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hypercalcemia

Elevation of serum/plasma Ca+2, clinically significant when ionized Ca+2 is increased. Albumin binds 45% of serum Ca+2, thus a normal calcium in the face of hypoalbuminemia may result in clinically significant hypercalcemia. Etiology: 1) common causes of hypercalcemia: a) primary hyperparathyroidism - most cases of hypercalcemia in ambulatory patients [2,3] - 85% are due to adenoma of a single gland - 15% due to hyperplasia of all 4 glands - 1% due to parathyroid carcinoma b) hypercalcemia of malignancy - responsible for most hypercalcemia found in hospitalized patients - see pathology 2) uncommon causes of hypercalcemia a) granulomatous disease - sarcoidosis - Wegener's granulomatosis - pulmonary mycosis - Mycobacterium tuberculosis or Mycobacterium leprae b) hyperthyroidism (thyrotoxicosis) c) prolonged immobilization d) familial hypocalciuric hypercalcemia e) renal failure f) adrenal insufficiency g) elevated plasma protein concentration 3) pharmacologic causes: a) antacids with absorbable alkali (milk-alkali syndrome) b) thiazides (not PTH-mediated) c) vitamin D, vitamin A [3] d) lithium carbonate (PTH-mediated) e) estrogens & antiestrogens f) androgens g) vitamin D & calcium supplementation in postmenopausal women [7] h) total parenteral nutrition [3] Epidemiology: - primary hyperparathyroidism a) common, especially in elderly women b) annual incidence of 2/1000 Pathology: 1) hypercalcemia of malignancy occurs largely via 2 mechanisms: a) local osteolytic hypercalcemia - cytokines produced by tumor cells act locally to stimulate bone resorption - extensive bone involvement of tumor, especially in breast carcinoma, multiple myeloma & lymphoma b) 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 - squamous cell carcinoma of the lung, head & neck cancer, esophageal cancer, kidney cancer, bladder cancer, & ovarian cancer are most frequently implicated - in B-cell lymphoma, increased 1-alpha hydroxylase activity can result in increased calcitriol [3,9] 2) granulomatous disease - in the setting of renal failure, macrophage 25-hydroxyvitamin D-1 alpha hydroxylase activity can result in increased calcitriol Clinical manifestations: 1) most patients with primary hyperparathyroidism have asymptomatic hypercalcemia found incidentally 2) GU: polyuria, polydypsia, nocturia, dehydration, nephrolithiasis, nephrocalcinosis, acute renal failure 3) GI: nausea/vomiting, anorexia, constipation, abdominal pain, pancreatitis 4) neurologic: muscle weakness, fatigue, confusion, psychosis, delirium, stupor, coma 5) cardiac: hypertension, increased susceptibility to digitalis toxicity 6) skeletal changes: bone pain, fractures, osteoporosis 7) clinical manifestations of hypercalcemia tend to occur when serum Ca+2 rises above 12 mg/dL - may include mental status changes & coma > 14 mg/dL 8) ectopic soft tissue calcification occurs when the Ca+2 rises above 13 mg/dL * Mnemonic: bones, stones, groans, thrones, psychiatric overtones Laboratory: 1) calcium in 24 hour urine excretion generally > 4 mg/kg - collect with urine creatinine, calculate calcium/creatinine in urine - high with hyperparathyroidism - high with sarcoidosis - low with familial hypocalciuric hypercalcemia, vitamin D toxicity, thiazide diuretics [3] - unnecessary if immobilization suspected causes 2) serum ionized Ca+2 3) serum Ca+2: high* - serum Ca+2 > 12 mg/dL = hypercalcemia of malignancy or milk-alkali syndrome 4) serum phosphate - low with primary hyperparathyroidism - normal or low with humoral hypercalcemia of malignancy, local osteolysis [3,6] - high with multiple myeloma, granulomatous disease (sarcoidosis, tuberculosis B-cell lymphoma), milk alkali syndrome 5) serum parathyroid hormone (PTH)* a) increased or inappropriately normal with primary hyperparathyroidism b) decreased with hypercalcemia of malignancy or local osteolysis, typically < 10-15 pg/mL [6] 6) serum parathyroid-related peptide [6] - elevated with humoral hypercalcemia of malignancy 7) bone alkaline phosphatase in serum if immobilization suspected cause [3] 8) 25-OH vitamin D in serum - suspected vitamin D toxicity - 1,25-dihydroxyvitamin D in serum if granulomatous disease suspected 9) other serum chemistries: serum chloride & serum albumin 10) complete blood count (CBC) 11) serum protein electrophoresis if proteinuria +/- anemia [11] 12) see ARUP consult [5] * simultaneous measurement of serum calcium & serum PTH facilitates classification as PTH-related or non-PTH-related hypercalcemia, thus serum PTH takes priority over serum ionized Ca+2 [3,11] Special laboratory: - electrocardiogram: a) shortened QT interval b) AV block (rare) Management: (see hypercalcemia of malignancy) 1) hydration with normal saline a) 1st line therapy for acute hypercalcemia (symptomatic or serum calcium > 14 mg/dL) b) follow with furosemide diuresis if renal failure, heart failure or hypervolemia, otherwise avoid loop diuretics [3] c) avoid thiazide diuretics which impair Ca+2 excretion 2) glucocorticoids for (1,25 (OH)2 vit D-mediated hypercalcemia - multiple myeloma, B-cell lymphoma, sarcoidosis 3) IV bisphosphonate (pamidronate, etidronate, zoledronate) for longer-term control 4) calcitonin causes a rapid but short-lived drop in serum Ca+2 & serum phosphate by promoting incorporation into bone 5) plicamycin (mithramycin) - reserved for volume-repleted patients who have failed pamidronate & calcitonin 6) oral phosphate 7) gallium nitrate

Related

calcium (Ca+2) in serum/plasma hyperparathyroidism milk-alkali syndrome (Burnett syndrome)

Specific

familial hypocalciuric hypercalcemia hypercalcemia of malignancy

General

disorder of calcium metabolism electrolyte disorder sign/symptom

References

  1. Harrison's Principles of Internal Medicine, 13th ed. Companion Handbook, Isselbacher et al (eds), McGraw-Hill Inc. NY, 1995, pg 830
  2. Manual of Medical Therapeutics, 28th ed, Ewald & McKenzie (eds), Little, Brown & Co, Boston, 1995, pg 490
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 680-681
  5. ARUP Consult: Hypercalcemia The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/hypercalcemia - Hypercalcemia Testing Algorithm https://arupconsult.com/algorithm/hypercalcemia-testing-algorithm
  6. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
  7. Gallagher JC et al Incidence of hypercalciuria and hypercalcemia during vitamin D and calcium supplementation in older women. Menopause. June 16m 2014 PMID: 24937025 http://journals.lww.com/menopausejournal/Abstract/publishahead/Incidence_of_hypercalciuria_and_hypercalcemia.98368.aspx
  8. Donovan PJ, Sundac L, Pretorius CJ et al Calcitriol-mediated hypercalcemia: causes and course in 101 patients. J Clin Endocrinol Metab. 2013 Oct;98(10):4023-9. PMID: 23979953
  9. NEJM Knowledge+ Question of the Week. Dec 29, 2020 https://knowledgeplus.nejm.org/question-of-week/1660/ - Goldner W. Cancer-related hypercalcemia. J Oncol Pract 2016 May; 12:426. PMID: 27170690 - Zagzag J et al. Hypercalcemia and cancer: differential diagnosis and treatment. CA Cancer J Clin 2018 Sep; 68:377. PMID: 30240520 DOI: Free article
  10. NEJM Knowledge+ Nephrology/Urology
  11. Insogna KL. Primary hyperparathyroidism. N Engl J Med. 2018;379:1050-1059. PMID: 30207907
  12. Hypercalcemia (PDQ) http://www.cancer.gov/cancertopics/pdq/supportivecare/hypercalcemia/HealthProfessional