What is the significance of a high high-sensitivity C-reactive protein (hsCRP) level with normal myeloperoxidase (MPO) and asymmetric dimethylarginine (ADMA) levels?

Why hsCRP is Elevated with Normal MPO and ADMA

An elevated hsCRP with normal MPO and ADMA indicates systemic inflammation that is not primarily driven by neutrophil activation (MPO) or endothelial dysfunction (ADMA), pointing toward alternative inflammatory sources such as infection, occult malignancy, metabolic syndrome, or non-vascular inflammatory conditions. 1

Understanding the Discordance

hsCRP is a non-specific acute phase reactant that rises in response to multiple inflammatory stimuli, while MPO and ADMA reflect more specific pathophysiologic processes:

• hsCRP reflects hepatic synthesis in response to IL-6 and other cytokines from diverse inflammatory sources including infection, tissue injury, metabolic dysfunction, and chronic disease 2
• MPO (myeloperoxidase) specifically indicates neutrophil activation and oxidative stress, typically elevated in acute coronary syndromes and active atherosclerotic plaque instability 3
• ADMA reflects endothelial dysfunction through impaired nitric oxide synthesis, correlating with flow-mediated dilation impairment 3, 4

The pattern of elevated hsCRP with normal MPO and ADMA suggests inflammation originating outside the vascular endothelium and without significant neutrophil-mediated oxidative stress. 3, 4

Systematic Evaluation Approach

Determine hsCRP Magnitude

• If hsCRP is 3-10 mg/L: This represents moderate cardiovascular risk elevation but may also indicate low-grade systemic inflammation from metabolic causes 1, 5
• If hsCRP >10 mg/L: Mandatory investigation for non-cardiovascular causes including acute infection, occult malignancy, or active inflammatory disease 2, 1

Primary Differential Considerations

Infectious causes produce the highest CRP elevations:

• Bacterial infections cause median CRP levels in the high inflammatory range 5
• Viral infections typically produce moderate elevations 5
• Screen for occult infection including dental abscess, sinusitis, urinary tract infection, or chronic infections 5

Malignancy-related inflammation:

• Solid tumors can significantly raise CRP to high inflammatory levels 5
• Consider age-appropriate cancer screening if persistently elevated without other explanation 5

Metabolic and lifestyle factors:

• Smoking approximately doubles the risk of elevated CRP 1, 5
• Metabolic syndrome and obesity are strongly associated with elevated hsCRP through adipose tissue cytokine production 6, 7
• Body mass index shows independent correlation with hsCRP (r=0.246, P<0.001) 7

Chronic inflammatory conditions:

• Rheumatoid arthritis and inflammatory bowel disease produce moderate CRP elevations 5
• Chronic kidney disease elevates CRP and predicts cardiovascular mortality 2, 5

Recommended Testing Algorithm

For hsCRP 3-10 mg/L with normal MPO/ADMA:

• Repeat hsCRP measurement in 2 weeks to confirm persistence 2, 1
• Calculate Framingham 10-year cardiovascular risk score 2, 1, 8
• If intermediate risk (10-20%), the elevated hsCRP may justify aggressive LDL-lowering targets 2, 1, 8
• Assess metabolic factors: BMI, waist circumference, fasting glucose, lipid panel 7
• Document smoking status and consider cessation counseling 1, 5

For hsCRP >10 mg/L with normal MPO/ADMA:

• Check temperature and assess for acute illness symptoms 5
• Obtain complete blood count with differential (elevated WBC count correlates independently with hsCRP, r=0.276, P<0.001) 7
• Liver enzymes to exclude fatty liver disease 5
• Age-appropriate cancer screening 5
• Consider rheumatologic evaluation if clinical suspicion exists 5
• Evaluate for chronic kidney disease 2, 5

Clinical Implications

The normal MPO and ADMA provide reassurance that:

• Active neutrophil-mediated vascular inflammation is not present 3
• Endothelial dysfunction is not the primary driver of the inflammatory state 3, 4
• The cardiovascular risk may be lower than hsCRP alone would suggest, as ADMA independently predicts endothelial dysfunction and cardiovascular events 3, 4

Critical pitfall to avoid: Do not assume elevated hsCRP alone represents cardiovascular risk without considering non-cardiovascular inflammatory sources, especially when hsCRP >10 mg/L 2, 1

Factors Affecting Interpretation

• Hormone replacement therapy in postmenopausal women may elevate hsCRP levels 2, 1
• Medications including aspirin, COX-2 inhibitors, and statins may affect CRP interpretation 2, 1
• Recent weight loss may lower inflammatory markers including CRP 1
• Age, sex, race, and socioeconomic status influence baseline CRP levels 5