Articles on Medical Diseases and Conditions

Tag: Hypercalcemia

  • Hypercalcemia and Malignancy

    In confirmed hypercalcemia, differential diagnosis is usually among PHPT, malignancy (metastatic to bone or the ectopic PTH syndrome), and all other etiologies. In most cases the differential eventually resolves into PHPT versus hypercalcemia of malignancy (HCM). There is no single laboratory test that can distinguish between PHPT and HCM every time with certainty. As noted previously, the better midmolecule PTH assays usually can differentiate normal from either PHPT or HCM and frequently can differentiate PHPT from HCM. If PHPT and HCM are not clearly separated, intact PTH assay might be obtained since it is generally better at separating PHPT and HCM. In any case a nomogram containing a scattergram of known cases is necessary. If the different PTH assays are not available, some other tests might indirectly provide evidence one way or the other. Hand x-rays are helpful if typical changes of PHPT are found (but this occurs in only a small percentage of cases). Renal stones are common in PHPT and uncommon in tumor. The quickest and easiest screening test for myeloma is serum protein electrophoresis, although serum and urine immunoelectrophoresis is more sensitive. A serum chloride value at the upper limit of the reference range or above is evidence against metastatic tumor. A bone scan and x-ray skeletal survey are useful to detect metastatic tumor. Some investigators advocate the assay of calcitonin, which is elevated with varying frequency in tumors associated with hypercalcemia and is usually not elevated in PHPT (some investigators report mild elevation in some patients). Unfortunately, regardless of the test results, PHPT may be present concurrently with malignancy in about 5% of patients with cancer.

    Serum calcitonin assay. Calcitonin (thyrocalcitonin, TCT) is secreted by nonfollicular C cells of the thyroid. An increased serum calcium level induces thyroid C cells to produce more calcitonin as part of hypercalcemia compensatory mechanisms. A major exception is PHPT, where the TCT level is usually normal or low, for poorly understood reasons (one report indicates an elevation in 10% of cases). The TCT level may be elevated in a considerable percentage of certain tumors known to metastasize to bone, such as lung carcinoma (about 30%-50% of cases; literature range 21%-62%) and breast carcinoma (about 50%; range, 38%-75%). Medullary thyroid carcinoma (MTC) produces elevated basal TCT in about 75% of cases (range, 33%-100%). Total serum calcium in MTC is usually normal. MTC or C-cell hyperplasia is found in >95% of patients with multiple endocrine neoplasia (MEN) syndromes type 2A and 2B. Type 2A also includes pheochromocytoma (about 50% cases) and PHPT (10%-25% cases). PHPT also is part of MEN type 1, which does not include MTC. The TCT level may be increased in the Zollinger-Ellison syndrome, as well as in certain nonneoplastic conditions such as chronic renal failure or pernicious anemia, and values may overlap with MCT. In summary, an elevated TCT level in a patient with possible PHPT raises the question of medullary carcinoma of the thyroid or some other malignancy, if the patient is not in renal failure.

    Ectopic parathyroid hormone syndrome.

    Nonparathyroid tumors that secrete PTH or PTH-like hormones (ectopic PTH syndrome) can produce considerable diagnostic problems. In one study, 19% of patients with tumor-associated hypercalcemia had no evidence of bone metastases. On the average, PTH assay values in ectopic PTH syndrome are lower than PTH values in PHPT. Although there is some overlap, the degree of overlap depends on the individual antiserum. There is disagreement regarding the nature of the ectopically produced hormone; that is, whether it is true PTH or a nonidentical molecule with a similar structure and PTH-like action that cross-reacts with most current PTH antisera. To further confuse matters, it is estimated that 5%-10% of patients with malignancy and hypercalcemia also will have a coexisting parathyroid adenoma with PHPT. It has also been stated that 15% of patients with PHPT have some coexisting disorder that could produce hypercalcemia.

  • Tests Useful in Differential Diagnosis of Hypercalcemia

    Serum calcium. Routine serum calcium assay measures the total serum calcium value. Total serum calcium contains about 50% bound calcium (literature range, 35%-55%) and about 50% nonbound calcium (literature range, 35%-65%). (Traditionally, nonbound calcium was called “ionized” calcium and is also known as “free” or “dialyzable” calcium.) Bound calcium is subdivided into calcium bound to protein and calcium complexed to nonprotein compounds. About 45% of total calcium (30%-50%) is protein-bound, of which 70%-80% is bound to albumin. The remaining 5% (5%-15%) of total calcium is complexed to ions such as citrate, phosphate, sulfate, and bicarbonate, which are not part of the serum proteins. Ionized calcium levels can be measured directly by ion-selective electrode techniques or less accurately can be estimated from total serum calcium and albumin or total protein values using certain formulas. The most commonly used calcium correction formula is that of R.B. Payne:

    Adjusted calcium = (measured calcium – serum albumin) + 4.0

    with calcium in mg/100 ml and albumin in g/100 ml. In international system (SI) units, the formula reads:

    Adjusted calcium = (calcium – 0.025 albumin) + 1.0

    with calcium in mmol/L and albumin in g/L. Ionized calcium values are affected by serum pH (a decreased of 0.1 pH unit increases ionization by 1.5%-2.5%). If serum is exposed to air and stands too long, the pH slowly increases. There is a small diurnal variation in ionized calcium, with the peak most often about 9 P.M. and the nadir about 9 A.M. There also is a small diurnal variation in urine calcium, with the peak most often about 11 P.M. and the nadir about 11 A.M.

    Ionized calcium is not affected by changes in serum albumin concentration, which is a significant advantage over total calcium assay. A decrease in the serum albumin level by 1 gm/100 ml produces an approximate decrease in the (total) serum calcium level of approximately 0.8 mg/100 ml from previous levels (this is an average value, and could be more or less in any individual patient). Since a decrease in the serum albumin level is frequent in patients with severe acute or chronic illness, an artifactual decrease of the serum calcium level is likewise frequent in hospitalized patients. The ionized calcium value is regarded by many investigators as more sensitive and reliable than the total calcium value in detection of PHPT. A certain number of their PHPT patients had elevated ionized calcium levels but normal total calcium levels. However, some investigators do not find that ionized calcium materially assists detection or diagnosis of PHPT. Also, certain conditions that produce hypercalcemia, such as myeloma, sarcoidosis, hypervitaminosis D, and metastatic carcinoma to bone, may in some cases be associated with increased ionized calcium levels. Most laboratories do not have the equipment necessary to perform ionized calcium assay, and although there are formulas that estimate ionized calcium from total calcium plus serum protein levels, there is disagreement in the literature concerning which formula is best. There is also disagreement whether such estimates are reliable enough to be used in the diagnosis of PHPT. The consensus in the literature seems to be that ionized calcium may be helpful in the diagnosis of PHPT in a minority of patients, such as those with borderline total calcium values or those with hypoalbuminemia, and is best determined using ion-selective electrode methodology.

    Serum phosphate. Decreased serum phosphate is one of the classic biochemical findings in PHPT. Phosphate usually is measured as the phosphorus ion. Only about 10%-15% is protein bound. There is a diurnal rhythm, with higher values in the afternoon and evening, which may be as much as double those in the morning. Serum phosphate (phosphorus) has not proved as useful as the earliest studies suggested, since phosphate levels in PHPT that are below the population reference range tend to be limited to patients with more severe disease. In fact, the serum phosphate level is decreased in only about 40%-50% of PHPT cases (literature range, 22%-80%). The reference range is fairly wide, which can mask small decreases; and some conditions such as a high-phosphate or a low-calcium diet increase serum phosphate levels. Renal dysfunction severe enough to produce an elevated blood urea nitrogen (BUN) level raises the serum phosphate level. Various conditions other than PHPT can decrease serum phosphate levels (discussed later in this chapter). Among those associated with hypercalcemia and hypophosphatemia, besides PHPT, are some patients with malignancy and occasional patients with sarcoidosis, myeloma, hyperthyroidism, and vitamin D intoxication.

    Serum alkaline phosphatase. Alkaline phosphatase in nonneoplastic calcium disorders is an index of bone involvement. X-ray bone abnormalities in PHPT are reported in 23%-36% of patients, with most of the relatively few reports being in the older literature. X-ray studies of the fingers demonstrate the most typical changes. It is estimated that alkaline phosphatase elevation occurs in about 95% of patients with PHPT who have bone x-ray changes but in only about 10%-15% of those who do not (therefore, there would be an ALP level increase in 20% to 30% of all PHPT cases; however, some find x-ray changes in present-day PHPT in only 15% of cases). Metastatic malignancy can produce elevated alkaline phosphatase levels due to either bone or liver involvement.

    Urine calcium excretion. Excretion of calcium in urine is increased in about 75% of patients with PHPT (literature range, 50%-91%). In addition to PHPT, a considerable number of other conditions may produce hypercalciuria (e.g., idiopathic hypercalciuria, said to be present in nearly 5% of the population; bone immobilization syndrome; Cushing’s syndrome; milk-alkali syndrome; hypervitaminosis D; renal tubular acidosis; and sarcoidosis).

    Assay is performed on 24-hour urine specimens. There is disagreement in the literature on whether to collect the specimens with the patient on a normal diet, a normal diet minus milk, cheese, and other milk products, or a standard 200-mg low calcium diet. Most investigators and urologists seem to prefer a normal diet, at least for screening purposes. Reference ranges differ according to type of diet. The Sulkowitch test is a semiquantitative chemical procedure for urine calcium measurement that was widely used before 1960 but is rarely performed today.

    Urine phosphate excretion. The older literature states that phosphate excretion is increased in most patients with PHPT. There are surprisingly little data on this subject in recent literature. However, hyperphosphaturia probably is not as frequent today, just as decreased serum phosphate levels are seen much less frequently. Increased urine phosphate excretion in PHPT is expected in 70%-75% of cases. Phosphate depletion (due to prolonged vomiting, nasogastric suction, or ingestion of aluminum-type antacids) and chronic renal disease can reduce or eliminate phosphate hyperexcretion. Conditions that can produce increased urine phosphate excretion besides PHPT include renal triple phosphate lithiasis, osteomalacia, and, in some patients, hyperthyroidism, sarcoidosis, Cushing’s syndrome, and malignancy. Reference values depend on diet.

  • Tests in Calcium Disorders: Hypercalcemia

    Symptoms referable to hypercalcemia itself are very nonspecific; they include vomiting, constipation, polydipsia and polyuria, and mental confusion. Coma may develop in severe cases. There may be renal stones or soft tissue calcification. Hypercalcemia is most often detected on routine multitest biochemical screening panels, either in asymptomatic persons or incidental to symptoms from some disease associated with hypercalcemia (see the box on this page). In asymptomatic persons, primary hyperparathyroidism (PHPT) accounts for about 60% of cases. In hospital admissions, however, malignancy is the etiology for 40%-50% of cases and PHPT accounts for about 15%.

    Regulation of Serum Calcium Levels

    Regulation of serum calcium levels is somewhat complex. The major control mechanism is parathyroid hormone (PTH). Normally, parathyroid secretion of PTH is regulated by a feedback mechanism involving the blood calcium level. A decreased serum calcium level induces increased secretion of PTH, whereas an acute increase of the

    Selected Etiologies of Hypercalcemia

    Relatively common

    Neoplasia (noncutaneous)
    Bone primary
    Myeloma
    Acute leukemia
    Nonbone solid tumors
    Breast
    Lung
    Squamous nonpulmonary
    Kidney
    Neoplasm secretion of parathyroid hormone-related protein (PTHrP, “ectopic PTH”)
    Primary hyperparathyroidism (PHPT)
    Thiazide diuretics
    Tertiary (renal) hyperparathyroidism
    Idiopathic
    Spurious (artifactual) hypercalcemia
    Dehydration
    Serum protein elevation
    Lab technical problem

    Relatively uncommon

    Neoplasia (less common tumors)
    Sarcoidosis
    Hyperthyroidism
    Immobilization (mostly seen in children and adolescents)
    Diuretic phase of acute renal tubular necrosis
    Vitamin D intoxication
    Milk-alkali syndrome
    Addison’s disease
    Lithium therapy
    Idiopathic hypercalcemia of infancy
    Acromegaly
    Theophylline toxicity

    serum calcium level decreases secretion of PTH. PTH has a direct action on bone, increasing bone resorption and release of bone calcium and phosphorus. In addition, PTH increases the activity of the activating enzyme cyclic adenosine monophosphate (AMP) in the proximal tubules of the kidney, which increases conversion of calcidiol (25-hydroxyvitamin D) to calcitriol (1,25-dihydroxy-vitamin D). Calcitriol has metabolic effects that help to increase serum calcium levels, such as increased renal reabsorption of calcium, increased GI tract absorption of calcium, and the drawing out of some calcium from bone. On the other hand, an increased calcitriol level also initiates a compensatory series of events that prevents the calcium-elevating system from overreacting. An increased calcitriol level inhibits renal tubule phosphate reabsorption, which results in loss of phosphorus into the urine. This leads to a decreased serum phosphate level, which, in turn, inhibits production of calcitriol. The actions of PTH, phosphate, and calcitriol produce a roughly reciprocal relationship between serum calcium and phosphate levels, with elevation of one corresponding to a decrease of the other. Both PTH (through cyclic AMP) and phosphate act on the same enzyme (25-OH-D 1 a-hydroxylase), which converts calcidiol to calcitriol.

    Besides PTH, a hormone called “calcitonin” has important, although subsidiary, effects on calcium metabolism. Calcitonin is produced in the thyroid gland, and secretion is at least partially regulated by serum calcium levels. Acute elevation of serum calcium leads to increased calcitonin secretion. Calcitonin inhibits bone resorption, which decreases withdrawal of calcium and phosphorus and produces a hypocalcemic and hypophosphatemic effect that opposes calcium-elevating mechanisms.