Hypercalcemia

Diagnostic Algorithm

  Hypercalcemia Testing Algorithm

Clinical Background

Hypercalcemia is a common metabolic abnormality frequently related to primary hyperparathyroidism and cancer.

Epidemiology

• Incidence – 8/100,000
• Age – 40s-50s; mean is 55 years
• Sex – M<F for primary hyperparathyroidism

Etiology

• Primary hyperparathyroidism
• Malignancy
  • Usually metastatic disease; 1/3 related to squamous cell carcinoma
  • Humoral mediated parathyroid hormone-related peptide (PTHrP) with cancer
• Drugs
  • Thiazides
  • Lithium
  • Vitamins – D and A
• Milk-alkali syndrome
• Immobilization
• Chronic renal disease
• Thyrotoxicosis
• Granulomatous disease – elevated vitamin D, 1,25-dihydroxy
  • Sarcoidosis
  • Leprosy
  • Wegener granulomatosis
  • Tuberculosis
  • Histoplasmosis
  • B-cell lymphomas
  • T/NK-cell lymphomas

Risk Factors

• Genetic
  • Multiple Endocrine Neoplasia (MEN)
    • MEN1 (Werner Syndrome)
      • Hyperparathyroidism, tumors of the anterior pituitary and enterohepatic tumors such as Zollinger-Ellison syndrome
    • MEN2A
      • Medullary carcinoma of the thyroid, pheochromocytoma and mild hyperparathyroidism
  • Familial hypocalciuric hypercalcemia
    • Hypercalcemia with subnormal urine calcium excretion
    • Removal of parathyroids does not correct hypercalcemia
  • Neonatal severe primary hyperparathyroidism
    • Rare, potentially lethal
    • Enlargement of all 4 parathyroids with very high parathyroid hormone (PTH)
  • Hyperparathyroidism – jaw tumor syndrome
    • Hyperparathyroidism with cementoossifying tumors of the jaw, Wilms tumor and renal cysts

Pathophysiology

• Hyperparathyroidism
  • Four parathyroid glands found within the thyroid gland secrete PTH
  • PTH acts directly on bone and induces calcium resorption with a tight negative feedback loop
  • Pathology
    • Adenoma
    • Hyperplasia
    • Carcinoma (rare)
  • Most patients are asymptomatic when hypercalcemia is discovered due to frequent use of screening chemistries

Clinical Presentation

• Clinical symptoms progress slowly
  • Renal – nephrolithiasis, nephrocalcinosis, polyuria
  • Cardiovascular – arrhythmias, bradycardia, short QT interval
  • Skeletal – classic finding is osteitis fibrosa (rare); bone pain; arthralgias
  • Neurologic – easy fatigability, proximal muscle weakness, muscle atrophy, lethargy, confusion
  • Gastrointestinal – nausea, bloating, constipation, anorexia
  • Cancer – usually fatigue, weakness as a result of very high calcium levels

Treatment

• Based on etiology of hypercalcemia

Diagnosis

Indications for Testing

• Fatigue, weakness, recurrent nephrolithiasis, coincidental discovery of elevated calcium on laboratory testing

Laboratory Testing

• Initial laboratory testing 
  • Electrolytes – including BUN and creatinine
  • Phosphorus
  • Calcium
    • Mild elevation (>10.3 but <11.0 mg/dL) – repeat with albumin measurement or ionized calcium; correct value if albumin decreased
    • Confirmed calcium elevation – order intact PTH 
• PTH (intact)
  • Elevated – hyperparathyroidism; order urine calcium (24-hour)
    • High – primary hyperparathyroidism
    • Low – familial benign hypercalcemia
  • Low – order PTHrP
    • Low or normal – order vitamin D, 1,25
      • High – lymphoma or granuloma
      • Low – consider testing for cancer
    • High – cancer
• Also consider testing for the following
  • Vitamin D excess – order vitamin D, 25
  • Milk-alkali syndrome
  • Hyperthyroidism – order TSH

Differential Diagnosis

• See Etiology for differential diagnoses

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Vitamin D, 25-Hydroxy 0080379 Method: Chemiluminescent Immunoassay
Vitamin D, 1, 25-Dihydroxy 0080385 Method: Radioimmunoassay	Differentiate type of cancer Primarily indicated during patient evaluation for hypercalcemia and renal failure Normal result does not rule out vitamin D deficiency The recommended test for diagnosing vitamin D deficiency is Vitamin D 25-hydroxy
Calcium, Serum or Plasma 0020027 Method: Spectrophotometry
Calcium, Ionized, Whole Blood 0020140 Method: Ion-Selective Electrode/pH-Electrode
Parathyroid Hormone, Intact 0070346 Method: Electrochemiluminescent Immunoassay
Parathyroid Hormone, CAP 0095611 Method: Immunoradiometric Assay
Urea Nitrogen, Serum or Plasma 0020023 Method: Spectrophotometry
Creatinine, Serum or Plasma 0020025 Method: Spectrophotometry
Electrolyte Panel 0020410 Method: Ion-Selective Electrode/Enzymatic
Albumin, Serum by Nephelometry 0050671 Method: Nephelometry
Phosphorus, Inorganic, Plasma or Serum 0020028 Method: Spectrophotometry
Glucose, Plasma or Serum 0020024 Method: Enzymatic
Potassium, Plasma or Serum 0020002 Method: Ion-Selective Electrode
Sodium, Plasma or Serum 0020001 Method: Ion-Selective Electrode
Chloride, Serum or Plasma 0020003 Method: Ion-Selective Electrode
Carbon Dioxide, Serum or Plasma 0020004 Method: Enzymatic
Albumin, Serum or Plasma by Spectrophotometry 0020030 Method: Spectrophotometry