Acute Phase Proteins, CRP, ESR and Viscosity

Acute phase proteins are proteins whose levels fluctuate in response to tissue injury, e.g. trauma, myocardial infarction, acute infections, burns, chronic inflammation (as in Crohn's disease, rheumatoid arthritis and malignancy). The acute-phase response is general and non-specific. Measurement can only be interpreted in the light of full clinical information.

The stimulus for production is likely to be inflammatory cytokines such as interleukin-1, interleukin-6 and TNF (Tumour Necrosis Factor).¹ Acute phase proteins include:

• C-reactive protein (CRP)
• Alpha-1 acid glycoprotein
• Alpha-1 anti-trypsin
• Haptoglobins
• Caeruloplasmin
• Serum amyloid A
• Fibrinogen
• Ferritin
• Complement components C3, C4

The ESR measures how fast red cells fall through a column of blood. It is an indirect index of acute phase protein concentrations and is a sensitive but non-specific index of plasma protein changes which result from inflammation or tissue damage.

• The ESR is affected by haematocrit variations, red cell abnormalities (e.g sickle cells) and delay in analysis (the sample should be analysed in the laboratory within four hours). It is therefore less reliable a measurement than plasma viscosity.
• It is also affected by age, sex, menstrual cycle, pregnancy and drugs (e.g. steroids).
• A normal ESR does not exclude organic disease. A mildly elevated ESR of 20-30 mm/hour probably doesn't mean very much in itself but above 100 mm/hour is very significant and indicates something is wrong.
• High ESR: any inflammatory disorder (e.g. infection, rheumatoid), tuberculosis, myocardial infarction (early response), anaemia, polymyalgia rheumatica/temporal arteritis.
• Low ESR: polycythaemia, hypofibrinogenaemia, congestive cardiac failure, spherocytosis, sickle cells.
• The ESR is more useful than serum CRP for diagnosis and monitoring of polymyalgia rheumatica or temporal arteritis and is more frequently elevated during relapse.
• Combined use of ESR and CRP is useful in assessing the severity of acute pelvic inflammatory disease.
• Men aged 45-64 years with ESR in the upper quintile have more than twice the risk of coronary heart disease death of men with ESR in the lowest quintile after adjusting for other risk factors.

• Is also a sensitive but non-specific index of plasma protein changes which result from inflammation or tissue damage. It provides similar information to the ESR.
• Increases in parallel with the ESR, but plasma viscosity is not affected by haematocrit variations (e.g. anaemia or polycythaemia) and delay in analysis. It is therefore considered to be vastly underutilised and more reliable than the ESR.
• It is not affected by gender but is affected by age (but less so than ESR), exercise and pregnancy.
• High level usually indicates underlying pathology but a low level can be ignored.
• Is better than ESR in monitoring hyperviscosity syndromes, e.g. myeloma.
• Sensitivity and specificity are better than for ESR and CRP in discriminating between active and inactive rheumatoid arthritis.
• Increased plasma viscosity and hyperfibrinogenaemia are risk factors for subsequent adverse events in unstable angina and stroke.
• Plasma viscosity increases in relation to progression of peripheral occlusive vascular disease and correlates with clinical stages of the disease.

• Is an acute phase protein which increases in connective tissue disorders and neoplastic disease. It is increased by bacterial infections and generally less elevated in viral infections.
• CRP is better than 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
• The name derives from its ability to react with the C polysaccharide of Streptococcus pneumoniae, but it may also bind to chromatin in nuclear DNA-histone complexes. Once bound, it is able to activate the classical complement pathway.
• CRP concentrations characteristically return to normal after 7 days of appropriate treatment or bacterial meningitis if no complications develop. Serial monitoring of serum and CSF CRP concentrations may be useful clinically.
• CRP is non-specific and its clinical usefulness is therefore limited, especially in diagnosis. 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:
  • Inflammatory disorders, e.g. inflammatory arthritis, vasculitis, Crohn's
  • Tissue injury or necrosis, e.g. burns, necrosis, myocardial infarction, pulmonary embolus
  • Infections, especially bacterial
  • Malignancy
  • Tissue rejection
• Little or no rise occurs in: osteoarthritis, SLE, leukaemia, 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 LDL-cholesterol.³ There is also evidence that CRP has a predictive power that is additive to that of cholesterol.⁴
• CRP has also been shown to have predictive value of the development of type 2 diabetes, even after adjustment for patient's body weight.⁵ It has been claimed that the CRP increases for each symptom of the metabolic syndrome present.

• Ferritin is an iron-protein complex found in most tissues, but particularly the bone marrow 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 is an alpha-2-globulin, whose function is to remove free plasm haemoglobin. Haptoglobins are therefore decreased during any cause of haemolysis.
• Haptoglobin is also an acute phase protein. Haptoglobins are increase in malignancy (especially if bone secondaries), inflammation, trauma, surgery, steroid or androgen therapy and also in diabetes.