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 (particularly IL-6 and TNF-α) that serves as a biomarker of systemic inflammation and tissue injury. 1
Fundamental Biology and Structure
CRP is a ring-shaped pentameric protein belonging to the ancient pentraxin family, arranged in a cyclic homopentameric structure that is highly conserved across vertebrates and many invertebrates. 2, 3
The protein is produced solely in the liver via CRP gene transcription, with its synthesis rate being the sole determinant of plasma levels, proportional to the intensity of inflammatory insult. 1, 4
CRP functions as a pattern recognition molecule in innate immunity, binding to phosphocholine on bacterial membranes, damaged cell membranes, lipoproteins, and nuclear constituents in damaged cells. 2, 3
Kinetics and Normal Values
Secretion begins 4-6 hours after inflammatory insult, with concentration doubling every 8 hours and reaching peak levels at 36-50 hours after the initial stimulus. 5, 1
Normal baseline CRP levels are typically below 3 mg/L in healthy individuals, though levels can rise above 500 mg/L during acute illness, representing increases of 10-1000-fold within 6-72 hours of tissue damage. 1, 4, 6
Production and elimination are not influenced by renal replacement therapy or immunosuppression (including systemic steroids and neutropenia), making it a reliable marker across diverse clinical contexts. 5, 1
Immune Function and Mechanisms
CRP participates in innate immunity through multiple mechanisms: it acts as an opsonin, activates the classical complement pathway (generating C3 convertase but not C5 convertase), and binds to Fc receptors on immune cells. 2, 3
Interaction with Fc receptors generates proinflammatory cytokines and reactive oxygen species from monocytes/macrophages while inhibiting neutrophil functions. 3
The protein can undergo conformational rearrangement into distinct structural isoforms with different solubility, antigenicity, and bioactivities beyond the native pentameric form measured in serum. 6
Clinical Interpretation Categories
CRP levels are stratified into risk categories: <1 mg/L (low risk), 1-3 mg/L (moderate risk), and >3 mg/L (high risk) for cardiovascular disease assessment using high-sensitivity CRP (hs-CRP). 7, 4
For acute inflammation assessment, levels are categorized as: <3 mg/L (normal), 3-10 mg/L (low-grade chronic inflammation), and >10 mg/L (acute inflammation or infection). 7
The American Heart Association recommends hs-CRP as the best inflammatory biomarker for detecting enhanced absolute risk of cardiovascular disease in the general population, with independent predictive value for cardiovascular events. 1
Diagnostic Applications
Cardiovascular Disease
- Elevated CRP predicts all-cause and cardiovascular mortality in both hemodialysis and peritoneal dialysis patients, and may be directly involved in atherothrombogenesis beyond its role as an inflammatory marker. 1
Surgical and Infectious Contexts
CRP demonstrates 68-92% sensitivity and 40-67% specificity as a marker of bacterial infection, though low specificity limits its diagnostic value when used in isolation. 5, 1
For appendicitis diagnosis, CRP shows 93.6-96.6% sensitivity in patients with histologically proven disease, though it lacks specificity and should not be used as the sole diagnostic criterion. 5, 1
Postoperative Monitoring
CRP below 75 mg/L on postoperative day 3 suggests uncomplicated recovery and may serve as a safe discharge criterion. 1
CRP above 215 mg/L on postoperative day 3 predicts complications and warrants investigation for infectious or thrombotic complications. 1
Exercise and Athletic Contexts
Short-term increases occur after exercise, with moderate acute increases peaking 24 hours post-exercise after activities like soccer games or 60 minutes of intense endurance running. 5
Long-term physical activity leads to decreased resting CRP levels, probably through decreased cytokine production, while exhaustive resistance training over several weeks can lead to chronic CRP increases. 5
Critical Limitations
CRP cannot differentiate between bacterial infection, viral infection, tissue injury, chronic inflammatory conditions, or malignancy without clinical context. 1, 7
Baseline CRP elevation from chronic conditions (obesity, smoking, metabolic syndrome) will be superimposed upon acute rises, making interpretation more complex. 1, 7
Smoking approximately doubles the risk of elevated baseline CRP, and a significant portion of adults exhibit CRP >3 mg/L even without acute pathology. 7
Management Principles
Treatment should target the underlying cause rather than the CRP level itself, and serial testing should not be used to monitor treatment effects according to the American College of Cardiology. 7
Serial CRP measurements are more informative than single values: a declining trend indicates normal recovery, while persistent elevation or secondary rise suggests complications. 1
Absolute CRP values must be interpreted in context of the clinical scenario, baseline patient factors, and temporal trends, serving as an additional tool that aids but cannot replace clinical observation and physical examination. 1