Resident Editor: Armond Esmaili, MD

Faculty Editor: Anne Schafer, MD

Background

• No formal guidelines; mild hypercalcemia ~10.5-11.9 mg/dL; severe ~ >14 mg/dL (can be life-threatening
• 98% total body calcium resides in bones. The remaining 2% circulates. Approximately ½ of serum Ca is free (ionized; the only form with physiologic effects). The remainder is bound (albumin, globulins, inorganic molecules).
• Ca must be corrected for hypoalbuminemia: Corrected Ca = 0.8 x (4-calculated albumin)
• Calcium homeostasis mediated by parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (calcitriol). These act to influence bone resorption, GI tract absorption, and renal excretion of calcium. Alterations in any of these mechanisms can lead to hypercalcemia.
  • PTH: Made by parathyroid glands. Acts on bone and kidneys to increase Ca and decrease phosphate (note:thus, phos low in PTH-mediated hyperCa)
    • Bone: Increases bone resorption
    • Kidneys: Increase resorption of calcium and excretion of phos; also increases production of calcitriol
  • Calcitriol (1,25-dihydroxy-D): The active form of vitamin D. Increases gut Ca and phos absorption (note:phos high in vitamin-D-mediated hypercalcemia)
    • Calciferol 1^st hydroxylated in liver to form 25-hydroxyvitamin D (calcidiol), then calcidiol hydroxylated in kidneys to form calcitriol

Signs and symptoms

• “Stones”, “bones”, “abdominal moans”, and neuromuscular “physic groans” are the classic symptoms. However, many patients are asymptomatic.
• Stones: nephrolithiasis, nephrocalcinosis, dehydration
• Bones: bone pain, arthritis, osteoporosis, osteitis fibrosa cystica (bone cysts and brown tumors in long bones)
• Moans(abdominal): nausea/vomiting, abdominal pain, constipation, anorexia, pancreatitis, PUD
• Groans/psychiatric overtones(often neuromuscular): impaired memory/concentration, lethargy/fatigue, weakness, seizure, altered mental status
• Also CV effects (HTN, short QT, arrhythmias), keratitis, conjunctivitis, pruritis

Differential diagnosis

• 90% due to either primary hyperparathyroidism (#1 in outpatient) or malignancy (#1 in inpatient);vitamin D-mediated, medications, endocrinopathies, genetic conditions, high bone turnover are the remaining etiologies
• PTH-mediated (phos often low): primary (sporadic, familial, MEN 1&2) or tertiary (chronic renal failure causes vitamin D deficiency, triggers chronic PTH elevation) hyperparathyroidism
  • Note: Ca is low in secondary hyperparathyroidism
• Malignancy: PTHrP-producing tumors (squamous cell of lung, head/neck, renal cell common) or osteolysis/bony destruction (multiple myeloma, breast cancer; note: alkaline phosphate high in osteolysis), also vitamin D (lymphoma)
• Vitamin D (phos often high): excess intake, granulomatous diseases (e.g. sarcoid TB with extra-renal production of calcitriol), lymphoma (Hodgkin’s)
• Medications: thiazides (mild effect), lithium, antacids (milk-alkali), vitamin A intoxication (bone resportion)
• Endocrinopathies: hyperthyroidism, adrenal insufficiency, acromegaly
• Genetic: familial hypocalciuric hypercalcemia (FHH; AD with ~100% penetrance; urine Ca low)
• Also high bone turn over states (Paget’s, prolonged immobilization, childhood growth) and rhabdomyolysis (Ca deposit in soft tissue mobilized)

Evaluation

• Primary objective is to determine if hypercalcemia is PTH-mediated or non-PTH-mediated
• Always repeat Ca (and consider iCal) and correct for albumin if appropriate
  • Pseduohypercalcemia: albumin elevation (severe dehydration) or Ca-binding protein (myeloma) increases total bound Ca with unchanged iCal
• After confirming Ca elevated, first check PTH
  • PTH high or inappropriately normal: check urine Ca to determine if primary hyperparathyroidism (normal/high urine Ca) or hypocalciuric hypercalcemia (FHH, low urine Ca); note: PTH <20 is rarely primary hyperparathyroidism
  • PTH low: consider sending PTHrP (solid tumors), 1,25(OH)₂D (high in granulomatous disease, lymphoma; consider CXR), 25(OH)D (high in D intoxication); normal PTHrP, calcitriol/calcidiol should prompt myeloma and endocrine (TSH/T4, cortisol) labs

Treatment

• No urgency for treatment if asymptomatic and <12 mg/dL. Hydrate, avoid/discontinue offending Rx, avoid immobilization, limit Ca (<1 mg/day), and treat underlying cause.
  • Parathyroidectomy: only urgent if hypercalcemic crisis; indications for non-urgent surgery referral are serum Ca 11.5+, marked hypercalciuria (>400 mg/day) and increased stone risk, nephrolithiasis or nephrocalcinosis, CrCL <60, osteitis fibrosa cystica, DXA T-score <-2.5, vertebral fracture, <50 y/o
• 14+ (even without sx) or severe symptoms (often see if acute rise in Ca) warrant emergent treatment (with hospitalization). Seek to treat the underlying etiology.
  • FLUIDS! Often at rate of 200-300 cc/hr. Patients are often markedly dehydrated on admission.
  • Bisphosphonates: mainstay for malignancy; inhibit osteoclast bone resorption; include zoledronic acid (rapid delivery, most potent) and pamidronate; caution in renal dysfunction
  • Calcitonin (subQ): inhibits bone resorption; rapid onset, use often just in 1^st 48 hours (due to limited effect, tachyphylaxis)
  • Glucocorticoids: inhibit calcitriol action; mainstay in granulomatous disease and hematologic malignancies
  • Denosumab: inhibits osteoclasts; delayed effect (several days); consider if renal dysfunction limits bisphosphonate use or refractory hypercalcemia
  • Lasix: inhibits resorption at distal renal tubule; consider use only after fluid repletion if refractory hypercalcemia
  • Dialysis is a treatment of last resort

References

Horowitz MJ, Hodak SP, Stewart AF. Non-parathyroid hypercalcemia. In: Primer on the metabolic bone diseases and disorders of mineral metabolism. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 176-89.

Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, Potts JT Jr. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the Fourth International Workshop. J Clin Endocrinol Metab. 2014 Oct;99(10):3561-9.

Minisola S, Pepe J, Piemonte S, Cipriani C. The diagnosis and management of hypercalcaemia. BMJ. 2015 Jun 2;350:h2723. doi: Stewart AF. Clinical practice.Hypercalcemia associated with cancer.N Engl J Med. 2005 Jan 27;352(4):373-9

Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005 Jan 27;352(4):373-9