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Hypercalcemia classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Anmol Pitliya, M.B.B.S. M.D.[2]

Overview

Overview

There are several ways in which hypercalcemia may be classified. Common Terminology Criteria for Adverse Events (CTCAE) grade classifies hypercalcemia into 4 grades on the basis of corrected serum calcium (CSC). Hypercalcemia may be classified according to severity into 3 groups including mild, moderate, and severe hypercalcemia. Hypercalcemia associated with malignancy may be classified according to mechanism of increased production of calcium.

Classification

Classification

Common Terminology Criteria for Adverse Events (CTCAE) grade:

Common Terminology Criteria for Adverse Events (CTCAE) grade classifies hypercalcemia into 4 grades on the basis of corrected serum calcium (CSC):[1]

Grade Corrected serum calcium (CSC)
Grade 1 Corrected serum calcium of >ULN – 11.5 mg/dL; >ULN – 2.9 mmol/L; Ionized calcium >ULN – 1.5 mmol/L
Grade 2 Corrected serum calcium of >11.5 – 12.5 mg/dL; >2.9 – 3.1 mmol/L; Ionized calcium >1.5 – 1.6 mmol/L; symptomatic
Grade 3 Corrected serum calcium of >12.5 – 13.5 mg/dL; >3.1 – 3.4 mmol/L; Ionized calcium >1.6 – 1.8 mmol/L; hospitalization indicated
Grade 4 Corrected serum calcium of >13.5 mg/dL; >3.4 mmol/L; Ionized calcium >1.8 mmol/L; life-threatening consequences
  • ULN= Upper limit of normal (10.8 mg/dL)
  • “Corrected calcium” may lead to confusion that the result is due to error and shall be corrected. So, the term “adjusted” calcium is preferred over “corrected” calcium.[2]
  • Adjusted total calcium(mg/dL) = Total calcium(mg/dL) + 0.8 [4−Albumin(g/dL)] or Adjusted total calcium(mmol/L) =Total calcium (mmol/L) + 0.02 [40−Albumin(g/L)][2][3]

Based on severity

Hypercalcemia may be classified according to severity into 3 groups:[4]

Severity Calcium concentration Key Points
Mild hypercalcemia <3.0 mmol/L
  • Often asymptomatic
  • No urgent correction needed
Moderate hypercalcemia 3.0–3.5 mmol/L
  • Tolerated well if there is a slow rise
  • Symptoms may be present
  • Treatment indicated in symptomatic cases
Severe hypercalcemia >3.5 mmol/L
  • Urgent correction is recommended
  • Risk of dysrhythmia and coma if not corrected

Classification of hypercalcemia associated with malignancy

Hypercalcemia associated with malignancy may be classified according to mechanism of increased production of calcium into four types:[5][6]

Disorder Mechanism of hypercalcemia Clinical features Laboratory findings
PTH Calcium Phosphate Other findings
Humoral hypercalcemia of malignancy[7][8][9][10] Tumor cells secretes parathyroid hormone-related protein (PTHrP) which has similar action as parathyroid hormone. — ↑ ↓/Normal ↑ PTHrP
Normal/↑ calcitriol
Osteolytic tumors[11][12] Multiple myeloma produces osteolysis of bones causing hypercalcemia. Osteolytic metasteses can cause bone resorption causing hypercalcemia. ↓ ↑ — —
Production of calcitirol[13] Some tumors has ectopic activity of 1-alpha-hydroxylase leading to increased production of calcitriol. Calcitriol is active form of vitamin D and causes hypercalcemia. — ↑ — ↑ Calcitriol
Ectopic parathyroid hormone[14] Some tumors leads to ectopic production of parathyroid hormone. ↑ ↑ ↓/Normal Normal/↑ calcitriol
References

References

  1. ↑ US Department of Health and Human Services . National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 5.0. Published: November 27, 2017.
  2. ↑ 2.0 2.1 Fraser, William D. (2018). “63. Bone and Mineral Metabolism”. In Rifai, Nader. Tietz textbook of clinical chemistry and molecular diagnostics. St. Louis, Missouri: Elsevier. ISBN 0323359213.
  3. ↑ Maier JD, Levine SN (2015). “Hypercalcemia in the Intensive Care Unit: A Review of Pathophysiology, Diagnosis, and Modern Therapy”. J Intensive Care Med. 30 (5): 235–52. doi:10.1177/0885066613507530. PMID 24130250.
  4. ↑ Walsh J, Gittoes N, Selby P, Society for Endocrinology Clinical Committee (2016). “SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute hypercalcaemia in adult patients”. Endocr Connect. 5 (5): G9–G11. doi:10.1530/EC-16-0055. PMC 5314807. PMID 27935816.
  5. ↑ Mirrakhimov AE (2015). “Hypercalcemia of Malignancy: An Update on Pathogenesis and Management”. N Am J Med Sci. 7 (11): 483–93. doi:10.4103/1947-2714.170600. PMC 4683803. PMID 26713296.
  6. ↑ Stewart AF (2005). “Clinical practice. Hypercalcemia associated with cancer”. N Engl J Med. 352 (4): 373–9. doi:10.1056/NEJMcp042806. PMID 15673803.
  7. ↑ Ratcliffe WA, Hutchesson AC, Bundred NJ, Ratcliffe JG (1992). “Role of assays for parathyroid-hormone-related protein in investigation of hypercalcaemia”. Lancet. 339 (8786): 164–7. doi:10.1016/0140-6736(92)90220-W. PMID 1346019.
  8. ↑ Ikeda K, Ohno H, Hane M, Yokoi H, Okada M, Honma T, Yamada A, Tatsumi Y, Tanaka T, Saitoh T (1994). “Development of a sensitive two-site immunoradiometric assay for parathyroid hormone-related peptide: evidence for elevated levels in plasma from patients with adult T-cell leukemia/lymphoma and B-cell lymphoma”. J. Clin. Endocrinol. Metab. 79 (5): 1322–7. doi:10.1210/jcem.79.5.7962324. PMID 7962324.
  9. ↑ Horwitz MJ, Tedesco MB, Sereika SM, Hollis BW, Garcia-Ocaña A, Stewart AF (2003). “Direct comparison of sustained infusion of human parathyroid hormone-related protein-(1-36) [hPTHrP-(1-36)] versus hPTH-(1-34) on serum calcium, plasma 1,25-dihydroxyvitamin D concentrations, and fractional calcium excretion in healthy human volunteers”. J. Clin. Endocrinol. Metab. 88 (4): 1603–9. doi:10.1210/jc.2002-020773. PMID 12679445.
  10. ↑ Stewart AF, Vignery A, Silverglate A, Ravin ND, LiVolsi V, Broadus AE; et al. (1982). “Quantitative bone histomorphometry in humoral hypercalcemia of malignancy: uncoupling of bone cell activity”. J Clin Endocrinol Metab. 55 (2): 219–27. doi:10.1210/jcem-55-2-219. PMID 7085851.
  11. ↑ Roodman GD (2004). “Mechanisms of bone metastasis”. N Engl J Med. 350 (16): 1655–64. doi:10.1056/NEJMra030831. PMID 15084698.
  12. ↑ Guise TA, Yin JJ, Taylor SD, Kumagai Y, Dallas M, Boyce BF; et al. (1996). “Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis”. J Clin Invest. 98 (7): 1544–9. doi:10.1172/JCI118947. PMC 507586. PMID 8833902.
  13. ↑ Seymour JF, Gagel RF, Hagemeister FB, Dimopoulos MA, Cabanillas F (1994). “Calcitriol production in hypercalcemic and normocalcemic patients with non-Hodgkin lymphoma”. Ann Intern Med. 121 (9): 633–40. PMID 7944070.
  14. ↑ VanHouten JN, Yu N, Rimm D, Dotto J, Arnold A, Wysolmerski JJ, Udelsman R (2006). “Hypercalcemia of malignancy due to ectopic transactivation of the parathyroid hormone gene”. J. Clin. Endocrinol. Metab. 91 (2): 580–3. doi:10.1210/jc.2005-2095. PMID 16263810.

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