Acute phase proteins in cats

Abstract

Acute phase proteins (APP) are proteins synthesized and released largely by hepatocytes upon the occurrence of cell damage or invasion by microorganisms. This article reviews the use of APP in feline diseases, identifying their usefulness in the clinical setting, analyzing 55 published papers. Serum amyloid A, alpha-1 acid glycoprotein, and haptoglobin are the indicators pointed out by the authors as useful in monitoring the acute inflammatory response in cats. Although, APP measurement is still not routinely used in veterinary medicine, together with clinical signs and other blood parameters, was of clinical interest and applicability in diseases such as feline infectious peritonitis, pancreatitis, renal failure, retroviral and Calicivirus infections. Although, there are commercially available kits for dosing feline APP, assay standardization aiming technical simplicity, more species specificity and with less associated costs will allow routine use in feline practice, as it is done in the human field.

Full text

Acute phase proteins in cats.
Ciência Rural, v.49, n.4, 2019.
1
Acute phase proteins in cats
Proteínas de fase aguda em gatos
Rita Mourão Rosa1 Lisa Alexandra Pereira Mestrinho2*
ISSNe 1678-4596
Ciência Rural, Santa Maria, v.49:04, e20180790, 2019
Received 09.27.18 Approved 03.08.19 Returned by the author 04.03.19
CR-2018-0790.R1
http://dx.doi.org/10.1590/0103-8478cr20180790
INTRODUCTION
The acute phase response (APR) is an
early, non-specic systemic innate immune reaction
to local or systemic stimulus, which helps to heal
and re-establish homeostasis and minimize tissue
damage when the body is aected by trauma,
infection, stress, surgery, neoplasia or inammation
(GRUYS et al., 2005; CRAY et al., 2009;
ECKERSALL & BELL, 2010). In this reaction we
observe several dierent systemic eects: fever,
leukocytosis, hormone shifts–mainly cortisol and
thyroxine concentrations, with a secondary catabolic
state and muscle protein depletion, serum depletion
of iron and zinc, among others (CERÓN et al. 2005,
JAVARD et al. 2017).
Under the inuence of IL-1β, TNF-α,
and especially IL-6, and about 90 minutes after
injury, protein synthesis is increased on hepatocytes,
lymph nodes, tonsils, and spleen as well as in blood
leukocytes. Those newly produced proteins are called
acute phase proteins (APP) (TIZARD, 2013b).
Acute phase proteins
The APP concentrations can increase
(positive APP) or decrease (negative APP)
(PALTRINIERI et al., 2008) in response to
inflammation (JOHNSTON & TOBIAS, 2018).
They can activate leukocytosis and the complement,
cause protease inhibition, lead to clotting and
opsonisation -a defense mechanism that lead to
the elimination of infectious agents, tissue repair
1Hospital Escolar Veterinário, Faculdade de Medicina Veterinária da Universidade de Lisboa (ULisboa), Lisboa, Portugal.
2Centro interdisciplinar de investigação em sanidade animal (CIISA), Faculdade de Medicina Veterinária da Universidade de Lisboa (Ulisboa),
Avenida da Universidade Técnica, 1300-477, Lisboa, Portugal. E-mail: lmestrinho@fmv.ulisboa.pt. *Corresponding author.
ABSTRACT: Acute phase proteins (APP) are proteins synthesized and released largely by hepatocytes upon the occurrence of cell damage or
invasion by microorganisms. This article reviews the use of APP in feline diseases, identifying their usefulness in the clinical setting, analyzing
55 published papers. Serum amyloid A, alpha-1 acid glycoprotein, and haptoglobin are the indicators pointed out by the authors as useful in
monitoring the acute inammatory response in cats. Although, APP measurement is still not routinely used in veterinary medicine, together
with clinical signs and other blood parameters, was of clinical interest and applicability in diseases such as feline infectious peritonitis,
pancreatitis, renal failure, retroviral and Calicivirus infections. Although, there are commercially available kits for dosing feline APP, assay
standardization aiming technical simplicity, more species specicity and with less associated costs will allow routine use in feline practice, as
it is done in the human eld.
Key words: inammation, acute phase proteins, cat.
RESUMO: As proteínas de fase aguda (PFA) são proteínas sintetizadas e libertadas em grande parte por hepatócitos ao mesmo tempo da
ocorrência de lesão celular ou invasão por microrganismos. Este artigo revê a utilização das PFA nas doenças do gato identicando a sua
potencial utilidade no contexto clínico, analisando 55 artigos publicados. A amiloide sérica A, a alfa-1 glicoproteina ácida e a haptoblobina
são os marcadores apontados pelos autores como úteis na monitorização da resposta aguda inamatória nesta espécie. Embora o doseamento
das PFA ainda não seja rotineiramente utilizado na medicina veterinária, o seu doseamento, em conjunto com sinais clínicos e outros meios
complementares de diagnóstico, revelou interesse e aplicabilidade clínica em doenças tais como a peritonite infeciosa felina, pancreatite,
insuciência renal, infeções retrovirais e por Calicivírus. Apesar de existirem kits comercialmente disponíveis para dosear as PFA felinas, será
necessária uma padronização de ensaios no sentido da melhoria da sua simplicidade técnica, da sua especicidade para o gato e com menores
custos associados, para que sejam utilizados de forma rotineira, tal como são utilizados em medicina humana.
Palavras-chave: inamação, proteínas de fase aguda, gato.
CLINIC AND SURGERY

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Ciência Rural, v.49, n.4, 2019.
Rosa & Mestrinho.
and restoration of the healthy state (CRAY et al.,
2009). The APP can have two functions, a pro-
or/and an anti-inflammatory effect, which must
be delicately balanced to promote homeostasis
(HOCHEPIED et al., 2003).
Three major groups of APP are recognized,
based on response magnitude and duration secondary
to stimulus (MURATA et al., 2004; PETERSEN et
al., 2004; CERÓN et al., 2005).Positive APP can be
divided in two groups: the rst group, which includes
APP with increases of 10 to 1000 times in humans or
10 to 100 times in domestic animals in the presence
of inammation–e.g. C-reactive protein (CRP) and
serum amyloid A (SAA); and a second group, which
corresponds to APP that increase 2 to 10 times
in inammatory response–e.g. haptoglobin and
alpha-globulins. The last group included negative
APP, where concentration decreases in response to
inammation – e.g. albumin (KANN et al., 2012).
Positive acute phase proteins
Positive APP are glycoproteins in which
serum concentrations increase by 25% upon
stimulation by pro inammatory cytokines during
disease process, being released in the blood stream.
These concentrations can be measured and used
in the diagnosis, prognosis, to monitor treatment
response, as well as for general health screening.
They also can be considered quantitative biomarkers
of disease, highly sensitive to inammation but
poorly specic, since elevation of APP can occur in
non-inammatory diseases as well (CERÓN et al.,
2005; ECKERSALL & BELL, 2010).
Positive APP respond dierently to
cytokines, being these groups divided into two
major classes. Type 1 APP, which include AGP,
complement component 3, SAA, CRP, haptoglobin
and hemopexin, are regulated by IL-1, IL-6 and
TNF-α and also by glucocorticoids. Type 2 which
includes the three brinogen chains (α-, β-, and
γ-brinogen) and various inhibitory proteases, are
regulated by IL-6 and glucocorticoid cytokines
(BAUMANN et al., 1990; BAUMANN &
GAULDIE, 1994).
In cats, SAA or alpha-1-acid glycoprotein
(AGP) are the most relevant APP. Blood SAA levels
can indicate inammatory conditions such as feline
infectious peritonitis (FIP) and other infectious
diseases such as caliciviral infection, chlamydiosis,
leukemia, and infectious immunodeciency since it
increases by 10- to 50-fold(TIZARD, 2013b). The
SAA can also be elevated in other diseases like
diabetes mellitus and cancer. Haptoglobin usually
increases 2- to 10-fold and is especially high in FIP
(TIZARD, 2013b). Table 1 summarizes each positive
APP in the context of feline disease.
Negative Acute Phase Proteins
Albumin is the most relevant negative
APP, with blood concentration decreasing during
APR, due to amino acid deviation towards the
synthesis of positive APP (CRAY et al., 2009;
PALTRINIERI, 2007a).Other negative APP are
transferrin, transthyretin, retinol ligand and cortisol
binding protein, proteins involved in vitamin and
hormone transport (JAIN et al., 2011).
Acute phase proteins in feline disease
Unlike cytokines, which have a small size
and are rapidly ltered by the kidney, the acute phase
proteins have a higher molecular weight (greater than
45kDa), and subsequently a longer permanence in the
plasma (SALGADO et al., 2011).
The APP levels can only assess
inammation and consequently their concentrations
can assist in diagnosis and disease monitoring.
APP can help to detect subclinical inammation,
dierentiate acute from chronic disease and to
predict its course (VILHENA et al, 2018; JAVARD
et al., 2017). Since the APR begins before specic
immunological changes occur, it can be used as an
early marker for disease, before leucogram changes
take place, being its magnitude related with the
severity of disease (PETERSEN et al., 2004;
CÉRON et al., 2005; VILHENA et al., 2018).For
this reason, disease monitoring can be considered
as one of the most interesting and promising
applications of APP.
APP levels, together with clinical signs
and blood tests have been evaluated in dierent
animal diseases (i.e.FIP, canine inammatory
bowel disease, leishmaniasis, ehrlichiosis and
canine pyometra), and proved to be useful in the
diagnosis, treatment response monitoring and
prognosis (ECKERSALL et al., 2001; MARTINEZ-
SUBIELA et al., 2005; SHIMADA et al., 2002;
JERGENS et al., 2003; GIORDANO et al., 2004;
PETERSEN et al., 2004; DABROWSKI et al.,
2009; VILHENA et al., 2018).
To obtain a complete information about
APR, one major and one moderate positive, as well
one negative APP should be done simultaneously
(CERÓN et al., 2008). High concentrations of major
APP are usually related with infectious diseases,
usually a systemic bacterial infection or an immune-
mediated disease (CERÓN et al., 2008; TROÌA et

Acute phase proteins in cats.
Ciência Rural, v.49, n.4, 2019.
3
al., 2017). Even though APP should be analyzed
together with white blood cell and neutrophil counts,
they are the most sensitive in detecting inammation
and infection earliest in time (CERÓN et al., 2008;
ALVES et al., 2010). However, the specicity of
these proteins is low in detecting the cause of the
process, being also increased in physiological states,
such as pregnancy (PALTRINIERI et al., 2008).
Figure 1 illustrates the expected behavior
of positive acute phase proteins based of the studies
revised. The AGP, SAA and haptoglobin were
pointed as useful indicators for monitoring the acute
inammatory response in cats (WINKEL et al., 2015;
PALTRINIERI et al., 2007a,b; KAJIKAWA et al.,
1999). The APP in cats were rstly identied after
comparative serum measurements in clinically normal
and diseased animals, in experimentally induced
inammation studies, and in post-operatory studies
(KAJIKAWA et al., 1999). The SAA concentration
was reported to be the rst to increase, with AGP and
haptoglobin increasing thereafter, opposing to a less
signicant increase of CRP (KAJIKAWA et al., 1999).
One study showed that CPR behaves similarly to SAA
and AGP in feline inammation (LEAL et al., 2014).
Serum amyloid a
The SAA is one of the major APP in
several species, important in both Humans and
Table 1 – Acute phase proteins studied in the context feline diseases.
APP Diseases References
FIP
DUTHIE et al., 1997; GIORDANO et al., 2004;
HAZUCHOVA et al. 2017;
Induced inflammation and surgery KAJIKAWA et al., 1999;
Various diseases (Pancreatitis, Renal failure, FLUTD,
Tumors, Diabetes mellitus; renal disease, injury, etc.)
SASAKI et al., 2003; KANN et al., 2012; TAMAMOTO et al.,
2013; TAMAMOTO et al., 2013;JAVARD et al., 2017;
SAA Sepsis TRÒIA et al., 2017;
FeLV; Hemotropicmycoplasms infections VILHENA et al., 2018;
Infection by Hepatozoonfelis and Babesia vogeli
VILHENA et al., 2017;
Dirofilariaimmitis
SILVESTRE-FERREIRAet al., 2017;
FIV cats treated with recombinant feline interferon
LEAL et al., 2014;
Infection by Chlamydophila psittaci;
TERWEE et al., 1998;
Pancreatitis and pancreatic tumors
MEACHEM et al., 2015;
Feline infectious peritonitis
DUTHIE et al., 1997; CECILIANI, et al., 2004; GIORDANO
et al., 2004; BENCE et al., 2005; PALTRINIERI et al., 2007b;
GIORI et al., 2011; HAZUCHOVA et al., 2017;
AGP Lymphoma and other tumors
SELTING et al., 2000; CORREA et al., 2001; WINKEL et al.
2015;
Induced inflammation and surgery
KAJIKAWA et al., 1999;
FIV cats treated with recombinant feline interferon
LEAL et al., 2014
Abscesses, pyothorax, Fat necrosis
OTTENJANN et al., 2006;
Various diseases (FLUTD, Tumors, Diabetes
mellitus; renal disease, injury, etc.)
KANN et al., 2012;
Feline infectious peritonitis
DUTHIE et al., 1997; GIORDANO et al., 2004;
HAZUCHOVA, K. et al. 2017;
Induced inflammation and surgery
KAJIKAWA, T. et al. 1999
Abscesses, Pyothorax, Fat necrosis,
OTTENJANN et al., 2006;
Haptoglobin
Various diseases (FLUTD, Tumors, Diabetes
mellitus; renal disease, injury, etc)
KANN et al. 2012
Infection by Hepatozoonfelis and Babesia vogeli
VILHENA et al., 2017;
FeLV, Hemotropicmycoplasms
VILHENA et al., 2018;
Dirofilariaimmitis
S
ILVESTRE
-F
ERREIRA
et al. 2017;
CRP
FIV cats treated with recombinant feline interferon
LEAl et al., 2014
Induced inflammation and surgery
KAJIKAWA et al., 1999;
Legend: Serum Amyloid A (SAA), α1-Acid Glycoprotein (AGP), Systemic Inflammatory Response Syndrome (SIRS) Feline Lower
Urinary Tract Disease (FLUTD), Feline Infectious Peritonitis (FIP), Feline Leukemia Virus (FeLV), Feline Immunodeficiency Virus
(FIV); Feline Calicivirus (FCV).

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Ciência Rural, v.49, n.4, 2019.
Rosa & Mestrinho.
cats (KAJIKAWA et al., 1999). Modulates the
immune response by attracting inammatory cells
to tissues and leading to the production of multiple
inammatory cytokines (GRUYS et al., 2005;
TIZARD, 2013a). Its concentration may rise more
than 1,000-fold in inammatory status, consequently
perceiving inammation (TAMAMOTO et al.,
2013). Such increase; however, is also seen in non-
inammatory diseases in inammatory diseases and
in neoplasia (TAMAMOTO et al., 2013). According
to a study performed in cats undergoing surgery, SAA
concentration begins to increase at approximately
3 to 6 hours, achieving the highest value 21 to 24
hours postoperatively (SASAKI et al.,2003).
Alpha 1–acid glycoprotein
Alpha 1–acid glycoprotein (AGP) is
an acute phase reactant protein reported in the
seromucoid portion of the serum (SELTING et
al., 2000; WINKEL et al., 2015). As most positive
APP, AGP is a glycoprotein synthesized mostly
by hepatocytes upon APR and released into the
bloodstream (CÉRON et al., 2005).
AGP can be used to monitor early
interferon treatment in cats infected with Feline
immunodeciency virus (FIV) (GIL et al., 2014).
AGP, as well as haptoglobin (Hp) is increased in
anemic cats suering from pyothorax, abscesses or
fat necrosis (OTTENJANN et al., 2006).
AGP changes in feline neoplasia seems
to be inconsistent among studies. Some describe
no changes in cats bearing lymphoma (CORREA et
al., 2001). On the contrary, others show increase of
both AGP or SAA in cats with sarcomas, carcinomas
or other round cell tumors (SELTING et al., 2000;
TAMAMOTO et al., 2013; MEACHEN et al., 2015;
HAZUCHOVA et al., 2017).
The AGP has been important as an
indicator test for FIP, specially used in Europe
(CECILIANI et al, 2004).GIORI et al. (2011)
studied the specicity and sensitivity of several
tests in 12 cats, where 33.33% were FIP negative
Figure 1 - Idealized behavior of acute phase proteins in the cat after an inammatory stimulus. The values depicting the
changes cannot be taken as absolute. Serum Amyloid A (SAA) increase 3 to 6 h after the stimulus, peak at 21 to
24 h, magnitude at peak 10 to 50 times its basal plasma concentration. α1 acid-glycoprotein (AGP) increase 8 h
after the stimulus, peak at 36 h, magnitude at peak 2 to 10 times its basal plasma concentration. Haptoglobulin
(Hp) increase 24 h after the stimulus, peak at 36 to 48 h, magnitude at peak 2 to 10 times its basal plasma
concentration value. C-Reactive protein (CRP) increase 8 h after the stimulus, peak at 36 h, magnitude at peak
1.5 times its basal values.

Acute phase proteins in cats.
Ciência Rural, v.49, n.4, 2019.
5
by histopathology and immunohistochemistry, and
66.66% of the cats were FIP positive conrmed
by histopathology and immunohistochemistry.
This author concluded that immunohistochemistry
must always be performed to conrm FIP,
but high concentrations of AGP may help to
support the diagnosis of FIP in case where
immunohistochemistry is not possible to perform,
and histopathology is not conclusive.
Haptoglobin
Haptoglobin (Hp) is one of the
most important acute-phase proteins in cattle,
sheep, goat, horses and cats (TIZARD, 2013a),
synthesized mostly by hepatocytes but also by
other tissues, like skin, lung and kidney (JAIN et al,
2011). The Hp binds to iron molecules and makes
them unavailable to invade bacteria, consequently
inhibiting bacterial proliferation and invasion.
Consequently it also binds to free hemoglobin,
preventing its oxidation with lipids and proteins
(TIZARD, 2013a), justifying the reduction of Hp
in case of hemolysis.
In cats, Hp usually increases 2- to 10-fold
in inammatory conditions, being especially high
in FIP (TIZARD, 2013a). However, both Hp and
SAA did not provide enough support to dierentiate
between FIP and other causes of eusion, compared
with AGP (HAZUCHOVA et at., 2017).
App measurement
The serum is composed by a large
number of individual proteins, in which detecting
changes in its fractions can provide important
diagnostic information (ECKERSALL, 2008).
Ideally, measurement of all serum proteins should be
available to be used as a diagnostic tool in the context
of inammatory diseases.
Nowadays, APP (Table 2) can be
determined using Enzyme-Linked Immunosorbent
Assay (ELISA), radioimmunoassay, nephelometry,
immunoturbidimetry (IT), Western blot, and
messenger ribonucleic acid (mRNA) analysis
(CÉRON et al., 2005;PALTRINIERI et al., 2008;
SCHREIBER et. al, 1989). Although, some APP
assays for Humans have been automated also for
veterinary medicine, species-specic tests are
still limited. Interspecies APP variations and the
limited availability of cross-reactive reagents have
contributed, for now, to a low routine determination
of APP in veterinary labs, especially for cats.
Regardless, technology is evolving, and it is possible
to foresee in the near future routine monitoring of the
clinically relevant APP in cats.
CONCLUSION
Acute phase proteins in cats are useful
biomarkers to monitor inammation, together with
other clinical and laboratory ndings, being useful
in diagnosing subclinical changes, monitoring the
evolution and the eect of a disease in the organism,
as well as evaluate treatment response.
In the cat, SAA is the APP expressing
the highest magnitude in response to inammation,
followed by AGP and haptoglobin, contrarily to CRP
as observed in other species.
Although, there are commercially
available kits for dosing feline APPs, assay
standardization aiming technical simplicity, more
Table 2 – Advantages and disadvantages of possible techniques in measuring APP.
Analyses
Advantages
Disadvantages
References
Radioimmunoassay
24 to 48 hours to get results,
specific skilles from the
operator
WHICHER et al., 1983
ELISA Commercially available
kits, species specific
Lack automation, expensive,
some imprecision between-run
JACOBSEN et al. 2006
TECLES et al. 2007
MARTÍNEZ-SUBIELA, S. et
al. 2005
Immunoturbidimetry
30 minutes to get results,
adaptable to biochemical
analyzers
WHICHER et al., 2003,
KURIBAYASHI et al.,
2003BENCE et al. 2005
Western Blot
Long period to process
immunoblots
CALLAHAN & YATES
2014
Nephelometric immunoassays
Depend on cross-reactivity of
antiserum raised
WEIDMEYER & SOLTER,
1996

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Ciência Rural, v.49, n.4, 2019.
Rosa & Mestrinho.
species specicity with less associated costs will
allow routine use in feline practice, as it done in
human medicine.
ACKNOWLEDGEMENTS
The authors acknowledge the support from the
Project UID/CVT/00276/2019 (CIISA) founded by FCT.
DECLARATION OF CONFLICT OF
INTERESTS
The authors declare no conict of interest. The
founding sponsors had no role in the collection, analyses, or
interpretation of data; in the writing of the manuscript, and in the
decision to publish the results.
AUTHORS’ CONTRIBUTIONS
The authors contributed equally to the manuscript.
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