INTRODUCTION — Hypocalcemia has many causes (table 1). It can result from inadequate parathyroid hormone (PTH) secretion, PTH resistance, vitamin D deficiency or resistance, abnormal magnesium metabolism, and extravascular deposition of calcium, which can occur in several clinical situations. (See "Etiology of hypocalcemia in adults" and "Etiology of hypocalcemia in infants and children".)
The diagnostic approach to hypocalcemia involves confirming, by repeat measurement, the presence of hypocalcemia and distinguishing among the potential etiologies. The diagnosis may be obvious from the patient's history; examples include chronic kidney disease and postsurgical hypoparathyroidism. When the cause is not obvious or a suspected cause needs to be confirmed, other biochemical tests are indicated.
This topic will review the evaluation of patients with hypocalcemia. The clinical manifestations and treatment of hypocalcemia are discussed separately. (See "Clinical manifestations of hypocalcemia" and "Treatment of hypocalcemia".)
CONFIRM HYPOCALCEMIA — The first step in the evaluation of hypocalcemia is to repeat the measurement to confirm that there is a true decrease in the serum calcium concentration:
●In most patients with normal serum albumin concentrations, the total serum calcium concentration can be used for both the initial and the repeat serum calcium measurements.
●If the diagnosis of hypocalcemia is in doubt, due to hypoalbuminemia, atypical or absent symptoms, or a minimally reduced serum calcium concentration, we obtain a serum ionized calcium for the repeat measurement.
●If a laboratory known to measure ionized calcium reliably is not available, the total calcium should be repeated and corrected for any abnormality in serum albumin, using a calcium correction formula. (See 'Hypoalbuminemia: Calcium correction' below.)
Previous values for serum calcium should also be reviewed, if available. If the patient has a low ionized calcium or serum total calcium (corrected for albumin in patients with hypoalbuminemia), further evaluation to identify the cause is indicated. (See 'Determining the etiology' below.)
Ionized calcium — Ionized calcium remains the gold standard for assessing calcium status because it measures the biologically active (or free) calcium. However, ionized calcium is not performed routinely, because it is more costly and must be handled carefully and stored under appropriate conditions to preserve a sample pH of 7.4. It is important to note that the affinity of calcium for albumin is increased in the presence of alkalosis. Thus, respiratory alkalosis may cause an acute decrease in ionized calcium. (See "Relation between total and ionized serum calcium concentrations", section on 'Acid-base disorders'.)
Hypoalbuminemia: Calcium correction — In patients with hypoalbuminemia, the total serum calcium concentration will change in parallel to the albumin concentration and may not accurately reflect the physiologically important ionized (or free) calcium concentration. 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)]. If the measured serum total calcium concentration is 8 mg/dL (2 mmol/L) and the serum albumin concentration is 2 g/dL (20 g/L) below normal, the corrected value will be 9.6 mg/dL (2.4 mmol/L), which is normal. Despite widespread use of this formula in clinical practice over the last several decades, more contemporary studies suggest the accuracy of this estimate is quite poor in a variety of populations, including patients hospitalized with critical illness and patients with advanced-stage chronic kidney disease. (See "Relation between total and ionized serum calcium concentrations", section on 'Hypoalbuminemia'.)
The etiology may be obvious from the patient's history and physical examination; examples include chronic kidney disease and postsurgical hypoparathyroidism. When the cause is not obvious or a suspected cause needs to be confirmed, other biochemical tests are indicated. (Related Lab Interpretation Monograph(s): "Low calcium in adults".)
Clinical clues — The etiology of hypocalcemia may be obvious from the clinical history. A family history of hypocalcemia suggests a genetic cause. Chronic familial hypocalcemia is often seen in patients with an activating mutation of the calcium-sensing receptor (autosomal dominant hypocalcemia [ADH] type 1) or, less frequently, of a downstream signaling molecule of the calcium-sensing receptor, GNA11 (ADH type 2), and in pseudohypoparathyroidism. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia".)
On the other hand, acquired hypoparathyroidism is most often the result of postsurgical or autoimmune damage to the parathyroid glands. Postsurgical hypoparathyroidism can occur after thyroid, parathyroid, or radical neck surgery for head and neck cancer. Thus, a history of head and neck surgery or the presence of a neck scar suggests postsurgical hypoparathyroidism. (See "Hypoparathyroidism".)
Autoimmune hypoparathyroidism can occur as an isolated abnormality and is also a common feature of polyglandular autoimmune syndrome type I, which is a familial disorder. The presence of chronic mucocutaneous candidiasis and adrenal insufficiency suggests a polyglandular syndrome. (See "Causes of primary adrenal insufficiency (Addison's disease)", section on 'Polyglandular autoimmune syndrome type 1'.)
There are several drugs that also may cause hypocalcemia (table 1).
Other causes of hypocalcemia that may be apparent from the history, physical examination, and routine laboratory data include acute or chronic kidney disease, acute pancreatitis, rhabdomyolysis, and marked increases in tissue breakdown with the release of phosphate from cells, as occurs in the tumor lysis syndrome (table 1). (See "Etiology of hypocalcemia in adults".)
The physical examination may reveal findings of latent tetany, such as Chvostek's and Trousseau's signs, which are strongly suggestive of hypocalcemia. (See "Clinical manifestations of hypocalcemia".)
Laboratory evaluation — Measurement of serum intact parathyroid hormone (PTH) should be performed in all patients with hypocalcemia; it is the most valuable laboratory test for determining the etiology of hypocalcemia (table 2) [1,2]. (Related Lab Interpretation Monograph(s): "Low calcium in adults".) (See 'Serum PTH concentrations' below.)
Additional laboratory evaluation to determine etiology may include measurements of serum magnesium, creatinine, phosphate, the vitamin D metabolites calcidiol (25-hydroxyvitamin D [25(OH)D]) and calcitriol (1,25-dihydroxyvitamin D, the active vitamin D hormone), alkaline phosphatase, amylase, and urinary calcium and magnesium excretion [1-4]. These tests should be performed selectively based upon the patient's history and physical examination.
Serum PTH concentrations — Serum intact parathyroid hormone (PTH) measurements provide critical information in patients with hypocalcemia but can be interpreted correctly only when serum calcium is measured simultaneously (figure 1). Hypocalcemia is the most potent stimulus of PTH secretion; as a result, a low or even normal serum PTH concentration in a patient with hypocalcemia is strong evidence of hypoparathyroidism. (See "Regulation of calcium and phosphate balance".)
●Serum PTH is reduced or inappropriately normal in patients with hypoparathyroidism.
●Serum PTH is elevated in patients with acute or chronic kidney disease, vitamin D deficiency, and pseudohypoparathyroidism.
●Serum PTH is typically normal or low in patients with hypomagnesemia or ADH, a rare disorder characterized by an activating mutation in the calcium-sensing receptor gene or in GNA11.
Magnesium — Hypomagnesemia (serum magnesium concentration below 0.8 mEq/L [1 mg/dL or 0.4 mmol/L]) causes hypocalcemia by inducing PTH resistance or deficiency. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion".)
Serum magnesium should be measured in any patient with hypocalcemia in whom the cause is not obvious. Hypocalcemia should resolve within minutes or hours after restoration of normal serum magnesium concentrations if hypomagnesemia was the cause of the hypocalcemia. (See "Treatment of hypocalcemia", section on 'Concurrent hypomagnesemia'.)
A few patients with magnesium-responsive hypocalcemia have normal serum magnesium concentrations. These patients are presumed to have tissue magnesium deficiency. Thus, magnesium supplementation may be indicated in patients with unexplained hypocalcemia who are at risk for hypomagnesemia, such as patients with chronic malabsorption or alcoholism. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Normomagnesemic magnesium depletion'.)
Phosphate — Phosphate levels may be elevated, low, or normal depending upon the etiology of hypocalcemia (table 2).
●Elevated – Persistent hypocalcemia and hyperphosphatemia is, in the absence of kidney disease or increased tissue breakdown, virtually diagnostic of either hypoparathyroidism (PTH deficiency) or pseudohypoparathyroidism (PTH resistance). The elevated serum phosphate concentration in patients with either disorder is due to loss of the stimulatory effect of PTH on urinary phosphate excretion and is therefore associated with an inappropriately low fractional excretion of phosphate. (See "Hypoparathyroidism", section on 'Laboratory findings' and "Overview of the causes and treatment of hyperphosphatemia", section on 'Increased tubular reabsorption of phosphate'.)
●Low – The presence of a low serum phosphate concentration indicates either excess PTH secretion, which in the context of hypocalcemia means secondary hyperparathyroidism (and some abnormality in vitamin D intake or metabolism), or low dietary phosphate intake, which is uncommon. (See "Hypophosphatemia: Causes of hypophosphatemia".)
●Normal – Normal serum phosphate in the setting of hypocalcemia may be consistent with hypomagnesemia or mild vitamin D deficiency.
Vitamin D metabolites — Vitamin D deficiency increases PTH secretion by causing hypocalcemia (due to the reduction in intestinal calcium absorption) and, to a lesser degree, by removing the normal inhibitory effect of calcitriol on PTH production . Vitamin D deficiency also diminishes intestinal phosphate absorption. Excess PTH enhances phosphate excretion and lowers the serum phosphate.
Measurement of serum 25(OH)D (calcidiol) provides more information about vitamin D deficiency than does measurement of serum 1,25-dihydroxyvitamin D (calcitriol) because the hypocalcemia-induced increase in PTH secretion stimulates renal 1,25-dihydroxyvitamin D production (in patients without underlying renal insufficiency). Thus, in individuals with vitamin D deficiency, serum 25(OH)D is low, whereas 1,25-dihydroxyvitamin D is typically normal or high. In contrast, patients with hypoparathyroidism may have normal serum 25(OH)D and low 1,25-dihydroxyvitamin D concentrations (table 2).
The various causes of vitamin D deficiency usually can be distinguished by the history and other clinical findings (deficient dietary intake, inadequate sunlight exposure, malabsorption, phenytoin therapy) and by measurement of 25(OH)D (calcidiol). A more in-depth discussion of the individual disorders can be found elsewhere. (See "Causes of vitamin D deficiency and resistance".)
Patterns of vitamin D metabolites and phosphate — The following patterns in vitamin D metabolites and serum phosphate may be seen in patients with hypocalcemia and secondary increases in PTH and point to different underlying causes of hypocalcemia (table 2):
●A low serum 25(OH)D concentration in a patient with hypocalcemia and hypophosphatemia usually indicates that vitamin D intake or absorption (usually coupled with decreased production in skin) is low. Other possibilities include phenytoin therapy, hepatobiliary disease, the nephrotic syndrome (in which vitamin D-binding protein is lost in the urine), or a rare familial disorder characterized by inability to 25-hydroxylate vitamin D in the liver (vitamin D-dependent rickets, type 1B). (See "Etiology and treatment of calcipenic rickets in children", section on '25-hydroxylase deficiency'.)
●The combination of normal or low serum 25(OH)D concentration and low serum 1,25-dihydroxyvitamin D concentration, with high-normal or elevated serum phosphate, indicates the presence of chronic kidney disease (easily diagnosed from the serum creatinine concentration). Chronic kidney disease is the only condition in which hypocalcemia and secondary hyperparathyroidism are not associated with low or low-normal serum phosphate (as a result of the inability of the diseased kidney to respond to the high PTH).
●The combination of normal or low serum 25(OH)D concentration, low serum 1,25-dihydroxyvitamin D concentration, and low serum phosphate suggests the presence of vitamin D-dependent rickets, type 1A (renal 1-alpha-hydroxylase deficiency), also called pseudo-vitamin D deficient rickets.
●Hereditary vitamin D-resistant rickets (also called vitamin D-dependent rickets, type 2) presents in early childhood and is associated with a defect in the vitamin D receptor. It should be suspected in hypocalcemic patients if serum phosphate is low and serum 1,25-dihydroxyvitamin D concentrations are high. (See "Etiology and treatment of calcipenic rickets in children", section on 'Hereditary resistance to vitamin D'.)
Other — Other tests that may be helpful in determining the cause of hypocalcemia include serum alkaline phosphatase, serum amylase, and 24-hour urinary excretion of calcium and magnesium:
●An elevated alkaline phosphatase is common in osteomalacia (as a result of severe vitamin D deficiency and secondary hyperparathyroidism) and can occur with osteoblastic bone metastases, which can cause hypocalcemia due to rapid deposition of calcium in bone metastases . (See "Clinical manifestations, diagnosis, and treatment of osteomalacia".)
●Serum amylase is elevated in acute pancreatitis but only slightly in chronic pancreatitis. (See "Clinical manifestations and diagnosis of acute pancreatitis", section on 'Laboratory findings'.).
●Low urinary calcium occurs in patients with untreated hypoparathyroidism or vitamin D deficiency. (See "Hypoparathyroidism", section on 'Laboratory findings' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)
●Assessment of urinary magnesium may be helpful in individuals with hypomagnesemia. In this setting, an elevated value is consistent with renal losses. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Calcium metabolism'.)
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●Basics topics (see "Patient education: Hypoparathyroidism (The Basics)")
SUMMARY AND RECOMMENDATIONS
●The first step in the evaluation of hypocalcemia is to repeat the measurement to confirm that there is a true decrease in the serum calcium concentration. (Related Lab Interpretation Monograph(s): "Low calcium in adults".)
In most patients with normal serum albumin concentrations, the total serum calcium concentration can be used for both the initial and the repeat serum calcium measurements. If the diagnosis of hypocalcemia is in doubt, due to hypoalbuminemia, atypical or absent symptoms, or a minimally reduced serum calcium concentration, we obtain a serum ionized calcium. If a laboratory known to measure ionized calcium reliably is not available, the total calcium should be repeated and corrected for the presence of hypoalbuminemia (when present), using a calcium correction formula. Previous values for serum calcium should also be reviewed, if available. (See 'Confirm hypocalcemia' above.)
●If the patient has a low albumin-corrected serum calcium or ionized calcium concentration, further evaluation to identify the cause is indicated. (See 'Determining the etiology' above.)
●Measurement of serum intact parathyroid hormone (PTH) should be performed in all patients with hypocalcemia; it is the most valuable laboratory test for determining the etiology of hypocalcemia (table 2). (See 'Laboratory evaluation' above.)
●Other measurements that may be helpful include serum magnesium, creatinine, phosphate, vitamin D metabolites (primarily 25-hydroxyvitamin D [25(OH)D]), and alkaline phosphatase. (See 'Laboratory evaluation' above.)