hypercalcemia of malignancy
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Etiology
- local osteolytic hypercalcemia
- humoral hypercalcemia of malignancy
- increased calcitriol
- immobilization worsens hypercalcemia
Epidemiology
- often discovered in hospitalized patients
- the most common cause of hypercalcemia in hospitalized patients[1]
- often occurs as an end-stage complication
Pathology
- local osteolytic hypercalcemia
- cytokines produced by tumor cells act locally to stimulate bone resorption
- extensive bone involvement of tumor, especially in breast carcinoma, myeloma & lymphoma
- humoral hypercalcemia of malignancy
- PTH-related peptide or other related peptides secreted by tumor cells act systemically to stimulate bone resorption &/or inhibit Ca+2 excretion
- *unregulated production of 1,25 (OH)2 vit D3 (generally B-cell lymphoma*)
- other implicated proteins
Clinical manifestations
- a diagnosis of malignancy is generally already established
- manifestations of volume depletion & general debility may dominate the clinical picture
- manifestations of hypercalcemia
- gastrointestinal:
- renal:
- central nervous system
- cognitive difficulties, confusion, apathy, somnolence, coma
- cardiovascular:
- hypertension, enhanced sensitivity to digitalis
- diffuse muscle weakness[1]
Laboratory
- hypercalcemia moderate to severe
- serum Ca+2 > 12 mg/dL virtually assures diagnosis
- 24 hour urinary Ca+2 excretion is markedly elevated (> 4 mg/kg)
- serum PTH: endogenous PTH is suppressed
- immunoassay for serum PTH-related peptide
- diagnostic test of choice for humoral hypercalcemia of malignancy
- serum calcitriol
- low or normal
- indications:
- multiple myeloma
- B-cell lymphoma
- hormone sensitive breast cancer
- serum phosphate is normal or low
- serum sodium: hypernatremia if patient is dehydrated
Diagnostic procedures
- electrocardiogram: shortened QT-interval
Radiology
- plain radiographs as indicated
- bone scan
Management
- treatment of underlying malignancy
- intravenous volume expansion with normal saline increases urinary Ca+2 excretion (& Na+ excretion)
- loop diuretics after volume expansion if needed
- loop diuretics only if hypervolemia & heart failure or renal failure[1]
- furosemide inhibits Ca+2 resorption in the thick ascending loop of Henle
- cinacalcet is not indicated with furosemide[12]
- hemodialysis for severe hypercalcemia (> 18 mg/dL) or refractory hypercalcemia, especially if associated with renal failure[1]
- calcitonin recommended for immediate management of symptomatic hypercalcemia
- results in a rapid but short-lived drop in serum Ca+2 & serum phosphate by promoting incorporation of calcium into bone
- intravenous bisphosphonate pamidronate 60-90 mg IV over 24 hours most appropriate step after volume expansion[12]
- zoledronate also acceptable [NEJM Knowledge+]
- denosumab suggested vs bisphosphonate[15]
- bisphosphonate for chronic treatment[1]
- zoledronate (Zometa) over 15 minutes[3]
- treatment of choice (GRS9)[9]
- etidronate
- denosumab[10][11]; not indicated (GRS9, MKSAP19)[1][9]
- indicated for hypercalcemia refractory to bisphosphates[15]
- zoledronate (Zometa) over 15 minutes[3]
- plicamycin (mithramycin) 25 ug/kg IV over 4 hours
- gallium nitrate 200 mg/m2/day IV infusion for 5 days
- glucocorticoids
- calcitriol-mediated hypercalcemia
- multiple myeloma
- B-cell lymphoma
- hormone sensitive breast cancer
- sarcoidosis
- prednisone
- methylprednisolone
- IV bisphosphonate or denosumab if glucocorticoid-refractory[15]
- calcitriol-mediated hypercalcemia
- ketoconazole blocks 1,25 (OH)2 vit D-mediated hypercalcemia
- parathyroid carcinoma may be treated with calcimimetic &/or antiresorptive therapy[15]
- hypercalcemia of malignancy is often a pre-terminal event & aggressive management may not be indicated
- median survival for humoral hypercalcemia of malignancy is 52 days from date of serum PTH-related peptide measurement[6]
More general terms
Additional terms
References
- ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2015, 2018, 2021
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 680-681
- ↑ 3.0 3.1 Prescriber's Letter 8(9):53 2001
- ↑ Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005 Jan 27;352(4):373-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/15673803
- ↑ Clines GA. Mechanisms and treatment of hypercalcemia of malignancy. Curr Opin Endocrinol Diabetes Obes. 2011 Dec;18(6):339-46 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21897221
- ↑ 6.0 6.1 Donovan PJ et al. PTHrP-mediated hypercalcemia: Causes and survival in 138 patients. J Clin Endocrinol Metab 2015 May; 100:2024. PMID: https://www.ncbi.nlm.nih.gov/pubmed/25719931
- ↑ Ziegler R Hypercalcemic crisis. J Am Soc Nephrol. 2001 Feb;12 Suppl 17:S3-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/11251025
- ↑ Rosner MH, Dalkin AC. Onco-nephrology: the pathophysiology and treatment of malignancy-associated hypercalcemia. Clin J Am Soc Nephrol. 2012 Oct;7(10):1722-9. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22879438 Free Article
- ↑ 9.0 9.1 9.2 Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
- ↑ 10.0 10.1 Mirrakhimov AE.3. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. N Am J Med Sci. 2015 Nov;7(11):483-93. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26713296 Free PMC Article
- ↑ 11.0 11.1 Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag. 2015 Dec 4;11:1779-88. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26675713 Free PMC Article
- ↑ 12.0 12.1 12.2 NEJM Knowledge+ Question of the Week June 13, 2017 https://knowledgeplus.nejm.org/question-of-week/1011/
- ↑ NEJM Knowledge+ Question of the Week March 19, 2019 https://knowledgeplus.nejm.org/question-of-week/938/
Broadus AE, Mangin M, Ikeda K et al. Humoral hypercalcemia of cancer. Identification of a novel parathyroid hormone-like peptide. N Engl J Med 1988 Sep 1; 319:556 PMID: https://www.ncbi.nlm.nih.gov/pubmed/3043221 https://www.nejm.org/doi/full/10.1056/NEJM198809013190906
Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med 2005 Jan 27; 352:373 PMID: https://www.ncbi.nlm.nih.gov/pubmed/15673803 https://www.nejm.org/doi/full/10.1056/NEJMcp042806 - ↑ NEJM Knowledge+ Question of the Week May 14, 2019 https://knowledgeplus.nejm.org/question-of-week/887/
Mirrakhimov AE. Hypercalcemia of malignancy: an update on pathogenesis and management. N Am J Med Sci 2015 Nov; 7:483. PMID: https://www.ncbi.nlm.nih.gov/pubmed/26713296 Free PMC Article - ↑ 15.0 15.1 15.2 15.3 15.4 Dickens LT, Derman B, Alexander JT Endocrine Society Hypercalcemia of Malignancy Guidelines. JAMA Oncol. Published online January 13, 2023 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36637830 https://jamanetwork.com/journals/jamaoncology/fullarticle/2800546
- ↑ El-Hajj Fuleihan G, Clines GA Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2023 Feb 15;108(3):507-528. PMID: https://www.ncbi.nlm.nih.gov/pubmed/36545746
- ↑ Guise TA, Wysolmerski JJ Cancer-Associated Hypercalcemia. N Engl J Med. 2022 Apr 14;386(15):1443-1451. PMID: https://www.ncbi.nlm.nih.gov/pubmed/35417639 Review. No abstract available. https://www.nejm.org/doi/pdf/10.1056/NEJMcp2113128
- ↑ Zagzag J, Hu MI, Fisher SB, Perrier ND. Hypercalcemia and cancer: Differential diagnosis and treatment. CA Cancer J Clin. 2018 Sep;68(5):377-386. PMID: https://www.ncbi.nlm.nih.gov/pubmed/30240520 Free article. Review.