Acute phase proteins

WHAT ARE ACUTE PHASE PROTEINS (APPs)?

 

APPs are blood proteins that are primarily produced by hepatocytes in the liver.1 They are produced as part of the acute phase response (itself part of the innate immune system’s systemic response or early defence system), which has the function of re-establishing homeostasis and promoting healing.1,2 APPs are generated in response to certain stimuli such as: trauma, infection or inflammation.2 As such, they are regarded as non-specific but when used correctly, can be valuable biomarkers of disease and of great clinical use.3

DIFFERENT TYPES OF ACUTE PHASE PROTEIN RESPONSE

APPs that increase in response to tissue injury can be defined as positive, and those which decrease, defined as negative.3 The majority of APPs are positive and can be further split into three broad categories: major, moderate and minor, depending on the magnitude of their response to stimuli.3

 

In dogs, C-reactive protein (CRP) is an example of a major APP, whilst in cats, a major APP is alpha-1-acid glycoprotein (AGP).1 Both of these major APPs are available from Avacta Animal Health.

APP response graph jan2022

DIFFERENT TYPES OF ACUTE PHASE PROTEIN RESPONSE

APPs that increase in response to tissue injury can be defined as positive, and those which decrease, defined as negative.3 The majority of APPs are positive and can be further split into three broad categories: major, moderate and minor, depending on the magnitude of their response to stimuli.3

 

In dogs, C-reactive protein (CRP) is an example of a major APP, whilst in cats, a major APP is alpha-1-acid glycoprotein (AGP).1 Both of these major APPs are available from Avacta Animal Health.

  CHANGE FROM RESTING SERUM LEVEL PEAK RESPONSE AFTER STIMULI RETURN TO NORMAL
Major

APPs

10 – 100 x ↑ 24 – 48 hours Rapid
Moderate

APPs

2 – 10 x ↑ 48 – 72 hours Slower than major APPs
Minor

APPs

1.5 – 2x ↑ Gradual Gradual
Negative

APPs

Variable ↓ Variable Variable

Minor APPs are not commonly measured because, as the name suggests, the magnitude of change for these APPs is relatively small; this makes it more challenging to differentiate between clinically significant levels and those within the range of normal limits.3

 

Regardless of the category, while the stimulus persists, the APP level will remain changed; for positive APPs this means elevated. After the stimulus is removed, the APP level will return to within normal limits.3 The speed of the return varies between the APP categories and is another point of differentiation between them. The table1,2 to the left and the graph3 above provide some further insight:

Minor APPs are not commonly measured because, as the name suggests, the magnitude of change for these APPs is relatively small; this makes it more challenging to differentiate between clinically significant levels and those within the range of normal limits.3

 

Regardless of the category, while the stimulus persists, the APP level will remain changed; for positive APPs this means elevated. After the stimulus is removed, the APP level will return to within normal limits.3 The speed of the return varies between the APP categories and is another point of differentiation between them. The table1,2 and graph3 below provide some further insight:

  CHANGE FROM RESTING SERUM LEVEL PEAK RESPONSE AFTER STIMULI RETURN TO NORMAL
Major

APPs

10 – 100 x ↑ 24 – 48 hours Rapid
Moderate

APPs

2 – 10 x ↑ 48 – 72 hours Slower than major APPs
Minor

APPs

1.5 – 2x ↑ Gradual Gradual
Negative

APPs

Variable ↓ Variable Variable
APP response graph jan2022

CLINICAL USE OF ACUTE PHASE PROTEINS

There are a number of ways in which acute phase proteins can be useful clinically:

CLINICAL USES OF ACUTE PHASE PROTEINS
Early indicator of inflammation Due to their high sensitivity, APPs can be useful as an early indicator of inflammation, possibly even at a sub-clinical stage.3 Relevant APPs increase more rapidly, and are more sensitive, than white blood cells; and when compared to measuring haematology alone, provide a more stable, responsive and accurate biomarker for detecting inflammation.3 A potential use for this would be pre-operative wellness testing or many of the indications for use listed below.2
Supporting diagnosis2 APPs can be a useful tool when considering differential diagnoses. For example, AGP has been shown to be useful in differentiating between feline infectious peritonitis (FIP) and other diseases, whilst CRP has been found to be of clinical value in supporting the diagnosis of steroid-responsive meningitis-arteritis (SRMA).4,5
Post-surgery monitoring An increase in APP levels is expected after surgical procedures in response to tissue trauma; this is expected to last a few days. A failure to decline subsequent to this, or a decline, which is then followed by an increase, could be an indicator that further evaluation is required to rule-out complications such as a post-operative infection. For example, monitoring of APPs (including CRP) following surgery for canine pyometra, enabled early detection of post-operative wound infections.6
Post-treatment monitoring Similar to post-surgical monitoring, sequential APP measurements can be used to help determine if treatment is successful. If responding as expected, a continual decline in APP levels towards the normal level would be anticipated. If the APP levels fail to decline, concurrent disease, lack of treatment response or subsequent development of the disease, should be considered. An example of where this could be useful is monitoring the response to antimicrobials when treating a bacterial infection.7
Disease surveillance APPs (including CRP) have been shown to be useful both for monitoring the progression of disease, and in the early detection of relapse. For example, in dogs with SRMA, not only was CRP found to be of clinical value in supporting the diagnosis but also for monitoring treatment response and in the identification of relapse.5

References

  1. Cray C, Zaias J & Altman NH (2009). Acute phase response in animals: a review. Comparative medicine; 59(6): 517–526.
  2. Eckersall PD & Bell R (2010). Acute phase proteins: Biomarkers of infection and inflammation in veterinary medicine. The Veterinary Journal; 185(1): 23-7.
  3. Bell R & Wilson C (2014). Acute phase proteins: how they are useful for practitioners. Veterinary Times.
  4. Hazuchova K, Held S, Neiger R (2017). Usefulness of acute phase proteins in differentiating between feline infectious peritonitis and other diseases in cats with body cavity effusions. Journal of Feline Medicine and Surgery; 19(8): 809-816.
  5. Lowrie M, Penderis J, Eckersall PD, McLaughlin M, Mellor D, Anderson TJ (2009). The role of acute phase proteins in diagnosis and management of steroid-responsive meningitis arteritis in dogs. The Veterinary Journal; 182(1): 125-30.
  6. Dabrowski R, Kostro K, Lisiecka U, Szczubiał M, Krakowski L (2009). Usefulness of C-reactive protein, serum amyloid A component, and haptoglobin determinations in bitches with pyometra for monitoring early post-ovariohysterectomy complications. Theriogenology; 1;72(4): 471-6.
  7. Seo KW, Lee JB, Ahn JO, Lee HW, Hwang CY, Youn HY, Lee CW (2012). C-reactive protein as an indicator of inflammatory responses to experimentally induced cystitis in dogs. J Vet Sci; 13(2): 179-85.