Full text of DOI:10.1111/j.1939-165X.2002.tb00268.x

Detection of Parathyroid Hormone–Related Protein
in Cats with Humoral Hypercalcemia of Malignancy
Anne Provencher Bolliger, Peter A. Graham, Virgile Richard, Thomas J.Rosol, Raymond F. Nachreiner, Kent R. Refsal
Background — Increased serum parathyroid hormone–related peptide (PTHrP) concentration is used to diagnose humoral
hypercalcemia of malignancy (HHM) in humans and animals. A commercially available assay for human PTHrP has diagnostic
utility in the dog, but has not been assessed in cats. Objectives —The goals of this study were to determine serum or plasma lev-
els of PTHrP in a population of hypercalcemic cats and to determine whether increased PTHrP concentration was associated with
malignancy. In addition, we validated immunoradiometric assays (IRMAs) for intact parathormone (iPTH) and PTHrP for use
with feline samples. Methods —A retrospective analysis of iPTH and PTHrP results from 322 hypercalcemic cats (ionized calci-
um concentration >1.4 mmol/L) was performed. Immunoassays for human iPTH and PTHrP (residues 1-84) were validated using
standard methods, and reference intervals were calculated using values from 31 healthy adult cats. Hypercalcemic cats were clas-
sified as parathyroid-independent (iPTH <2.3 pmol/L), equivocal (iPTH 2.3-4.6 pmol/L), or parathyroid-dependent (iPTH >4.6
pmol/L). Seven cats with detectable or increased PTHrP concentrations were evaluated further for underlying disease. Formalin-
fixed neoplastic tissues were immunohistochemically stained using rabbit antibody to human midregion PTHrP. Results —
Assays for iPTH and PTHrP showed acceptable precision for feline samples. The reference interval for iPTH was 0.8-4.6 pmol/L
and for PTHrP was <1.5 pmol/L. The majority of hypercalcemic cats (263/322, 81.7%) were parathyroid-independent, with fewer
cats in the equivocal (32/322, 9.9%) and parathyroid-dependent (27/322, 8.4%) groups. In 31 (9.6%) cats, PTHrP concentration was
>1.5 pmol/L (range 1.5-26.6 pmol/L). All 7 cats for which follow-up information was available had HHM; 6 had carcinomas (4 lung
carcinomas, 1 undifferentiated carcinoma, 1 thyroid carcinoma) and 1 had lymphoma. All tumors had mild to moderate positive
staining for PTHrP; however, lung carcinomas from normocalcemic cats also stained positive. Conclusions — Human IRMA for
PTHrP (1-84) can be used to measure PTHrP in cats. Malignancies, particularly carcinomas, appear to secrete PTHrP and induce
HHM in this species. Immunohistochemistry alone cannot predict the occurrence of HHM in cats. (Vet Clin Pathol. 2002;31:3-8)
Key Words: Calcium, cat, hypercalcemia, malignancy, parathyroid, parathyroid hormone–related protein
———◆———
Hypercalcemia is a common biochemical abnormality
in humans and animals. In cats, it can be associated with
malignancies, renal failure, primary hyperparathyroid-
ism, hypoadrenocorticism, and ingestion of cholecalcif-
erol-containing poisons.1 Additionally, idiopathic hyper-
calcemia of unexplained etiology has been increasingly
recognized.1 Acidifying diets or urinary acidifiers also
have been reported as an emerging cause of hypercal-
cemia in this species.2
When considering mechanisms of hypercalcemia, 2
categories are usually distinguished: parathyroid-depen-
dent hypercalcemia associated with dysfunction of the
parathyroid gland (ie, primary hyperparathyroidism) and
parathyroid-independent hypercalcemia associated with
appropriate parathyroid gland function (eg, humoral hy-
percalcemia of malignancy [HHM], vitamin D toxicosis).3
In humans and animals, including cats, one of the
main causes of parathyroid-independent hypercalcemia
is HHM associated with certain tumors. Although a
variety of mechanisms are involved in HHM, most com-
monly there is excessive osteoclastic bone resorption
induced by humoral factors produced by tumor cells.
The most common humoral factor secreted by tumor
cells and causing hypercalcemia is parathyroid hor-
mone–related protein (PTHrP).4 Detection of increased
concentrations of PTHrP in animals with parathyroid-
independent hypercalcemia can help to diagnose HHM.
The purpose of this study was to determine the
prevalence of detectable or increased serum levels of
PTHrP in a population of hypercalcemic cats and to
determine whether increased PTHrP concentration was
associated with malignancies. In addition, we validated
an immunoradiometric assay (IRMA) for human intact
parathormone (iPTH) and PTHrP for use with feline
samples.
Materials and Methods
Samples
A retrospective analysis of laboratory results from 322
hypercalcemic cats (ionized calcium [iCa]>1.40 mmol/L,
From the Endocrine Diagnostic Section, Animal Health Diagnostic Laboratory, Michigan State University, East Lansing, MI 48824 (Bolliger, Graham,
Nachreiner, Refsal); and the Department of Veterinary Biosciences, Ohio State University, Columbus, OH 43210 (Richard, Rosol). Corresponding
author:Anne Provencher Bolliger, DVM, MSc, DACVP, Zentrallabor, Departement fuer Klinische Veterinaermedizin, Universitaet Bern, 124 Laenggass
Strasse, CH-3012 Bern, Switzerland (acbolliger@bluewin.ch).
Vol. 31 / No. 1 / 2002
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PTHrP Detection in Hypercalcemic Cats
reference interval 1.0-1.4 mmol/L) was performed.
values from 31 healthy adult normocalcemic cats pre-
sented to the Michigan State University Teaching
Hospital for health checks and vaccinations. The refer-
ence interval was defined as the 5th and 95th per-
centiles.
Samples were obtained from veterinarians in the
United States and Canada through the Endocrine
Diagnostic Section of the Animal Health Diagnostic
Laboratory at Michigan State University between Octo-
ber 1996 and October 1999. In all cats, iCa, iPTH, and
PTHrP concentrations had been measured. In nearly all
cats, those analyses were performed on serum; howev-
er, in some cats, PTHrP was assayed in EDTA plasma.
Blood samples were collected according to specific han-
dling instructions provided by the laboratory. Whole
blood was centrifuged and serum or EDTA plasma was
separated within 30-60 minutes following collection and
immediately frozen. Samples were shipped frozen the
day of collection by overnight courier on frozen ice
packs. Upon receipt by the laboratory, the temperature
of samples was recorded. Samples received that were
cooler than 15°C were accepted for analysis. Clinical
data, history, and signalment information including sex
and age were provided by the referring veterinarian on
the laboratory submission form.
Parathyroid hormone–related protein. PTHrP was deter-
mined using a PTHrP IRMA (1-84, complete molecule,
sandwich assay; DiaSorin, Stillwater, Minn, USA). Using
feline plasma samples, the sensitivity, precision, and
parallelism of the assay were determined. To determine
sensitivity, 10 replicate measurements were made of the
zero calibrator provided by the kit’s manufacturer.
Sensitivity was defined as the mean PTHrP value of this
calibrator plus 2 SD.
To determine intra-assay precision using cat plas-
ma, the mean, SD, and CV were determined on dupli-
cate measurements of PTHrP from cats with positive
detection of PTHrP (n=5). The mean CV was defined as
precision. The limited availability of positive cats pre-
cluded the determination of an interassay CV by tradi-
tional methods. Replicates from a zero plasma pool
from cats (n=10) run 10 times consecutively within an
assay and at the beginning of each assay run for 10 con-
secutive assay days always produced nondetectable
results.
To determine the dilutional parallelism, a feline
plasma sample in which an increased concentration of
PTHrP (24.8 pmol/L) had been detected was diluted 1:2,
1:4, and 1:8 with a cat plasma pool (n=10) with nonde-
tectable PTHrP concentration. PTHrP values at each
dilution were compared with expected values calculated
from the undiluted concentration measured by the
assay. The reference interval was calculated using plas-
ma from the same 31 healthy adult normocalcemic cats
as those used for PTH reference intervals.
Assays and validation
Ionized calcium. Ionized calcium was measured using an
ion-specific electrode (Nova CRT 8 Analyzer, Nova
Biomedical, Waltham, Mass, USA).
Parathyroid hormone. Parathyroid hormone (PTH) con-
centration was determined using an iPTH IRMA (com-
plete molecule, sandwich assay; DPC, Los Angeles,
Calif, USA). Using feline serum samples, the analytical
sensitivity, precision, and parallelism were determined.
To determine sensitivity, 10 replicate measurements of
the zero calibrator were made. Sensitivity was defined
as the mean PTH value of the sample plus 2 SD. To
determine precision, a low-PTH serum pool (n=10) and
a high-PTH serum pool (n=10) were made from feline
serum samples in which PTH was measured and detect-
ed. The pooled samples were assayed at the beginning
of each assay run for 10 consecutive assay days. The
mean, SD, and coefficient of variation (CV) were deter-
mined for each pool; the CV was defined as the interas-
say precision. Ten replicate measurements of each pool
also were made within a single assay.The mean, SD, and
CV were determined for each pool; the CV was defined
as the intra-assay precision.
Classification of cats
To determine the most likely cause of hypercalcemia,
cats were classified into 3 groups according to the con-
centration of iPTH. The “parathyroid-independent”
group comprised hypercalcemic animals showing
appropriate response from the parathyroid gland and a
concentration of iPTH in the lower half of the reference
interval (iPTH <2.3 pmol/L, reference interval 0.8-4.6
pmol/L). A midnormal to high concentration of iPTH is
considered inadequately suppressed in association with
hypercalcemia.5 The “equivocal” group comprised
hypercalcemic animals showing an equivocal response
from the parathyroid gland and a concentration of iPTH
between the mid and the upper limit of the reference
interval (2.3-4.6 pmol/L). The “parathyroid-dependent”
group comprised hypercalcemic cats showing an inap-
To determine the dilutional parallelism, the low-
PTH and high-PTH serum pools were diluted 1:2, 1:4,
and 1:8 with the zero calibrator provided by the kit’s
manufacturer. PTH values at each dilution were com-
pared with expected values calculated from the undilut-
ed concentration measured by the assay.
A reference interval was calculated using serum
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Veterinary Clinical Pathology
Vol. 31 / No. 1 / 2002

Bolliger, Graham, Richard, et al.
Table 1. Classification of 322 hypercalcemic cats based on intact
parathyroid hormone (iPTH) concentration.
propriate response from the parathyroid gland and an
elevated concentration of iPTH (iPTH >4.6 pmol/L).The
numbers and percentages of cats in each group were
determined.
Cats
iPTH
Cats with detectable serum or plasma PTHrP con-
centrations were identified and classified as described
above. Where possible, these cats were further investi-
gated for underlying disease and malignancies.
Formalin-fixed neoplastic tissues were obtained for
histopathologic diagnosis and immunohistochemistry.
Group
(pmol/L)*
Number
263
%
81.7
9.9
Parathyroid-independent
Equivocal
<2.3
2.3-4.6
>4.6
32
Parathyroid-dependent
27
8.4
*iPTH reference interval 0.8-4.6 pmol/L.
Immunohistochemical staining
was established at the limit of detection for the assay,
<1.5 pmol/L.
Immunohistochemical staining for midregion PTHrP
(34-53) was performed on formalin-fixed neoplastic tis-
sues from cats with increased PTHrP concentration
using an avidin-biotin-complex immunohistochemistry
method and rabbit PTHrP AB/2 affinity-purified poly-
clonal antibody raised to residues 34-53 of human
PTHrP (Oncogene Science, Uniondale, NY, USA). Four
to 5 representative high-power fields of the sections
were examined. Diffuse cytoplasmic and/or nuclear
positive staining in the majority, if not all, neoplastic
cells was qualified as homogeneous. Positive staining
that showed some variation in intensity among neoplas-
tic cells was qualified as heterogeneous. Positive
immunohistochemistry was scored from mild to marked
according to the intensity of the signal for PTHrP.
Classification of cats
Cats were classified according to iPTH concentration
and parathyroid gland response (Table 1). The majority
of hypercalcemic cats (263/322, 81.7%) had parathyroid-
independent hypercalcemia; there were fewer cats in
the equivocal group (32/322, 9.9%) and in the parathy-
roid-dependent hypercalcemia group (27/322, 8.4%). In
31/322 (9.6%) cats, the concentration of PTHrP was >1.5
pmol/L (range 1.5-26.6 pmol/L). Cats with PTHrP con-
centrations of >1.5 pmol/L also were classified accord-
ing to iPTH level (Table 2). Most cats with detectable or
increased PTHrP concentrations (28/31, 86.8%) were in
the parathyroid-independent hypercalcemia group,
with only 3/31 (13.2%) cats in the equivocal group and
no cats in the parathyroid-dependent hypercalcemia
group.
Results
Assay validation
Of the 31 cats with detectable or increased PTHrP
concentration, information about underlying disease
was available for 7 cats, including 2 cats with detectable
PTHrP but at concentrations below the assay’s lower
analytical limit of detection (1.0 and 1.2 pmol/L). Al-
though PTHrP concentrations were within the reference
interval for the latter 2 cats, we felt the borderline results
were of biological significance since most hypercalcemic
cats (284/322) had undetectable PTHrP concentration (0
Parathyroid hormone. The sensitivity of the assay for PTH
using feline serum samples run with the human kit and
according to manufacturer’s instructions was 0.8
pmol/L. Intra-assay precision for the low-PTH serum
pool and the high-PTH serum pool was 10.2% and 3.3%,
respectively. Interassay precision for the low-PTH ser-
um pool and the high-PTH serum pool was 11.8% and
10.8%, respectively. Results from the dilutional parallel-
ism study were satisfactory with 100%, 104%, and 112%
of expected concentrations at 1:2, 1:4, and 1:8 dilutions,
respectively.The reference interval was 0.8-4.6 pmol/L.
Table 2. Classification of hypercalcemic cats with detectable or
increased levels of parathyroid hormone–related peptide (>1.5
pmol/L) based on intact parathyroid hormone (iPTH) concentration.
Parathyroid hormone–related protein. The sensitivity of the
PTHrP assay using feline plasma samples run with the
human kit and according to manufacturer’s instructions
was 1.5 pmol/L. Intra-assay precision was 8.8%. Results
from the dilutional parallelism study were satisfactory
with 130%, 85%, and 91% of expected concentrations at
1:2, 1:4, and 1:8 dilutions, respectively. All PTHrP con-
centrations in cat samples used for reference interval
calculations were undetectable. The reference interval
Cats
iPTH
Group
(pmol/L)*
Number
%
86.8
13.2
0
Parathyroid-independent
Equivocal
<2.3
28
3
2.3-4.6
>4.6
Parathyroid-dependent
0
*iPTH reference interval 0.8-4.6 pmol/L.
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PTHrP Detection in Hypercalcemic Cats
Table 3. Clinical and laboratory data and final diagnoses for 8 cats with humeral hypercalcemia of malignancy.
Cat
No.
Age,
y
iCa,
iPTH,
pmol/L
PTHrP,
pmol/L
Sex* History†
mmol/L‡
Classification
Histologic Diagnosis
1
10
F
Weight loss,
hypercalcemia
2.84
1.8
6.3
Parathyroid-independent
hypercalcemia
Undifferentiated carcinoma
in the kidney
2
14
MC
Pleural effusion,
collapsed lung lobe,
hypercalcemia
1.70
1.6
1.0
Parathyroid-independent
hypercalcemia
Anaplastic carcinoma of the
lung and diaphragm
3
13
8
FS
Neck mass,
hypercalcemia
1.63
2.11
2.8
1.8
1.2
Equivocal
Multifocal adenomatous
thyroid hyperplasia and
carcinoma in situ
4§
MC
Thrombocytopenia,
multiple pulmonary
nodular densities,
hypercalcemia
11.7
Parathyroid-independent
hypercalcemia
Bronchogenic
adenocarcinoma
5
10.5
FS
Decreased appetite, 2.47
fever, caudal dorsal
lung mass, left
0.9
4.0
Parathyroid-independent
hypercalcemia
Metastatic carcinoma of the
scapula, probable primary
bronchogenic carcinoma
forelimb lameness,
hypercalcemia
6
7
15
10
FS
FS
Persistent
hypercalcemia
1.37
1.39
3.8
1.7
8.8
4.4
Equivocal
Equivocal
Pulmonary squamous cell
carcinoma
Hypercalcemia
Lymphoma of duodenum and
jejunum
Reference Interval
1.0-1.4
0.8-4.6
<1.5
* F indicates female; MC, castrated male; FS, spayed female.
† A history of hypercalcemia was based on increased total calcium concentration.
‡
iCa indicates ionized calcium, iPTH indicates intact parathyroid hormone; PTHrP indicates parathyroid hormone–related peptide.
§ See Anderson, et al.6 for a complete description of this case.
pmol/L) and only 7/322 cats had PTHrP concentrations
of 1.0-1.4 pmol/L. In addition, the borderline values of
PTHrP were within the 90th percentile of the population.
Based on available follow-up information, all 7 cats
with increased PTHrP concentration had malignant neo-
plasia (Table 3). Five cats were hypercalcemic. Cats 6 and
7 had high-normal iCa concentrations, which should
have excluded them from the retrospective study group.
However, both cats had significantly increased PTHrP
values (8.8 and 4.4 pmol/L, respectively) and persistent
hypercalcemia. In addition, both cats had received
intensive fluid therapy prior to submission of samples to
our laboratory, which could have explained why iCa
concentrations were within the reference interval.
One cat (cat 3) was re-evaluated 5 months following
surgery for thyroid neoplasia. Results of the parathyroid
function panel revealed normocalcemia (iCa=1.33 pmol
/L) and a slight decrease in iPTH concentration (0.0
pmol/L). Unfortunately, there was not enough sample to
measure PTHrP.
PTHrP immunohistochemical staining
Formalin-fixed tissues of malignant tumors from cats 1,
2, 3, 4, and 6 were immunohistochemically stained for
PTHrP. As a negative control, formalin-fixed tissues
from lung tumors originating from 6 normocalcemic
cats also were stained.
PTHrP staining was slightly positive in normal tis-
sues surrounding neoplastic foci. Both normal renal and
bronchiolar epithelium showed much paler staining
when compared with their neoplastic counterparts. All
tumors, from both hypercalcemic and normocalcemic
animals, showed mild to marked positive staining. The
tumor from cat 1 had marked homogeneous staining.
Tumors from cats 2, 3, 4, and 6 had moderate homoge-
neous or heterogeneous staining. Lung tumors from
normocalcemic cats showed mild to marked heteroge-
neous or homogeneous staining. In all tumors, positive
staining was mainly cytoplasmic and occasionally
nuclear.
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Bolliger, Graham, Richard, et al.
Discussion
Our results suggest that HHM in cats can be asso-
ciated with detectable or increased concentrations of
PTHrP, as reported in human beings and other animal
species, especially dogs.8 Hypercalcemia has been
Assay validation results indicated that the complete
molecule iPTH and PTHrP IRMA were acceptable for
use with feline samples. The sandwich IRMA has the
advantage of measuring a larger PTHrP molecule (1-84).
The amino acid sequences in PTHrP are highly con-
served among species up to residue 111, which includes
the biologically active N-terminus (1-36), which can acti-
vate PTH receptors.7 The IRMA utilizes 2 antibodies for
2 specific regions of the molecule, 1-40 and 57-80.
Measuring PTHrP with this 2-site assay avoids detection
of small fragments that can give false-positive results, as
may occur when using a midregion or amino-terminal
assay.8 According to the manufacturer,7 PTHrP is best
measured in EDTA plasma but serum can also be used.
EDTA plasma has been reported to be more sensitive
for PTHrP detection in dogs.4 We were not able to estab-
lish the importance of sample type for cats. In this study,
all samples were received within 24 hours of blood col-
lection and were kept cold at all times, which assured
preservation of the protein to be measured. Similar con-
clusions were reported for a canine PTH assay.9
13
reported in cats with multiple myeloma, squamous cell
14
15
carcinoma, bronchogenic carcinoma,6 lymphoma, and
10
other malignancies. Although a PTH-like effect was the
main hypothesis for hypercalcemia in most reported
cases, PTHrP was not measured, with the exception of a
cat with bronchogenic carcinoma6 that was also includ-
ed in this study. Our data showed that most cats (6 of 7)
with detectable or increased PTHrP levels had carcino-
mas, 5 of which were lung carcinomas. These findings
differ from those reported for dogs, in which the most
common neoplasms associated with detectable or in-
creased concentrations of PTHrP are lymphomas and
adenocarcinomas derived from apocrine glands of the
anal sac.16 In humans, the most common malignancies
associated with HHM and increased PTHrP concentra-
tions are lung and breast carcinomas.17 Although hyper-
calcemia can be observed in people with lymphoma, it is
uncommon and usually related to unregulated extra-
17
renal production of 1,25-dihydroxyvitamin D. The dis-
In a recent retrospective study of hypercalcemic
cats, the most common causes of hypercalcemia were
neoplasia and renal disease.10 Cats with hypercalcemia
related to renal disease were not evaluated in this study.
Data provided by referring veterinarians rarely includ-
ed information about renal function. Most cats with
tribution of PTHrP-positive tumor types in cats may be
more similar to that in humans than that in dogs.
Results of immunohistochemical staining suggest-
ed that identification of midregion PTHrP may not be
sufficient to determine whether there is increased
PTHrP in the circulation. As indicated by positive stain-
ing in normocalcemic cats, many tumors can be positive
for PTHrP but not necessarily associated with HHM.18
Such tumors may secrete too small amounts of PTHrP,
there may be enzymatic degradation of PTHrP, the
PTHrP secreted may not be biologically active, or the
tumors may accumulate hormone from the circulation.17
Criteria used to confirm hormone expression by tumor
cells include detection of hormone, presence of mRNA
for the hormone in tumor tissue, and hormone secre-
tion by tumor cells in culture.17
In conclusion, of 7 cats diagnosed with HHM, 5
had increased concentrations of PTHrP, and 2 had bor-
derline-high PTHrP concentrations. A human PTHrP
(1-84) IRMA kit can be used without modification with
feline samples, possibly because of the high level of
conservation of the PTHrP molecule among species.
Most hypercalcemic cats in this study had parathyroid-
independent hypercalcemia, which concurs with previ-
ously published data. Our findings suggest that mea-
surement of PTHrP in cats may help in the differential
diagnosis of hypercalcemia. The most common tumor
type in cats with HHM was carcinoma, which differs
from dogs with HHM.
11
renal disease have normal iCa concentration. Because
our determination of hypercalcemia was based on ele-
vated iCa concentration, cats with renal disease were
most likely not included in this study.
Neoplasia is associated with parathyroid-indepen-
dent hypercalcemia. Our data showed a predominance
of hypercalcemic cats having parathyroid-independent
hypercalcemia (81.7%). However, other causes of
parathyroid-independent hypercalcemia (cholecalcifer-
ol-containing poison ingestion, hypoadrenocorticism,
idiopathic hypercalcemia, acidifying diet intake) could
not be completely ruled out. Primary hyperparathy-
roidism, the main cause of parathyroid-dependent
hypercalcemia, is rare in cats.12 Parathyroid-dependent
hypercalcemia constituted only a small percentage of
cats (8.4%) with hypercalcemia. For cats with an equivo-
cal response from the parathyroid gland, it was difficult
to determine the cause of the hypercalcemia. Additional
information and a final diagnosis would be needed for
each cat; the type of study herein did not permit this
type of exploration. However, the percentage of cats
within this equivocal group was low (9.9%) and agreed
with other published data indicating that most hyper-
calcemic cats have parathyroid-independent hypercal-
cemia.
Vol. 31 / No. 1 / 2002
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PTHrP Detection in Hypercalcemic Cats
Addendum
nized and sections of lung, pancreas, liver, kidney, adren-
al glands and small intestine were submitted for histo-
logic evaluation. A lung carcinoma was diagnosed. ◊
At the time of manuscript submission, an additional
case of HHM in a cat with elevated PTHrP concentration
and carcinoma was identified. Serum and EDTA plasma
from a 12-year-old female spayed cat with a history of
lethargy, anorexia, weight loss and elevated total calcium
concentration were submitted. Results of the parathy-
roid function panel confirmed parathyroid-independent
hypercalcemia with increased ionized calcium concen-
tration (1.88 mmol/L) and an appropriately suppressed
concentration of iPTH (0.6 pmol/L). The PTHrP concen-
tration was increased at 7.0 pmol/L. The cat was eutha-
Acknowledgments
The authors thank Susan Lombardini and Enass Bassioumy for
technical assistance, and the contribution of the following veteri-
narians in referring cases and providing follow-up information:
Drs Tammy Anderson, Susan Best, Garrett Davis, David Gamble,
Carla Gartrell, Steven Gilbertson, Paul Hanna, AL Hickman,
Marlene Kalin, Anne Kincaid, S. Lobojko, Michael McEntee,
Darcy Shaw, and Liz Wilson.
© 2002 American Society forVeterinary Clinical Pathology
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