Hypercalcemia

GENERAL PRINCIPLES

• A serum calcium >10.3 mg/dL with a normal serum albumin or an ionized calcium >5.2 mg/dL defines hypercalcemia.

• Clinically significant hypercalcemia typically requires both an increase in ECF calcium and a decrease in renal calcium clearance.

• Primary hyperparathyroidism causes most cases of hypercalcemia in ambulatory patients.

• Malignancy is responsible for most cases of hypercalcemia among hospitalized patients. Patients usually have advanced, clinically obvious disease. In these patients, hypercalcemia may develop from stimulation of osteoclast bone resorption from tumor cell products, tumor-derived PTH-related peptide (PTHrP), and tumor calcitriol production.

• Less common causes account for about 10% of cases of hypercalcemia and include increased vitamin D activity (exogenous exposure to vitamin D or increased generation of calcitriol in chronic granulomatous diseases), the milk-alkali syndrome (acute or chronic development of hypercalcemia, alkalosis, and renal failure from the ingestion of large quantities of calcium-containing antacids), adrenal insufficiency, prolonged immobilization, Paget disease, and acromegaly.

DIAGNOSIS

Clinical Presentation

Clinical manifestations generally are present only if serum calcium exceeds 12 mg/dL and tend to be more severe if hypercalcemia develops rapidly. Most patients with primary hyperparathyroidism have asymptomatic hypercalcemia that is found incidentally. Symptoms include renal manifestations (polyuria and nephrolithiasis and risk of renal failure with nephrocalcinosis when calcium level rises above 13 mg/dL), GI symptoms (anorexia, vomiting, constipation), and neurologic symptoms (weakness, fatigue, confusion, stupor, and coma).

Diagnostic Testing

• Serum calcium should be interpreted with knowledge of the serum albumin, or an ionized calcium should be measured. Corrected [Ca²⁺ ] = [Ca²⁺] + {0.8 ? (4.0 - [albumin])}. Many patients with primary hyperparathyroidism will have a calcium level that is chronically within the high-normal range.

• Intact serum PTH may be the most important first step in the evaluation of hypercalcemia.

î Elevations in ECF calcium typically result in suppression of PTH. Thus, the finding of a normal or elevated intact PTH in the setting of hypercalcemia is suggestive of primary hyperparathyroidism.

° When the intact PTH is appropriately suppressed, PTHrP can be measured to investigate possible humoral hypercalcemia of malignancy.

• 1,25(OH)₂D₃ levels are elevated in granulomatous disorders, primary hyperparathyroidism, calcitriol overdose, and acromegaly.

• Serum phosphorus is often decreased in hyperparathyroidism because of stimulation of phosphaturia, whereas Paget disease and vitamin D intoxication both tend to have increased phosphorus levels.

• Urine calcium may be elevated in primary hyperparathyroidism because of a filtered load of calcium that exceeds the capacity for renal reabsorption. If the family history and clinical picture are suggestive, patients with familial hypocalciuric hypercalcemia can be distinguished from patients with primary hyperparathyroidism by documenting a low calcium clearance by 24-hour urine collection (13.5 mg/dL), 90 mg can be given over the same duration. A hypocalcemic response is typically seen within 2 days and may persist for 2 weeks or longer. Treatment can be repeated after 7 days if hypercalcemia recurs. Zoledronate is a more potent bisphosphonate that is given as a 4-mg dose infused over at least 15 minutes. Hydration should precede bisphosphonate use. Renal insufficiency is a relative contraindication.

• Other options

î Calcitonin inhibits bone resorption and increases renal calcium excretion.

î Glucocorticoids are effective in hypercalcemia due to hematologic malignancies and granulomatous production of calcitriol. The initial dose is 20-60 mg/d of prednisone or its equivalent. After serum calcium stabilizes, the dose should be gradually reduced to the minimum needed to control symptoms of hypercalcemia.

î Denosumab is a receptor activator of nuclear factor kappa-B ligand inhibitor that can be used in patients with hypercalcemia that is refractory to bisphosphonates or in patients with a contraindication to bisphosphonate therapy, such as patients with chronic kidney disease. It is given at a dose of 120 mg SC weekly for 4 weeks and then monthly.

î Dialysis. Hemodialysis and peritoneal dialysis using low calcium dialysate are effective for patients with very severe hypercalcemia (>16 mg/dL) and CHF or renal insufficiency.

• Chronic management of hypercalcemia

î Primary hyperparathyroidism. In many patients, this disorder has a benign course, with minimal fluctuation in serum calcium concentration and no obvious clinical sequelae. Parathyroidectomy is indicated in patients with (1) corrected serum calcium >1.0 mg/dL above the upper limit of normal, (2) creatinine clearance by one of the following:

î Transcellular shift occurs in rhabdomyolysis, tumor lysis syndrome, and massive hemolysis as phosphorus is released from cells into the ECF. Metabolic acidosis and hypoinsulinemia reduce phosphorus flux into cells and contribute to the hyperphosphatemia sometimes seen in DKA.

î Increased intake leading to hyperphosphatemia usually occurs in the setting of renal insufficiency, either with dietary indiscretion in chronic kidney disease or as an iatrogenic complication.

î Decreased renal excretion occurs most commonly in the setting of renal failure. Occasionally, hypoparathyroidism and pseudohypoparathyroidism reduce renal phosphorus clearance as well.

DIAGNOSIS

Clinical Presentation

• Signs and symptoms are typically attributable to hypocalcemia and the metastatic calcification of soft tissues. Occasionally, skin deposition can result in severe pruritus. Calciphylaxis describes the tissue ischemia that may result from the calcification of smaller blood vessels and their subsequent thrombosis.

• Chronic hyperphosphatemia contributes to the development of renal mineral/bone disorders such as secondary hyperparathyroidism (see Chapter 13, Renal Diseases).

Diagnostic Testing

The elevated serum phosphorus can be accompanied by hypocalcemia as a result of intravascular chelation of calcium by phosphorus.

TREATMENT

• Acute hyperphosphatemia is treated by increasing renal excretion of phosphorus, and as such, treatment is limited when renal insufficiency is present.

î Recovery of renal function will often correct the hyperphosphatemia in the patient within 12 hours. Saline and/or acetazolamide (15 mg/kg q4h) can be given to further encourage phosphaturia, if needed.

î Hemodialysis may be required, especially if irreversible renal insufficiency or symptomatic hypocalcemia is present.

• Chronic hyperphosphatemia is almost always associated with chronic kidney disease. Its management consists of reducing phosphorus intake through dietary modification and the use of phosphate binders. This is discussed more fully in Chapter 13, Renal Diseases.