Hypercalcemia

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 or normal – suggests hyperparathyroidism (elevated calcium should suppress PTH); order urine calcium (24-hour)
  - High – primary hyperparathyroidism
  - Low (<100) – familial benign hypercalcemia
- Low – order PTHrP
  - Low or normal – order vitamin D, 1,25
    - High – lymphoma or granulomatous disease (sarcoidosis)
    - Low – consider testing for cancer
  - High – cancer
Also consider testing for the following
- Vitamin D excess – order vitamin D, 25(OH)
- Milk-alkali syndrome
- Hyperthyroidism – order TSH

Differential Diagnosis

See Etiology for differential diagnoses

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
- B-cell lymphomas
- T/NK-cell lymphomas
Drugs
- Thiazides
- Lithium
- Vitamin excess – D and A
Milk-alkali syndrome
Immobilization
Chronic renal disease
Thyrotoxicosis
Granulomatous disease – elevated vitamin D, 1,25-dihydroxy
- Sarcoidosis
- Leprosy
- Wegener granulomatosis
- M. tuberculosis
- Histoplasma spp
- Coccidioides immitis
- Berylliosis

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

Tests generally appear in the order most useful for common clinical situations

Test name: Renal Function Panel

ARUP #: 0020144

Methodology: Refer to individual components

Use:

Screen kidney function

Panel includes albumin, calcium, carbon dioxide, creatinine, chloride, glucose, phosphorous, potassium, sodium, and BUN

Test name: Parathyroid Hormone, Intact with Calcium

ARUP #: 0070172

Methodology: Quantitative Electrochemiluminescent Immunoassay

Use: Diagnose hyperparathyroidism or hypercalcemia; result may also suggest differential diagnosis

Test name: Parathyroid Hormone-Related Peptide (PTHrP)

ARUP #: 0093014

Methodology: Quantitative Immunoradiometric Assay

Use: Differential diagnosis of hyperparathyroidism

Test name: Calcium, Ionized, Serum

ARUP #: 0020135

Methodology: Ion-Selective Electrode/pH-Electrode

Use: Diagnose hyperparathyroidism

Test name: Vitamin D, 25-Hydroxy

ARUP #: 0080379

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Assess vitamin D status

Additional Tests Available

Test name: Vitamin D, 1, 25-Dihydroxy

ARUP #: 0080385

Methodology: Quantitative Radioimmunoassay

Comments:

Primarily indicated during patient evaluations for hypercalcemia and renal failure

Should not be used to diagnose vitamin D deficiency; however, normal result does not rule out vitamin D deficiency

The recommended test for diagnosing vitamin D deficiency is Vitamin D 25-hydroxy

Test name: Calcium, Serum or Plasma

ARUP #: 0020027

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Calcium, Ionized, Whole Blood

ARUP #: 0020140

Methodology: Ion-Selective Electrode/pH-Electrode

Comments:

Test name: Parathyroid Hormone, Intact

ARUP #: 0070346

Methodology: Quantitative Electrochemiluminescent Immunoassay

Comments:

Test name: Parathyroid Hormone, CAP

ARUP #: 0095611

Methodology: Immunoradiometry

Comments:

Test name: Urea Nitrogen, Serum or Plasma

ARUP #: 0020023

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Creatinine, Serum or Plasma

ARUP #: 0020025

Methodology: Quantitative Enzymatic

Comments:

Test name: Electrolyte Panel

ARUP #: 0020410

Methodology: Quantitative Ion-Selective Electrode/Enzymatic

Comments:

Test name: Albumin, Serum by Nephelometry

ARUP #: 0050671

Methodology: Quantitative Nephelometry

Comments:

Test name: Phosphorus, Inorganic, Plasma or Serum

ARUP #: 0020028

Methodology: Quantitative Spectrophotometry

Comments:

Test name: Glucose, Plasma or Serum

ARUP #: 0020024

Methodology: Quantitative Enzymatic

Comments:

Test name: Potassium, Plasma or Serum

ARUP #: 0020002

Methodology: Quantitative Ion-Selective Electrode

Comments:

Test name: Sodium, Plasma or Serum

ARUP #: 0020001

Methodology: Quantitative Ion-Selective Electrode

Comments:

Test name: Chloride, Serum or Plasma

ARUP #: 0020003

Methodology: Quantitative Ion-Selective Electrode

Comments:

Test name: Carbon Dioxide, Serum or Plasma

ARUP #: 0020004

Methodology: Quantitative Enzymatic

Comments:

Test name: Albumin, Serum or Plasma by Spectrophotometry

ARUP #: 0020030

Methodology: Quantitative Spectrophotometry

Comments:

General

ARUP Institute for Clinical and Experimental Pathology®

Comprehensive Review: March 2011
Last Update: March 2011

Electrolyte Abnormalities, Life Threatening

Nephrolithiasis

Pheochromocytoma

Sarcoidosis