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CLIN.CHEM.37/2, 142-143
(1991)
Immunometric Assays of Parathyrin in the Diagnosis of Hypercalcemic Individuals
The application of immunometric
assays to the measurement of parathyrin
(PTH) has provided the sensitivity and specificity required to measure the intact,
circulating, biologically active form of the molecule,
PTH 1-84. These assays have been an important advance in permitting
study of the regulation of PTH
secretion in response to rapid changes of mineral ions,
in disorders of altered skeletal activity such as hyperthyroidism, and in understanding
the recovery of remaining parathyroid
gland function after parathyroid
adenomectomy. Nonetheless, a paramount question remains: Do these assays offer advantages to the clinician
for the diagnosis of hypercalcemic individuals?
Malignancy
and hyperparathyroidism
account
for
>90% of all cases of hypercalcemia.
Hypercalcemia
associated
with malignancy is the most common cause
of hypercalcemia
in hospitalized patients (1), whereas
the majority of ambulatory
patients will have hyperparathyroidism,
which is increasingly being recognized
as a consequence of biochemical screening of asymptomatic individuals.
In this issue of Clinical Chemistry, Endres et al. (2)
provide us with a study comparing a mid-molecule assay
(recognizing PTH 44-68) with two immunometric
assays, an immunochemiluminometric
assay (Magic Lite
PTH; Ciba Corning Diagnostics, Stoughton, MA) and an
immunoradiometric
assay (IRMA) (Allegro Intact PTH;
Nichols Institute
Diagnostics, San Juan Capistrano,
CA) in the diagnosis of hypercalcemic
disorders and
hypoparathyroidism.
The mid-molecule
assay principally identifies biologically inactive mid- and carboxylterminal fragments that are either derived from the
metabolism of PTH 1-84 or secreted by the parathyroid
gland.
Their data clearly confirm what has been published in
other reports (3-7) on immunometric
PTH assays,
namely, that these assays can virtually
completely
separate individuals
with hyperparathyroidism
from
those with malignancy
or other non-parathyroidinduced hypercalcemic
states. The USC/Los Angeles
County Medical Center study population included 29
patients with hyperparathyroidism,
12 of whom had
surgically confirmed
disease and four of whom had
coexistent malignancy. In the IRMA, 73% of hyperparathyroid patients had P’FH values >65 ngIL, whereas
97% of hyperparathyroid
patients had above-normal
serum
values of PTH 1-84 in the immunochemiluminometric
assay. In contrast, all hyperparathyroid
patients had above-normal
serum
concentrations
of
PTH in the mid-molecule assay.
There are several possible explanations
for these
findings. There was an excellent correlation between
the two immunometric
assays (r = 0.978), and the only
real difference in the results obtained with these assays
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CLINICALCHEMISTRY,Vol. 37, No. 2, 1991
was that 65 ng/L was considered to be the upper limit of
normal in the IRMA vs 55 ngfL in the immunochemiluminometric assay. Patients with hyperparathyroidism
and coexistent malignancy, who were initially thought
to have hypercalcemia of malignancy, had PTH concentrations in the high normal range or only slightly above
normal, suggesting that osteoclastic bone resorption
with release of calcium from the skeleton may have
partially suppressed above-normal
concentrations
of
PTH in serum.
The recently described peptide, parathyrin-related
protein (PTHrP), is responsible for hypercalcemia-complicating epidermoid cancers, including renal and lung
carcinoma. PTHrP has amino-terminal
homology with
human PTH (eight of the first 13 amino acids are
identical) and binds to a common PTHIPTHrP receptor
on bone and kidney target tissue (8). PTH and PTHrP
amino acid sequences diverge considerably
beyond
amino acid position 13, and antisera used in midmolecule PTH assays, in carboxyl-terminal
P’FH assays,
and as the capture antibody in imniunometric assays do
not recognize PTHrP.
PTH secretion has been shown to be pulsatile (9), and
measurements
of the intact hormone, which has a halflife of minutes, may represent sampling from a trough.
The relatively increased concentrations
of mid- and
carboxyl-terminal
fragments, with their longer halflives, are a direct result of the metabolism of increased
amounts
of intact
PTH secreted
in hyperparathyroidism. Furthermore,
PTH fragments secreted by
the adenomatous
or hyperplastic
parathyroid
tissue
probably contribute further to increased mid- and carboxyl PTH fragments.
Immunometric
assays for PTH 1-84 have been available for three years and have become widely applied in
the diagnosis of hypercalcemic
patients. Discussion of
PTH assays at the recently convened NIH consensus
conference on asymptomatic
hyperparathyroidism
(October 29-31, 1990, in Bethesda, MD) yielded an overall
agreement that these immunometric
assays measure
above-normal concentrations
of PTH in 90% of hyperparathyroid
patients, whereas the remaining
10% of
patients have serum PTH 1-84 near the upper limit of
normal. Dr. John Bilezikian, of Columbia University
College of Physicians and Surgeons,
presenting data
from a longitudinal natural history study of >100 patients with asymptomatic
hyperparathyroidism,
reported serum concentrations of PTH 1-84 by IRMA to be
above normal in 92% of the patients. Our own experience with the IRMA at the Massachusetts
General Hospital is that above-normal PTH concentrations in serum
are found in 90% of patients who are operated on for
primary hyperparathyroidism.
A hormone assay must be interpreted in light of its
clinical correlation data: in this case, the ranges found
for normal subjects, hyperparathyroid patients, cancer
patients with hypercalcemia, and the other diseases
that account for the remaining
5% of hypercalcemic
individuals.
Most often, patients with hypercalcemia of malignancy have symptoms attributable to the underlying
malignancy,
and the hypercalcemia
is of recent
onset.
The greatest failing of mid-molecule assays is that they
give above-normal values for P’FH in 20-25% of patients
with hypercalcemia
associated
with malignancy
(10,
11); at times, therefore, they may mislead the clinician
to consider hyperparathyroidism
and subject a patient
to unwarranted
parathyroid surgery. It is our hope that
the advent of immunometric
assays for PTH, in conjunction with clinical judgment, will permit reliable discrixnination
between hypercalcemia associated
with malignancy and that of hyperparathyroidism.
References
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