I. Problem/Condition.

Hypercalcemia (plasma calcium > 10.5mg/dL) is a common electrolyte abnormality. The condition is generally related to primary hyperparathyroidism or malignancy, which account for over 90% of all cases. Primary hyperparathyroidism is the most common cause of hypercalcemia among the ambulatory population, and malignancy accounts for up to 65% of hypercalcemia in hospitalized patients.

Hypercalcemia is generally classified on the basis of total serum and ionized calcium levels, as follows:

  • Mild: Total Ca 10.5-11.9 mg/dL (2.5-3 mmol/L) or ionized Ca 5.6-8 mg/dL (1.4-2 mmol/L)

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  • Moderate: Total Ca 12-13.9mg/dL (3-3.5mmol/L) or ionized Ca 8-10 mg/dL (2-2.5mmol/L)

  • Hypercalcemic crisis: Total Ca 14-16 mg/dL (3.5-4 mmol/L) or ionized Ca 10-12 mg/dL (2.5-3mmol/L)

Only 1-2% of total body calcium is in the exchangeable form in the circulation. Approximately one-half of the exchangeable calcium is available in the active ionized form with the remainder being bound primarily to albumin. Because only unbound calcium is biologically active, the measured serum calcium level must be adjusted for abnormal albumin values. This can be done by checking ionized calcium directly or using the equation:

Corrected Ca = ([4 – plasma albumin in g/dL] x 0.8 + serum calcium)

Patients with mild hypercalcemia may be asymptomatic, or they may present with non-specific symptoms (depression, fatigue, or constipation). A patient may tolerate chronically elevated serum calcium with few or no symptoms, but acute rises in calcium levels can cause marked symptoms. Hypercalcemia can cause multisystem signs and symptoms including:

  • Renal: polyuria, polydipsia, nephrolithiasis, nephrocalcinosis, nephrogenic diabetes insipidus, acute and chronic renal insufficiency

  • GI: anorexia, nausea, vomiting, abdominal pain, constipation, pancreatitis

  • Musculoskeletal: muscle weakness, bone pain, osteopenia/osteoporosis

  • Neurologic: confusion, fatigue, coma

  • Cardiovascular: shortening of the QT interval, bradycardia, hypertension

The precise pathophysiology of hypercalcemia is related to its etiology, which is described below. However, calcium is principally controlled by parathyroid hormone (PTH) and 1,25(OH)2D (the active form of Vitamin D). The release of parathyroid hormone (PTH) is stimulated by hypocalcemia which stimulates the release of calcium from the bone, decreases urinary loss of calcium and stimulates calcium absorption in the small intestine by stimulating synthesis of 1,25(OH)2D in the kidney.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

The etiology of hypercalcemia is best understood through two principal pathophysiologic mechanisms: 1) bone resorption and 2) altered calcium absorption.

  • Primary hyperparathyroidism

  • Secondary and tertiary hyperparathyroidism

  • Malignancy (via pseudo hyperparathyroidism, release of cytokines that mediate local osteoclast activation, osteolytic metastases)

  • Thyrotoxicosis

  • Paget disease of bone

  • Immobilization

  • Hypervitaminosis A

  • Increased calcium intake (usually only results in hypercalcemia when there is concurrent reduced calcium excretion)

  • Hypervitaminosis D

  • Granulomatous disease

  • Drugs (thiazide diuretics, lithium, theophylline)

  • Familial hypocalciuric hypercalcemia

  • Pheochromocytoma

  • Adrenal insufficiency

B. Describe a diagnostic approach/method to the patient with this problem

Although the signs and symptoms of hypercalcemia are similar regardless of etiology, there are several features of the clinical evaluation that may help to differentiate the etiology of hypercalcemia. However, because the vast majority of hypercalcemia is caused by primary hyperparathyroidism and malignancy, the investigation ought to be focused there.

Once hypercalcemia has been confirmed (a repeat level always needs to be done first to confirm the presence of hypercalcemia), and in the absence of signs of an underlying malignancy, a serum PTH is a reasonable place to start.

  • A non-suppressed level in the setting of hypercalcemia strongly suggests primary or secondary hyper parathyroidism or possibly familial hypocalciuric hypercalcemia. A subsequent 24-hour urine calcium level can help differentiate these if the diagnosis is uncertain. A low serum PTH, on the other hand, suggests non-PTH mediated hypercalcemia. Subsequent testing should include Vitamin D metabolites, PTH-related protein (PTHrp), chest x-ray, SPEP/UPEP, thyroid-stimulating hormone (TSH) and vitamin A.

1. Historical information important in the diagnosis of this problem.

  • Symptoms attributable to hypercalcemia (see introduction)

  • Presence of constitutional symptoms such as weight loss, fevers, fatigue

  • Presence of bone pain

  • Presence of easy bruising or bleeding (hematologic malignancy)

  • Presence of cough, dyspnea or chest pain

  • Presence of any “lumps or bumps” (lymphoma, granulomatous disease)

  • Symptoms of hyperthyroidism (irritability, increased perspiration, palpitations, tremor, etc.)

  • Thorough medication history (include over the counter supplements, herbal remedies)

  • Tobacco use

  • Family history of hyperparathyroidism

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

In general the physical exam findings will be nonspecific. A few maneuvers may be helpful to identify the presence of malignancy or granulomatous disease, though they are neither sensitive nor specific.

  • Lung: Auscultatory findings

  • Abdomen: Check for presence of hepato/splenomegaly

  • Lymph: Check for presence of lymphadenopathy

  • Dermatologic: Hyperpigmentation consistent with primary adrenal insufficiency

3. Laboratory, radiographic and other tests that are likely to be useful in the work-up of the cause of hypercalcemia.

  • Ionized calcium

  • Albumin

  • Creatinine

  • Serum bicarbonate (milk-alkali syndrome)

  • Serum phosphorous (decreased in primary hyperparathyroidism)

  • Intact PTH: If laboratory evidence of hyperparathyroidism, CT scan of the head, MRI, ultrasound or nuclear parathyroid scans may be helpful.

  • Vitamin D, 25: If elevated check medications, vitamins, herbal supplements.

  • 1,25 Vitamin D: If elevated check chest x-ray for lymphoma, sarcoidosis.

  • PTHrp: If elevated, evaluate for malignancy.

  • Alkaline phosphatase

  • SPEP/UPEP: multiple myeloma.

  • 24-hour urinary calcium excretion: If low (<100 mg/24 hours, Ca/Cr < 0.01) in setting of elevated PTH, consider familial hypocalciuric hypercalcemia. If elevated (> 200 mg/24 hours) consider primary hyperparathyroidism

  • TSH

  • Vitamin A

Other diagnostic tests
  • ECG

  • CXR/CT

  • Mammogram

C. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

All testing should be done after a thorough history and physical, which will help narrow down what testing needs to be performed and minimize the overuse of potentially expensive and harmful (e.g. radiation) testing.

III. Management while the Diagnostic Process is Underway

A. Management of Clinical Problem Hypercalcemia

Patients with mild or moderate asymptomatic hypercalcemia generally do not require treatment; however, they should be closely monitored while evaluating the cause of their hypercalcemia. In addition, care should be taken to avoid worsening the hypercalcemia (e.g., starting a thiazide diuretic or lithium, high calcium diet, or volume depletion) while the work-up is underway. Patients with severe or symptomatic hypercalcemia require treatment. Since patients generally have intravascular volume depletion, the initial goals of treatment are focused on adequate hydration, which will subsequently increase renal calcium clearance and dilute the calcium level.

Fluid therapy
  • Rate dependent on degree of hypercalcemia and severity of dehydration (generally 200-300 ml/hour that is adjusted to maintain urine output at 100 to 150 ml/hour).

  • Volume status should be checked frequently to avoid iatrogenic volume overload, especially in the setting of renal insufficiency or CHF.

  • Hydration will be ineffective in patients with end-stage renal disease; these patients will need urgent/emergent dialysis.

  • Onset of action is hours.

  • Most effective for patients with severe, symptomatic hypercalcemia, when combined with hydration and bisphosphonates.

  • Give salmon calcitonin 4 IU/kgIM or SQ and then repeat calcium level several hours later.

  • If the serum calcium level decreases, then the patient is deemed calcitonin-sensitive and calcitonin can then be given every 6-12 hours as 4-8 IU/kg.

  • Nasal calcitonin is not useful for hypercalcemia.

  • Can rapidly reduce serum calcium by 1 to 2 mg/dL beginning within 4-6 hours.

  • Efficacy limited to the first 48 hours due to development of tachyphylaxis.

  • Primarily for malignancy-related hypercalcemia.

  • Can be given within 1-2 days for severe hypercalcemia, after calcium level has been stabilized.

  • Zolendronic acid (4mg IV over 15 minutes) is the preferred bisphosphonate because of its potency and shorter administration time.

  • Use with caution in patients with renal failure.

  • Onset of action is generally within 2-5 days.

  • For treatment of hypercalcemia secondary to overproduction of 1,25-Vitamin D (e.g. sarcoidosis or lymphoma).

  • Generally given at doses of 20 to 40 mg/day.

  • Effective in 2 to 5 days.

Loop diuretics
  • Only use if the patient becomes hypervolemic following IV fluids.

  • Onset of action is within hours.

Calcimimetics (cinacalcet)
  • For severe hypercalcemia due to parathyroid carcinoma and in hemodialysis patients with elevated calcium-phoshate product (Ca x P >55 is elevated) and secondary hyperparathyroidism.

  • Onset of action is within 2-3 days.

  • For severe hypercalcemia in patients with ESRD and CHF in whom fluids cannot be safely administered.

  • Considered to be treatment of last resort.

  • Onset of action is within hours.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Although the first focus ought to be on rapidly reducing serum calcium levels, it is important to identify and resolve the underlying cause. It is important to conduct a thorough history and physical to help elucidate the underlying cause. In particular, use of over the counter medicines such as antacids and vitamin supplements should be elicited.

Total serum calcium is a poor predictor of ionized calcium concentration. If available, an ionized calcium is useful to check.

Because the treatment of hypercalcemia generally includes aggressive volume resuscitation, it is important to monitor fluid status closely.

IV. What's the evidence?

Lafferty, FW. “Differential diagnosis of hypercalcemia”. J Bone Miner Res. vol. 6. 10/1991. pp. S51

Shane, E, Dinaz, I, Favus, MJ. “Hypercalcemia: Pathogenesis, clinical manifestations, differential diagnosis, and management”. Primer on the metabolic bone diseases and disorders of mineral metabolism. 2006. pp. 26-176.

Inzucchi, SE. “Understanding hypercalcemia. Its metabolic basis, signs, and symptoms”. Postgrad Med. vol. 115. 2004. pp. 69

Maier, JD, Levine, SN. “Hypercalcemia in the Intensive Care Unit: A Review of Pathophysiology, Diagnosis, and Modern Therapy”. J Intensive Care Med. vol. 30. 2015. pp. 235

Carroll, MF, Schade, DS. “A practical approach to hypercalcemia”. . vol. 67. 2003 May 1. pp. 1959-1966.