Hypocalcemia may be subdivided into nonionized hypocalcemia (decrease in serum total calcium value) and true hypocalcemia (decrease in ionized calcium value).

Selected Etiologies of Hypocalcemia
Primary hypoparathyroidism
Vitamin D-related
Vitamin D deficiency
Renal failure
Magnesium deficiency
Chronic alcoholism
Tumor lysis syndrome
Alkalosis (respiratory or metabolic)
Acute pancreatitis
Drug-induced hypocalcemia
Large doses of magnesium sulfate

The most common cause of nonionized (“laboratory”) hypocalcemia is a decrease in the serum albumin level, which lowers the total serum calcium value by decreasing the metabolically inactive bound fraction without changing the nonbound “ionized” metabolically active fraction. Therefore, this type of hypocalcemia is artifactual as far as the patient is concerned, since the metabolically active fraction is not affected. Sometimes nonionized hypocalcemia occurs with serum albumin values within the lower part of the population reference range, presumably because the previous albumin level was in the upper portion of the reference range. Although laboratory hypocalcemia is fairly common in hospitalized patients, true hypocalcemia is considerably less common than hypercalcemia. In one study, only 18% of patients with a decreased total serum calcium level had true hypocalcemia. Symptoms of decreased ionized calcium include neuromuscular irritability (Chvostek’s or Trousseau’s sign), which may progress to tetany in severe cases; mental changes (irritability, psychotic symptoms); and sometimes convulsions. Some causes of hypocalcemia are listed in the box on this page.

Neonatal hypocalcemia. Neonatal serum calcium levels are lower than adult levels, with adult levels being attained at about 2 weeks of life for full-term infants and at about 4 weeks for premature infants. Neonates may develop hypocalcemia early (within the first 48 hours of life) or later (between age 4-30 days). Late-onset hypocalcemia can be due to a high-phosphate diet (cow’s milk), malabsorption, dietary vitamin D deficiency, alkalosis, and congenital disorders. The etiology of early-onset hypocalcemia is poorly understood. Symptoms include muscular twitching, tremor, and sometimes convulsions. Since one or more episodes of tremor or twitching are not uncommon in neonates, hypocalcemia is a rather frequent consideration in the newborn nursery. Conditions that predispose to early-onset neonatal hypocalcemia include maternal insulin-dependent diabetes, birth hypoxia, acidosis, respiratory distress, and low birth weight (usually associated with prematurity). There is a general inverse relationship between serum calcium level and birth weight or infant gestational age. Infants who are severely premature or have very low birth weight tend to develop hypocalcemia very early; in one study of such patients, one third became hypocalcemic by 15 hours after birth. In adult hypocalcemia, the diagnosis can be easily made with a serum total calcium assay if the patient has typical symptoms and if hypoalbuminemia is excluded. Ionized calcium assay may be necessary in equivocal cases. Although several formulas exist to predict ionized calcium using total calcium and serum albumin data, there is considerable disagreement in the literature whether these formulas are sufficiently accurate to be clinically useful. In one study on seriously ill adult patients, only about 20% of those who had formula-predicted ionized calcium deficit had measured ionized calcium abnormality. In newborns, serum calcium assay is much more difficult to interpret. First, neonatal calcium reference values increase with increasing gestational age, so that the reference range for prematures is different from the range for term infants. Second, there are surprisingly few data on neonatal reference ranges for calcium in the literature, and the data available are contradictory. For example, in laboratories with adult calcium reference range values of 9-11 mg/100 ml (2.25-2.75 mmol/L), the lower limit for premature infants varies in the literature from 6.0 to 8.0 mg/100 ml (1.50-2.0 mmol/L), and for full-term infants, from 7.3 to 9.4 mg/100 ml (1.83-2.35 mmol/L). If some other laboratory’s adult reference range were lower than 9-11 mg/100 ml, presumably the neonatal reference lower limit could be even lower than those quoted. High levels of bilirubin or hemoglobin (hemolysis) can affect (falsely decrease) several methodologies for serum calcium. Thus, laboratory results in possible early-onset neonatal hypocalcemia may be difficult to interpret.

Laboratory tests

Laboratory tests helpful in differential diagnosis are serum albumin, BUN, calcium, phosphorus, pH, and PCO2. These help to exclude hypoalbuminemia, chronic renal disease (BUN and phosphorus levels are elevated, pH is decreased), and alkalosis (respiratory or metabolic). Medication effect can be detected by a good patient history. Serum magnesium assay can exclude magnesium deficiency. If malabsorption is possible, serum carotene is a good screening test (Chapter 26). PTH assay is needed to diagnose hypoparathyroidism (PTH deficiency with decreased PTH levels) or pseudohypoparathyroidism (renal or skeletal nonresponse to PTH with increased PTH levels). N-terminal or “intact” PTH assay is better for this purpose than midregion or C-terminal assay if the patient has renal failure, since midregion and C-terminal fragments have a long half-life and thus accumulate in renal failure more than intact PTH or N-terminal fragments. If the BUN level is normal, there should be no difference between the various PTH assays.

Vitamin D compound assay. Vitamin D is a fat-soluble steroid-related molecule that is absorbed in the small intestine. After absorption it is carried in chylomicrons or bound to an alpha-1 globulin called “transcalciferin.” Normally, about one third is metabolized to calcidiol (25-hydroxy-vitamin D) in the liver, and the remainder is stored in adipose tissue. Calcidiol is primarily regulated by the total amount of vitamin D in plasma from exogenous or endogenous sources; therefore, calcidiol is an indicator of vitamin D body reserves. Estrogen increases calcidiol formation. Calcidiol is altered to calcitriol (1,25-dihydroxy-vitamin D, the active form of vitamin D) in kidney proximal tubules by a 1-hydroxylase enzyme. Normal values decline with age. About 10% is metabolized to 24,25-dihydroxy-vitamin D by a different enzyme. As noted previously, calcitriol has actions affecting calcium availability in bone, kidney, and intestine. PTH and blood phosphate levels can influence the hydroxylase enzyme, with the effects of PTH being produced through its action on cyclic AMP.

The vitamin D group includes two other compounds: Vitamin D2(ergocalciferol), derived from plant sources; and vitamin D3 (cholecalciferol), synthesized in the epidermis and therefore a naturally occurring form of vitamin D in humans.

Laboratory assays for both calcidiol and calcitriol are available in some of the larger reference laboratories. These assays are useful mainly in patients with possible vitamin D overdose (hypervitaminosis D), in children with rickets, and in some adults with osteomalacia (the adult equivalent of rickets). Both osteomalacia and rickets are characterized by defective calcification of bone osteoid, and both involve some element of vitamin D deficiency.

Vitamin D excess can produce hypercalcemia, hyperphosphatemia, soft tissue calcification, and renal failure. Calcidiol assay is the test of choice; the calcidiol level should be considerably elevated. In some patients with PHPT, the serum calcium level may be normal or borderline, and PTH assay may be equivocal. In these few patients, calcitriol assay may be useful, since it should be elevated in PHPT.