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Hypercalcemia. ARUP Consult®. Retrieved March 06, 2021, https://arupconsult.com/content/hypercalcemia

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Hypercalcemia

Hypercalcemia is a metabolic abnormality with widespread effects. Mild or chronic persistent hypercalcemia may be asymptomatic, whereas acute onset hypercalcemia may present with musculoskeletal, gastrointestinal, and psychiatric changes. If a patient is taking calcium supplements and has a test result bordering on hypercalcemia, testing should be repeated after cessation of supplementation. Accurate calcium testing includes correction with a concurrent albumin concentration. Testing for ionized calcium can remove variability due to albumin or confirm a possible abnormal value. Confirmed high serum calcium is frequently associated with hyperparathyroidism or undetected cancer. Laboratory testing includes parathyroid hormone (PTH) testing, testing to identify organ involvement, and, in the event of low PTH, testing for cancer.

Quick Answers for Clinicians

Which testing algorithms are related to this topic?
Hypercalcemia Testing Algorithm

Diagnosis

Indications for Testing

  • Fatigue, muscle weakness, recurrent nephrolithiasis, bone pain, constipation, changes in mental status
  • Elevated calcium on laboratory testing

Laboratory Testing

  • Initial testing – comprehensive metabolic panel (CMP)
    • Abnormalities in other lab results may provide clues to underlying pathology
    • Chronic kidney disease with metabolic bone disease results in abnormalities of calcium, phosphorus, PTH, and bone turnover
  • Calcium
    • Calculate corrected calcium
      • Corrected calcium = serum calcium + [0.8 x (normal albumin - serum albumin)]
      • Normal albumin is usually 4-4.5 g/dL, depending on testing lab
    • Consider ionized calcium if albumin is low
    • Total serum calcium
      • In asymptomatic patient with concentration >10.3 but <11.0 mg/dL, repeat with albumin measurement or ionized calcium
      • In symptomatic patient and/or patient with concentration >11.0 mg/dL – order PTH
  • PTH (intact)
    • Elevated or normal – indicates primary hyperparathyroidism; order urine calcium, 24-hour collection
      • High urine calcium (≥100 pg/mL) – primary hyperparathyroidism
      • Low urine calcium (<100 pg/mL) – familial benign hypercalcemia
    • Low – order PTH-related peptide (PTHrP)
      • High PTHrP – consider cancer
      • Low or normal PTHrP – order vitamin D, 1,25-dihydroxy [1,25-(OH)2-D]
        • High 1,25-(OH)2-D – consider lymphoma or granulomatous disease
        • Low or normal 1,25-(OH)2-D – consider vitamin D excess, cancer, milk-alkali syndrome, or hyperthyroidism
  • Other testing
    • Thyroid-stimulating hormone (TSH) – rarely, hyperthyroidism can cause hypercalcemia

Differential Diagnosis

See Etiology in Background

Background

Epidemiology

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

Etiology

  • Hyperparathyroidism
  • Drugs/supplements
    • Thiazides
    • Lithium
    • Vitamin excess – D and A
    • Calcium and alkali (milk-alkali syndrome)
    • Parathyroid hormone
  • Cancer
    • Usually metastatic disease
    • Osteolysis due to bone metastases
    • Humoral-mediated PTHrP (ectopic production)
    • Most common malignancies
      • Squamous cell – lung, head and neck
      • Breast
      • Multiple myeloma
      • Lymphomas – T/NK cell most common
      • Renal cell
      • Ovarian
  • Immobilization
  • Chronic kidney disease with metabolic bone disease
  • Endocrine disorders
  • Granulomatous disease
  • Syndromic diseases
    • Multiple endocrine neoplasias (MEN)
    • Hypocalciuric hypercalcemia
    • Hyperparathyroidism – jaw tumor syndrome
    • Neonatal severe hyperparathyroidism

Pathophysiology

  • ~90% of hypercalcemia is caused by hyperparathyroidism or malignancy (Minisola, 2015)
  • Hyperparathyroidism – usually causes mild hypercalcemia
    • Four parathyroid glands found within the thyroid gland secrete PTH
    • PTH acts directly on bone and kidneys and induces calcium resorption with a tight negative feedback loop
    • Pathology for hyperparathyroidism and excess secretion of PTH
    • Due to frequent use of screening chemistries, most patients are asymptomatic when hypercalcemia is discovered
  • Cancer – may cause severe hypercalcemia; there are several etiologies for hypercalcemia in malignancy
    • Presence of humoral factors that mimic PTH action
      • Secretion of PTHrP by tumor tissue or tumor metastasis
    • Osteolytic or nonosteolytic activity related to bone metastases
    • Ectopic secretion of 1-alpha hydroxylase (calcitriol) by tumor tissue
      • Stimulates gastrointestinal calcium absorption
    • Impaired renal function caused by tumor or treatment
  • Calcium is bound to plasma proteins
    • ~45% is free and active (this is measured by ionized calcium)
    • Total calcium measures are highly dependent on albumin level
    • Also influenced by pH changes

Clinical Presentation

  • Clinical symptoms progress slowly in hyperparathyroid-related disease
    •  Rate of increase related to presence of symptoms
  •  Symptoms
    • Renal – nephrolithiasis, nephrocalcinosis, polyuria
    • Cardiovascular – arrhythmias, bradycardia, short QT interval with prolonged PR and QRS intervals
      • Atrioventricular block or complete heart block can develop with severe hypercalcemia
    • Skeletal – bone pain, arthralgias; classic finding is osteitis fibrosa (rare)
    • Neurologic – easy fatigability, proximal muscle weakness, muscle atrophy, lethargy, confusion
      • Can progress to seizures, coma
    • Gastrointestinal – nausea, bloating, constipation, anorexia
  • Syndromic diseases associated with hypercalcemia
    • MEN
    • Familial hypocalciuric hypercalcemia
      • Hypercalcemia with subnormal urine calcium excretion; removal of parathyroids does not correct hypercalcemia
    • Neonatal severe primary hyperparathyroidism
      • Enlargement of all four parathyroids with very high PTH; rare and potentially lethal
    • Hyperparathyroidism – jaw tumor syndrome
      • Hyperparathyroidism with cemento-ossifying tumors of the jaw, Wilms tumor, and renal cysts

ARUP Laboratory Tests

Use to diagnose disorders of calcium metabolism

May assist in assessing nutritional status or in indicating a possible chronic process

Use to evaluate calcium dysregulation

Aid in the evaluation of unexplained hypercalcemia, particularly in suspected hypercalcemia of malignancy

Aid in the diagnosis of and monitoring of treatment for hypercalcemia

Highly specific test for PTHrP

Amino (N)- and carboxy (C )-terminus PTHrP fragments, such as those produced by some patients with renal insufficiency, do not interfere with this assay

Results should not be interpreted as absolute evidence of presence of hypercalcemia

Distinguish between primary hyperparathyroidism and familial benign hypercalcemia

Related Tests

Evaluate for kidney dysfunction

Panel includes albumin, calcium, carbon dioxide, creatinine, chloride, glucose, phosphorous, potassium, sodium, blood urea nitrogen (BUN), and a calculated anion gap value

May be useful for evaluating calcium metabolism in individuals with hypercalcemia or renal failure in addition to vitamin D, 25-hydroxy testing

Test is not appropriate for diagnosing vitamin D deficiency or insufficiency

Preferred test to diagnose vitamin D insufficiency and monitor response to therapy

Testing is recommended only for patients at risk for vitamin D insufficiency

Screening test to evaluate kidney function

Screening test to evaluate kidney function

Assay interference (negative) may be observed when high concentrations of N-acetylcysteine (NAC) are present

Negative interference has also been reported with NAPQI (an acetaminophen metabolite) but only when concentrations are at or above those expected during acetaminophen overdose

Medical Experts

Contributor

Pearson

Lauren N. Pearson, DO, MPH
Lauren N. Pearson, DO, MPH
Assistant Professor of Clinical Pathology, University of Utah
Laboratory Director for ARUP at University of Utah Health and Huntsman Cancer Institute
Laboratory Director, South Jordan and Sugarhouse Health Center Clinical Laboratories
Contributor

References

Additional Resources
Resources from the ARUP Institute for Clinical and Experimental Pathology®

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