a. Definition. Hypercalcemia is an elevated level of calcium in the blood (usually defined as a serum calcium level greater than 10.5 mg/dL). It is frequently encountered in both outpatient and inpatient settings. In hospitalized patients, hypercalcemia is often due to malignancy. In the outpatient setting, primary hyperparathyroidism is the most common cause.
b. It is important to correct the measured calcium for the level of albumin. For every 1 mg/dL decrease in albumin (normal level is 4 mg/dL), the corrected calcium will be 0.8 mg/dL higher. For example, if the serum calcium is 10.6 mg/dL and the albumin is 5 mg/dL, the corrected calcium is 9.8 mg/dL (and the patient is not hypercalcemic). Conversely, if the serum calcium is 10 mg/dL and the albumin is 3 mg/dL, the corrected calcium is 10.8 mg/dL (and the patient is hypercalcemic).
B. Clinical Manifestations of Hypercalcemia
a. Symptoms are nonspecific and tend to be more obvious when the serum calcium level exceeds 12 mg/dL. The severity of symptoms is dependent on the acuity of the calcium elevation. The phrase “Stones (renal), Moans (abdominal), Bones (skeletal), and Groans (psychiatric)” is a good way to recall common symptoms.
i. Gastrointestinal symptoms include constipation, nausea, vomiting, and anorexia. Patients may develop acute pancreatitis.
ii. Bone pain, arthritis, osteoporosis, and osteitis fibrosa cystica (rare) may occur.
iii. Central nervous system (CNS) symptoms can range from depression and fatigue to confusion, lethargy, and weakness. Progression to coma and death may occur with severe, untreated hypercalcemia.
b. Signs of hypercalcemia include hypertension, hypotonia, decreased deep tendon reflexes, and a shortened QT interval on the electrocardiogram (EKG).
C. Causes of Hypercalcemia. There are many causes of hypercalcemia. The mnemonic “MISHAP + F” will help you remember the most important ones.
MNEMONIC: Causes of Hypercalcemia (“MISHAP + F”)
Intoxication (vitamin D) or Immobilization
Sarcoidosis (and other granulomatous diseases)
Adrenal disease and Milk-Alkali syndrome
Primary hyperparathyroidism and Paget’s disease
a. Malignancy. Hypercalcemia occurs secondary to local osteolysis (occurs with extensive bone involvement by the tumor) or humoral influences (induced by parathyroid hormone [PTH]-related peptide). Lymphomas may produce excess 1,25-dihydroxyvitamin D to increase calcium levels.
b. Intoxication with vitamin D. Some patients take large amounts of vitamin D leading to hypercalcemia. Check serum 25-hydroxyvitamin D (25-OHD) or 1,25-dihydroxyvitamin D (DHVD) levels (depending on what form of vitamin D was ingested) to confirm the diagnosis.
c. Immobilization. Hypercalcemia can occur in the setting of prolonged immobilization. Most commonly seen in patients with active bone turnover, such as younger patients with maturing bone or older patients with Paget’s disease, spinal cord injury, or cerebrovascular accident (CVA).
d. Sarcoid and other granulomatous diseases (e.g., tuberculosis, berylliosis). Hypercalcemia results from increased formation of 1,25-dihydroxyvitamin D in granulomatous tissues.
e. Hydrochlorothiazide. Patients receiving thiazide diuretics may have elevated serum calcium levels due to decreased calcium excretion.
f. Adrenal disease. Addison’s disease and pheochromocytoma are uncommon causes of hypercalcemia.
g. Alkali ingestion. Hypercalcemia can occur as a result of excess calcium carbonate ingestion (e.g., patients with peptic ulcer disease who ingest large amounts of calcium-containing antacids).
h. Primary hyperparathyroidism. Primary hyperparathyroidism is caused by solitary adenomas (85% of patients), four-gland hyperplasia (10% of patients), or carcinoma (≤5% of patients). Patients usually do not have symptoms at the time of diagnosis. Low serum phosphate levels should make you consider this diagnosis.
i. Paget’s disease, a metabolic bone disease of unknown etiology, is characterized by excessive bone destruction and disorganized repair, leading to skeletal deformities (e.g., kyphosis, tibial bowing, and skull enlargement).
j. FHH is a benign, autosomal dominant genetic disease characterized by hypercalcemia, hypocalciuria (<100 mg/24 hr), and occasionally hypermagnesemia. The serum PTH level may be slightly elevated, which can lead to a mistaken diagnosis of hyperparathyroidism. However, in primary hyperparathyroidism, urinary calcium is typically normal or elevated.
D. Treatment.Treatment is warranted if symptoms are present or if serum calcium exceeds 12 mg/dL.
a. Initial therapy entails fluids, fluids, and more fluids, followed by loop diuretics primarily to prevent fluid overload. Other therapies include bisphosphonates, calcitonin, corticosteroids, and denosumab.
b. Definitive treatment will depend on the underlying cause of hypercalcemia.
Suggested Further Readings
Ahmad S, Kuraganti G, Steenkamp D. Hypercalcemic crisis: a clinical review. Am J Med 2015;128:239–45.Find this resource:
Bilezikian JP, Bandeira L, Khan A, Cusano NE. Hyperparathyroidism. Lancet 2017.Find this resource:
Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ 2015;350.Find this resource:
Strewler GJ. The physiology of parathyroid hormone–related protein. N Engl J Med 2000;342:177–85. (Classic Article.)Find this resource:
Wermers RA, Khosla S, Atkinson EJ, et al. The rise and fall of primary hyperparathyroidism: a population-based study in Rochester, Minnesota, 1965–1992. Ann Intern Med 1997;126:433–40. (Classic Article.)Find this resource: