Cause specific treatment.

• Primary hyperparathyroidism: parathyroidectomy for symptomatic disease, calcium more than 0.25 mmol/L over the upper limit, osteoporosis (T score of -2.5 or lower) or fragility fracture, kidney stones or nephrocalcinosis, creatinine clearance under 60 mL/min, age under 50 years. Observation with yearly calcium, creatinine and bone density for asymptomatic mild disease. Keep fluid intake high, avoid thiazides and lithium, and maintain vitamin D at 50 nmol/L or more.
• Malignancy: treat the cancer, bisphosphonates or denosumab every 3 to 4 weeks, and palliative care decisions made from the prognosis.
• Vitamin D toxicity: stop vitamin D and calcium, low calcium diet, prednisolone 40 to 60 mg orally once daily for 3 to 10 days, and monitor for 1 to 3 months because of the long half life.
• Drugs: stop thiazides, calcium, vitamin D, lithium (specialist advice), vitamin A.
• Immobilisation: mobilise as possible, bisphosphonate.
• Thyrotoxicosis and adrenal insufficiency: treat the primary disease (hydrocortisone 100 mg IV then 50 mg every 6 hours in adrenal crisis).

Monitoring. Calcium (corrected or ionised), creatinine, sodium, potassium, magnesium and phosphate daily during treatment, with ECG monitoring in severe cases, hourly urine output during rehydration, and neurological observations. Calcium usually falls by 48 to 72 hours after a bisphosphonate.

Referral and escalation. Endocrinology or endocrine surgery for hyperparathyroidism. Oncology or haematology for malignancy. Nephrology for kidney failure and dialysis. Critical care for calcium over 3.5 mmol/L with neurological or cardiac effects. Palliative care for advanced cancer.

Admission criteria. Corrected calcium over 3.0 mmol/L with symptoms, over 3.5 mmol/L at any level, kidney injury, dehydration, neurological symptoms, ECG changes, or new diagnosis of malignancy related hypercalcaemia. Mild asymptomatic hypercalcaemia (under 3.0 mmol/L) can be managed as an outpatient.

Discharge and safety netting. Discharge when calcium is under 3.0 mmol/L, the patient is eating, drinking and able to mobilise, and a cause and follow up are arranged, with a repeat calcium and creatinine in 1 week. Advise adequate fluids (2 to 3 litres daily) and avoidance of calcium and vitamin D supplements, thiazides and dehydration. Patients return for confusion, drowsiness, vomiting, abdominal pain, reduced urine output, or palpitations.