Hypercalcaemia

A hypercalcaemic crisis is an emergency situation with a severe hypercalcaemia, generally above approximately 14 mg/dL (or 3.5 mmol/L).[9]

The main symptoms of a hypercalcaemic crisis are oliguria or anuria, as well as somnolence or coma.[10] After recognition, primary hyperparathyroidism should be proved or excluded.[10]

In extreme cases of primary hyperparathyroidism, removal of the parathyroid gland after surgical neck exploration is the only way to avoid death.[10] The diagnostic program should be performed within hours, in parallel with measures to lower serum calcium.[10] 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).[11]

• Primary hyperparathyroidism
  • Solitary parathyroid adenoma[14]
  • Primary parathyroid hyperplasia[15]
  • Parathyroid carcinoma[16]
  • Multiple endocrine neoplasia (MEN1 & MEN2A)[17]
  • Familial isolated hyperparathyroidism[18]
• Lithium use
• Familial hypocalciuric hypercalcemia/familial benign hypercalcemia[19][20][21]

Micrograph of ovarian small cell carcinoma of the hypercalcemic type. H&E stain.

• 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[22] or kidney cancer, phaeochromocytoma)
• Haematologic cancers (multiple myeloma, lymphoma, leukaemia)
• Ovarian small cell carcinoma of the hypercalcemic type

• Hypervitaminosis D (vitamin D intoxication)
• Elevated 1,25(OH)₂D (see calcitriol under Vitamin D) levels (e.g. sarcoidosis and other granulomatous diseases such as tuberculosis, berylliosis, histoplasmosis, Crohn's disease, and granulomatosis with polyangiitis)
• Idiopathic hypercalcaemia of infancy[23]
• Rebound hypercalcaemia after rhabdomyolysis

• Hyperthyroidism
• Multiple myeloma
• Prolonged immobilization
• Paget's disease
• Thiazide use
• Vitamin A intoxication[15]

• Tertiary hyperparathyroidism
• Aluminium intoxication
• Milk-alkali syndrome[15]

• Acromegaly
• Adrenal insufficiency
• Zollinger–Ellison syndrome
• Williams Syndrome

An Osborn wave, an abnormal EKG tracing that can be associated with hypercalcemia.

Abnormal heart rhythms can also result, and ECG findings of a short QT interval[26] suggest hypercalcaemia. Significant hypercalcaemia can cause ECG changes mimicking an acute myocardial infarction.[27] Hypercalcaemia has also been known to cause an ECG finding mimicking hypothermia, known as an Osborn wave.[28]

Initial therapy:

• hydration, increasing salt intake, and forced diuresis.
  • hydration is needed because many patients are dehydrated due to vomiting or kidney defects in concentrating urine.
  • increased salt intake also can increase body fluid volume as well as increasing urine sodium excretion, which further increases urinary calcium excretion.
  • after 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 calcium reabsorption by the kidney thereby helping to lower blood calcium levels
  • can usually decrease serum calcium by 1–3 mg/dL within 24 hours
  • caution must be taken to prevent potassium or magnesium depletion

Additional therapy:

• 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 people 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 person with hypercalcaemia of malignancy. Use of bisphosphonates in such circumstances, then, becomes both therapeutic and preventative
  • people in kidney failure and hypercalcaemia should have a risk-benefit analysis before being given bisphosphonates, since they are relatively contraindicated in kidney failure.
• Denosumab is a bone anti-resorptive agent that can be used to treat hypercalcemia in patients with a contraindication to bisphosphonates such as severe kidney failure or allergy.
• Calcitonin blocks bone resorption and also increases urinary calcium excretion by inhibiting calcium reabsorption by the kidney
  • Usually used in life-threatening hypercalcaemia along with rehydration, diuresis, and bisphosphonates
  • Helps prevent recurrence of hypercalcaemia
  • Dose is 4 international units per kilogram via subcutaneous or intramuscular route every 12 hours, usually not continued indefinitely due to quick onset of decreased response to calcitonin

• rarely used, or used in special circumstances
  • plicamycin inhibits bone resorption (rarely used)
  • gallium nitrate inhibits bone resorption and changes structure of bone crystals (rarely used)
  • glucocorticoids increase urinary calcium excretion and decrease intestinal calcium absorption
    • no effect on calcium level in normal or primary hyperparathyroidism
    • effective in hypercalcaemia due to osteolytic malignancies (multiple myeloma, leukaemia, Hodgkin's lymphoma, carcinoma of the breast) due to antitumour properties
    • also effective in hypervitaminosis D and sarcoidosis
  • dialysis usually used in severe hypercalcaemia complicated by kidney failure. Supplemental phosphate should be monitored and added if necessary
  • phosphate therapy can correct the hypophosphataemia in the face of hypercalcaemia and lower serum calcium

Household pets such as dogs and cats are found to develop hypercalcemia. It is less common in cats, and many feline cases are idiopathic.[29] In dogs, lymphosarcoma, Addison’s disease, primary hyperparathyroidism, and chronic kidney failure are the main causes of hypercalcemia, but there are also environmental causes usually unique to indoor pets.[29] Ingestion of small amounts of calcipotriene found in psoriasis cream can be fatal to a pet.[31] Calcipotriene causes a rapid rise in calcium ion levels.[31] Calcium ion levels can remain high for weeks if untreated and lead to an array of medical issues.[31] There are also cases of hypercalcemia reported due to dogs ingesting rodenticides containing a chemical similar to calcipotriene found in psoriasis cream.[31] Additionally, ingestion of household plants is a cause of hypercalcemia. Plants such as Cestrum diurnum, and Solanum malacoxylon contain ergocalciferol or cholecalciferol which cause the onset of hypercalcemia.[29] Consuming small amounts of these plants can be fatal to pets. Observable symptoms may develop such as polydipsia, polyuria, extreme fatigue, or constipation.[29]

Trisetum flavescens (yellow oat grass)

In certain outdoor environments, animals such as horses, pigs, cattle, and sheep experience hypercalcemia commonly. In southern Brazil and Mattewara India, approximately 17 percent of sheep are affected, with 60 percent of these cases being fatal.[30] Many cases are also documented in Argentina, Papua New Guinea, Jamaica, Hawaii, and Bavaria.[30] These cases of hypercalcemeia are usually caused by ingesting Trisetum flavescens before it has dried out.[30] Once Trisetum flavescens is dried out, the toxicity of it is diminished.[30] Other plants causing hypercalcemia are Cestrum diurnum, Nierembergia veitchii, Solanum esuriale, Solanum torvum, and Solanum malacoxylon.[30] These plants contain calcitriol or similar substances that cause rises in calcium ion levels.[30] Hypercalcemia is most common in grazing lands at altitudes above 1500 meters where growth of plants like Trisetum flavescens is favorable.[30] Even if small amounts are ingested over long periods of time, the prolonged high levels of calcium ions have large negative effects on the animals.[30] The issues these animals experience are muscle weakness, and calcification of blood vessels, heart valves, liver, kidneys, and other soft tissues, which eventually can lead to death.[30]