Acute Phase Reactants
The acute phase response is a facet of the innate immune system that occurs in response to infection, trauma or other insults. Certain mediators, known as acute phase reactants, are increased or decreased in the context of acute inflammation. These markers are commonly measured in clinical practice as indicators of acute illness.
An acute phase reaction classically presents with fevers, rigors and tachycardia.
- Positive acute phase reactants are those whose concentration increases with inflammation. These include:
- C-reactive protein (CRP)
- Complement proteins C3 / C4
- Serum amyloid A (not measured)
- Negative acute phase reactants are those whose concentrations decrease in an acute phase response. These include:
- Serum albumin
The acute phase response is predominantly mediated by the pro-inflammatory cytokines tumour necrosis factor (TNF), interleukin 1 (IL-1) and interleukin 6 (IL-6) secreted by macrophages and other immune cells.
Causes of Acute Phase Response
- Infection - bacterial, viral, fungal, parasitic
- Tissue infarction - e.g. myocardial infarction, renal infarction, splenic infarction, acute limb ischaemia
- Exogenous substances (i.e. foreign bodies)
- Endogenous substances - uric acid crystals, calcium pyrophosphate crystals
- Autoimmune disease
C-reactive protein is an acute phase protein that is involved in innate immunity, and is responsible for activating the complement pathway.
Serum CRP rises rapidly, with a maximal concentration reached within two days; it falls quickly once inflammation has resolved.
CRP has little efficacy as a screening tool for inflammation, however the trend in CRP is useful for monitoring resolution or progression of an inflammatory process.
Ferritin is an intracellular iron storage protein whose levels are indicative of the body's total iron stores. An elevated ferritin is classically a marker of iron overload, however ferritin is also an acute phase reactant and may be elevated in the context of acute inflammation.
Procalcitonin is a protein normally produced by the thyroid; it is secreted by extrathyroid tissue in the context of infection or inflammation.
Procalcitonin rises rapidly with maximal concentration reached within two days, and falls quickly once inflammation has resolved.
Haptoglobin is an alpha-2 glycoprotein secreted mainly by the liver that binds plasma free haemoglobin.
Haptoglobin is primarily used as a marker of intravascular haemolysis, in which its level will reduce.
It is also an acute phase reactant, however, and haptoglobin will be increased in the presence of infection, inflammation or malignancy.
Fibrinogen is a coagulation factor that is converted to fibrin and is essential for the formation of a clot. Inflammation and coagulation are tightly linked, and as such the fibrinogen level will rise in the presence of acute inflammation.
Erythrocyte Sedimentation Rate
The erythrocyte sedimentation rate (ESR) is a measure of the number of red bloods cells that precipitate in a tube over an hour. ESR is a surrogate for the fibrinogen, as erythrocyte sedimentation occurs in the context of hyperfibrinogenaemia.
An elevated ESR is classically used as a marker of chronic inflammation.
Caeruloplasmin is a copper-containing protein that may be measured for use as an inflammatory marker, however it is very uncommonly used in this fashion.
Albumin is a negative acute phase reactant, meaning that its level will fall in the context of acute inflammation. This occurs as a result of reduced hepatic production, as well as proteolysis.
Important differential diagnoses for reduced albumin include malnutrition, liver disease and protein loss (nephrotic syndrome, protein-losing enteropathy, severe burns).
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