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Diagnostic work-up of patients with suspected hypercalcemia of malignancy
Diagnostic work-up of patients with hypercalcemia of unknown origin
Hypercalcemia of malignancy is a common cause of hypercalcemia in hospitalized patients. Hypercalcemia of malignancy is typically not due to excess parathyroid hormone (PTH). In these disorders, PTH is usually suppressed due to elevated serum calcium concentrations. A variety of other mechanisms lead to inappropriate hypercalcemia in hypercalcemia of malignancy. These include:
-Impaired renal function due to a tumor or its treatment
-Osteolytic activity within bony metastases
-Release of calcemic cytokines by non-osteolytic bony metastases
-Eectopic 1-alpha hydroxylase activity in tumor tissues
-Secretion of humoral factors mimicking PTH action (humoral hypercalcemia of malignancy: HHM), usually associated with secretion of parathyroid hormone-related peptide (PTHrP) by the primary tumor (or more commonly its metastases)
-Other, as yet unknown factors
Frequently, a single cause cannot be pinpointed. Amongst the defined causes of the condition, PTHrP secretion is believed to be the most common culprit.
PTHrP is a single monomeric peptide that exists in several isoforms, ranging from approximately 60 amino acids to 173 amino acids in size, which are created by differential splicing and post-translational processing by prohormone convertases. PTHrP is produced in low concentrations by virtually all tissues. The physiological role of PTHrP remains incompletely understood. Its functions can be broadly divided into 4 categories, not all of which are present in all PTHrP isoforms or in all tissues:
-Transepithelial calcium transport, particularly in the kidney and mammary gland
-Smooth muscle relaxation in the uterus, bladder, gastrointestinal tract, and arterial wall
-Regulation of cellular proliferation
-Cellular differentiation and apoptosis of multiple tissues
-As an indispensable component of successful pregnancy and fetal development (embryonic gene deletion is lethal in mammals)
PTHrP's diverse functions are mediated through a range of different receptors, which are activated by different portions of PTHrP. Among the many receptors that respond to PTHrP is the PTH receptor, courtesy of the fact that 8 of the 13 N-terminal amino acids of PTH and of 3 common PTHrP isoforms are identical. Since most of PTHrP's actions in normal physiology are autocrine or paracrine, with circulating levels being very low, this receptor cross-talk only becomes relevant when there is extreme and sustained over-production of PTHrP. This is seen occasionally in pregnancy, lactation and, rarely, in a variety of non-malignant diseases. However, most commonly it is observed when tumors secrete PTHrP ectopically. In rough correlation with physiological production levels of PTHrP in the corresponding healthy tissues, ectopic PTHrP production is most commonly seen in carcinomas of breast, lung (squamous), head and neck (squamous), kidney, bladder, cervix, uterus, and ovary. Neuroendocrine tumors may also occasionally produce PTHrP. Most other carcinomas, sarcomas, and hemato-lymphatic malignancies only sporadically produce PTHrP, with the notable exceptions of T-cell lymphomas and myeloma.
Patients with HHM may have increased PTHrP values before treatment. PTHrP level decreases and PTH level increases, accompanied by decreased serum calcium values, with successful treatment.
See Diagnostic Use of Parathyroid Hormone Assays in Publications.
Depending on the patient population, up to 80% of patients with malignant tumors and hypercalcemia will be suffering from humoral hypercalcemia of malignancy (HHM). Of these, 50% to 70% might have an elevated parathyroid hormone-related peptide (PTHrP) level. These patients will also usually show typical biochemical changes of excess parathyroid hormone (PTH)-receptor activation, namely, besides the hypercalcemia, the might have hypophosphatemia, hypercalcuria, hyperphosphaturia and elevated serum alkaline phosphatase. Their PTH levels will typically be less than 30 pg/mL or undetectable.
In patients with biochemical findings that suggest but do not prove primary hyperparathyroidism (eg, hypercalcemia, but normal or near normal serum phosphate and a PTH level that is within the population reference range, but above 30 pg/mL), HMM should be considered as a diagnostic possibility, particularly if the patient is elderly, has a history of malignancy or risk factors for malignancy. An elevated PTHrP level in such a patient is highly suggestive of HHM as the cause for the hypercalcemia.
The test should not be used to exclude cancer or screen tumor patients for humoral hypercalcemia of malignancy.
Parathyroid hormone-related peptide (PTHrP) can be elevated in pregnant and lactating women and in newborn infants. Nonmalignant conditions that have been described in association with elevated plasma PTHrP levels include systemic lupus erythematosus, HIV-associated lymphadenopathy, lymphedema of chest or pleural cavities, and with benign tumors of the ovary, kidney and the neuroendocrine system.
Because of the complexity of PTHrP isoforms, the differences between various PTHrP assays and the lack of a common calibration standard, PTHrP measurements performed with different assays can not be compared easily.
The complex isoform mixture of PTHrP can occasionally lead to pronounced nonlinearity on dilution of patient specimens. In these situations an accurate measurement of PTHrP concentrations might be impossible.
Like all immunometric assays, PTHrP assays are susceptible to false low results at extremely high analyte concentrations ("hooking") and to rare false positive results due to heterophile antibody interference. Therefore, if test results are incongruent with the clinical picture, the laboratory should be contacted.
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