Differential Diagnosis for Hypercalcemia

The following is a comprehensive differential diagnosis for hypercalcemia, categorized into the single most likely diagnosis, other likely diagnoses, do not miss diagnoses, and rare diagnoses.

• Single Most Likely Diagnosis
  • Primary Hyperparathyroidism: This is the most common cause of hypercalcemia, accounting for approximately 80% of cases. It is characterized by an overproduction of parathyroid hormone (PTH) due to a parathyroid adenoma, hyperplasia, or carcinoma. Labs to differentiate: Elevated PTH levels, hypercalcemia, and hypophosphatemia.
• Other Likely Diagnoses
  • Malignancy-Associated Hypercalcemia: Hypercalcemia can occur in various types of cancer, including breast, lung, and multiple myeloma, due to the production of parathyroid hormone-related protein (PTHrP) or other factors. Labs to differentiate: Elevated PTHrP levels, hypercalcemia, and abnormal serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP) in multiple myeloma.
  • Vitamin D Intoxication: Excessive intake of vitamin D can lead to hypercalcemia due to increased absorption of calcium from the gut. Labs to differentiate: Elevated 25-hydroxyvitamin D levels, hypercalcemia, and hyperphosphatemia.
  • Familial Hypocalciuric Hypercalcemia (FHH): A rare genetic disorder characterized by hypercalcemia, hypocalciuria, and elevated PTH levels. Labs to differentiate: Elevated PTH levels, hypercalcemia, and low urinary calcium excretion.
• Do Not Miss Diagnoses
  • Hypercalcemia of Malignancy with PTHrP: Although not the most common cause, it is crucial to identify and treat promptly due to its association with poor prognosis. Labs to differentiate: Elevated PTHrP levels, hypercalcemia, and abnormal imaging studies (e.g., CT or PET scans).
  • Multiple Myeloma: A type of blood cancer that can cause hypercalcemia due to bone destruction and release of calcium into the bloodstream. Labs to differentiate: Abnormal SPEP or UPEP, hypercalcemia, and anemia.
  • Vitamin A Intoxication: Excessive intake of vitamin A can lead to hypercalcemia due to increased bone resorption. Labs to differentiate: Elevated vitamin A levels, hypercalcemia, and liver function tests (LFTs) abnormalities.
• Rare Diagnoses
  • Sarcoidosis: A systemic granulomatous disease that can cause hypercalcemia due to increased production of 1,25-dihydroxyvitamin D. Labs to differentiate: Elevated 1,25-dihydroxyvitamin D levels, hypercalcemia, and abnormal chest imaging (e.g., chest X-ray or CT scan).
  • Thyroidosis: Hyperthyroidism can cause hypercalcemia due to increased bone turnover. Labs to differentiate: Elevated thyroid hormone levels (e.g., T4 or T3), hypercalcemia, and suppressed thyroid-stimulating hormone (TSH) levels.
  • Pheochromocytoma: A rare tumor of the adrenal gland that can cause hypercalcemia due to increased production of PTHrP or other factors. Labs to differentiate: Elevated metanephrines or catecholamines, hypercalcemia, and abnormal imaging studies (e.g., CT or MRI scans).
  • Williams Syndrome: A rare genetic disorder characterized by hypercalcemia, intellectual disability, and distinctive facial features. Labs to differentiate: Elevated PTH levels, hypercalcemia, and genetic testing for Williams syndrome.