Acute-phase proteins, CRP, ESR and viscosity

What are acute-phase proteins?

Acute-phase proteins are proteins whose levels fluctuate in response to tissue injury - eg, trauma, myocardial infarction, acute infections, burns or chronic inflammation (for example, in Crohn's disease, rheumatoid arthritis and malignancy). An acute-phase response is general and nonspecific. 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 tumour necrosis factor (TNF). Acute-phase proteins include:

• C-reactive protein (CRP).¹

• Alpha-1 acid glycoprotein.

• Alpha-1 antitrypsin.

• Haptoglobins.

• Ceruloplasmin.

• Serum amyloid A.

• Fibrinogen.

• Ferritin.

• Complement components C3, C4.

Erythrocyte sedimentation rate

The erythrocyte sedimentation rate (ESR) measures how fast red cells fall through a column of blood. It is an indirect index of acute-phase protein concentrations (particularly depends on the concentration of fibrinogen) and is a sensitive but nonspecific index of plasma protein changes which result from inflammation or tissue damage.

• The ESR is affected by haematocrit variations, red cell abnormalities (for example, in sickle cell disease) 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 (eg, 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 levels above 100 mm/hour are very significant and indicates something is wrong.

• High ESR: any inflammatory disorder (eg, infection, rheumatoid), tuberculosis, myocardial infarction (early response), anaemia, polymyalgia rheumatica/temporal arteritis.

• Low ESR: polycythaemia, hypofibrinogenaemia, congestive cardiac failure, spherocytosis, sickle cells.

• The ESR was previously thought to be more useful than serum CRP for diagnosis and monitoring of polymyalgia rheumatica or temporal arteritis; there is conflicting recent evidence for CRP being more useful but they are both thought to have value in assessing PMR.²

• Combined use of ESR and CRP is useful in assessing the severity of acute pelvic inflammatory disease.

• Raised ESR is also a marker for acute coronary heart disease.³ Raised ESR also appears to have a strong correlation with the risk of death from coronary heart disease, even in apparently healthy individuals.⁴

Plasma viscosity

• This is also a sensitive but nonspecific index of plasma protein changes which result from inflammation or tissue damage. It provides similar information to the ESR.

• It increases in parallel with the ESR, but plasma viscosity is not affected by haematocrit variations (eg, anaemia or polycythaemia) and delay in analysis. It is therefore considered to be vastly under-utilised 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.

• It is better than ESR in monitoring hyperviscosity syndromes - eg, myeloma.

• 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.

C-reactive protein

• 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.

• 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 seven days of appropriate treatment for bacterial meningitis if no complications develop. Serial monitoring of serum and CSF-CRP concentrations may be useful clinically.

• CRP is nonspecific and its clinical usefulness is therefore limited, especially in diagnosis. CRP is useful in monitoring disease activity in certain conditions (eg, 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 - eg, inflammatory arthritis, vasculitis, Crohn's disease.

  • Tissue injury or necrosis - eg, burns, necrosis, myocardial infarction, pulmonary embolus.

  • Infections, especially bacterial:⁵⁶
    Levels of CRP rise significantly during acute inflammation, and so can be used for to indicate the presence of significant inflammatory or infectious disease, especially in children.

    • Low specificity may be a drawback as a biomarker of sepsis in adults, but it is commonly used to screen for early-onset sepsis in neonates.

  • Malignancy.

  • Tissue rejection.

• Little or no rise occurs in osteoarthritis, systemic lupus erythematosus (SLE), leukaemia, anaemia, polycythaemia, viral infection, ulcerative colitis, pregnancy, oestrogens or steroids.

• There is evidence for raised CRP possibly being a risk factor for atherosclerotic cardiovascular disease. High CRP levels are also associated with a poorer prognosis for patients with acute coronary syndrome.⁷ However, the role of CRP in atherosclerosis is controversial and further investigation is needed.⁸

• CRP has also been shown to have predictive value of the development of type 2 diabetes.⁹

• However, current data does not provide good evidence supporting further use of CRP as a marker for chronic disease although it clearly has benefits in acute infection or inflammation.¹⁰

• Future research is likely to show that CRP isoforms will be able to provide benefits in assessing more chronic inflammation and progression.¹¹

Ferritin

• 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.

• Only 10% of cases of elevated ferritin levels are due to iron overload. Chronic alcohol consumption, metabolic syndrome, obesity, diabetes, malignancy, infection and inflammatory conditions explain 90% of cases of elevated serum ferritin.¹²

The British Society for Haematology recommends that, in patients with a finding of elevated serum ferritin levels, first-line investigations should include full blood count and film, repeat serum ferritin, transferrin saturation, inflammatory markers (CRP, ESR or plasma viscosity) to detect inflammatory disorders, serum creatinine and electrolytes for renal function, LFTs with consideration of viral hepatitis screening and abdominal ultrasonography (if abnormal liver function), and blood glucose and lipid studies.

In otherwise well patients with unexplained and moderately elevated serum ferritin levels (<1000 lg/L) and normal transferrin saturation, a period of observation, with lifestyle adjustment if appropriate, may be reasonable with repeat assessment after 3-6 months.¹³However, referral should be made to a gastroenterologist or haematologist if the ferritin persists > 1000 lg/L.¹²

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, steroid or androgen therapy and also in diabetes.

Procalcitonin

• Procalcitonin is considered a specific biomarker for bacterial infection.

• It can be used to determine antibiotic initiation. It is currently mainly used in determining de-escalation of antibiotic therapy in patients with sepsis.¹⁴