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).
