Hypercalcemia Clinical Presentation

The mnemonic "stones," "bones," "abdominal moans," and "psychic groans" describes the constellation of symptoms and signs of hypercalcemia. These may be due directly to the hypercalcemia, to increased calcium and phosphate excretion, or to skeleton changes. The history of hypercalcemia is dependent on its cause and the sensitivity of the individual to higher calcium levels. Individuals with mild prolonged hypercalcemia may have mild or no symptoms, or, they may have recurring problems such as kidney stones. Those with more sudden onset and severe hypercalcemia may experience dramatic symptoms, usually including confusion and lethargy, possibly leading quickly to death.

• Central nervous system effects include the following:

  • Lethargy
  • Weakness
  • Confusion
  • Coma
• Renal effects include the following:

  • Polyuria
  • Nocturia
  • Dehydration
  • Renal stones
  • Renal failure
• Gastrointestinal effects include the following:

  • Constipation
  • Nausea
  • Anorexia
  • Pancreatitis
  • Gastric ulcer
• Cardiac effects include syncope from arrhythmias.

Most patients with hypercalcemia do not have any specific findings upon physical examination. Those with higher calcium levels may have findings that are more striking. Evidence of the underlying cause may be found, such as a suggestive breast mass in someone with hypercalcemia secondary to malignancy.

• Nervous system findings include the following:

  • Confusion
  • Hypotonia
  • Hyporeflexia
  • Paresis
  • Coma
• Renal findings include the following:

  • Volume depletion
  • Signs of renal failure
• Gastrointestinal findings include the following:

  • Fecal impaction (from constipation)
  • Signs of pancreatitis
  • Signs of malignancy (eg, enlarged liver or masses)
• Cardiac findings include the following:

  • Arrhythmias
  • Hypotension
  • Shortened QT interval
• General findings may include band keratopathy, which is calcium precipitation in a horizontal band across the cornea in the palpebral aperture.

Approximately 90% of cases of hypercalcemia are caused by malignancy or hyperparathyroidism. About 20-30% of patients with cancer have hypercalcemia during the course of the disease, and its detection may signify an unfavorable prognosis. Of the cases due to malignancy, approximately 80% are due to bony metastases, while the other 20% are due to PTHrP effects. Hypercalcemia secondary to malignancy may be classified into the following 4 types, based on the mechanism involved:

• Humoral hypercalcemia of malignancy (HHCM) from an increased secretion of PTHrP - Most common form, accounting for up to 80% of cases
• Osteolytic hypercalcemia from osteoclastic activity and bone resorption surrounding the tumor tissue - The second most common mechanism, accounting for about 20% of cases
• Secretion of active vitamin D by some lymphomas
• Ectopic PTH secretion - Very rare

The remaining 10% of cases of hypercalcemia are caused by many different conditions, including vitamin D–related problems, disorders associated with rapid bone turnover, thiazides or renal failure, and in rare cases, familial causes. Treatment with recombinant human parathyroid hormone for postmenopausal osteoporosis is also a cause.^[5]

• Causes of hypercalcemia that are related to malignancy (lung, breast, and myeloma are the most common tumors) include the following:

  • Solid tumor metastases
  • Solid tumors with humoral effects
  • Hematologic malignancies
• Causes of hypercalcemia that are related to the parathyroid include the following:

  • Primary hyperparathyroidism
    • Solitary adenoma
    • Generalized hyperplasia
    • Multiple endocrine neoplasia type 1 or type 2A
  • Lithium-related release of PTH
  • Familial cases of high PTH
• Those related to vitamin D include the following:

  • Vitamin D toxicity^[6]
  • Granulomatous disease (especially sarcoidosis)
• Those related to high bone turnover include the following:

  • Hyperthyroidism
  • Immobilization (especially in Paget disease)
  • Thiazides
  • Vitamin A intoxication
• Renal failure (milk-alkali syndrome)
• Other causes related to particular mechanisms are as follows:

  • Increased intestinal calcium absorption
    • Idiopathic infantile hypercalcemia (Williams syndrome)
    • Vitamin D intoxication
    • Vitamin A intoxication
    • Granulomatous disorders, eg, sarcoidosis
  • Decreased renal calcium excretion
    • Hyperparathyroidism
    • Familial hypocalciuric hypercalcemia
    • Thiazide diuretics
  • Increased bone resorption
    • Immobilization
    • Hyperparathyroidism
    • Malignancy
  • Mutations of the calcium-sensing receptor
    • Familial benign hypocalciuric hypercalcemia
    • Neonatal severe hyperparathyroidism
  • Uncertain mechanism
    • Hypophosphatasia
    • Subcutaneous fat necrosis
    • Blue diaper syndrome
    • Dietary phosphate deficiency