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.
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
- Calculate corrected calcium
- 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
- Elevated or normal – indicates primary hyperparathyroidism; order urine calcium, 24-hour collection
- 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
- Sarcoidosis
- Mycobacterium leprae
- Granulomatosis with polyangiitis
- Mycobacterium tuberculosis
- Histoplasma spp
- Coccidioides immitis
- Berylliosis
- 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
- Adenoma
- Hyperplasia
- Carcinoma (rare)
- 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
- Presence of humoral factors that mimic PTH action
- 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
- 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
- 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
- MEN
ARUP Laboratory Tests
Use to diagnose disorders of calcium metabolism
Ion-Selective Electrode/pH Electrode
May assist in assessing nutritional status or in indicating a possible chronic process
Quantitative Spectrophotometry
Use to evaluate calcium dysregulation
Quantitative Electrochemiluminescent Immunoassay
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
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Distinguish between primary hyperparathyroidism and familial benign hypercalcemia
Quantitative Spectrophotometry
Evaluate for kidney dysfunction
Quantitative Chemiluminescent Immunoassay/Quantitative Enzyme-Linked Immunosorbent Assay
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
Quantitative Chemiluminescent Immunoassay
Preferred test to diagnose vitamin D insufficiency and monitor response to therapy
Testing is recommended only for patients at risk for vitamin D insufficiency
Quantitative Chemiluminescent Immunoassay
Screening test to evaluate kidney function
Quantitative Spectrophotometry
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
Quantitative Enzymatic Assay
Quantitative Spectrophotometry
Quantitative Electrochemiluminescent Immunoassay
Quantitative Ion-Selective Electrode/Enzymatic Assay
Quantitative Spectrophotometry
Quantitative Enzymatic Assay
Quantitative Ion-Selective Electrode
Quantitative Ion-Selective Electrode
Quantitative Ion-Selective Electrode
Quantitative Enzymatic Assay
Quantitative Chemiluminescent Immunoassay
References
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Medical Experts
Pearson

Straseski

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