What is C-reactive protein (CRP) and what conditions can increase its levels?

What is C-Reactive Protein (CRP) and What Increases It?

C-reactive protein (CRP) is an acute-phase protein synthesized by the liver in response to inflammatory cytokines (particularly IL-6 and TNF-α), serving as a highly sensitive but non-specific marker of inflammation and tissue injury. 1, 2

Structure and Basic Biology

• CRP is a phylogenetically conserved plasma protein belonging to the pentraxin family, arranged in a cyclic homopentameric structure 2
• It functions as a pattern recognition molecule in innate immunity, binding to phosphocholine on bacterial membranes, damaged cell membranes, and nuclear constituents 2, 3
• CRP activates complement via the classical pathway and interacts with Fc receptors, generating proinflammatory cytokines and reactive oxygen species 3

Normal Reference Ranges

• Normal CRP levels are typically below 3-5 mg/L in healthy individuals 1, 4
• Moderate elevation (5-10 mg/L) indicates chronic low-grade inflammation 1, 4
• Significant elevation (>10 mg/L) strongly suggests active inflammatory or infectious processes 1, 4
• Levels >100 mg/L strongly suggest bacterial infection 4

Kinetics of CRP Response

• CRP rises 4-6 hours after inflammatory insult, doubles every 8 hours, and peaks at 36-50 hours 4
• Levels can increase up to 1000-fold rapidly after onset of inflammation 3, 5
• Under normal circumstances after surgery, CRP generally returns to baseline within 2 months 6

Primary Causes of CRP Elevation

Infections (Highest Elevations)

• Bacterial infections cause the most significant CRP elevations, with median levels of ~120 mg/L 1
• Bacterial sepsis/septicemia produces median CRP ~120 mg/L 4
• Pneumonia elevations are incorporated into diagnostic guidelines 4
• Appendicitis shows 93.6-96.6% sensitivity in histologically proven cases 4
• Bacterial meningitis demonstrates 69-99% sensitivity and 28-99% specificity 4
• Prosthetic joint infections show CRP sensitivity of 73-91% and specificity of 81-86% when using cutoff of 13.5 mg/L 6

Inflammatory Diseases

• Rheumatoid arthritis and inflammatory bowel disease commonly elevate CRP with median levels of ~65 mg/L 1
• CRP ≥50 mg/L has 98.5% sensitivity and 75% specificity for identifying probable or definite sepsis 6

Malignancy

• Solid tumors cause significant CRP elevation with median levels of ~46 mg/L 1

Cardiovascular Disease

• CRP serves as an independent predictor of cardiovascular events, with typically lower elevations (median ~6 mg/L) 1
• Minor CRP elevation (>3 mg/L) is associated with increased risk of future major cardiovascular events 2, 7
• The CDC and American Heart Association recommend CRP measurement for patients at intermediate risk of coronary heart disease 2

Tissue Injury and Trauma

• Fractures trigger CRP elevation through release of IL-6 and TNF-α following tissue injury 8
• Persistent elevation or secondary rises after initial decrease may indicate complications such as infection 8

Chronic Kidney Disease

• Elevated CRP predicts all-cause and cardiovascular mortality in dialysis patients 1

Non-Pathological Factors Affecting CRP

Lifestyle Factors

• Approximately 20% of smokers have CRP >10 mg/L from smoking alone 1, 4
• Obesity significantly affects CRP levels, with 30-40% of US adults having CRP >3 mg/L due to obesity and lifestyle factors 1, 4

Demographic Factors

• Age, sex, and socioeconomic status influence baseline CRP levels 1

Critical Interpretation Pitfalls

• Serial measurements of CRP are more valuable than single values for diagnosis and monitoring treatment response 1
• A single normal CRP does not rule out infection, as timing of measurement is critical 1, 4
• One-third of hospitalized patients with CRP >10 mg/L have non-infectious causes 4
• Confounding factors including neutropenia, immunodeficiency, and NSAID use can affect CRP concentrations 1
• CRP cannot reliably differentiate bacterial from viral infections at moderate elevations (10-100 mg/L) and should be interpreted alongside clinical context and procalcitonin when available 4

Optimal Diagnostic Approach

• Combining CRP ≥50 mg/L with procalcitonin ≥1.5 ng/mL yields 98.5% sensitivity and 75% specificity for sepsis 4
• For prosthetic joint infections, combining CRP with ESR, interleukin-6, and synovial fluid alpha-defensin yields 93% sensitivity and 100% specificity 4
• Abnormal results for at least 2 of 3 tests (CRP >0.93 mg/L, ESR >27 mm/h, and fibrinogen >432 mg/dL) provide 93% sensitivity, 100% specificity, and 97% accuracy for diagnosing prosthetic joint infection 6