Endocrinology Made Simple : Hypercalcemia

Hypercalcemia

Hypercalcemia  is an elevated calcium  level in the blood

Normal range: 9–10.5 mg/dL or 2.2–2.6 mmol/L.

Causes

Primary hyperparathyroidism and malignancy account for about 90% of cases of hypercalcaemia.

Abnormal parathyroid gland function

Primary hyperparathyroidism

Solitary parathyroid adenoma

Primary parathyroid hyperplasia

Parathyroid carcinoma

Multiple endocrine neoplasia (MEN)

Familial isolated hyperparathyroidism

Lithium use

Familial hypocalciuric hypercalcaemia/familial benign hypercalcaemia

Malignancy

Solid tumour with metastasis (e.g. breast cancer or classically squamous cell carcinoma, which can be PTHrP-mediated)

Solid tumour with humoral mediation of hypercalcaemia (e.g. lung cancer, most commonly non-small 

cell lung cancer or kidney cancer, phaeochromocytoma)

Haematologic malignancy (multiple myeloma, lymphoma, leukaemia)

Ovarian small cell carcinoma of the hypercalcemic type

Vitamin-D metabolic disorders

Hypervitaminosis D (vitamin D intoxication)

Elevated 1,25(OH)2D (see calcitriol under Vitamin D) levels (e.g. sarcoidosis and other granulomatous 

diseases)

Idiopathic hypercalcaemia of infancy

Rebound hypercalcaemia after rhabdomyolysis

Disorders related to high bone-turnover rates

Hyperthyroidism

Prolonged immobilization

Thiazide use

Vitamin A intoxication

Multiple myeloma

Renal failure

Severe secondary hyperparathyroidism

Aluminium intoxication

Milk-alkali syndrome

Signs and symptoms

The neuromuscular symptoms of hypercalcemia are caused by a negative bathmotropic effect due to the increased interaction of calcium with sodium channels. Since calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibers, increased calcium raises the threshold for depolarization.

There is a general mnemonic for remembering the effects of hypercalcaemia: "Stones, Bones, Groans, 

Thrones and Psychiatric Overtones"

Stones (renal or biliary)

Bones (bone pain)

Groans (abdominal pain, nausea and vomiting)

Thrones (polyuria - also looks like Osborn wave on ECG)

Psychiatric overtones (Depression 30–40%, anxiety, cognitive dysfunction, insomnia, coma)

Other symptoms can include fatigue, anorexia, and pancreatitis

Limbus sign seen in eye due to hypercalcemia.

Hypercalcemia has a negative chronotropic effect (decrease in heart rate), and a positive inotropic effect (increase in contractility).

Abnormal heart rhythms can also result, and ECG findings of a short QT interval suggest hypercalcaemia.

Significant hypercalcaemia can cause ECG changes mimicking an acute myocardial infarction.

Hypercalcaemia has also been known to cause an ECG finding mimicking hypothermia, known as an Osborn wave.

Hypercalcaemia can increase gastrin production, leading to increased acidity so peptic ulcers may also occur.

Symptoms are more common at high calcium blood values (12.0 mg/dL or 3 mmol/l). Severe hypercalcaemia (above 15–16 mg/dL or 3.75–4 mmol/l) is considered a medical emergency: at these levels, coma and cardiac arrest can result.

The high levels of calcium ions decrease the neuron membrane permeability to sodium ions, thus decreasing the excitability, which leads to hypotonicity of smooth and striated muscle. This explains the fatigue, muscle weakness, low tone and sluggish reflexes in muscle groups.

The sluggish nerves also explain drowsiness, confusion, hallucinations, stupor and / or coma. In the gut this causes constipation. Hypocalcaemia causes the opposite by the same mechanism.

Treatments

The goal of therapy is to treat the hypercalcaemia first and subsequently effort is directed to treat the 

underlying cause.

Initial therapy: fluids and diuretics

Hydration, increasing salt intake, and forced diuresis.

Hydration is needed because many patients are dehydrated due to vomiting or renal defects in concentrating urine.

Increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion, which further increases urinary potassium excretion.

Aafter rehydration, a loop diuretic such as furosemide can be given to permit continued large volume intravenous salt and water replacement while minimizing the risk of blood volume overload and pulmonary oedema. 

In addition, loop diuretics tend to depress renal calcium reabsorption thereby helping to lower blood calcium levels

Can usually decrease serum calcium by 1–3 mg/dL within 24 h

Caution must be taken to prevent potassium or magnesium depletion

Additional therapy: bisphosphonates and calcitonin

Bisphosphonates are pyrophosphate analogues with high affinity for bone, especially areas of high bone-turnover.

They are taken up by osteoclasts and inhibit osteoclastic bone resorption

Current available drugs include (in order of potency): (1st gen) etidronate, (2nd gen) tiludronate, IV pamidronate, alendronate (3rd gen) zoledronate and risedronate

All patients with cancer-associated hypercalcaemia should receive treatment with bisphosphonates since the 'first line' therapy (above) cannot be continued indefinitely nor is it without risk. 

Further, even if the 'first line' therapy has been effective, it is a virtual certainty that the hypercalcaemia will recur in the patient with hypercalcaemia of malignancy. 

Use of bisphosphonates in such circumstances, then, becomes both therapeutic and preventative

patients in renal failure and hypercalcaemia should have a risk-benefit analysis before being given bisphosphonates, since they are relatively contraindicated in renal failure.

Calcitonin blocks bone resorption and also increases urinary calcium excretion by inhibiting renal calcium reabsorption

Usually used in life-threatening hypercalcaemia along with rehydration, diuresis, and bisphosphonates

Helps prevent recurrence of hypercalcaemia

Dose is 4 Units per kg via subcutaneous or intramuscular route every 12 hours, usually not continued indefinitely

Hypercalcaemic crisis

A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14 mg/dL (or 3.5 mmol/l).

The main symptoms of a hypercalcaemic crisis are oliguria or anuria, as well as somnolence or coma.

After recognition, primary hyperparathyroidism should be proved or excluded

In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck exploration is the only way to avoid death.

The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium.

Treatment of choice for acutely lowering calcium is extensive hydration and calcitonin, as well as bisphosphonates (which have effect on calcium levels after one or two days).