What is C-reactive protein (CRP)?

What is C-Reactive Protein (CRP)?

C-reactive protein (CRP) is an acute-phase protein synthesized exclusively by the liver in response to inflammatory cytokines (primarily IL-6), serving as a highly sensitive but non-specific marker of inflammation, tissue injury, and infection. 1

Fundamental Biology and Production

CRP is produced solely in the liver following stimulation by inflammatory cytokines, particularly interleukin-6 (IL-6), with additional signals from tumor necrosis factor-α (TNF-α) and IL-1β. 2, 1

• Secretion begins 4-6 hours after an inflammatory insult, with concentrations doubling every 8 hours and reaching peak levels at 36-50 hours after the initial stimulus 2, 1, 3
• The sole determinant of CRP plasma levels is its hepatic synthesis rate, which is directly proportional to the intensity of the inflammatory insult 2, 1
• Production and elimination are not influenced by renal replacement therapy or immunosuppression (including systemic steroids and neutropenia) 2, 1

Normal Values and Clinical Thresholds

Normal CRP levels in healthy individuals are typically below 3-5 mg/L, but can rise above 500 mg/L during acute illness. 1, 3

The American College of Emergency Physicians and NICE guidelines categorize CRP levels as follows: 3

• <3-5 mg/L: Normal range in healthy individuals
• 5-10 mg/L: Chronic low-grade inflammation
• 10-100 mg/L: Moderate elevation (can occur in both viral and bacterial infections)
• >100 mg/L: Strongly suggests bacterial infection

Clinical Applications

Infection and Inflammation Detection

CRP has a sensitivity of 68-92% but specificity of only 40-67% as a marker of bacterial infection, making it unable to reliably differentiate bacterial infections from non-infectious causes of inflammation when used in isolation. 2, 1

• The World Society of Emergency Surgery recommends that CRP can help diagnose surgical infections when used in conjunction with clinical assessment 2
• In bacterial sepsis, median CRP is approximately 120 mg/L 3
• In appendicitis, CRP demonstrates 93.6-96.6% sensitivity in histologically proven cases, though it lacks specificity and should not be used as a sole diagnostic criterion 1, 3

Postoperative Monitoring

CRP below 75 mg/L on postoperative day 3 suggests uncomplicated recovery and may serve as a safe discharge criterion, while CRP above 215 mg/L on postoperative day 3 predicts complications requiring investigation. 2, 1

• Only IL-6 and CRP are consistently associated with the magnitude of operative injury across all types of elective operations 2
• The negative predictive value of CRP improves each day after surgery, reaching 90% at postoperative day 3 for a pooled CRP cutoff of 159 mg/L 2

Cardiovascular Disease Risk Assessment

The American Heart Association identifies CRP as an independent predictor of cardiovascular events, with high-sensitivity CRP (hs-CRP) being the best inflammatory biomarker for detecting enhanced absolute risk of cardiovascular disease in the general population. 2, 1

• Elevated CRP predicts all-cause and cardiovascular mortality in dialysis patients 1
• CRP may be directly involved in atherothrombogenesis beyond its role as an inflammatory marker 1

Critical Limitations and Pitfalls

CRP cannot differentiate between bacterial infection, viral infection, tissue injury, chronic inflammatory conditions, or malignancy without clinical context. 1, 3

Common Confounding Factors

• One-third of hospitalized patients with CRP >10 mg/L have non-infectious causes, including inflammatory diseases (median CRP 65 mg/L), solid tumors (median CRP 46 mg/L), and cardiovascular disease (median CRP 6 mg/L) 3
• Approximately 20% of smokers have CRP >10 mg/L from smoking alone 3
• 30-40% of US adults have CRP >3 mg/L due to obesity, lifestyle factors, and chronic inflammation 3
• Age, sex, obesity, and comorbidities can influence baseline CRP levels 4

Interpretation Algorithm

When CRP exceeds 10 mg/L, examine for sources of both infection AND inflammation, as CRP elevation occurs in numerous non-infectious conditions including inflammatory bowel disease, rheumatoid arthritis, long-term alcoholism, and chronic cardiovascular disease. 3

For differentiating bacterial from viral infections, procalcitonin is superior to CRP, with PCT ≥1.5 ng/mL having 100% sensitivity and 72% specificity for sepsis. 3

• Combined CRP ≥50 mg/L and PCT ≥1.5 ng/mL has 98.5% sensitivity and 75% specificity for sepsis 3
• Absolute CRP values must be interpreted in context of the clinical scenario, baseline patient factors, and temporal trends 1

Role in the Inflammatory Response

CRP is a member of the pentraxin family and is part of the innate immune response to tissue injury, functioning as a classical mediator of innate immunity through interaction with both humoral and cellular effector systems of inflammation. 2

• The systemic inflammatory response involves proinflammatory cytokines, cell adhesion molecules, and chemokines as part of an innate stress response to help repair tissue injury 2
• When sustained, this inflammatory response adversely affects cardiac structure and function, making CRP a useful biomarker for assessing risk and providing insights into pathogenic mechanisms 2