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Author: Meghan Sebasky
Found in ~15% of hospitalized adult patients (often incidentally)
- 1% of total body Ca circulates in the body and is exchangeable with extracellular fluid; the rest resides in bone
- ~50% of extracellular calcium is ionized - physiologically active
- ~40% bound to protein (mostly albumin) - affected by protein levels
- Correction of total serum Ca for hypoalbuminemia: Add 0.8 mg/dL to measured serum Ca for every 1 g/dL decrease in albumin (with normal albumin value of 4 mg/dL)
- Remainder complexed with anions to form calcium salts
- Entry of Ca into the circulation exceeds excretion in urine/deposition into bone
- Accelerated bone resorption, increased gastrointestinal absorption, decreased renal excretion (or combination of these factors)
- #1 cause - primary hyperparathyroidism (usually due to parathyroid adenoma)
- Activated osteoclasts resorb bone + increased intestinal absorption of Ca
- #2 cause - malignancy (this is the most common cause in hospitalized patients)
- Bone metastases cause local osteolysis; multiple myeloma causes release of osteoclast activating factors; solid tumors secrete PTHrp; lymphoma causes PTH-independent extrarenal production of calcitriol
- Less common causes
- Increased bone resorption - thyrotoxicosis, immobilization (several weeks), Paget disease, vitamin A intoxication
- Increased calcium absorption in intestine - increased calcium ingestion, milk-alkali syndrome, increased endogenous production of 1,25(OH)2D (granulomatous disease, vitamin D excess)
- Misc: Lithium, thiazide diuretics, tamoxifen, adrenal insufficiency, theophylline toxicity, familial hypocalciuric hypercalcemia (FHH)
- Symptoms depend on degree and acuity of increase in Ca level
- Mild hypercalcemia (up to 11-11.5 mg/dL)
- Symptoms, if present at all, are nonspecific (fatigue, constipation, depression)
- Moderate/severe hypercalcemia (>12-14 mg/dL)
- Chronic elevation may be well tolerated
- Patient may still develop nephrolithiasis (from chronic hypercalciuria) and type 1 renal tubular acidosis
- Acute rise can cause marked symptoms
- Polyuria (decreased concentrating ability of distal tubule), polydipsia, dehydration, acute renal insufficiency, anorexia, nausea, muscle weakness, bone pain, altered mental status
- EKG may show shortened QT interval, AV block, bradycardia
- Chronic elevation may be well tolerated
- Neuropsychiatric disorders most common in patients with primary hyperparathyroidism (anxiety, depression, cognitive dysfunction)
- No characteristic physical exam findings
First, confirm elevated calcium level.
- Recheck value. Correct for albumin vs. check ionized Ca.
Second, check PTH.
- Elevated or high normal PTH indicates PTH-mediated cause - primary hyperparathyroidism (and very rarely FHH)
- PTH at the upper end of normal range is inappropriate as the PTH should be suppressed in patients with high serum Ca
- Low serum PTH indicates non-PTH mediated cause - continue workup
If PTH is low, then check:
- Parathyroid hormone-related peptide (PTHrp)
- Vitamin D (1,25-dihydroxyvitamin D and 25-hydroxyvitamin D)
- Elevated 25(OH)D suggests vitamin D intoxication
- Elevated 1,25(OH)2D suggests granulomatous disease/lymphoma
If PTHrp and Vitamin D levels are normal, then check:
- Serum and urine protein electrophoresis, TSH, Vitamin A
- Mild elevation in PTH can also be due to familial hypocalciuric hypercalcemia (low urine Ca level confirms)
- Thiazide diuretics enhance Ca resorption in distal tubule - low urine Ca
- Low or low-normal serum phosphorous - hyperparathyroidism and humoral hypercalcemia of malignancy
- PTH inhibits proximal tubule phosphate reabsorption
- Calcium > 13 mg/dL usually due to malignancy; <11 mg/dL or high normal typical of hyperparathyroidism
- Indicated if Ca > 14 or Ca > 12 in symptomatic patient (if asymptomatic then only hydration necessary for Ca of 12)
- Hydration, usually aggressive, is mainstay of treatment
- Normal saline at 200-300 cc/hour if severe/symptomatic
- Consider furosemide 20-100 mg IV after volume replete
- Mainly to avoid volume overload (does not reduce Ca quickly)
- Bisphosphonates indicated in malignancy-associated hypercalcemia
- Pamidronate or zoledronic acid (peak effect takes 48-72 hours)
- Calcitonin useful if rapid lowering not accomplished with hydration
- Rapid onset but short duration, patients can develop tolerance (tachyphylaxis within 48-72 hours).
- Glucocorticoids are first line after hydration in hematologic malignancies or vitamin D intoxication (suppress 1,25(OH)2D)
- Hemodialysis can be used for resistant, life-threatening hypercalcemia
- And, of course, treat the underlying condition
- Consider parathyroidectomy in patients with primary hyperparathyroidism who meet criteria set forth by National Institutes of Health (age <50, T score < -2.5, Creat clearance < 60, calcium > 1mg/dl above normal).
- Carroll Mary F and Schad David S. A Practical Approach to Hypercalcemia. Am Fam Physician 2003; 67:1959-66. (Contains a great diagnostic algorithm)
- French Sarah, Subauste Jose, Geraci Stephen. Calcium Abnormalities in Hospitalized Patients. Southern Medical Journal 2012; 105(4):231-7.
- Khosia, Sundeep. Hypercalcemia and Hypocalcemia. In: Longo, Dan L et al, eds. Harrison’s Principles of Internal Medicine – 18th ed. New York, NY: McGraw-Hill; 2012:360.