Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 21-08: Hypercalcemia + Key Features Download Section PDF Listen +++ +++ Essentials of Diagnosis ++ Most common causes: primary hyperparathyroidism and malignancy-associated hypercalcemia Hypercalciuria usually precedes hypercalcemia Asymptomatic, mild hypercalcemia (≥ 10.5 mg/dL [or 2.6 mmol/L]) is usually due to primary hyperparathyroidism Symptomatic, severe hypercalcemia (≥ 14 mg/dL [or 3.5 mmol/L]) is due to hypercalcemia of malignancy +++ General Considerations ++ Important causes of hypercalcemia are listed in Table 21–7 Primary hyperparathyroidism and malignancy account for 90% of cases Primary hyperparathyroidism is the most common cause of hypercalcemia (usually mild) in ambulatory patients Chronic hypercalcemia (over 6 months) or some manifestation such as nephrolithiasis also suggests a benign cause Tumor production of PTH-related proteins (PTHrP) Most common paraneoplastic endocrine syndrome, accounting for most cases of hypercalcemia in inpatients The neoplasm is clinically apparent in nearly all cases when the hypercalcemia is detected Granulomatous diseases, such as sarcoidosis and tuberculosis, cause hypercalcemia via overproduction of active vitamin D3 (1,25 dihydroxyvitamin D3) Milk-alkali syndrome has had a resurgence due to calcium ingestion for prevention of osteoporosis Hypercalcemia causes nephrogenic DI through activation of calcium-sensing receptors in collecting ducts, which reduces ADH-induced water permeability Volume depletion further worsens hypercalcemia ++Table Graphic Jump LocationTable 21–7.Causes of hypercalcemia.View Table||Download (.pdf) Table 21–7. Causes of hypercalcemia. Increased intake or absorption Milk-alkali syndrome Vitamin D or vitamin A excess Endocrine disorders Primary hyperparathyroidism Secondary or tertiary hyperparathyroidism (usually associated with hypocalcemia) Acromegaly Adrenal insufficiency Pheochromocytoma Thyrotoxicosis Neoplastic diseases Tumors producing PTH-related proteins (ovary, kidney, lung) Plasma cell myeloma (elaboration of osteoclast-activating factor) Lymphoma (occasionally from production of calcitriol) Miscellaneous causes Thiazide diuretics Granulomatous diseases (production of calcitriol) Paget disease of bone Hypophosphatasia Immobilization Familial hypocalciuric hypercalcemia Complications of kidney transplantation Lithium intake PTH, parathyroid hormone. + Clinical Findings Download Section PDF Listen +++ +++ History and physical examination ++ Should focus on the duration of hypercalcemia and evidence for a neoplasm +++ Symptoms and Signs ++ May affect gastrointestinal, kidney, and neurologic function Mild hypercalcemia is often asymptomatic Symptoms usually occur if the serum calcium is > 12 mg/dL (or > 3 mmol/L) and tend to be more severe if hypercalcemia develops acutely Constipation and polyuria Polyuria is absent in hypocalciuric hypercalcemia Polyuria from hypercalciuria-induced nephrogenic diabetes insipidus can result in volume depletion and acute kidney injury Other abdominal symptoms include Nausea Vomiting Anorexia Peptic ulcer disease Renal colic Hematuria from nephrolithiasis Neurologic manifestations may range from mild drowsiness to weakness, depression, lethargy, stupor, and coma in severe cases Ventricular ectopy and idioventricular rhythm occur and can be accentuated by digitalis + Diagnosis Download Section PDF Listen +++ +++ Laboratory Tests ++ The ionized calcium exceeds 1.32 mmol/L A high serum chloride concentration and a low serum phosphate concentration in a ratio > 33:1 (or > 102 if SI units are utilized) suggests primary hyperparathyroidism where PTH decreases proximal tubular phosphate reabsorption A low serum chloride concentration with a high serum bicarbonate concentration, along with elevated BUN and creatinine, suggests milk-alkali syndrome Severe hypercalcemia (> 15 mg/dL [3.75 mmol/L]) generally occurs in malignancy More than 300 mg (7.5 mmol) per day of urinary calcium excretion suggests hypercalciuria; < 100 mg (2.5 mmol) per day suggests hypocalciuria Hypercalciuric patients (such as those with malignancy or those receiving oral active vitamin D therapy) May easily develop hypercalcemia in case of volume depletion Serum phosphate may or may not be low, depending on the cause. Hypocalciuric hypercalcemia occurs in milk-alkali syndrome, thiazide diuretic use, and familial hypocalciuric hypercalcemia +++ Imaging Studies ++ Chest radiograph: to exclude malignancy or granulomatous disease +++ Diagnostic Procedures ++ ECG: shortened QT interval + Treatment Download Section PDF Listen +++ +++ Medications ++ Renal excretion of calcium is promoted through aggressive hydration and forced calciuresis until the primary cause can be identified and treated In volume-depleted patients with normal cardiac and kidney function, 0.45% saline or 0.9% saline can be given rapidly (250–500 mL/h) Bisphosphonates Treatment of choice for hypercalcemia of malignancy; they are safe, effective, and normalize calcium in more than 70% of patients May require up to 48–72 hours before reaching full therapeutic effect Calcitonin may be helpful in the short-term until bisphosphonates reach therapeutic levels Denosumab A monoclonal antibody against RANKL Inhibits osteoclasts, reducing bone resorption and serum calcium levels FDA-approved for malignancy-associated hypercalcemia refractory to bisphosphonate therapy Cinacalcet Calcimimetic agent Suppresses PTH secretion and decreases serum calcium concentration Has been recommended for use in patients with symptomatic or severe primary hyperparathyroidism who are unable to undergo parathyroidectomy and patients with inoperable parathyroid carcinoma Loop diuretics Should generally be avoided due to possible complications, such as nephrolithiasis May be carefully used in the context of preventing or managing volume overload, particularly in patients with heart failure or kidney dysfunction Thiazides can worsen hypercalcemia +++ Therapeutic Procedures ++ In emergency cases, dialysis with low calcium dialysate may be needed Hypercalcemia in dialysis patients Usually occurs in the presence of hyperphosphatemia Metastatic calcification may occur Malignancy should be considered as a cause of the hypercalcemia + Outcome Download Section PDF Listen +++ +++ Prognosis ++ Depends on the underlying disease Poor prognosis in malignancy +++ Prevention ++ Prevent dehydration that can further aggravate hypercalcemia +++ When to Refer ++ Patients may require referral to an oncologist or endocrinologist depending on the underlying cause of hypercalcemia Patients with granulomatous diseases (eg, tuberculosis and other chronic infections, granulomatosis with polyangiitis, sarcoidosis) may require consultation with infectious disease specialists, rheumatologists, or pulmonologists +++ When to Admit ++ Patients with symptomatic or severe hypercalcemia require immediate treatment Unexplained hypercalcemia with associated conditions, such as acute kidney injury or suspected malignancy, may also require urgent treatment and expedited evaluation + References Download Section PDF Listen +++ + +Ahmad S et al. Hypercalcemic crisis: a clinical review. Am J Med. 2015 Mar;128(3):239–45. [PubMed: 25447624] + +Bazari H et al. Case Records of the Massachusetts General Hospital. Case 24-2016. A 66-year-old man with malaise, weakness, and hypercalcemia. N Engl J Med. 2016 Aug 11;375(6):567–74. [PubMed: 27509105] + +Minisola S et al. The diagnosis and management of hypercalcaemia. BMJ. 2015 Jun 2;350:h2723. [PubMed: 26037642] + +Tebben PJ et al. Vitamin D-mediated hypercalcemia: mechanisms, diagnosis, and treatment. Endocr Rev. 2016 Oct;37(5):521–47. [PubMed: 27588937] + +Thosani S et al. Denosumab: a new agent in the management of hypercalcemia of malignancy. Future Oncol. 2015;11(21):2865–71. [PubMed: 26403973]