Overview

Multiple causes for hypercalcemia to consider:

• Most common is primary hyperparathyroidism (pHPT).
  • One or more parathyroid glands produce high amounts of parathyroid hormone (PTH) causing hypercalcemia.
  • Diagnosed with blood tests measuring calcium and PTH levels in the blood.
    • If calcium and PTH levels are elevated (or inappropriately normal) at the same time, on 3 different occasions, the diagnosis of pHPT is made.
  • With pHPT being the most common cause for hypercalcemia, PTH levels should be the first lab obtained after discovering hypercalcemia.
• If PTH levels are low normal or very low, excluding the diagnosis of pHPT, further work-up should include:
  • Reviewing how much calcium and Vitamin D the patient is taking in supplement form and eating in their diet.
    • All calcium and Vitamin D supplements should be stopped, and dietary sources of calcium (e.g., dairy or calcium fortified foods) should be restricted before repeating calcium measurements in the blood.
    • This will rule out excess intake of calcium as the cause for hypercalcemia (milk-alkali syndrome).
  • Discontinue any medications that can elevate calcium levels and then repeat labs to ensure calcium returns to normal levels.
    • These medications include:
      • Calcium supplements, thiazide diuretics (e.g., hydrochlorothiazide), lithium, high dose Vit D supplements, Tamoxifen.
  • Measure TSH (thyroid stimulating hormone) and free T4 in the blood.
    • Hyperthyroidism (diagnosed by low TSH and elevated free T4) can cause hypercalcemia by stimulating bones to release calcium into the blood.
  • Measure PTHrp (PTH related protein) in the blood.
    • PTHrp mimics the function of normal PTH and can elevate calcium levels in the blood.
    • PTHrp can be produced by some cancers (e.g. breast, lung, etc.) and benign neuroendocrine tumors.
    • If PTHrp levels are elevated, the diagnosis of hypercalcemia of malignancy is made and a generalized cancer work-up should be performed.
  • Measure Vitamin D 25
    • Vitamin D 25 is the most common form of Vitamin D supplement.
    • If Vitamin D 25 levels are elevated, it can cause hypercalcemia and indicate too much Vitamin D 25 intake from supplements.
  • Measure Vitamin D 1,25 in the blood.
    • Vitamin D 1,25 is the active form of Vitamin D in the body and increases calcium absorption in the GI tract and decreases the amount of calcium excreted in the urine, leading to increased calcium in the blood.
      • Vitamin D 1,25 levels can be elevated in lymphoproliferative disorders (including lymphomas and leukemias) and granulomatous disease (including sarcoidosis and tuberculosis), fungal infections (including cryptococcosis, candidiasis, and coccidiomycosis), and inflammatory bowel disease.
  • Measure ACE (Angiotensin Converting Enzyme) levels in the blood.
    • Elevated ACE levels can cause hypercalcemia.
    • ACE levels will be elevated in Sarcoidosis.
  • Measure Alkaline Phosphatase (ALP) in the blood.
    • ALP causes bone to release calcium (resorption) into the blood (via increased osteoclast activity).
    • Elevated ALP levels can cause hypercalcemia.
    • Elevated ALP levels are seen in metastatic cancer to the bone and Paget’s disease.
    • If elevated ALP levels are discovered, a generalized cancer work-up should be performed.
  • SPEP (serum protein electrophoresis) in the blood, UPEP (urine protein electrophoresis) in the urine.
    • SPEP and UPEP will be abnormal in Multiple Myeloma (cancer of a specific type of white blood cell in the bone marrow) which is another cause for hypercalcemia.