What are the causes of an elevated C‑reactive protein (CRP) level?

Causes of Elevated C-Reactive Protein (CRP)

CRP elevation occurs primarily from bacterial infections (median ~120 mg/L), inflammatory diseases like rheumatoid arthritis (median ~65 mg/L), solid tumors (median ~46 mg/L), cardiovascular disease (median ~6 mg/L), and chronic kidney disease, with the degree of elevation helping distinguish between acute infectious/inflammatory processes versus chronic low-grade inflammation. 1

Understanding CRP as an Inflammatory Marker

CRP is an acute-phase protein synthesized by the liver in response to inflammatory cytokines, particularly IL-6 and TNF-α. 2, 3 The protein functions physiologically by enhancing cell-mediated immunity through promoting phagocytosis, accelerating chemotaxis, and activating platelets. 4

Normal CRP concentrations are typically below 3-5 mg/L in healthy individuals. 1, 3

Primary Pathological Causes

Infectious Causes

• Bacterial infections cause the highest CRP elevations, with median levels around 120 mg/L, making them the most likely cause when CRP is markedly elevated. 1
• Viral infections typically cause moderate elevations, generally lower than bacterial infections. 2
• In meningitis, neonatal sepsis, and occult bacteremia, CRP is usually elevated, though a normal CRP should never delay antibiotic coverage. 5
• CRP may be elevated with complications or treatment failures in pneumonia, pancreatitis, pelvic inflammatory disease, and urinary tract infections. 5

Inflammatory Diseases

• Rheumatoid arthritis and inflammatory bowel disease commonly elevate CRP to median levels of approximately 65 mg/L. 1
• In Crohn's disease, CRP levels correlate well with clinical disease activity and can predict prognosis and relapse. 6
• CRP is less reliable in ulcerative colitis except for severe, extensive colitis. 6
• In acute pancreatitis, CRP levels correlate well with clinical disease activity and can predict prognosis. 6

Malignancies

• Solid tumors can significantly raise CRP, with median levels around 46 mg/L. 2, 1
• Elevated CRP levels are associated with increased risk of colorectal cancer and serve as a marker of poor prognosis, indicating more advanced disease and possibly reduced survival. 6

Cardiovascular Disease

• Cardiovascular disease is associated with lower but clinically significant CRP elevations, with median levels around 6 mg/L. 2, 1
• CRP >3 mg/L predicts future coronary events in asymptomatic individuals and is a stronger predictor of cardiovascular events than LDL-cholesterol levels. 3
• The American Heart Association suggests that high-sensitivity CRP may be used at the physician's discretion in patients at intermediate cardiovascular risk. 3

Chronic Kidney Disease

• Elevated CRP in dialysis patients independently predicts all-cause and cardiovascular mortality. 2, 1, 3

Non-Pathological Factors Affecting CRP Levels

Lifestyle Factors

• Smoking approximately doubles the risk of elevated CRP, with 20% of smokers having CRP >10 mg/L from smoking alone. 7, 2, 1
• Obesity significantly affects CRP levels, with elevated body mass index consistently associated with higher baseline CRP. 2, 1
• Moderate alcohol consumption and increased physical activity/endurance exercise decrease CRP levels. 1
• Acute exercise can cause short-term CRP increases (up to 152-fold after ultradistance races >24 hours), while long-term physical activity decreases resting CRP levels. 1

Demographic Factors

• Age, sex, race, and socioeconomic status influence baseline CRP levels. 2, 1, 3

Dietary and Sleep Factors

• Diet composition affects baseline CRP levels. 2
• Poor sleep quality is associated with elevated CRP. 2

Medications and Hormonal Factors

• Estrogen/progestogen hormone use increases CRP levels. 1
• Statins, fibrates, and niacin decrease CRP levels. 1

Clinical Interpretation Framework

CRP Level Categories

• <3 mg/L: Normal range, low cardiovascular risk 3, 8
• 3-10 mg/L: Moderate elevation suggesting chronic low-grade inflammation 2, 3
• >10 mg/L: Significant elevation strongly suggesting active inflammatory or infectious process 2, 1

Diagnostic Accuracy Considerations

• CRP has moderate diagnostic accuracy for sepsis, with an area under the ROC curve of 0.73, sensitivity of 80%, and specificity of 61%. 1
• CRP must be interpreted in clinical context; no single value can rule in or rule out a specific diagnosis. 5
• Serial measurements of CRP are more valuable than single values for diagnosis and monitoring treatment response. 1

Critical Pitfalls to Avoid

• A single normal CRP should not be used to rule out infection, and a normal CRP level should never delay antibiotic coverage in suspected serious infections. 1, 5
• Approximately 20% of smokers have CRP >10 mg/L from smoking alone, but levels >80-90 mg/L are too high to attribute solely to lifestyle factors. 1
• Confounding factors such as neutropenia, immunodeficiency, and NSAID use can affect CRP concentrations. 1
• Single measurements may not reflect chronic inflammation and should be interpreted in clinical context. 1
• The nonspecificity of elevated CRP may necessitate multiple determinations and potentially expensive searches for noncardiovascular causes. 7

Population-Level Considerations

The distribution of CRP values in the current population differs significantly from historical norms, with 30-40% of US adults now exhibiting CRP levels >3 mg/L. 2, 1 This population shift affects interpretation of what constitutes "normal" versus "elevated" CRP in contemporary clinical practice.