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.

Tabs Content

Clinical Overview

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
- 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
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

ARUP Lab Tests

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.

Calcium, Ionized, Serum 0020135
Method: Ion-Selective Electrode/pH Electrode

Recommended Use

Use to diagnose disorders of calcium metabolism

Albumin by Nephelometry 0050671
Method: Quantitative Nephelometry

Recommended Use

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

Parathyroid Hormone, Intact with Calcium 0070172
Method: Quantitative Electrochemiluminescent Immunoassay

Recommended Use

Use to evaluate calcium dysregulation

Parathyroid Hormone-Related Peptide (PTHrP) by LC-MS/MS, Plasma 2010677
Method: Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry

Recommended Use

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

Limitations

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

Calcium, Urine 0020472
Method: Quantitative Spectrophotometry

Recommended Use

Distinguish between primary hyperparathyroidism and familial benign hypercalcemia

Medical Experts

Pearson, Lauren N., DO, MPH, Medical Director, University of Utah Health Hospital Clinical Laboratory; Assistant Professor of Clinical Pathology, University of Utah

Straseski, Joely A., PhD, MS, MT(ASCP), DABCC, Medical Director, Endocrinology and Automated Core Laboratory at ARUP Laboratories; Associate Professor of Clinical Pathology, University of Utah

References

General References

Chang WW, Radin B, McCurdy MT. Calcium, magnesium, and phosphate abnormalities in the emergency department. Emerg Med Clin North Am. 2014; 32(2): 349-66. PubMed

Cooper MS. Disorders of calcium metabolism and parathyroid disease. Best Pract Res Clin Endocrinol Metab. 2011; 25(6): 975-83. PubMed

Endres DB. Investigation of hypercalcemia. Clin Biochem. 2012; 45(12): 954-63. PubMed

Lynn J, Patel T. Blood testing diagnostic for parathyroid disease. Practitioner. 2007; 251(1692): 69-70, 72-3. PubMed

Marcocci C, Cetani F. Clinical practice. Primary hyperparathyroidism. N Engl J Med. 2011; 365(25): 2389-97. PubMed

Michels TC, Kelly KM. Parathyroid disorders. Am Fam Physician. 2013; 88(4): 249-57. PubMed

Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ. 2015; 350: h2723. PubMed

Sharma B, Misicko NE, Hitchcock K, Neher JO. Clinical inquiries. How should you evaluate elevated calcium in an asymptomatic patient? J Fam Pract. 2008; 57(4): 267-9. PubMed

Walsh J, Gittoes N, Selby P, Society for Endocrinology Clinical Committee. Society for Endocrinology Endocrine Emergency Guidance: Emergency management of acute hypercalcaemia in adult patients. Endocr Connect. 2016; 5(5): G9-G11. PubMed

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Abraham D, Sharma PK, Bentz J, Gault PM, Neumayer L, McClain DA. Utility of ultrasound-guided fine-needle aspiration of parathyroid adenomas for localization before minimally invasive parathyroidectomy. Endocr Pract. 2007; 13(4): 333-7. PubMed

Fritchie K, Zedek D, Grenache DG. The clinical utility of parathyroid hormone-related peptide in the assessment of hypercalcemia. Clin Chim Acta. 2009; 402(1-2): 146-9. PubMed

Hoofnagle AN, Whiteaker JR, Carr SA, Kuhn E, Liu T, Massoni SA, Thomas SN, Townsend R, Zimmerman LJ, Boja E, Chen J, Crimmins DL, Davies SR, Gao Y, Hiltke TR, Ketchum KA, Kinsinger CR, Mesri M, Meyer MR, Qian W, Schoenherr RM, Scott MG, Shi T, Whiteley GR, Wrobel JA, Wu C, Ackermann BL, Aebersold R, Barnidge DR, Bunk DM, Clarke N, Fishman JB, Grant RP, Kusebauch U, Kushnir MM, Lowenthal MS, Moritz RL, Neubert H, Patterson SD, Rockwood AL, Rogers J, Singh RJ, Van Eyk JE, Wong SH, Zhang S, Chan DW, Chen X, Ellis MJ, Liebler DC, Rodland KD, Rodriguez H, Smith RD, Zhang Z, Zhang H, Paulovich AG. Recommendations for the Generation, Quantification, Storage, and Handling of Peptides Used for Mass Spectrometry-Based Assays. Clin Chem. 2016; 62(1): 48-69. PubMed

Kushnir MM, Rockwood AL, Strathmann FG, Frank EL, Straseski JA, Meikle W. LC-MS/MS Measurement of Parathyroid Hormone-Related Peptide. Clin Chem. 2016; 62(1): 218-26. PubMed

Testing Algorithms

Hypercalcemia Testing Algorithm

Read more about Hypercalcemia Testing Algorithm

Educational Videos

Last Update: July 2018

Hypercalcemia

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Etiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Hypercalcemia Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult


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	Hypercalcemia. ARUP Consult^©. Retrieved June 20, 2019, from: https://arupconsult.com/content/hypercalcemia

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Hypercalcemia

Diagnosis

Indications for Testing

Laboratory Testing

Differential Diagnosis

Background

Epidemiology

Etiology

Pathophysiology

Clinical Presentation

ARUP Lab Tests

Medical Experts

References

General References

Resources from the ARUP Institute for Clinical and Experimental Pathology®

Hypercalcemia Testing Algorithm

ARUP Laboratories

ARUP Websites

ARUP Consult