Parathyroid hormone related protein (PTHrP) is released by certain tumors to cause humoral hypercalcemia of malignancy.
Several isoforms (139 to 173 AA's in man) are produced by a gene separate from the parathyroid hormone (PTH) gene and subjected to post-translational modification. Multiple metabolic fragments of PTHrP may exist in circulation including carboxyl fragments. The biological action of these C-terminal fragments, if any, is not known.
Normal physiological role appears to be in calcium homeostasis in the fetus and during lactation in addition to other local autocrine/paracrine properties in adults. Its role in most adult tissues is unknown.
Amino (N-) terminal homology with PTH. 8 of first 13 amino-acids identical between human PTH and PTHrP. The N-terminal (AA's 1-34) confers biological activity that mimics most functions of PTH. Remainder of molecule shows little homology with PTH.
Uses
Alone
To determine the presence of humoral hypercalcemia of malignancy as the source of a parathyroid-independent hypercalcemia (high ionized calcium with low PTH).
In combination
Often used in combination with ionized calcium and PTH or following their use to confirm parathyroid independent hypercalcemia.
Other sample types are not acceptable in most analytical labs.
Sample collection technique
Collect sample and separate within 30 minutes.
Sample transport details should be obtained from individual laboratory. Expect to ship cold overnight.
Addition of protease inhibitors can be helpful in preserving the sample. Special sample handling required.
Quality control
Timing of test
Not critical.
Sample storage
Must be chilled immediately following sample and then frozen to -10 to -20°C after separation. Sample deteriorates dramatically at room temperature (~50% loss by 24 hours) and significantly at refrigerator temperatures (~30% lost by 36 hours).
Most assays use one set of antibodies directed against the N-terminal (AA's 1-40) and another set directed against the mid-molecule (~AA's 60-70).
Two sites ensure that PTHrP measured independently of PTH and that only intact molecule and not cross-reacting fragments are measured.
Availability
Limited to veterinary endocrine reference laboratories and regional human laboratories.
Veterinary labs use assay kits developed for use in humans and validate for use with animal plasma (dog, cat, horse).
Validity
Sensitivity
PTHrP is the mechanism by which only a proportion of cancers cause hypercalcemia. Some neoplasms use different mechanisms including direct osteolysis (eg osteosarcoma , myeloma , metastatic carcinoma, the secretion of cytokines and the production of calcitriol.
The PTHrP test is can only be described as sensitive for PTHrP mediated hypercalcemia. Its diagnostic sensitivity for hypercalcemia of malignancy in general is quite poor.
For example, only about 30-40% of hypercalcemic canine lymphoma patients have detectable plasma PTHrP. A negative PTHrP result, therefore, does not rule out lymphoma as a cause of the hypercalcemia.
Specificity
Generaly considered to be highly specific. Yields few false positive results.
Rare positive PTHrP in the face of lab evidence for primary hyperparathyroidism might suggest parathyroid carcinoma.
Predictive value
Depends on prevalence of PTHrP-mediated-hypercalcemia in population being tested.
Provencher-Bolliger A L, Graham P A, Richard V, Rosol T J, Nachreiner R F & Refsal K R (2002) Detection of parathyroid hormone-related protein in cats with humoral hypercalcemia of malignancy.Vet Clin Path 31, 3-8 PubMed.
Rosol T J, Nagode L A, Couto C G, Hammer A S, Chew D J, Peterson J L, Ayl R D, Steinmeyer C L & Capen CC (1992) Parathyroid hormone (PTH)-related protein, PTH and 1,25 dihydroxyvitamin D in dogs with cancer-associated neoplasia.Endocrinol131, 1157 - 1164 (uses N-terminal assays only not modern intact molecule assays).
Other sources of information
Refsal K R, Provencher-Bolliger A L, Graham P A & Nachreiner R F (2001) Update on the diagnosis and treatment of disorders of calcium regulation.Vet Clin N Amer 5, 1043-1062.
Vetstream contributor(s)
Dr Peter A Graham, BVMS, PhD, CertVR, MRCVS, North Western Laboratories Ltd, Lancefield House, 23 Mains Lane, Poulton-le-Fylde, Lancashire, FY6 7LJ, UK.
Dr Anne Provencher-Bolliger DVM, MSc, DipACVP, Department of Veterinary Clinical Sciences, University of Bern, Laengass Strasse 124, CH-3012 Bern, Switzerland.
Organization(s)
Endocrinology Section, Diagnostic Center for Population and Animal Health, Michigan State University, PO Box 30076, Lansing, Michigan USA. Ph. +1-517-353-0621, Fx. +1-517-353-4426 www.ahdl.msu.edu
Special sample handling required.