Diagnosis

Hypercalcemia

Etiology

Cause

• Primary hyperparathyroidism (adenoma) is the most common cause (87%) [asw][qsc]

• Tertiary hyperparathyroidism: Renal failure --> chronic overstimulation --> parathyroid hyperplasia [cdh]

• Drugs: Thiazid diuretics, Lithium, Vitamin D, Calcium supplements, Theophylline, Tamoxifen [pgn]

• Cancer:

  • Excessive production of parathyroid hormone–related protein by tumors [cdh]

  • Osteolytic bone metastasis (breast, multiple myeloma, MEN): 0.5-3% of all malignancies [bpg][nbi]

• Immobilization: Imbalance of increased osteoclast activity and decreased osteoblast activity --> bone resorption and hypercalcemia

• Less common causes: Sarcoidosis, renal failure, hyperthyroidism (rapid bone turnover), adrenal insufficiency, pheochromocytoma, acromegaly, milk-alkali syndrome, vitamin A derivates (acne-treatment), vitamin D toxicity, immobilisation, Paget disease, familial hypocalciuric hypercalcemia, Williams syndrome, parenteral nutrition, cardiac event, pre-eclampsia, rhabdomyolysis, pheochromocytoma, congenital lactase deficiency [nbi]

Pathophysiology [cdh]

1. Calcium plays an integral role in neural transmission, enzyme activity, myocardial function, coagulation, intracellular signaling, and hormonal secretion.

2. Most of the calcium is found in the bones as calcium phosphate, whereas a small percentage is found in cells and extracellular fluids.

3. Approximately 50% of total calcium is protein bound, and the total calcium level will vary with protein-binding capacity (albumin).

4. Acidosis (increased hydrogen ions) occupy binding sites on albumin, leading to increased free calcium levels. Thus, calcium levels should be adjusted for serum pH.

5. The main regulators of calcium homeostasis: [cdh]

   • Parathyroid hormone: Binding to osteoclasts --> increases bone resorption --> increase serum calcium

   • Vitamin D: Increases intestinal absorption of calcium

   • Calcitonin: Increasing calcium deposition in bones + inhibiting renal and intestinal absorption of calcium + increasing urinary calcium excretion --> lowers serum calcium levels

Complications [cdh]

• Severe hypercalcemia

• Osteoporosis/bone fractures

• Nephrolithiasis

• Renal failure

• Pancreatitis

• Gastric ulcer

• Paresthesias

• Syncope and arrhythmias

• Altered mental status

Epidemiology

Incidence per 100.000 [asw][qsc][3rt][ug6][bpg]

Prevalence per 100.000 [asw][qsc][3rt][ug6][bpg]

Approach

• Blood test: Ca, Mg, PTH, albumin, vitamin D

• Urine: 24 hour urinary calcium

• Xray: bone density, pathologic fractures, bony metastases

• UL or CT: renal stones, parathyroid adenoma

Treatment

1. Goal of treatment: [cdh]

   • Increased elimination from the extracellular fluid

   • Reduced gastrointestinal absorption

   • Decreased bone resorption

2. Treat the underlying cause:

   • Parathyroidectomy: if primary hyperparathyroidism

   • Discontinue thiazide

   • Inhibit osteoclasts

3. Adequate hydration with increased urinary excretion of calcium [nbi]:

   • Hydration: Isotonic NaCl (0.9% saline until adequate urine output)

   • Loop diuretics

4. Electrolyte replacement: [cdh]

   • Hypokalemia

   • Hypomagnesemia

   • Hypophosphatemia

5. Calcitonin 4 units/kg every 12 hours to acutely lower calcium levels

6. Biophosphonates: treating hypercalcemia of malignancy, takes 3 days to lower calcium

7. Denosumab: treating hypercalcemia of malignancy, antibody inhibits osteoclasts

8. Corticoids: if lymphoma or granulomatous disease, Prednisone 20-40 mg daily

9. Mithramycin: inhibits osteoclast RNA synthesis

10. Cinacalcet (suppression of PTH): treating secondary hyperparathyroidism due to renal failure

11. Peritoneal dialysis or hemodialysis is rarely needed

Differential diagnoses

Brain tumor, Breast cancer, Cervical cancer, Drug side effects, Hyperparathyroidism, Hypovolemia, Leukemia, Lung cancer, Lymphoma, Multiple myeloma, Ovarian cancer, Renal cancer, Sarcoidosis, Urolithiasis