C-Reactive Protein (CRP), High-sensitivity CRP (hs-CRP)

Sample

1. This test can be done on serum(clotted blood 3-5ml).
2. It is advisable to perform the test on the fresh sample.
3. Serum Can be stored at 4 °C for < 72 hours.
   1. This can be stored at -20 °C for 6 months.
4. Avoid hemolyzed or lipemic samples.

Precautions

1. Keep in mind that:
   1. Cigarette smoking may increase the level.
   2. Estrogen and progesterone may increase the level.
   3. Niacin and statin may decrease the value.
   4. There may be an increased level of CRP in hypertension, diabetes mellitus, and metabolic syndrome.
2. Avoid lipemic or hemolyzed samples.

Purpose of the test (Indications)

1. This is done in inflammatory diseases like acute rheumatic fever or rheumatoid arthritis and bacterial infection.
2. It will help in the diagnosis of coronary artery disease.
3. This test can be done to diagnose bacterial endocarditis.
4. To diagnose appendicitis.
5. To diagnose active collagen vascular diseases.

Pathophysiology

1. History of CRP:
   1. In 1930 Tillet and Francis found substance in the sera of acutely ill patients.
   2. This substance binds the C-polysaccharides cell wall of Strept. pneumomiae.
   3. This leads to the agglutination of the bacteria.
   4. In 1940, this substance was shown to be a protein and given the name of C-reactive protein (CRP).
   5. Its detection limit for infection and autoimmune diseases was 3 to 8 mg/L.
      1. CRP molecular weight is ∼115 kDa.
      2. It is synthesized in the liver and has little or no carbohydrates.
2. Mechanism of action:
   1. It binds the C-polysaccharide of streptococcus pneumoniae and agglutinates the bacteria.
   2. It binds to polysaccharides present in many bacteria, fungi, protozoal parasites, and histones.
   3. Its production is under the control of IL-6.
3. C-reactive protein name is derived from its reaction with streptococcal capsular (C) polysaccharides.
   1. CRP is the fastest responding acute-phase protein, as with infection it increases 100 folds time.
   2. So this is the most sensitive indicator.
   3. This increases in many diseases so this has no specificity.
4. This is a nonspecific acute-phase protein that has gamma mobility and is very helpful in the monitoring of inflammation.
   1. C-reactive protein on serum electrophoresis is found in the gamma region.
      

      C-reactive protein

3. CRP is synthesized in the liver and its synthesis is initiated by antigen complexes.
   1. Its production is controlled by interleukin-6.
4. CRP form complex on the surface of bacteria (E.coli, S.pneumoniae), fungi, and another microorganism.
   1. CRP binds to polysaccharides present in many bacteria, fungi, protozoal parasites, and histones.

5. C R P level increases almost 1000 folds or more in response to severe trauma, bacterial infections, inflammation, surgery, or Neoplastic cell proliferation.
   1. This does not consistently rise in viral infection.
6. This complexed CRP is a potent opsonin for monocytes, leading to phagocytosis activating the complement system.
7. It activates the classical complement pathway.

8. CRP also leads to binding of T- lymphocytes, inhibition of clot retraction, suppression of platelets and lymphocytes function, and increase phagocytosis by the neutrophils.
9. It increases in the first 12 hours of the infection.
   1. It will fall within 2-3 days of the inciting event. Therefore it can be used to follow the response to therapy (antibiotics or activity of the disease and chronic disease).
   2. CRP precedes the rise in ESR while in the recovery it is the reverse.
   3. CRP half-life is 5 to 7 hours. So it falls rapidly than the other acute-phase protein when mostly have a half-life of 2 to 3 days.
10. CRP increases 4 to 6 hours after the surgery and begins to decrease after 3 to 4 days pf postop surgery.
    1. If the level does not come down then suspect infection or pulmonary infarction.
11. CRP helps in the differential diagnosis of bacterial meningitis versus viral meningitis.
    1. In viral meningitis, CRP is mostly normal which will exclude bacterial meningitis.
12. CRP can be used to monitor:
    1. Rheumatic fever.
    2. Crohn’s disease.
    3. Rheumatoid arthritis.
    4. Ankylosing spondylitis.
    5. Reiter’s syndrome.
    6. Psoriatic arthropathy.
    7. Still’s a disease.
13. Chronic inflammations are a key factor in the formation and progression of atherosclerosis.
    1. There are so many studies indicating that an increased level of CRP positively associated with increased risk of future coronary diseases such as coronary artery disease, cerebrovascular disease or peripheral arterial disease.
    2. This can be used as a predictive of future acute coronary artery syndrome, and patients with stable angina and coronary artery stents.
14. hs-CRP and its relation to vascular diseases:
    1. hs-CRP is a high predictor for myocardial infarction, stroke, peripheral vascular disease, and sudden cardiac death.
    2. The association between hs-CRP and vascular diseases is independent of age, smoking, hypertension, and diabetes mellitus.
    3. hs-CRP is a stronger predictor of risk than LDL-cholesterol.
    4. Measurement of hs-CRP does not replace but complements the evaluation of lipids and classical coronary heart disease risk factors in primary prevention.
    5. High sensitivity assay can find CRP as little as <0.5 mg/L.
15. hs-CRP has a significant association for future risk of metabolic syndrome, diabetes mellitus, and hypertension.

Normal

Source 2

• Normally it is negative or < 1 mg/dl (<10.0 mg/L).
  • Anothere reference, normal value = <2  to 3 mg/L.
  • >10 mg/L indicates active inflammation.
• Cardiac risk:
  • Low < 1.0 mg/dl
  • average level 1.0 to 3.0 mg/dl
  • High level > 3.0 mg /dl

Source 2

• Normal = <1 mg/dL
  • For conversion to SI units x 10 = mg/L.

Source 4

• Normal  = <0.8 mg/dL  (<8.0 mg/L) by nephlometry method.
  • 0.02 to 0.800 mg/dL (0.2 to 8.0 mg/L0 by RIA methodology.

 CRP Versus ESR:

1. It is more sensitive than ESR.
2. CRP level increases before there is a rise in antibody titer and ESR.
3. In the acute inflammatory response, CRP rises earlier than ESR.
4. CRP disappears when the inflammatory response is suppressed whereas ESR may take more time.
   

   Clinical parameters	ESR	CRP (C-reactive protein)
   Normal level	Men = 0 to 5  Women = 5 to 15 mm/hour	<1.0 mg/dL
   Sensitivity	Less sensitive	More sensitive
   Pathophysiology (etiology)	Fibrinogen level goes up in the serum, which causes RBCs to clump	Dead and dying cells release chemical factors, which stimulate the liver to produce CRP
   Increase in the level	No relation to antibody	Increases before the increase in the antibody level
   Response to inflammation	Late response	Early response
   After the inflammation	Take more time	Disappears early
   Acute myocardial infarction	No relation	Increased and correlate with other enzymes
   Coronary anginal attack	No relation	Normal

Coronary artery disease:

1. The CRP level increase in the myocardial infarction and its level correlates with the level of myocardial infarction enzymes (Isoenzyme CK-MB).
2. If the CRP level persists that may indicate ongoing damage to the heart muscles.
3. CRP will be normal in Angina.
4. CRP baseline level is a good predictor of cardiovascular disease than even low-density lipoprotein (LDL).

Increased values are seen in:

1. It is raised in Inflammation, necrosis, or tissue injury.
2. Acute, noninfectious diseases like arthritis, acute rheumatic fever, and Crohn’s disease.
3. Collagen vascular diseases like lupus erythematosus and vasculitis.
4. Acute myocardial infarction.
5. Bacterial infections like postoperative wound infection, urinary tract infection, or tuberculosis and meningitis.
6. Pulmonary infarction.
7. Malignant diseases.
8. Transplant rejection (kidney or bone marrow).
9. Active Rheumatic disease (Rheumatoid Arthritis, Rheumatic fever).
10. Burns complicated with infection.
11. Infection in immunocompromised patients.
12. Postoperative complications like a subphrenic abscess or septicemia.

Decreased values are seen in:

• The use of steroids and non-steroidal anti-inflammatory drugs can significantly lower the CRP level.

CRP level is useful in:

1. clinical evaluation of SLE, Leukaemia, Blast crisis, and ulcerative colitis.
2. There is a good correlation with ESR, but CRP appears and disappears earlier than changes in ESR.
3. The level of CRP increases dramatically than other Acute-phase proteins. So CRP is more useful as acute-phase proteins.
4. The quantitative test is more useful than a qualitative test.

Jones criteria for the diagnosis of Rheumatic fever:

Manifestations	Signs and symptoms
Major	Polyarthritis, carditis, subcutaneous nodule, chorea, Erythema marginatum
Minor	Fever and arthralgia
Minor	Raised CRP, raised ESR, evidence of group A streptococcal infection, and prolonged PR interval on ECG

Interpretation: For the diagnosis of rheumatic fever,  two major manifestations or one major and two minor manifestations are needed.

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