What condition is indicated by a high erythrocyte sedimentation rate (ESR) with a normal C-reactive protein (CRP) level?

High ESR with Normal CRP: Differential Diagnosis

A markedly elevated ESR (109 mm/h) with normal CRP most commonly suggests conditions where ESR is artificially elevated by non-inflammatory factors (anemia, hypergammaglobulinemia, renal disease) or specific inflammatory conditions where CRP remains disproportionately low, including multiple myeloma, systemic lupus erythematosus, or polymyalgia rheumatica in certain phases. 1, 2

Key Pathophysiologic Mechanisms

The discordance between ESR and CRP occurs because these markers measure different aspects of inflammation:

• ESR reflects blood viscosity and is influenced by plasma proteins (fibrinogen, immunoglobulins), red blood cell characteristics, and non-inflammatory factors 2
• CRP is a direct acute-phase reactant that rises and falls rapidly with active inflammation, independent of ESR 3, 2
• ESR can be spuriously elevated by anemia, hypergammaglobulinemia (multiple myeloma, chronic infections), azotemia, and elevated immunoglobulins even without active inflammation 1, 2

Primary Diagnostic Considerations

Conditions Causing Artifactual ESR Elevation

• Anemia artificially elevates ESR independent of inflammation and is a common cause of ESR-CRP discordance 1, 2
• Renal insufficiency (azotemia) elevates ESR through multiple mechanisms including anemia and altered plasma proteins 1, 2
• Hypergammaglobulinemia from multiple myeloma, chronic infections, or monoclonal gammopathies increases blood viscosity and ESR 2

Inflammatory Conditions with ESR-CRP Discordance

Polymyalgia Rheumatica (PMR):

• ESR >40 mm/h is characteristic and a prognostic factor for relapse risk 1
• During certain disease phases or relapses, ESR may remain elevated while CRP normalizes more rapidly 4
• Clinical features include bilateral shoulder/hip girdle pain, morning stiffness >45 minutes, and constitutional symptoms 1

Giant Cell Arteritis (GCA):

• ESR >40 mm/h has 93.2% sensitivity for GCA 1, 5
• Approximately 4% of biopsy-proven GCA patients have normal inflammatory markers at diagnosis, though an ESR of 109 would be elevated 5
• ESR may remain elevated longer than CRP during treatment 4

Systemic Lupus Erythematosus:

• Can present with elevated ESR but normal or minimally elevated CRP due to disease-specific inflammatory patterns 2

Diagnostic Algorithm

Immediate Laboratory Assessment

1. Complete blood count with differential to identify anemia (normochromic, normocytic suggests chronic inflammation), leukocytosis, or thrombocytosis 1
2. Comprehensive metabolic panel including creatinine (assess azotemia), liver enzymes, and albumin (hypoalbuminemia suggests severe inflammation) 3, 1
3. Serum protein electrophoresis if hypergammaglobulinemia suspected to rule out multiple myeloma or monoclonal gammopathy 2
4. Repeat CRP measurement to confirm it is truly normal, as CRP normalizes faster than ESR during inflammation resolution 3, 2

Clinical Assessment for Specific Conditions

Screen for PMR/GCA if:

• Age >50 years with new-onset localized headache, jaw claudication, visual symptoms, or temporal artery tenderness (urgent specialist referral required) 1
• Bilateral shoulder/hip pain with morning stiffness >45 minutes 1

Screen for hematologic disorders if:

• Unexplained anemia, bone pain, hypercalcemia, or renal insufficiency present 1, 2

Screen for chronic infections if:

• Fever, weight loss, night sweats, or localized symptoms suggesting osteomyelitis or endocarditis 1, 6

Follow-Up Strategy

• Repeat ESR and CRP in 2-4 weeks to determine if elevation is persistent or transitory 1
• Consider temporal artery biopsy if GCA suspected clinically, even with discordant markers 5
• Imaging studies (chest X-ray, echocardiography) only if clinical features suggest specific organ involvement 1, 6

Critical Pitfalls to Avoid

• Do not dismiss significantly elevated ESR (109 mm/h) as insignificant even with normal CRP; this degree of elevation warrants thorough investigation 1
• Anemia and azotemia are the most common causes of artifactual ESR elevation and must be excluded first 1, 2
• ESR remains elevated longer than CRP after IVIG therapy or during inflammation resolution, which can create discordance 3
• In elderly patients, ESR normally increases with age and women have higher baseline values, but 109 mm/h exceeds age-adjusted norms 1
• Liver insufficiency or protein-losing conditions can lower acute-phase reactants including CRP, masking inflammation 2