Biomarkers of Inflammation: High-Sensitivity CRP

Optimal Takeaways

High-sensitivity CRP measurements can detect very low levels of circulating C-reactive protein and low levels are most desirable. Elevated levels are associated with systemic inflammation, cardiometabolic disorders, atherosclerosis, CVD risk, depression, muscle wasting, NAFLD, metabolic syndrome, and an increased risk of diabetes. 

Standard Range:  

0.00 - 1.00 mg/L (0.00 - 9.52 nmol/L)

The ODX Range:  

Male 0.00 - 0.55 mg/L (0.00 - 5.24 nmol/L)        

Female 0.00 - 1.00 mg/L (0.00 - 9.52 nmol/L)

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

High levels of hs-CRP are associated with systemic inflammation. It is a marker of increased risk of adverse cardiovascular events, including myocardial infarction or death in susceptible individuals (Pagana 2021). Elevated hs-CRP is also associated with sarcopenia, weakness (Lee 2020), treatment-resistant depression (Qiao 2019), progression of diabetes (Tutuncu 2016), cardiovascular mortality, all-cause mortality (Li 2017), atherosclerosis, non-alcoholic fatty liver disease (Yu 2018), and metabolic syndrome (Oda 2006).

Overview

The high-sensitivity C-reactive protein assay (hs-CRP) was developed to detect and assess CRP even at lower levels than had been traditionally possible. Characteristics of hs-CRP are generally the same as those for CRP although reference ranges are lower for hs-CRP, ideally below 0.55 mg/L in men, and below 1 mg/L in women (Pahwa 2022).

C-reactive protein (CRP) is an acute-phase reactant and inflammatory marker produced by the liver. Levels increase with inflammation, infection, and malignancy and are controlled by cytokines in circulation, primarily IL-6, which directly increases CRP production. The immune-particle enhanced high-sensitivity CRP test was developed to detect and report lower levels of CRP more accurately (Han 2022).

According to the American Association of Clinical Endocrinologist and the American College of Endocrinology, serum hs-CRP below 1 mg/L (9.52 nmol/L) is considered “normal” while 1-3 mg/L (9.52-28.6 nmol/L) reflects intermediate CVD risk, and greater than 3 mg/L is considered “high risk” (Jellinger 2017). Meta-analysis of 14 studies comprising 83,995 subjects confirmed that increasing hs-CRP increases all-cause mortality and cardiovascular mortality, especially at a level of 1 mg/L or above (Li 2017).  Ideally, the evaluation of hs-CRP for cardiovascular purposes should include two serial measurements taken at least 2 weeks apart due to individual variability (Pagana 2021, Connelly 2017).

Baseline levels of hs-CRP were found to correlate significantly with the severity of atherosclerosis as well. Subjects without atherosclerosis had a mean hs-CRP of 0.87 mg/L (8.29 nmol/L), while those with atherosclerosis had a mean hs-CRP of 1.46 mg/L (13.9 nmol/L). The most severe atherosclerosis was associated with a mean hs-CRP of 1.83 mg/L (17.43 nmol/L) (Swastini 2019).

Elevated hs-CRP may also be indicative of other cardiometabolic disorders. Levels of hs-CRP were found to increase significantly as the severity of non-alcoholic liver disease (NAFLD) increased. In a cross-sectional study of 10,181 individuals undergoing health checkups, mean hs-CRP levels in those without NAFLD were 0.5 mg/L (4.76 nmol/L), 0.9 mg/L (8.57 nmol/L) in those with mild NAFLD, and 1.6 mg/L (15.24 nmol/L) in those with moderate to severe NAFLD (Yu 2018).

The risk of metabolic syndrome may be reflected in hs-CRP levels as well. A cut-off of 0.65 mg/L was recommended for identifying metabolic syndrome in a study of 179 Japanese men and 166 Japanese women. Researchers note that C-reactive protein levels in general, are substantially lower in Japan compared to Western countries (Oda 2006).

Increasing elevations of hs-CRP may reflect the more advanced progression of diabetes in newly diagnosed diabetics. Data obtained from a population-based study of 26,499 adults found that a hs-CRP of 1.8 mg/L (16.9 nmol/L) or above helped identify diabetes in greater than 50% of new cases (Tutuncu 2016).

Elevated hs-CRP may help identify treatment-resistant depression as well. In a study of 206 depressed patients, those with treatment-resistant disease (TRD) had significantly higher hs-CRP than those not resistant to treatment though both groups had above optimal hs-CRP. Levels of hs-CRP in those with TRD at baseline and post-treatment were 12.05 and 9.02 mg/L (114.8-85.9 nmol/L) respectively. In those with non-TRD, mean hs-CRP levels were 7.85-6.1 mg/L (74.8-58.1 nmol/L), respectively. Depression scores, the occurrence of anxiety/somatization, and disordered sleep were associated with elevated hs-CRP as well. Researchers suggest that an hs-CRP of 10.5 mg/L (100 nmol/L) or above may indicate the presence of TRD (Qiao 2019).

Assessing hs-CRP can also help determine if low albumin is related to inflammation (where hs-CRP will be elevated) versus compromised nutrition status and poorer outcomes in end-stage renal disease patients (Mukai 2018).

Note: Some labs may categorize hs-CRP as "CRP, Cardiac"

References

Connelly, Margery A et al. “GlycA, a novel biomarker of systemic inflammation and cardiovascular disease risk.” Journal of translational medicine vol. 15,1 219. 27 Oct. 2017, doi:10.1186/s12967-017-1321-6

Han, Emilie et al. “Comparison of High-Sensitivity C-Reactive Protein vs C-reactive Protein for Cardiovascular Risk Prediction in Chronic Cardiac Disease.” The journal of applied laboratory medicine vol. 7,6 (2022): 1259-1271. doi:10.1093/jalm/jfac069

Jellinger, Paul S et al. “American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease.” Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists vol. 23,Suppl 2 (2017): 1-87. doi:10.4158/EP171764.APPGL

Lee, Wei-Ju et al. “Sex-different associations between serum homocysteine, high-sensitivity C-reactive protein and sarcopenia: Results from I-Lan Longitudinal Aging Study.” Experimental gerontology vol. 132 (2020): 110832. doi:10.1016/j.exger.2020.110832

Li, Yunwei et al. “Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: A meta-analysis.” Atherosclerosis vol. 259 (2017): 75-82. doi:10.1016/j.atherosclerosis.2017.02.003

Nehring, Sara M., et al. “C Reactive Protein.” StatPearls, StatPearls Publishing, 10 May 2021.    

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

Pahwa, Roma, et al. “Chronic Inflammation.” StatPearls, StatPearls Publishing, 8 August 2022.

Swastini, Dewa Ayu et al. “Atherosclerosis Prediction with High Sensitivity C-Reactive Protein (hs-CRP) and Related Risk Factor in Patient with Dyslipidemia.” Open access Macedonian journal of medical sciences vol. 7,22 3887-3890. 14 Nov. 2019, doi:10.3889/oamjms.2019.526

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

Qiao, Juan et al. “Correlation of clinical features with hs-CRP in TRD patients.” Experimental and therapeutic medicine vol. 17,1 (2019): 344-348. doi:10.3892/etm.2018.6914

Yu, En et al. “Inflammatory Biomarkers and Risk of Atherosclerotic Cardiovascular Disease.” Open medicine (Warsaw, Poland) vol. 13 208-213. 24 May. 2018, doi:10.1515/med-2018-0032