Pediatric Hypercalcemia Workup

Overall, creating an all-encompassing algorithm for diagnosing the etiology of hypercalcemia is difficult. Clearly, the differential diagnosis widely varies on the basis of the child's age. Much of the laboratory workup should be guided by the history and physical examination. In infancy, a syndromic appearance of a child or dietary review may lead to very different diagnostic paths. If the history and physical examination yield no clear direction, a laboratory workup may reveal the diagnosis.

• Initially, a physician must verify that the hypercalcemia is not a laboratory error. The most common reasons for falsely elevated serum calcium levels are hemoconcentration and elevated serum protein levels (eg, multiple myeloma). Acidosis increases the level of ionized calcium (but not total calcium) by changing plasma protein binding. A high intake of phosphate may also falsely elevate the serum calcium level.

• In the neonate, in addition to calcium, determine serum protein, phosphate, and parathyroid hormone (PTH) levels as well as the levels of maternal calcium and maternal PTH. Serum calcium levels from other family members may also be helpful. In a baby with hypercalcemia, the serum PTH level should be lower than 10 pg/mL. A definitive diagnosis of hyperparathyroidism is confirmed by a PTH level higher than 50 pg/mL. In the situation of inappropriately normal or high PTH, consider hyperparathyroidism, familial hypocalciuric hypercalcemia, secondary hyperparathyroidism, and, rarely, malignancy. When PTH is suppressed, malignancy, granulomatous disease, iatrogenic causes, adrenal insufficiency, thyrotoxicosis, and vitamin D intoxication are possibilities.

  A study on the failure to diagnose primary hyperparathyroidism by Balentine et al reviewed data on 10,432 patients diagnosed with hypercalcemia and reported that only 31% of hypercalcemic patients had PTH levels measured and only 22% of 2666 patients with classic hyperparathyroidism were referred to surgeons. ^[12]

• Other laboratory findings that may be abnormal include sodium, potassium, and magnesium measurements. The reabsorption of these electrolytes is decreased in the proximal tubule, lowering their serum levels. Sensitivity to digitalis is increased, and a level should be assessed if the patient is taking digoxin. Perform BUN and creatinine tests to evaluate renal function, pancreatic enzyme tests to evaluate for pancreatitis, and stool hemoccult tests to evaluate for gastritis or a peptic ulcer if symptoms point toward these possibilities.

• In childhood, the history and physical examination are extremely important. Inquire about symptoms or family history consistent with a multiple endocrine neoplasia (MEN) syndrome and perform molecular testing if appropriate. Consider the possibility of a malignancy, and direct the diagnostic evaluation toward that if symptoms or results from a CBC count point to this direction. Review the history and chest radiography for the possibility of granulomatous disease. Query about a history of signs or symptoms of thyrotoxicosis, and assess the level of thyroid-stimulating hormone (TSH) if indicated. Use history and creatinine clearance to eliminate renal failure. Ensure no medications, herbal preparations, or recent immobilizations are responsible. If this initial screen does not reveal the etiology, begin with serum PTH and phosphate, urine calcium, and serum bicarbonate measurements, and consider the other studies listed in the table below.

• High PTH levels usually indicate primary hyperparathyroidism if the urine calcium–to–creatinine ratio is high and indicates familial hypocalciuric hypercalcemia if the urine calcium–to–creatinine ratio is low (confirm with DNA sequence analysis for CASR gene). Low PTH levels usually indicate hypervitaminosis D if 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are high and indicate malignancy if they are low (confirm with high PTHrP level).

• All laboratories have different reference-range values, examples of which are listed in the table below. Table 1. Normal Laboratory Values

  Table. (Open Table in a new window)

  Laboratory Test	Reference Range	Normal Response to Increased Calcium
  Serum calcium	8.5-10.2 mg/dL	NA
  Ionized calcium	1-1.3 mmol/L	NA
  PTH (intact)	10-55 pg/mL*	Decrease
  Serum phosphate	Age-dependent	Increase
  1,25-dihydroxyvitamin D	36-108 pmol/L	Decrease
  Alkaline phosphatase	68-217 U/L	Normal
  Urine calcium	4 mg/kg/d	Increase
  Urine Ca/Cr ratio	See note†	Increase
  Urine cAMP‡	< 5 mol	Decrease
  *Note that 1 mmol/L equals 4 mg/dL. †In infants younger than 7 months, the reference range is less than 0.86; in infants aged 7-18 months, the reference range is less than 0.6. By age 6-7 years, the adult reference range of less than 0.21 is reached.‡The urine cAMP level generally parallels the PTH level.

• Depending on the age of the patient and history obtained, consider all of the above tests.

• When testing for hypervitaminosis D, assess the serum levels of 25-hydroxyvitamin D because they reflect the intake of vitamin D better than levels of 1,25-dihydroxyvitamin D. The exception to this is when 1,25-dihydroxyvitamin D is overingested or overproduced. Table 2. Additional Laboratory Values

  Table. (Open Table in a new window)

  Condition	Serum Phosphorus	Serum Alkaline Phosphatase	Urine Calcium	Urine Phosphate	PTH
  Hyperparathyroidism	Low	Normal-high	High*	High	High
  Vitamin D excess	Normal-high	Low	High	High
  Malignancy	Often low	High †	Variable	High
  Granulomatous disease	Normal-high	Normal-high	High	Normal
  Milk alkali syndrome	Normal-high	Normal	Normal	Normal
  FHH	Normal or low	Normal	Low (< 200mg/d)	Normal	Low
  *67% of the time † Except hematologic malignancies, in which alkaline phosphatase is normal

Plain radiography may reveal demineralization, pathologic fractures, bone cysts, and bony metastases.

Renal imaging, ultrasonography, CT urography, or intravenous pyelography (IVP) may reveal evidence of calcifications or stones.

Perform ultrasonography of the parathyroid glands if hyperplasia or adenoma is a primary diagnosis. A sestamibi nuclear scan may be helpful in locating a parathyroid adenoma.

Other imaging tests may be necessary to exclude alternative diagnoses (eg, gallstone vs hypercalcemic pancreatitis) or to find a primary or associated malignancy if the laboratory tests or history produce suspicious findings.

Other tests include the following:

• ECG

  • Shortened QT interval

  • Bradycardia

  • Coving of ST-T wave

  • Widened T wave

• Ophthalmologic examination

  • Band keratopathy

  • Conjunctivitis

Localization of a parathyroid adenoma may be assisted by catheterization of the appropriate veins and measurements of PTH.