Acute Phase Proteins

APPLICATION OF ACUTE PHASE PROTEINS AS BIOMARKERSIN MODERN VETERINARY PRACTICE

M. PradeepDepartment of Veterinary Pathology,

College of Veterinary and Animal Sciences,Pookode, Wayanad, Kerala.

Received : 17.05.2013 Accepted : 05.11.2013

Key words: acute phase proteins, biomarker, animal disease diagnosis, Serum amyloid A,C-reactive protein

INTRODUCTION

Current researches in disease diagnosisare aimed to identify ailments well before theclinical manifestation. In case of animals thisearly identification is important not only forthe well being of the animals but also for the

ABSTRACT

Animal body reacts to all kinds of injuries and stress to keep thehomeostasis. Such resistance can be specific or non specific. Non specificinnate resistance of the body like cytological and cytokine reactions includingfever, leukocytoses etc. are known as acute phase response. In this response,there will be increase or decrease of serum concentration of particularproteins. These proteins are known as acute phase proteins. Measurementof serum concentration of these acute phase proteins are found to be usefulin assessment of health status and prediction of diseases of the man andanimals. Acute phase proteins like Serum amyloid A, C- reactive proteins,Haptoglobin, alpha 1 acid glycoprotein etc. are found to be more sensitiveand specific than the routine diagnostic methods like white blood cell count.Use of acute phase proteins as biomarkers for animal disease diagnosisand health status assessment has got high potential in modern veterinarypractice. Usefulness of the acute phase protein analysis in veterinary practiceespecially in dog, cat, cattle and pig practices is discussed in this review.

humans who consume the animal and itsproducts. Scientists are consistently in searchof such predictive biomarkers in man andanimals. Research on serum acute phaseproteins (APP) provides a lime light in the areaof non specific biomarkers.

Ind. J. Vet & Anim. Sci. Res. 43 (1) 1-13, January - February 2014 1

Corresponding author E-mail : [email protected]

Review Article

Animal body shows two types ofimmune reaction to any type of injury. One isspecific immune reaction mediated byantibodies and the other is innate nonspecificimmune reaction like fever, cytologicalreactions etc. This innate nonspecific immunereaction of the body is otherwise known asacute phase response. The main aim of acutephase response is to maintain homeostasis andtissue healing. In the acute phase responseserum/ plasma level of some kind of proteinsare found to decrease while the levels of someother proteins increase many folds. Theseproteins are known as acute phase proteins(APP). These proteins include proteaseinhibitors (eg. alpha 1 antitrypsin, alpha 1antichymotrypsin), coagulation proteins (e.g.fibrinogen, prothrombin), complement proteins( e.g., C2, C3, C4, C5, etc.), transportproteins (e.g., Haptoglobin (Hp),Ceruloplasmin (Cp), hemopexin) and someother kind of proteins, like C reactiveprotein (CRP), serum amyoloid A (SAA),serum amyloid P (SAP), acid glycoprotein(AGP) etc.

Those APP whose serum levelsdecrease in acute phase response are called asnegative acute phase proteins (eg. albumin,transferrin etc.) and whose serum levelsincrease are called as positive acute phaseproteins (Kaneko, 1997). Among the positiveacute phase proteins, the serum level of someAPP increase 10 to 100 or even1000 foldswithin a few hours after injury. They are calledas major APPs. Proteins whose levels increase2-10 times and their value decline to normalafter longer period are known as moderateAPPs and those with slight increase in serumlevel (approximately 2 times or lesser) are

known as minor APPs. Moderate and minorAPPs are more pronounced in chronicinflammation (Ceron et al., 2005).

Acute phase proteins are primarilysynthesized by the liver. Their production istriggered by different stimuli including trauma,infection, stress, inflammation and neoplasia.The mechanism for stimulation of the hepaticproduction of the acute phase protein is mainlyby pro-inflammatory cytokines. Induction ofthe acute phase proteins by IL-6, followingbinding to the IL-6 receptor, is via thephosphorylation of the transcription factor,NF-IL6 which is then translocated to thenucleus, where it mediates the transcription ofacute phase genes. IL1 and TNF alpha, afterlinking to their respective receptors causephosphorylation and degradation of IkB, theinhibitor of transcription factor NFkB leadingto release of NFkB and subsequent activationof acute phase genes in the nucleus.

The functions of positive acute-phaseproteins (APP) are regarded as important inoptimization and trapping of microorganismsand their products, in activating thecomplement system, in binding cellularremnants like nuclear fractions, in neutralizingenzymes, scavenging free hemoglobin andradicals, and in modulating the hosts immuneresponse.

The first APP identified was C reactiveprotein (CRP) in pneumococcal infection ofmonkeys and human in early 1930s (Tillett andFrancis, 1930). Now the CRP has become amajor biomarker in human for trauma, tumor,myocardial infarction and wellness assessment.

Ind. J. Vet & Anim. Sci. Res. 43 (1) 1-13, January - February 20142

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Applications of APP assay in animals

Up to 1990s the uses of APP in animalswere limited to research work. By the mid of1990s use of APPs have gained importance inveterinary medicine. APPs are used inveterinary medicine with the followingobjectives

Objectives of APP assay in animals1. Checking the health status of the individual

animal or herd in a farm

2. Quantification of inflammatory activity - itindicates how intense or serious theinflammation is.

3. Monitoring inflammatory activity - duringthe course of treatment, efficacy oftreatment can be monitored at the earliestby detecting a drop in APP levels.

4. Detection of post operative recovery /complications- normally the APP levelsdecline 48 to 72 hours after the surgicalprocedure. A contradiction to same mayindicate complication and need for changingantibiotics / procedure.

5. Helps in ante-mortem inspections of largeherds in slaughter houses. Animals withvaried APP values need in-depth checking.

Assay of APP provides better sensitivityand specificity in finding whether, theinflammation is acute or chronic. Incomparison, neutrophil counts had much lowersensitivity and specificity (30% to 70%)(Horadagoda et al., 1999). In a retrospectiveevaluation of inflammatory conditions in dogs,APP showed significant changes even in theabsence of changes in the total or differentialWBC count (Solter et al., 1991). In a reviewof more than 900 cases of inflammation in dogswith various diseases, CRP concentrationswere significantly correlated with disease,whereas only slight or no correlation was foundwith total WBC and band neutrophil counts(Nakamura et al., 2008).

Acute phase proteins of importance inanimals

Albumin is considered to be one of themajor negative APP in all classes of animals.Paraoxonase (PON) is another negative APP.Transferrin is considered to be a positive APPin birds but negative APP in most of mammals.Alpha 1 acid glycoprotein is a positive APP inanimals except in pigs where it has beenrecently identified as a negative APP(Heegaard et al., 2013). The major APP ofdifferent animals are listed in the Table 1.


Application of acute phase proteins as biomarkers


Table - 1 Acute phase proteins of significance in different species

Species Major APP Moderate APPHuman CRP, SAA AGP, fibrinogen, HpDog CRP, SAA AGP, Cp, HpCow SAA, Hp AGP, CRP, fibrinogenCat AGP,SAA HpGoat Hp, SAA FibrinogenPig Hp, SAA, MAP AGPChicken None AGP, Cp, SAA

SAA: Serum Amyloid A CRP: C- reactive Protein Hp: Haptoglobin AGP: alpha 1 acid glycoprotein

Species Specific Application of APP

Studies on acute phase response ofmany species of animals are made worldwide.Species of importance as companion animalslike dog and cat and farm animals like cattleand swine are reviewed in this article.

Dog : In canines CRP is the major APP used asmarker for systemic inflammation / infection.Normally the level of CRP is less than 1.5 mg/dL or even lower than 0.5 mg/dl. The normalrange may be 0.08 to 2.26 mg/dl (Otabe et al.,1998). The level rises within 4 to 6 hrs afteronset of inflammation / infection. Serum CRPlevel above 3.5 mg/dl, indicates presence ofsystemic inflammation. Level above 5 mg/dlis a strong evidence of systemic inflammation.

Elevated concentration of CRP at the timeof diagnosis of lymphoma carries a poorerprognosis in humans. Similar study of relationbetween elevation of CRP level and lymphomain canines by Joana (2013) revealed that, the

level of CRP is elevated in lymphoma ofcanines both at times of diagnosis and at thetime of relapse of the disease but did not showany prognostic significance. But a trend ofreduced survival time was observed for thosedogs with CRP concentration of more than 3mg/dl. Some diagnostic manufacturingcompanies have recently introduced lymphomadiagnostic kits using the CRP and Haptoglobin(eg. Tridelta Development Ltd)

Cases like pyometra, panniculitis, acutepancreatitis, polyarthritis, leptospirosis,babesiosis, parvo infection,glomerulonephritis, immune mediated diseaseand malignant neoplasia show significantlyhigh CRP (Nakamura et al., 2008). Rise in CRPmay not be observed in local tumors likeleiomyosarcoma, upper respiratory tractinfection, diabetes, neurological problemsinvolving intracranial disorders. Since the CRPconcentration did not increase in patients withintervertebral disk protrusion, it might be usefulin distinguishing arthritis from spinal / brain

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diseases in patients with lameness. Thus,although CRP is a nonspecific inflammatorymarker, it could facilitate diagnosis byindicating the presence and the extent (e.g.,localized vs. generalized, neurological vs.other) of inflammation. In canine babesiosis,the serum CRP is significantly higher whileserum Haptoglobin is significantly lower whencompared to healthy dogs (Ulutas et al., 2005).

Albumin, a negative APP is asignificant biomarker for bacterial infection.The serum level of fibrinogen, a positive APPis more reliable than albumin as its levelpersistently raised up to 21 days of postinoculation with staphylococci (Zapryanovaet al., 2013).

PON 1 is a negative acute phaseprotein in canines. But contrarily to CRP and2-globulins, PON1 activity was notsignificantly different between dogs with andwithout inflammation. Hence PON1 does notprovide any diagnostic value as a negative acutephase protein in dogs (Gabriele et al., 2013).

Examination of CRP concentration asa routine diagnostic test is needed to be evolvedand incorporated in canine practices, as it ismore sensitive and specific than the WBCcounts.

Cat : SAA, AGP and Hp are the main acutephase proteins of cat. Concentration of acutephase proteins in healthy cat is not yet wellstandardized. APP values vary widely indifferent studies. Kann et al. (2012) reportednormal concentration of APP in cats as follows:SAA- 1.8 2.3 g/ml; AGP-532.8 204.1 g/ml; Hp- 2.5 2.1 mg/ml and Albumin28.2 4.7 g/l. But the concentrations reportedby Giordano et al. (2004) were 10.21 8.32

g/ml, 1200 620g/ml, 1.3 0.64 mg/mlfor SAA, AGP and Hp respectively. Thedifference may be due to the differentmethodology adopted by different scientists.In general concentration of APP in healthy catsincreases with age and there is variation withgender.

Values of SAA, AGP and Hp are foundto be increased in a variety of pathologicalconditions like infections, injuries, renalfailure, hospitalization, surgery and neoplasms(Paltrinieri, 2008). SAA level is found to beincreased in pancreatitis (Tamamoto et al.,2009) and neoplasia like malignantmesothelioma. Serum level of AGP increasesin feline immunodeficiency diseases, felinechlamydiosis, non symptomatic feline coronavirus infections, carcinoma, sarcoma, roundcell tumour etc. SAA value increases inconditions like renal failure, injury, andhospitalization while Hp level increases ininflammations, feline infectious peritonitis andsplenectomy.

Though there is report of decrease inconcentration of albumin in many felineinflammatory reactions (Ottenjann et al., 2006),confirmatory data are not yet available forconsidering albumin as negative acute phaseprotein in cats.

Cattle : SAA, Hp and fibrinogen are the majorAPPs of cattle while albumin and PON arenegative APPs. Unlike canines, clinicalapplication of acute phase proteins in largeanimals has not been sufficiently standardizedin routine practice. Many studies have beenmade on the serum concentration of APPs ofcattle and its significance in different agegroups, during parturition, lactation period,



acute and chronic infections, non-infectiousand metabolic diseases.

Calves show higher concentration ofAPPs than the adult cattle. This is due tovarious physiological needs and challengesfaced by the calves in its growing stage. Theaverage concentration of Hp and SAA in onemonth old healthy calf is 6.8 mg/dl and 5.9 mg/dl respectively which will lower to about 2.1mg/dl and 1.9 mg/dl respectively in the age ofsix months (Tothova et al., 2011 B). Eventhough CRP is not a major APP in cattle, highconcentration of CRP is noticed in healthycalves believed to be transferred throughcolostrum (Schroedl et al., 2003).

SAA and Hp estimation is useful indifferentiating acute and chronic inflammationin cattle. Seven different isoforms of SAA arenoticed in chronic inflammation of cow andout of this only three - SAA 1, SAA 2 and SAA3 are elevated in acute phase response. SAA1and SAA 2 are produced by liver and SAA 3 isproduced extra hepatically from adipose tissue,mammary duct etc. Serum Amyloid A hasmaximum clinical sensitivity while Hp hashighest serum specificity (Horadagoda et al.,1999). Various studies on serum concentrationof APP in bronchopneumonia showed that SAAconcentration rises rapidly while Hpconcentration increases with severity of thedisease (Heegaard et. al., 2000). Hp level inserum increases with the number ofantimicrobial treatment given and estimationof Hp alone has got better predictive value(Berry et al., 2004)

Anaplasma marginale infected cowsshowed significantly increased serum Hp (20.3mg/dl) and serum amyloid-A concentrations

(13.4 mg/dl) (Coskun, 2012). In naturallyinfected brucellosis cows there is significantincrease of SAA but no significant increase inHp (Sharifiyazdia et al., 2012).

Most important application of APPassay in cow is diagnosis of subclinicalmastitis. SAA of serum and milk increases inmastitis. It is to be remembered that normalcolostrum contains high concentration of milkassociated SAA which provides protection tothe gastrointestinal tract of the calf bystimulating mucin production and reducing theadherence of injurious agents. It wasdemonstrated that SAA levels increased muchearlier in milk than in serum and precededincreased somatic cell count in milk (Pedersenet al., 2003).

Milk SAA does not increase withinflammatory process outside the udder(Nielsen et al., 2004). In experimental E.colimastitis, the concentration of SAA increasedafter 12 hours and its highest concentration wasobserved 60 hours after the infection (Suojalaet al., 2008). In natural subclinical infectionthe milk level of SAA was found to raise to0.65 - 22.16 mg/dl (control group-0.5 -1.9mg/dl) and that of Ceruloplasmin raised to 3.35 to8.02 U/g of protein (control group-0.73 2.11U/g of protein) and both were found to be goodindicators of subclinical mastitis (Szczubial etal., 2012).

Haptoglobin concentration in bothserum and milk increase in clinical mastitis ofcow (Petersen et al., 2004). Hp in milk is foundto be locally synthesized by the mammary glandand neutrophils. Using a threshold value of 0.02mg/ml for milk Hp and 0.55 g/ml for milk SAA,both tests show a high specificity (100%) with

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no false positive results, and a reasonablesensitivity for the diagnosis of mastitis. Wenzet al. (2010) observed that concentration of Hpin the group of cows affected by Gram-negativebacterial mastitis was approximately twice thatof the group infected by Gram-positive bacteria(1,126 vs 575 mg/ml, respectively).

A significant rise of Hp and SAAconcentrations in milk was observed in udderquarters with chronic subclinical mastitis(Gronlund et al., 2005). Hp and SAAconcentrations below the detection limit wereconsidered as good indicators of healthy udderquarters.

SAA concentration was found to beenhanced in cows fed with high grainconcentration (Emmanuel, 2008). Sub acuteruminal acidosis produced by reduced fibre diethas no role in rising serum APP (Mulligan andDoherty, 2008). Study by Cannizzol et al.(2012) indicated that ruminal pH / acidosis isnot able to produce acute phase response. Butdevelopment of fatty liver is indicated by a highAPP level (Ametaj et al., 2005)

Concentration of SAA and Hp is foundto increase after parturition, attaining highestlevel within 3 days after calving (mean valuemore than 6.6 mg/dl and 13 mg/dl respectively).Chan et al. (2010) noticed high levels of SAA(more than 8.5 mg/dl) in cows with post partummetritis. Dubuc et al. (2010) opined that highblood Hp (above 80 mg/dl) is a marker forreproductive disorders in the first week ofcalving. Holstein cows diagnosed with uterineinfection had reduced serum albuminconcentration 21 days before calving, lowerparaoxonase (PON) activity at 7 days aftercalving, and increased Hp in multiparous cowsat 7 days in milk compared to healthy cows

(Schneider et al., 2013). These studies showthe significance of APPs in early diagnosis ofuterine infection.

High concentration of SAA is noticedin lame cows with sole ulcers (Kujala et al.,2010). Serum Hp didnt show any differencebetween healthy and lame cows. But Tthovet al. (2011a) found significantly higherconcentration of SAA, Hp and fibrinogen inheifers with foot disease. It is to be noted thatSerum Amyloid A is found to increase in stresscondition like transportation, slippery floor, etc.

An age wise study of the activity ofPON1 in cattle by Giordano et al. (2013)revealed that the activity increases from 2 to21 days of age in healthy calves and from 21to 120 days no significant increase in PON1activity was reported. But activity issignificantly high in adult cattle. The PON1activity is significantly lowered in calves ofless than 7 days of age with diarohea and incalves of 21 to 120 days of age with respiratorydiseases, showing that PON1 is a diagnosticallysignificant negative acute phase protein incattle.

It is always better to include both majorand moderate positive and negative APPs inan assay. An Acute phase index can be madeusing the formula given below to enhancespecificity of APP to detect non healthy animalin the herd.

Acute phase index =Value of major APP x Value of moderate APPValue of rapid negative APP x Value ofmoderate negative APP.

Pigs :In pigs five acute phase proteins namelyC-reactive protein (CRP), serum amyloid A



(SAA), haptoglobin (Hp), pig-MAP andalbumin are found to be significant. In porcinereproductive and respiratory syndrome virus(PRRSV) all the above APPs except the pigMAP level were found to be elevated. InAujeszkys disease virus (ADV) infection, onlyHp level was elevated. Porcine circovirus type2 (PCV2) had elevation of all APPs.Haptoglobin has the highest sensitivity in pigs(Parra et al., 2006) when compared to otherAPPs.

Increased level of CRP, SAA, Hp andPig MAP were noted well before the rise ofantibody titre in experimental inoculation withswine influenza(H1N1) and Pasteurellamultocida in pigs (Pomorska-Ml et al., 2013).

Pallares et al.(2008) found that serumconcentration of Hp and CRP are high infattening pigs with clinical disease thanapparently healthy pigs with gross lesion (2.1times) at slaughter and healthy pigs withoutgross lesion (2.6 times) and hence can be usedas markers for presence of lesions at slaughter.Heegaard et al. (2013) revealed that Pig AGPbehave as a negative acute phase protein duringa range of experimental infections and asepticinflammation with significant decrease inserum concentration.

Gutierrez et al. (2012) had made a longitudinalanalysis of APP in pig saliva using time-resolved immunofluorometric assays(TR-IFMA) and found that their level isconcomitant with the serum level and usefulfor monitoring of diseases in pigs.

METHODS AND MATERIALS

Total protein and Albumin are usuallyassayed using the automated chemical serum

analyzer. Protein electrophoresis has also beenemployed for assessing the APP for many years.ELISA is the widely used method for assayingthe individual APP. This method is bestemployed for batch analysis of many samples.Species specific ELISA kits have to be usedfor reliable results. Serum collected for APPassay can be kept for 2 days under refrigerationat -4oC or for one month in deep frezer at-20oC. For prolonged storage it is better to keepthe serum at -80oC. Radioimmunoassay,nephelometry, immunoturbidimetry, Westernblot and mRNA analyses (Paltrinieri, 2008)have also been employed for the assay. Forqualitative / semi quantitative methods latextest kits can be employed.

Immunosensor assay is found to be aquick and reliable technique for detection ofHp in mastitis milk (Tan et al., 2012).Haptoglobin in haemolysed samples can beestimated using a correction equation, Hpcorrected = Hp raw Hp endogenous activity Hp due to Hb; where Hp due to Hb = 0.118 Hbfree + 0.015. (Slocombe et al., 2012) .

It is conclusion the acute Phaseproteins are found to be elevated in animalsbefore the manifestation of clinical signs inmany diseases. As their elevation is a nonspecific reaction, the information cannot beused for diagnosing a specific condition butcan be used as health monitoring tool.Researches so far conclude that APPs are moresensitive than the conventional methods likethe WBC count, Somatic cell count in milk,etc. It is better to assay two or more APPstogether to get a valid result. New technologiesneed to be developed for economically feasibleestimation of APPs. More research is needed

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to be done for making these biomarkers aperfect predictive tool for animal health status.

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Acute Phase Proteins