Hypercalcemia

Definition, Etiology, PathogenesisTop

Hypercalcemia is defined as a serum [Ca2+] >2.62 mmol/L (>10.5 mg/dL). Slight interlaboratory variations may exist.

Causes:

1) Hypercalcemia with high parathyroid hormone (PTH) levels (PTH-dependent hypercalcemia) due to primary hyperparathyroidism (sporadic, induced by lithium salts); multiple endocrine neoplasia syndromes type 1, 2A, and 4; inactivating mutations of the calcium-sensing receptor gene (familial hypocalciuric hypercalcemia); antibodies to the calcium-sensing receptor; or, rarely, PTH secretion by neoplasms.

2) Hypercalcemia with low PTH levels (PTH-independent hypercalcemia) due to cancer (oversecretion of parathyroid hormone–related peptide [PTHrP] and other substances), thyrotoxicosis (increased osteolysis), overdose of vitamin D or its metabolites, production of 1,25(OH)2D3 by granulomas (sarcoidosis) or lymphomas, vitamin A overdose (increased osteolysis), milk-alkali syndrome, long-term immobilization (mobilization of calcium from bone), thiazide diuretics, theophylline (decreased urinary calcium excretion), or Williams syndrome.

3) Hypercalcemia with normal PTH levels: Jansen syndrome (activating mutations of the PTH-PTHrP receptor gene).

The most common causes (90%) of hypercalcemia are hyperparathyroidism and malignancy.

Clinical FeaturesTop

Mild hypercalcemia (<3 mmol/L) may be asymptomatic or manifested by signs and symptoms of the underlying condition.

In moderate to severe or rapidly developing hypercalcemia, clinical manifestations of hypercalcemic syndrome are present: renal dysfunction (polyuria, hypercalciuria, nephrocalcinosis, and nephrolithiasis), gastrointestinal (GI) tract dysfunction (loss of appetite, nausea, vomiting, constipation, peptic ulcer disease, pancreatitis, cholelithiasis), cardiovascular dysfunction (hypertension, tachycardia, arrhythmia, increased susceptibility to digitalis), neuromuscular manifestations (muscle weakness, hyperreflexia, transient facial muscle paresis), cerebral manifestations (headache, depression, confusion, somnolence, coma), and dehydration. Hypercalcemic crisis is caused by severe hypercalcemia (usually >3.75 mmol/L) and manifests as altered mental status, nausea, vomiting, abdominal pain, arrhythmia, polyuria, and dehydration. Features of the underlying condition are often present.

Electrocardiography (ECG) features of hypercalcemia may include a long PR interval and a short QT interval.

DiagnosisTop

The diagnosis of hypercalcemia is based on measurement of serum [Ca2+] (>2.62 mmol/L [>10.5 mg/dL]).

In patients with hypoalbuminemia or hyperalbuminemia, adjust serum [Ca2+] (see Hypocalcemia). Ionized calcium levels are a more accurate indicator of the severity of hypercalcemia. In all patients with hypercalcemia, measure serum levels of creatinine, chloride, phosphate, magnesium, potassium, PTH, thyroid-stimulating hormone (TSH), and alkaline phosphatase, and consider performing blood gas analysis. The majority of cases of hypercalcemia with normal or increased PTH levels are caused by hyperparathyroidism.

In patients with low PTH levels perform diagnostic workup for malignancy, unless the available data indicate another cause of PTH-independent hypercalcemia. Malignancies that most frequently cause hypercalcemia include breast cancer, lung cancer, kidney cancer, multiple myeloma, lymphoma, and leukemia.

In patients with suspected excess of exogenous or endogenous vitamin D, measure blood levels of vitamin D metabolites. PTHrP levels can be measured.

TreatmentTop

1. Treatment of the underlying condition is the mainstay of the management of hypercalcemia.

2. Reduce total body calcium content:

1) Increase renal calcium excretion by intensive administration of fluids (up to ~5 L of 0.9% NaCl on the first day). Based on fluid status and renal function, IV furosemide 20 to 40 mg can be added to the regimen. Carefully monitor urine output and electrolyte levels.

2) Decrease calcium mobilization from bone. The available options include IV calcitonin 100 IU bid to qid, pamidronate disodium (INN pamidronic acid) 60 to 90 mg in 200 mL of 0.9% NaCl as an IV infusion over 2 hours, or IV zoledronate disodium (INN zoledronic acid) 4 mg in 50 mL of 0.9% NaCl over 15 minutes. Zoledronate is preferred over pamidronate in malignancy-related hypercalcemia.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to the risk of bias from indirectness (a selective patient population in available randomized controlled trials). Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001 Jan 15;19(2):558-67. PubMed PMID: 11208851. Use caution when administering bisphosphonates in patients with kidney injury. In patients with hypercalcemia associated with malignancy and resistant to bisphosphonates, use subcutaneous denosumab 120 mg every 7 days for 3 weeks and then every 4 weeks. In patients with advanced chronic kidney disease, denosumab should be used with caution and requires close monitoring of calcium levels because of the risk of severe symptomatic hypocalcemia.

3) Inhibit GI absorption of calcium using IV hydrocortisone 100 mg every 6 hours.

3. In patients with renal failure and symptomatic or refractory hypercalcemia, elimination of calcium using hemodialysis may be necessary.