Hypercalcemia

Background

• Definitions: Mild is Ca<12 mg/dL; moderate 12-14; severe >14
• Etiology: Usually from hyperparathyroidism or malignancy; less commonly from granulomatous diseases such as sarcoidosis
  
• In hyperparathyroidism, PTH activates osteoclasts, which precipitate bone resorption, thus increasing serum calcium. 
• More severe hypercalcemia is usually due to malignancy, especially if there are bone metastases. This is usually due to secretion of PTH-related protein (PTHrP) in solid tumors and calcitriol production in lymphomas.
• Epidemiology: 
• 20-40% of cancer patients will have hypercalcemia; once this occurs, prognosis is poor
• Hyperparathyroidism is more common in older women

• Can be asymptomatic if mild elevation or have nonspecific symptoms such as fatigue, abdominal pain, depression
  
• Symptoms are more severe if the hypercalcemia is more acute and in the elderly
  
• In more moderate/severe hypercalcemia, patients can have bone pain, GI symptoms like nausea/vomiting or constipation, nephrolithiasis, kidney failure, altered mental status/coma, hypertension, bradycardia
• Some proposed mechanisms include affecting action potentials in muscle cells (decreased smooth muscle tone in the GI tract can cause constipation and shortening myocardial action potentials can cause arrythmias) and calcium depositions (in the pancreatic duct can cause pancreatitis; in the heart can cause cardiomyopathy)
• "Stones, bones, groans, moans" etc etc
• EKG may demonstrate a shortened QT interval due to altered transmembrane potential
• There are no reliable physical exam findings, however there might be evidence of underlying conditions such as malignancy

Workup

• Check an ionized calcium and calculate a corrected total calcium (because calcium binds albumin): corrected calcium = serum Ca + 0.8(4- serum albumin)
  
• Check renal function/BMP, PTH, PTHrP, phosphate
• Imaging would be to evaluate for malignancy

Treatment

• When to treat:
• Acute hypercalcemia (usually accompanied by GI or neuro symptoms)
• Severe (>14mg/dL) hypercalcemia 
• Ways to get rid of calcium: increase renal excretion, decrease gut absorption, decrease bone resorption, reduce PTH, dialysis
  
• Increase excretion: normal saline (inhibits proximal reabsorption of calcium), calcitonin, loop diuretics (note: lasix was thought to inhibit distal reabsorption of calcium, but this is unclear; the more important mechanism is that when given with NS, it causes excretion of saline, thus calcium gets washed out)
• Decrease gut absorption: glucocorticoids
• Decrease bone resorption: calcitonin, bisphosphonates (both inhibit osteoclasts)
• Reduce PTH: calcimimetics
• Initial treatment:
• Normal Saline at 250 mL/hr, titrate to urine output of 100-150 mL/hr
• Calcitonin (4-8 units/kg) q6-12 hours. This works quickly (onset in ~4 hours) and has minimal side effects. Only works for the first 48 hours. 
• Long term management:
• Bisphosphonates: more potent than calcitonin but takes 24-72 days to start working. Side effects include AKI, jaw osteonecrosis, uveitis
• Glucocorticoids: also delayed onset of 48+ hours. In addition to decreasing gut absorption, steroids can also decrease calcitriol (which can be elevated in hypercalcemia due to granulomatous diseases)
• Common mismanagement
• Giving too much NS, causing pulmonary edema
• Giving lasix without giving NS (in fact, don't use loop diuretics in hypercalcemia in general, unless there is concern for volume overload with aggressive hydration, such as in patients with CHF or CKD)
• Things that make hypercalcemia worse
• Thiazides
• Lithium
• Dehydration
• Diet high in calcium