Hypercalcemia

Hypercalcaemia (or Hypercalcemia) is an elevated calcium level in the blood. (Normal range: 9-10.5 mg/dL or 2.2-2.6 mmol/L). It can be an asymptomatic laboratory finding, but because an elevated calcium level is often indicative of other diseases, a diagnosis should be undertaken if it persists. It can be due to excessive skeletal calcium release, increased intestinal calcium absorption, or decreased renal calcium excretion.

Signs and symptoms
Hypercalcemia per se can result in fatigue, depression, confusion, anorexia, nausea, vomiting, constipation, pancreatitis or increased urination; if it is chronic it can result in urinary calculi (renal stones or bladder stones). Abnormal heart rhythms can result, and an EKG finding of a short QT interval suggests hypercalcemia.

Symptoms are more common at high calcium levels (12.0 mg/dL or 3 mmol/l). Severe hypercalcemia (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.

Causes

 * hyperparathyroidism and malignancy account for ~90% of cases
 * 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 hypercalcemia/familial benign hypercalcaemia
 * malignancy
 * solid tumor with metastasis (e.g. breast cancer)
 * solid tumor with humoral mediation of hypercalcemia (e.g. lung or kidney cancer, pheochromocytoma)
 * hematologic malignancy (multiple myeloma, lymphoma, leukemia)
 * 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 hypercalcemia of infancy
 * rebound hypercalcemia after rhabdomyolysis
 * disorders related to high bone-turnover rates
 * hyperthyroidism
 * prolonged immobilization
 * thiazide use
 * vitamin A intoxication
 * Paget's disease of the bone
 * renal failure
 * severe secondary hyperparathyroidism
 * aluminum intoxication
 * milk-alkali syndrome

Treatments
The goal of therapy is to treat the hypercalcemia 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 calcium excretion (In other words, calcium and sodium (salt) are handled in a similar way by the kidney. Anything that causes increased sodium (salt) excretion by the kidney will, en passant, cause increased calcium excretion by the kidney)
 * 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 thence pulmonary edema. 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, risedronate, and (3rd gen) zolendronate
 * all patients with cancer-associated hypercalcemia 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 hypercalcemia will recur in the patient with hypercalcemia of malignancy. Use of bisphoponates in such circumstances, then, becomes both therapeutic and preventative
 * patients in renal failure and hypercalcemia 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 hypercalcemia along with rehydration, diuresis, and bisphosphonates
 * Helps prevent recurrence of hypercalcemia
 * Dose is 4 Units per kg via subcutaneous or intramuscular route every 12 hours, usually not continued indefinitely

Other therapies

 * rarely used, or used in special circumstances
 * plicamycin inhibits bone resorption (rarely used)
 * gallium nitrate inhibits bone resprotion and changes structure of bone crystals (rarely used)
 * glucocorticoids increase urinary calcium excretion and decrease intestinal calcium absorption
 * no effect in calcium level in normal or 1' hyperparathyroidism
 * effective in hypercalcemia due to osteolytic malignancies (multiple myeloma, leukemia, Hodgkin's lymphoma, carcinoma of the breast) due to antitumor properties
 * also effective in hypervitaminosis D and sarcoidosis
 * dialysis usually used in severe hypercalcemia complicated by renal failure. Supplemental phosphate should be monitored and added if necessary
 * phosphate therapy can correct the hypophosphatemia in the face of hypercalcemia and lower serum calcium