Biomarkers of Inflammation: C-Reactive Protein (CRP)

Optimal Takeaways

C-reactive protein increases with inflammation and bacterial infection and is a good biomarker of acute inflammatory changes. Although its production is increased by inflammation, CRP can have some beneficial effects and can help clear pathogens and damaged cells during infection and inflammation. Elevated levels may be predictive of CVD, cardiac damage, heart failure, impaired glucose tolerance, metabolic syndrome, diabetes, and all-cause mortality. Low levels of CRP don’t necessarily rule out the presence of inflammation.

Standard Range: 0.00 - 7.9 mg/L (0.00 - 75.24 nmol/L)

The ODX Range: 0.00 – 3.0 mg/L (0.00 – 28.57 nmol/L)

Low levels of CRP suggest the absence of systemic inflammation though other inflammatory markers may detect inflammation even when CRP is normal.

High levels of CRP can be seen with inflammation and inflammatory disorders such as rheumatoid arthritis and Crohn’s disease, vasculitis, myocardial infarction, soft tissue trauma, cancer, transplant rejection, wound infection, and urinary tract infection. Levels may also be elevated in hypertension, obesity, dyslipidemia, and during estrogen or progesterone therapy as well (Pagana 2021).

Increased CRP can be seen with colorectal cancer (Farwell 2010), autoimmune disorders, pregnancy, depression, pancreatitis, periodontitis, gingivitis, cigarette smoking, sedentary lifestyle, disordered sleep, and genetic polymorphisms. Statin drugs and NSAIDS may falsely elevate CRP (Nehring 2022). Elevations in serum CRP may also be an indicator of impaired glucose tolerance, overt type 2 diabetes (Tutuncu 2016), metabolic syndrome, and increased risk of cardiovascular events (Ridker 2003).

Overview

C-reactive protein is an acute-phase protein produced in the liver, and it increases with inflammation and infection, especially bacterial infection. Levels of CRP will rise more quickly and recover more rapidly than the erythrocyte sedimentation rate (ESR), making CRP a better marker of acute inflammatory changes. Persistently elevated CRP may indicate ongoing heart damage following myocardial infarction and is considered a better predictor of adverse cardiac events than LDL cholesterol (Pagana 2021).

Although the synthesis of CRP is stimulated by inflammation, it can have both pro-inflammatory and anti-inflammatory actions. It helps clear damaged cells and pathogens and can activate the complement pathway. However, this process may become pathogenic, and notable elevations in CRP can be seen, especially in autoimmunity, chronic inflammation, or chronic infection. While minor elevations can be seen with pregnancy, obesity, depression, and cigarette smoking, most healthy individuals will maintain a CRP below 3.0 mg/L (28.57 nmol/L) (Nehring 2022). Levels of CRP can increase up to 50,000 higher than baseline during acute inflammation and should be monitored (Bardagjy 2019).

Elevated CRP levels are observed in metabolic syndrome, a condition associated with persistent inflammation. In one cohort study of 14,719 healthy women, the number of metabolic syndrome components increased as CRP levels increased. The absence of components was associated with a baseline median CRP of 0.68 mg/L (6.47 nmol/L), while the presence of 3 components was associated with a median CRP of 3.01 (28.66 nmol/L). The highest median CRP of 5.75 mg/L (54.76 nmol/L) was associated with all five components of metabolic syndrome. Having a CRP above 3.0 mg/dL and three or more components of metabolic syndrome was associated with a significantly increased risk of cardiovascular events over the 8-year follow-up period (Ridker 2003),

C-reactive protein is considered a “high-value” protein biomarker for identifying increased risk of heart failure, all-cause mortality, and cardiovascular disease and mortality (Ho 2018). However, to detect low levels of C-reactive protein, especially when evaluating cardiac risk, high-sensitivity CRP (hs-CRP) testing is recommended.

Evaluation of the NHANES Linked Mortality cohort data (1999-2011) revealed that total mortality increased as CRP levels increased, especially in men overall and in women who died within the first two years of evaluation. The association between CRP and cardiovascular mortality was modified by diet quality. Individuals with higher CRP, especially those above 3.8 mg/L (36.19 nmol/L), had higher blood pressure, dyslipidemia, and diabetes, and lower diet quality and physical activity levels (Liu 2020).

Vitamin D appears to decrease as CRP increases, and research suggests evaluating both markers together and supplementing with vitamin D as needed (Ostadmohammadi 2019, Li 2019, Hernandez-Alvarez 2019).

References

Bardagjy, Allison S, and Francene M Steinberg. “Relationship Between HDL Functional Characteristics and Cardiovascular Health and Potential Impact of Dietary Patterns: A Narrative Review.” Nutrients vol. 11,6 1231. 30 May. 2019, doi:10.3390/nu11061231

Farwell, Wildon R, and Eric N Taylor. “Serum anion gap, bicarbonate and biomarkers of inflammation in healthy individuals in a national survey.” CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne vol. 182,2 (2010): 137-41. doi:10.1503/cmaj.090329

Hernández-Álvarez, Elena et al. “Association between 25-OH-vitamin D and C-reactive protein as a marker of inflammation and cardiovascular risk in clinical practice.” Annals of clinical biochemistry vol. 56,4 (2019): 502-507. doi:10.1177/0004563219851539

Ho, Jennifer E et al. “Protein Biomarkers of Cardiovascular Disease and Mortality in the Community.” Journal of the American Heart Association vol. 7,14 e008108. 13 Jul. 2018, doi:10.1161/JAHA.117.008108

Li, Qian et al. “Association of C-reactive protein and vitamin D deficiency with cardiovascular disease: A nationwide cross-sectional study from National Health and Nutrition Examination Survey 2007 to 2008.” Clinical cardiology vol. 42,7 (2019): 663-669. doi:10.1002/clc.23189

Liu, Junxiu et al. “Associations of C-reactive protein and fibrinogen with mortality from all-causes, cardiovascular disease and cancer among U.S. adults.” Preventive medicine vol. 139 (2020): 106044. doi:10.1016/j.ypmed.2020.106044

Nehring, Sara M., et al. “C Reactive Protein.” StatPearls, StatPearls Publishing, 18 July 2022. 

Ostadmohammadi, Vahidreza et al. “The Effects of Vitamin D Supplementation on Glycemic Control, Lipid Profiles and C-Reactive Protein Among Patients with Cardiovascular Disease: a Systematic Review and Meta-Analysis of Randomized Controlled Trials.” Current pharmaceutical design vol. 25,2 (2019): 201-210. doi:10.2174/1381612825666190308152943

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Ridker, Paul M et al. “C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14 719 initially healthy American women.” Circulation vol. 107,3 (2003): 391-7. doi:10.1161/01.cir.0000055014.62083.05

Tutuncu, Yildiz et al. “A Comparison of hs-CRP Levels in New Diabetes Groups Diagnosed Based on FPG, 2-hPG, or HbA1c Criteria.” Journal of diabetes research vol. 2016 (2016): 5827041. doi:10.1155/2016/5827041