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Differential Diagnosis: Hypercalcemia

Julie Allen, BVMS, MS, MRCVS, DACVIM (SAIM), DACVP, Cornell University

Internal Medicine

|February 2020|Peer Reviewed

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Differential Diagnosis: Hypercalcemia

Most (≈99%) calcium in the body is stored in the bones. The remaining calcium is stored in extracellular fluid and is composed of 3 parts: protein-bound, complexed, and unbound/ionized (active form) calcium. As a result, protein concentrations can affect total calcium; however, formulas to correct for albumin concentration should not be used, as they are often inaccurate. Any increase in total calcium should be rechecked and an ionized calcium test performed if calcium is still increased. Some conditions can cause hypercalcemia via multiple mechanisms.

Following are differential diagnoses for patients presented with hypercalcemia.*

  • Artifactual hypercalcemia
    • Severe lipemia or icterus
  • Physiologic hypercalcemia (mild hypercalcemia due to bone growth in young animals)
  • Increased protein binding
    • Hemoconcentration (ie, hyperalbuminemia)
    • Hyperproteinemia (ie, paraproteinemia)
  • Malignant hypercalcemia (most common cause in dogs)
    • Lymphoma
    • Anal sac apocrine gland adenocarcinoma
    • Other carcinomas (eg, mammary, thyroid, lung, clitoral), particularly if metastatic to bone
    • Thymoma
    • Multiple myeloma
    • Osteosarcoma or other primary bone tumor
    • Melanoma
  • Hypoadrenocorticism
  • Idiopathic hypercalcemia (most common cause in cats)
  • Primary hyperparathyroidism
  • Chronic kidney disease (less commonly, acute kidney injury)
  • Raisin/grape toxicity
  • Hypervitaminosis D
    • Cholecalciferol toxicity
    • Calcipotriene/calcipotriol (eg, antipsoriasis creams) ingestion
    • Calcitriol or vitamin D overdose (eg, due to inappropriate dietary supplementation)
    • Plant (eg, day-blooming jessamine) ingestion
  • Drug-induced effect
    • Thiazide diuretics
    • Excessive calcium (eg, calcium carbonate) supplementation
    • Aluminum-based phosphate binders
    • Dimethyl sulfoxide when used extra-label in the treatment of calcinosis cutis
  • Localized osteolysis
  • Osteomyelitis
  • Hypertrophic osteodystrophy
  • Disuse osteoporosis
  • Granulomatous disease
    • Blastomycosis
    • Histoplasmosis
    • Hepatozoonosis
    • Schistosomiasis
    • Pythiosis
    • Angiostrongylus vasorum infection
    • Heterobilharzia americana infection
    • Secondary to biologic implants
  • Benign humoral hypercalcemia
    • Benign mixed mammary tumors
    • Benign renal angiomyxoma
    • Benign esophageal/vaginal leiomyoma
  • Hypervitaminosis A
  • Retained fetus (dogs)
*Differential diagnoses for hypercalcemia do not have a determined order of likelihood and are listed in no particular order.


For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

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