High Sensitivity CRP (C-reactive Protein)

C-reactive protein (CRP) is an acute-phase protein produced in the liver as part of the body’s natural inflammatory response.1,2 It is produced in greater volumes when inflammatory conditions are present, with high concentrations indicating more serious inflammation of the patient’s system.1 CRP tests, which measure the concentration of CRP in blood plasma, are a useful non-specific indicator of inflammation and for detecting infection.2 High sensitivity CRP (hs-CRP) is a much more sensitive form of standard CRP tests.

High sensitivity CRP tests can determine slight changes to normal CRP levels, which would otherwise be missed by standard tests.1,3 These tests can help identify more specific issues and chronic inflammation over the long term.2 Due to this, high hs-CRP results can be a good early indicator of cardiovascular disease (CVD) and atherosclerosis in otherwise asymptomatic patients.4,5

Relevant Measures & Metrics

Levels of CRP in blood plasma is measured in milligrams of the protein per liter of plasma (expressed as mg/L). In blood plasma from healthy patients, the baseline median concentration of CRP is approximately 1 mg/L but may be lower. In cases of acute illness, levels can increase to 300 mg/L or higher, which is readily detectable with a standard CRP test.1

Small increases in the baseline levels of CRP, typically to between 1 and 3 mg/L, that are only detectable with a high sensitivity CRP test are early signs of certain diseases, especially cardiovascular conditions.1,4  When hs-CRP is referred to, it usually indicates small measurements that fall into this range. Higher baseline concentrations of CRP indicate higher risk of cardiovascular incident, with hs-CRP levels over 3 mg/L representing the highest risk.1

Presentation & Causes of Elevated High Sensitivity CRP

Higher hs-CRP test results are often found among patients at risk of cardiovascular incidents that have no prior history of CVD.1 It also indicates the patient’s risk of atherosclerosis.5 This typically takes the form of minor increases to the baseline level of the patient’s CRP that remain consistent over time. These increases suggest that the patient is experiencing systemic inflammation.1

Elevated high sensitivity CRP results are frequently observed prior to cases of myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death in otherwise healthy people.1,4 They are also indicative of recurring incidents and death in patients with acute or stable coronary conditions across most other measures of coronary health (eg, LDL cholesterol, blood pressure, etc.).1

This is because systemic inflammation is strongly implicated in increased risk of various cardiovascular conditions, and may make recovery from incidents more difficult.3 While hs-CRP is a generally reliable marker of systemic inflammation, it is unclear whether CRP plays a role in causing or worsening this systemic inflammation or is only produced in response to it.1 That CRP contributes to atherosclerotic plaque and clot formation suggests that it should be viewed as a risk factor.6

Symptoms of chronic inflammation can include chronic ulcers, chronic abscess cavities, and fibrosis.7 However, these symptoms will not necessarily indicate that a patient should receive high sensitivity CRP tests as the low levels of CRP visible in these tests can have subtler impacts. The value of hs-CRP test, therefore, partly rests in detecting cardiovascular risk in otherwise healthy/asymptomatic patients.4

Diagnostic Workup

High sensitivity CRP tests are most often done for people who are in a high-risk demographic group for CVD, such as men over 50 and women over 60.8 They may also be carried out as part of several types of biochemical assay to test LDL, triglycerides, and other common measures of cardiovascular health to give a more complete picture of the patient’s risks.9

There is no single standard technique used for CRP tests. Immunonephelometry and immunoturbidimetry are both common assay types used.10 The more sensitive assays used in hs-CRP tests include immunolatex, an immunonephelometry technique.1,5,10 The main distinction between the standard and more sensitive nephelometry assays lie in the degrees of sample dilution and calibration.1

The most optimal hs-CRP results can be achieved by averaging test results from two blood serum samples taken two weeks apart. If one of the samples shows a level higher than 10 mg/L, this suggests that infection or some other acute cause of inflammation is present. In this case, discard the sample and perform another test two weeks later.1

Differential Diagnosis

Although high sensitivity CRP tests are most often used as a measure of cardiovascular health, CVD and atherosclerosis are not the only disorders that trigger a CRP response.11 Other conditions, such as asthma, migraine, diabetes, and metabolic syndrome, are thought to be influenced by the levels of systemic inflammation identified by hs-CRP tests.12,13,14,15 Therefore, other tests and visible symptoms indicative of each of these conditions should be considered in cases of elevated hs-CRP results.

High Sensitivity CRP Treatment & Management

As noted above, tracking changes in high sensitivity CRP test results from a patient’s baseline can help predict future risk of CVD and atherosclerosis in otherwise healthy patients. It can be a useful predictor to guide therapeutic decisions, particularly as part of a broader battery of tests tracking other risk factors.1,4

Elevated hs-CRP results can also predict difficulty recovering from prior CVD incidents and slow remission of lasting conditions such as hypertension. It has been suggested that lower baseline hs-CRP levels predict more effective hypertension remission when treated with dietary interventions, independent of any other known predictive factors.15 It therefore follows that hs-CRP tests could form part of a management plan for hypertensive patients.

Determining inflammatory status with high sensitivity CRP may also prove valuable in preventing first time cardiovascular incidents among patients with existing atherosclerosis diagnoses. Interventions that selectively reduce or limit inflammation can reduce risk of cardiovascular events in such cases even if LDL is already effectively controlled.16

Reference List

1. Back JL. Cardiac injury, atherosclerosis, and thrombotic disease. In: McPherson A, ed. Henry’s Clinical Diagnosis and Management by Laboratory Methods. 14th ed. Elsevier; 2022:267-275.

2. Luan Y, Yao Y. The clinical significance and potential role of C-reactive protein in chronic inflammatory and neurodegenerative Diseases. Front Immunol. 2018;9:1302. doi: 10.3389/fimmu.2018.01302

3. Helal I, Zerelli L, Krid M, et al. Comparison of C-reactive protein and high-sensitivity C-reactive protein levels in patients on hemodialysis. Saudi J Kidney Dis Transpl. 2012;23(3):477-83.

4. Bassuk SS, Rifai N, Ridker PM. High-sensitivity C-reactive protein: Clinical importance. Curr Probl Cardiol. 2004;29(8):439-93.

5. Oh SW, Moon JD, Park SY. Evaluation of fluorescence hs-CRP immunoassay for point-of-care testing. Clin Chim Acta. 2005;356(1-2):172-7. doi: 0.1016/j.cccn.2005.01.026

6. Castro AR, Silva SO, Soares SC. The use of high sensitivity C-reactive protein in cardiovascular disease detection. J Pharm Pharm Sci. 2018;21(1):496-503. doi: 10.18433/jpps29872

7. Stephenson TJ. Inflammation. In: Cross S, ed. Underwood’s Pathology. 7th ed. Elsevier; 2019:159-76.

8. Gulati M, Merz NB. Cardiovascular disease in women. In: Libby P, ed. Braunwald’s Heart Disease. 12th ed. Elsevier; 2022:1710-22.

9. Hoogeveen RC, Ballantyne CM. Residual cardiovascular risk at low LDL. Clin Chem. 2021;67(1):143-153. doi: 10.1093/clinchem/hvaa252

10.Moutachakkir M, Hanchi AL, Barou A, Boukhira A, Chellak S. Immunoanalytical characteristics of C-reactive protein and high sensitivity C-reactive protein. Ann Biol Clin (Paris). 2017;75(2):225-9. doi: 10.1684/abc.2017.1232

11.Soeki T, Sata M. Inflammatory biomarkers and atherosclerosis. Int Heart J. 2016;57(2):134-9. doi: 10.1536/ihj.15-346

12. Kilic H, Karalezli A, Hasanoglu HC, Erel O, Ates C. The relationship between hs-CRP and asthma control test in asthmatic patients. Allergol Immunopathol (Madr). 2012;40(6):362-7. doi: 10.1016/j.aller.2011.10.002

13.Tanik N, Celikbilek A, Metin A, Gocmen AY, Inan LE. Retinol-binding protein-4 and hs-CRP levels in patients with migraine. Neurol Sci. 2015;36(10):1823-7. doi: 10.1007/s10072-015-2262-6

14. Sinha SK, Nicholas SB, Sung JH, et al. Hs-CRP is associated with incident diabetic nephropathy: Findings from the Jackson Heart Study. Diabetes Care. 2019;42(11):2083-9. doi: 10.2337/dc18-2563

15. Carbone F, Elia E, Casula M, et al. Baseline hs-CRP predicts hypertension remission in metabolic syndrome. Eur J Clin Invest. 2019;49(8):13128. doi: 10.1111/eci.13128

16. Libby P. Inflammation in atherosclerosis-No longer a theory. Clin Chem. 2021;67(1):131-42. doi: 10.1093/clinchem/hvaa275

Author Bio

Martyn Bryson is a medical writer living in Philadelphia, Pennsylvania. They have over a decade of experience as a writer and editor covering a wide range of health and wellness topics.