Diagnostic approach to hypercalcemia

INTRODUCTION — Hypercalcemia is a relatively common clinical problem. Among all causes of hypercalcemia, primary hyperparathyroidism and malignancy are the most common, accounting for greater than 90 percent of cases [1-3]. Therefore, the diagnostic approach to hypercalcemia typically involves distinguishing between the two.

It is usually not difficult to differentiate between them. Malignancy is often evident clinically by the time it causes hypercalcemia, and patients with hypercalcemia of malignancy usually have higher calcium concentrations and are more symptomatic from hypercalcemia than individuals with primary hyperparathyroidism. Although hypercalcemia in otherwise healthy outpatients is usually due to primary hyperparathyroidism and malignancy is more often responsible for hypercalcemia in hospitalized patients, other potential causes of hypercalcemia must be considered (table 1).

This topic will review the diagnostic approach to hypercalcemia. The clinical manifestations, etiology, and treatment are reviewed separately. (See "Clinical manifestations of hypercalcemia" and "Etiology of hypercalcemia" and "Treatment of hypercalcemia".)

CONFIRM HYPERCALCEMIA — The first step in the evaluation of a patient with hypercalcemia is to verify with repeat measurement (total calcium corrected for albumin) that there is a true increase in the serum calcium concentration. If available, previous values for serum calcium should also be reviewed. The presence of longstanding asymptomatic hypercalcemia is more suggestive of primary hyperparathyroidism and also raises the much less common possibility of familial hypocalciuric hypercalcemia.

The degree of hypercalcemia also may be useful diagnostically. Primary hyperparathyroidism is often associated with borderline or mild hypercalcemia (serum calcium concentration often below 11 mg/dL [2.75 mmol/L]). Values above 13 mg/dL (3.25 mmol/L) are unusual in primary hyperparathyroidism, although they do occur; they are more common in patients with malignancy-associated hypercalcemia. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation" and "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia" and "Hypercalcemia of malignancy: Mechanisms".)

Albumin-calcium correction — In almost all patients, hypercalcemia is due to an elevation in the physiologically important ionized (or free) calcium concentration. However, 40 to 45 percent of the calcium in serum is bound to protein, principally albumin. As a result, the total serum calcium concentration will change in parallel to the albumin concentration and may not accurately reflect the physiologically important ionized calcium concentration. If a laboratory known to measure ionized calcium reliably is available, some authorities prefer to measure the serum ionized calcium in this situation. (See "Relation between total and ionized serum calcium concentrations".)

●In patients with hypoalbuminemia due to chronic illness or malnutrition, there may be an associated reduction in the serum total calcium concentration due to proportionally reduced binding of calcium to albumin. In this setting, the severity of hypercalcemia may be underestimated, or the diagnosis of hypercalcemia may be entirely overlooked as the total serum calcium concentration may be normal when serum ionized calcium is elevated.

●In patients with hyperalbuminemia (eg, due to severe dehydration), serum albumin is elevated, and there may be an associated elevation in the serum total calcium concentration due to proportionally increased binding of calcium to albumin, without any rise in the serum ionized calcium concentration. This phenomenon is called pseudohypercalcemia (or factitious hypercalcemia) since the patient has a normal ionized serum calcium concentration.

Rarely, patients with hypergammaglobulinemia due to multiple myeloma may have a calcium-binding paraprotein, usually a globulin; such patients may demonstrate elevated total serum calcium with normal ionized serum calcium, but in this situation, the calcium is bound to the abnormal globulin rather than albumin.

In patients with hypoalbuminemia, the measured calcium concentration can be corrected for the abnormality in albumin. There are a number of formulas which have been used to correct the total calcium for serum albumin concentrations, but none appears to be universally acceptable when examined for their correlation with ionized calcium. Furthermore, different chemistry laboratories may use different correction formulas. Traditionally, one of the most widely utilized equations to estimate the total calcium concentration in clinical practice assumes the serum calcium to fall by 0.8 mg/dL (0.2 mmol/L) for every 1 g/dL (10 g/L) fall in the serum albumin concentration (calculator 1) or for standard units (calculator 2).

DETERMINING THE ETIOLOGY — Hypercalcemia has many causes (table 1) [4]. The etiology may be obvious from the patient's history and physical examination. When the cause is not obvious or a suspected cause needs to be confirmed, other biochemical tests are indicated.

Clinical clues — Although the signs and symptoms of hypercalcemia are similar regardless of the etiology, there are several features of the clinical evaluation that may help to differentiate the etiology of hypercalcemia. Clinical findings that favor the diagnosis of primary hyperparathyroidism include an asymptomatic patient with chronic hypercalcemia, a postmenopausal woman, a normal physical examination, no other obvious cause of hypercalcemia (such as sarcoidosis), a family history of hyperparathyroidism, and evidence of multiple endocrine neoplasia. (See "Classification and genetics of multiple endocrine neoplasia type 2" and "Multiple endocrine neoplasia type 1: Genetics".)

Patients with hypercalcemia of malignancy often have higher concentrations of, and more rapid increases in, serum calcium and consequently are more symptomatic (table 2) (see "Clinical manifestations of hypercalcemia"). In addition, patients with this disorder typically have advanced disease and a poor prognosis.

A review of diet and medications (prescription and nonprescription drugs, herbal preparations, calcium and vitamin supplements) is important to assess for the milk-alkali syndrome and drug-induced hypercalcemia (table 1) (see "Etiology of hypercalcemia", section on 'Medications' and "The milk-alkali syndrome"). Dietary calcium (from food and drinks) does not usually cause hypercalcemia in an otherwise healthy individual. If possible, any medication that may be causing hypercalcemia should be discontinued. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Drugs'.)

Laboratory evaluation — The initial goal of the laboratory evaluation is to differentiate parathyroid hormone (PTH)-mediated hypercalcemia (primary and tertiary hyperparathyroidism, and familial hyperparathyroid syndromes) from non-PTH mediated hypercalcemia (primarily malignancy, vitamin D intoxication, granulomatous disease) (table 1). Thus, once hypercalcemia is confirmed, the next step is measurement of serum PTH (algorithm 1). (See "Parathyroid hormone assays and their clinical use".)

There appears to be a higher incidence of primary hyperparathyroidism in patients with malignancy than in the general population [2,3]. Thus, despite the increased cost, it is reasonable to order an intact PTH assay as part of the routine evaluation for hypercalcemia, even in a patient with known malignant disease. (See "Hypercalcemia of malignancy: Mechanisms", section on 'Coexisting primary hyperparathyroidism' and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Malignancy'.)

Elevated parathyroid hormone — A frankly elevated PTH concentration in the setting of hypercalcemia is highly likely to be the result of primary hyperparathyroidism (figure 1 and algorithm 1) [3,5,6]. Additional evaluation in such patients to determine management is reviewed separately. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

Mid- to upper-normal or minimally elevated parathyroid hormone — Ten to 20 percent of patients with primary hyperparathyroidism have a serum PTH concentration in the upper end of the normal range; such a "normal" level (ie, not suppressed but not frankly elevated) is also virtually diagnostic of primary hyperparathyroidism since it is still inappropriately high considering the presence of hypercalcemia [6]. However, in this circumstance, the diagnosis of familial hypocalciuric hypercalcemia also should be considered, and urinary calcium excretion (24-hour urinary calcium or calcium-to-creatinine ratio) should be measured (algorithm 1). (See 'Other tests' below and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on '24-hour urinary calcium'.)

Low-normal or low parathyroid hormone — A low or low-normal serum intact PTH level (below 20 pg/mL) is most consistent with non-PTH-mediated hypercalcemia (figure 1 and table 1). While it is unusual for a patient with proven primary hyperparathyroidism to have a serum PTH concentration in the lower half of the normal range, it may occur. (See "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Serum PTH'.)

In the presence of low serum PTH concentrations (<20 pg/mL), vitamin D metabolites should be measured to assess for vitamin D intoxication and PTH-related protein (PTHrP) to assess for hypercalcemia of malignancy (if no obvious malignancy is apparent) (algorithm 1). If vitamin D metabolites and PTHrP are also low, another source for the hypercalcemia must be considered (table 1).

Additional laboratory data (including serum protein electrophoresis [SPEP] for possible multiple myeloma, thyroid-stimulating hormone [TSH], vitamin A) may lead to the correct diagnosis (algorithm 1).

Vitamin D metabolites — Serum concentrations of the vitamin D metabolites, 25-hydroxyvitamin D (25[OH]D, calcidiol) and 1,25-dihydroxyvitamin D (calcitriol), should be measured if there is no obvious malignancy and PTH is not elevated [7].

●An elevated serum concentration of 25(OH)D is indicative of vitamin D intoxication due to the ingestion of either vitamin D or calcidiol itself [8,9]. Although the serum concentration of 25(OH)D at which hypercalcemia typically occurs is undefined, many experts define vitamin D intoxication as a value >150 ng/mL (374 nmol/L) [10].

●On the other hand, increased levels of 1,25-dihydroxyvitamin D may be induced by direct intake of this metabolite, extrarenal production in granulomatous diseases or lymphoma, or increased renal production that can be induced by primary hyperparathyroidism but not by PTHrP [11]. (See "Hypercalcemia in granulomatous diseases".)

In patients with elevated 1,25-dihydroxyvitamin D, chest radiograph (looking for malignancy or sarcoidosis) may be helpful. Patients with granulomatous disease or lymphoma generally have widespread pulmonary and extrapulmonary disease. In the absence of such involvement, a systematic search for occult pulmonary, renal, hepatic, ocular, and bone marrow granulomas is indicated when no other cause for increased 1,25-dihydroxyvitamin D is apparent.

PTH-related protein — Humoral hypercalcemia of malignancy is one of the most common causes of non-parathyroid hormone (PTH)-mediated hypercalcemia. It should be particularly suspected if there is clinical evidence of malignancy, usually a solid tumor, and the hypercalcemia is of relatively recent onset. Thus, if the patient has longstanding hypercalcemia and a low serum PTH, one should consider one of the other non-PTH-mediated disorders rather than a malignancy (table 1 and algorithm 1).

If the underlying tumor causing humoral hypercalcemia of malignancy is not apparent, the diagnosis can be confirmed by demonstrating an elevated serum concentration of PTHrP [3], which is the primary mediator of this etiology of hypercalcemia in most cases [7]. However, this assay is usually not necessary for diagnosis, since most patients have clinically apparent malignancy. Levels of PTH and 1,25-dihydroxyvitamin D (calcitriol) are usually appropriately suppressed in these patients [3,11,12].

PTHrP is reviewed in more detail elsewhere. (See "Hypercalcemia of malignancy: Mechanisms", section on 'PTH-related protein'.)

Other tests — The presence of low serum levels of PTH, PTHrP, and low or normal vitamin D metabolites suggests some other source for the hypercalcemia. In the absence of malignancy or increased PTHrP, unsuspected stimulation of bone resorption (as with multiple myeloma, thyrotoxicosis, immobilization, or vitamin A toxicity) and unrecognized calcium intake in the face of renal insufficiency (as in the milk-alkali syndrome) are the most likely candidates [13] (see "Etiology of hypercalcemia"). Additional laboratory data (including SPEP and urinary protein electrophoresis [UPEP] for possible multiple myeloma, TSH, vitamin A) will often provide the correct diagnosis.

Measurement of the serum phosphate concentration and urinary calcium excretion also may be helpful in selected cases. Hyperparathyroidism and humoral hypercalcemia of malignancy (due to PTHrP) may be associated with frank hypophosphatemia or low-normal serum phosphate levels resulting from inhibition of renal proximal tubular phosphate reabsorption. In comparison, the serum phosphate concentration is normal or elevated in granulomatous diseases, vitamin D intoxication, immobilization, thyrotoxicosis, milk-alkali syndrome, and metastatic bone disease. The serum phosphate concentration is variable in familial hypocalciuric hypercalcemia.

Urinary calcium excretion may be normal, high-normal, or elevated in hyperparathyroidism and hypercalcemia of malignancy. In contrast, there are three disorders in which an increase in renal calcium reabsorption leads to relative hypocalciuria (less than 100 mg/day [2.5 mmol/day]):

●The milk-alkali syndrome in which the associated metabolic alkalosis enhances calcium reabsorption via an uncertain mechanism [13]. (See "The milk-alkali syndrome".)

●Thiazide diuretics, which directly enhance active calcium reabsorption in the distal tubule. (See "Diuretics and calcium balance".)

●Familial hypocalciuric hypercalcemia in which the fractional excretion of calcium is often less than 1 percent. Other clues to the possible presence of this disorder are a young age of onset (usually before age 30), family history of hypercalcemia, and few (if any) hypercalcemic symptoms. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

Other tests that may also be helpful in selected cases are the serum chloride concentration and bone radiographs. A serum chloride concentration above 103 mEq/L (associated with a mildly depressed serum bicarbonate concentration) is consistent with primary hyperparathyroidism, while a lower serum chloride concentration and metabolic alkalosis are characteristic of the milk-alkali syndrome. Evidence of osteitis fibrosa on bone films is very specific for primary hyperparathyroidism but is only seen in approximately 5 percent of cases.

AFTER DIAGNOSIS — Treatment for hypercalcemia should be aimed at lowering the serum calcium concentration and, if possible, correcting or decreasing the underlying disease. Effective treatments are discussed separately. (See "Treatment of hypercalcemia" and "Primary hyperparathyroidism: Management" and "Hypercalcemia in granulomatous diseases" and "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)

SUMMARY AND RECOMMENDATIONS

●Overview of approach – The diagnostic approach to hypercalcemia typically involves clinical evaluation and laboratory testing to distinguish between primary hyperparathyroidism and malignancy, which together account for greater than 90 percent of cases. The remaining 10 percent of patients with hypercalcemia may have one of many causes (table 1) that must be systematically considered and evaluated (algorithm 1). (See 'Introduction' above.)

●Confirm hypercalcemia – The first step in the evaluation of a patient with hypercalcemia is to verify with repeat measurement (total calcium corrected for albumin or ionized calcium) that there is a true increase in the serum calcium concentration. If available, previous values for serum calcium should also be reviewed. (See 'Confirm hypercalcemia' above.)

●Determine the etiology

•Clinical assessment – Clinical evaluation, including duration of hypercalcemia, presence or absence of symptoms, family history, and medications, may help determine the etiology of hypercalcemia. (See 'Clinical clues' above.)

•Measure PTH – Measurement of intact parathyroid hormone (PTH) is important to distinguish PTH-mediated from non-PTH-mediated causes of hypercalcemia.

-Elevated PTH – A frankly elevated PTH concentration in the setting of hypercalcemia is highly likely the result of primary hyperparathyroidism (figure 1 and algorithm 1). (See 'Elevated parathyroid hormone' above and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation".)

-Mid- to upper-normal or minimally elevated PTH – A PTH value that is minimally elevated or in the upper half of the normal range in the setting of hypercalcemia is likely the result of primary hyperparathyroidism. However, in this circumstance, the diagnosis of familial hypocalciuric hypercalcemia also should be considered. (See 'Mid- to upper-normal or minimally elevated parathyroid hormone' above and "Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation", section on 'Familial hypocalciuric hypercalcemia'.)

-Low normal or low PTH – PTH concentrations below 20 pg/mL in the setting of hypercalcemia are usually not consistent with primary hyperparathyroidism and indicate the need for evaluation for other causes of hypercalcemia (table 1 and algorithm 1). This evaluation should include measurement of vitamin D metabolites and PTH-related protein (PTHrP) if no obvious malignancy is apparent. (See 'PTH-related protein' above and 'Vitamin D metabolites' above.)

If the diagnosis is still not clear, other tests should be considered, including thyroid-stimulating hormone (TSH), serum protein electrophoresis (SPEP), urinary protein electrophoresis (UPEP), and vitamin A. (See 'Other tests' above.)