Acute Phase Proteins
Acute phase reaction is a general term attributed to a group of systemic and metabolic changes that
occur within hours of an inflammatory stimulus.
An acute-phase protein has been defined as one whose plasma concentration increases (positive acutephase proteins) or decreases (negative acute-phase proteins) by at least 25 percent during
inflammatory disorders.
Conditions that commonly lead to substantial changes in the plasma concentrations of acute-phase
proteins include infection, trauma, surgery, burns, tissue infarction, various immunologically mediated
and crystal-induced inflammatory conditions, and advanced cancer. Moderate changes occur after
strenuous exercise, heatstroke, and childbirth. Small changes occur after psychological stress and in
several psychiatric illnesses.
Acute phase response takes place, by changes in a heterogeneous group of proteins which consists of
around 30 proteins in response to bacterial infection, trauma, myocardial infarction, collagen tissue
disorders which result in the production of IL-1, IL-6, TNF-α.
If the inflammatory response is self limiting or treated, the level of acute phase proteins returns to
normal within days or weeks. The stronger the stimulus for inflammation, the greater is the change in
the concentration of acute phase proteins, and will continue the high levels as long as the stimulus
remains.
The acute-phase response is general and nonspecific. Measurement can only be interpreted in the light
of full clinical information.
The changes in the concentrations of acute-phase proteins are due largely to changes in their
production by hepatocytes. The magnitude of the increases varies from about 50 percent in the case of
ceruloplasmin and several complement components to as much as 1000-fold in the case of C-reactive
protein and serum amyloid A, the plasma precursor of amyloid A (the principal constituent of secondary
amyloid deposits) Many soluble tissue and serum substances help to suppress the grow of or kill
microorganisms.
Induction of Acute-Phase Proteins by Cytokines
 Cytokines are intercellular signalling polypeptides produced by activated cells.
 Most cytokines have multiple sources, multiple targets, and multiple functions.
 The cytokines that are produced during and participate in inflammatory processes are the
chief stimulators of the production of acute-phase proteins.
 These inflammation-associated cytokines include interleukin-6, interleukin-1 b, tumour necrosis
factor a , interferon- g , transforming growth factor b , 2 and possibly interleukin-8.
 They are produced by a variety of cell types, but the most important sources are macrophages
and monocytes at inflammatory sites.
 Interleukin-6 is the chief stimulator of the production of most acute-phase proteins, whereas
the other implicated cytokines influence subgroups of acute-phase proteins.
 All acute phase proteins may not rise in all inflammatory pathologies. For example, in systemic
lupus erythematosus, sedimentation rate increases, while CRP level decreases.
Classification of Acute-phase Proteins
(1) On the basis of protein concentrations
Negative acute-phase proteins
The liver responds by producing a large number of APRs. At the same time, the production of a
number of other proteins is reduced; these are therefore referred to as “negative” APPs. Negative
APPs are albumin, transferring, transthyretin, transcortin, and retinol-binding protein.
Positive acute-phase proteins
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Positive APPs are CRP, D-dimer protein, mannose-binding protein, alpha 1 antitrpysin, alpha 1
antichymotrypsin, alpha 2 macroglobulin, fibrinogen, prothrombin, factor VIII, von-Willebrand
factor, plasminogen, complement factors, ferritin, SAP complement, SAA, ceruloplasmin (Cp), and
haptoglobin (Hp).
Positive APPs serve different physiological functions for the immune system. Some act to destroy or
inhibit growth of microbes, e.g., CAA and Hp. Others give negative feedback on the inflammatory
response, e.g., serpins, alpha 2 macroglobulin and coagulation factors affect coagulation. Positive APPs
are produced during the APR associated with anorexia and changed metabolism.
(2)On the basis of their mode of action
APP classified as below:
 Protease inhibitors, e.g., alpha 1 antitrypsin, alpha 1 antichymotrypsin.
 Coagulation proteins, e.g., fibrinogen, prothrombin.
 Complement proteins, e.g., C2, C3, C4, C5, etc.
 Transport proteins, e.g., Hp, Cp, hemopexin.
 Other proteins, e.g., CRP, SAA, SAP, acid glycoprotein (AGP).
Acute phase proteins measured routinely include:

C-reactive protein
 Alpha-1 acid glycoprotein
 Alpha-1 antitrypsin
 Haptoglobins
 Ceruloplasmin
 Serum amyloid A
 Fibrinogen
 Ferritin
 Complement components C3, C4
C-reactive proteinPlasma CRP production occurs via the stimulation of IL-6 in the liver. It assists in the
recognition of damaged host cells and foreign pathogens, and their removal. When CRP binds to its
ligand, it activates the complement system via the classical pathway and increases phagocytosis. The
name derives from its ability to react with the C polysaccharide of streptococcus pneumonia, but also
bind to chromatin in nuclear DNA-histone complexes. It rises within a few hours of stimulus. It peaks
within 2-3 days. Its half-life is 19 hours. The increase in CRP levels is proportional to the inflammatory
stimulus. With a greater stimulus, a higher and longer lasting level of CRP will be measured. After the
inflammatory stimulus is removed, the CRP levels will quickly decrease. In healthy individuals the CRP
level is generally below 0.2 mg/dl. Due to micro-traumas that occur during the day, this level can
increase up to 1 mg/dl. After a single stimulus it can increase up to 5 mg/dl within 6 hours, and can
reach a peak value within 48 hours.
It is an acute phase protein which increases in connective tissue disorder and neoplastic disease.
It is increased by bacterial infections and generally less elevated in viral infections.
 C-reactive protein (CRP) is better than erythrocyte sedimentation rate (ESR) for monitoring fast
changes as it does not depend on fibrinogen or immunoglobulin levels, and is not affected by red
blood cell numbers and shape.2
 CRP concentrations characteristically return to normal after 7 days of appropriate treatment for
bacterial meningitis if no complications develop. Serial monitoring of serum and cerebro spinal
fluid CRP concentrations may be useful clinically.
 CRP is nonspecific and its clinical usefulness is therefore limited, especially in diagnosis.
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CRP is useful in monitoring disease activity in certain conditions, e.g. rheumatoid arthritis,
infections or malignancy, and as a prognostic marker for conditions such as acute pancreatitis.
An increased CRP may be due to:
o Inflammatory disorders, e.g. inflammatory arthritis, vasculitis, Crohn's disease
o Tissue injury or necrosis, e.g. burns, necrosis, myocardial infarction, pulmonary embolus
o Infections, especially bacterial
o Malignancy
o Tissue rejection
Little or no rise occurs in: osteoarthritis systemic lupus erythematosus (SLE), leukemia, anaemia,
polycythaemia, viral infection, ulcerative colitis, pregnancy, oestrogens or steroids.
There is evidence that CRP has a stronger predictive value for the risk of coronary heart disease
and stroke events than low-density lipoprotein (LDL) cholesterol. There is also evidence that CRP
has a predictive power that is additive to that of cholesterol.
CRP has also been shown to have predictive value of the development of diabetes type 2, even
after adjustment for a patient's body weight. It has been claimed that the CRP increases for each
symptom of the metabolic syndrome present.
Normal/Insignificant
Mild
Very high
(1 mg/ dl <)
(1-10 mg/dl)
(>10 mg/dl)
Heavy exercise
Influenza
Pregnancy
Gingivitis
Cerebrovascular accident
Stroke
Angina pectoris
Myocardial Infarction
Malignancy
Pancreatitis
Mucosal Infections (bronchitis,
cystitis)
Collage tissue diseases
Acute bacterial infections (%8085)
Major trauma
Systemic vasculitis
Ferritin
 Ferritin is an iron-protein complex found in most tissues, but particularly the bone and
reticuloendothelial system. It is an acute phase protein and may be increased in inflammation,
malignancy and liver disease.
 It is a primary iron-storage protein and often measured to assess a patient's iron status.
However, this will not be an appropriate test of iron stores when any of the above causes of
increased ferritin are present.
Haptoglobin
 Haptoglobin is an alpha-2 globulin, whose function is to remove free plasma haemoglobin.
Haptoglobins are therefore decreased during any cause of haemolysis.
 Haptoglobin is also an acute phase protein. Haptoglobins are increased in malignancy (especially
if there are bone secondaries), inflammation, trauma, surgery, and steroid or androgen therapy
and also in diabetes.
Document references
1. Gabay C, Kushner I; Acute-phase proteins and other systemic responses to inflammation. N Engl
J Med. 1999 Feb 11;340(6):448-54.
2. Black S, Kushner I, Samols D; C-reactive Protein. J Biol Chem. 2004 Nov 19;279(47):48487-90.
Epub 2004 Aug 26. [abstract]
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3. Ridker PM, Rifai N, Rose L, et al; Comparison of C-reactive protein and low-density lipoprotein
cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002 Nov
14;347(20):1557-65. [abstract]
4. Dehghan A, van Hoek M, Sijbrands EJ, et al; Risk of type 2 diabetes attributable to C-reactive
protein and other risk factors. Diabetes Care. 2007 Oct;30(10):2695-9. Epub 2007 Jul 10.
[abstract]
5. Christine M. Albert, MD, MPH; Jing Ma, MD, PhD; Nader Rifai, PhD; Meir J. Stampfer, MD,
DrPH; Paul M. Ridker, MD, MPH Prospective Study of C-Reactive Protein, Homocysteine, and
Plasma Lipid Levels as Predictors of Sudden Cardiac Death Circulation.2002; 105: 2595-2599
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