Hypercalcemia

Associate Editor-In-Chief:

Hypercalcaemia (in US English 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.
 * Calcium is the most abundant mineral in the the body
 * 99% of the calcium in the body is stored in the bone
 * Calcium in the plasma is either ionized or protein-bound and readily available for use
 * An increase in total plasma calcium concentration above 10.4 mg/dL signifies hypercalcemia
 * Serum concentration is regulated through parathyroid hormone (PTH), vitamin D and calcitonin

Main causes
hyperparathyroidism and malignancy account for ~90% of cases
 * Drugs
 * Exogenous vitamin D
 * Humoral hypercalcemia of malignancy
 * Immobilization
 * Primary hyperparathyroidism
 * Sarcoidosis
 * Secondary hyperparathyroidism

Complete Differential Diagnosis of the Causes of Hypercalcemia
(In alphabetical order)
 * Abnormal parathyroid gland function
 * Acromegaly
 * Acute osteoporosis
 * Acute renal failure
 * Addison's disease
 * Adrenal insufficiency
 * After kidney transplant
 * Aluminum intoxication
 * Aspirin (in large amounts)
 * Autonomous hyperparathyroidism (post long-term renal failure)
 * Bartter's Syndrome
 * Berylliosis
 * Bone fracture
 * Breast cancer
 * Bronchial carcinoma
 * Carcinoma
 * Chronic renal failure
 * Coccidioidomycosis
 * Cushing's syndrome
 * Dehydration
 * Drugs
 * Familial hypocalcuric hypercalcemia
 * Familial isolated hyperparathyroidism
 * Gitelman syndrome
 * Granulomatous diseases with tuberculosis
 * Hematologic malignancy (multiple myeloma, lymphoma, leukemia)
 * Hepatocellular carcinoma
 * Histoplasmosis
 * Hodgkin's Lymphoma
 * Hyperparathyroidism (in the preceding oliguric-anuric phase)
 * Hyperthyroidism
 * Hypervitaminosis D (vitamin D intoxication)
 * Idiopathic hypercalcemia (in infants)
 * Immobilization
 * Isolated or multinodal adenoma
 * Kidney cancer
 * Leprosy
 * Leukemia
 * Lithium
 * Lymphoma
 * Malignancy
 * Medullary sponge kidney
 * Milk-alkali syndrome
 * Multiple endocrine neoplasia (MEN)
 * Multiple myeloma
 * Oral candidiasis
 * Osteomalacia
 * Ovarian cancer
 * Paget's disease
 * Paraplegia
 * Parathyroid carcinoma
 * Parathyroid hyperplasia
 * Pheochromocytoma
 * Plasma cell granuloma
 * Polycythemia
 * Primary hyperparathyroidism
 * Primary Parathyroid hyperplasia
 * Rebound hypercalcemia after rhabdomyolysis
 * Renal failure
 * Sarcoidosis
 * Secretion of prostaglandins
 * Severe secondary hyperparathyroidism
 * Silicone-induced granuloma
 * Sjogren's syndrome
 * Solid tumor with humoral mediation of hypercalcemia (e.g. lung or kidney cancer, pheochromocytoma)
 * Solid tumor with metastasis (e.g. breast cancer)
 * Solitary parathyroid adenoma
 * Thiazide diuretics
 * Total parenteral nutrition
 * Tuberculosis
 * Vasoactive intestinal polypeptide-producing tumor (VIPoma)
 * Vitamin A intoxication
 * Vitamin D intoxication
 * Vitamin D metabolic disorders
 * William's syndrome

Complete Differential Diagnosis of the Causes of Hypercalcemia
(By organ system)

Signs and symptoms
Hypercalcemia per se can result in fatigue, depression, confusion, anorexia, nausea, vomiting, constipation, pancreatitis or increased urination "Bones, stones, groans, and psychic moans" is a saying which will help you remember the signs and symptoms of hypercalcemia; if it is chronic it can result in urinary calculi (renal stones or bladder stones). Abnormal heart rhythms can result, and EKG findings of a short QT interval and a widened T wave suggest hypercalcemia.

Symptoms are more common at high calcium blood values (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.

Complete List of Possible Symptoms

 * Renal stones
 * Headaches
 * Bone pain and/or weakness
 * Abdominal pain
 * Confusion
 * Nausea/vomiting
 * Constipation
 * Peptic ulcer disease
 * Hallucinations
 * Bradycardia
 * Insulin resistance
 * Glucose intolerance
 * Muscle weakness
 * Hyporeflexia
 * Polyuria
 * Shortened QT interval
 * Pancreatitis
 * Psychosis
 * Depression
 * Anxiety

Physical Examination

 * Evaluate for increased urination and/or renal stones
 * Mental status changes
 * Confusion
 * Tiredness
 * Hyporeflexia
 * Arrhythmias
 * Coma

Laboratory Findings

 * Complete blood count (CBC)
 * Serum and urinary calcium
 * Blood urea nitrogen (BUN)/creatinine
 * Parathyroid hormone (PTH)
 * PTH-related peptide
 * Albumin
 * Phosphate
 * Alkaline phosphatase
 * Vitamin D
 * Magnesium

Electrocardiographic Findings

 * 1) A shortening of the QTc interval
 * 2) The decrease is at the expense of the ST segment which becomes shortened or absent.
 * 3) This is true for Ca of up to 16 meq/li, after this QTc prolongation occurs

Treatment
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 resorption 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