In an adult with an elevated erythrocyte sedimentation rate and elevated hemoglobin concentration, what is the differential diagnosis and recommended workup?

Elevated ESR with Elevated Hemoglobin: Diagnostic Approach

Initial Assessment

In an adult with ESR 74 mm/h and hemoglobin 17.2 g/dL, the elevated hemoglobin (polycythemia) is the critical finding that must be addressed first, as it can artificially elevate ESR and represents a distinct diagnostic pathway from typical inflammatory conditions. 1

The combination of elevated ESR with elevated hemoglobin is unusual because anemia typically elevates ESR, while polycythemia should theoretically lower it. 1 This discordance suggests either:

• A significant underlying inflammatory process overriding the polycythemia effect
• Primary polycythemia with concurrent inflammatory disease
• Secondary polycythemia from chronic hypoxia with inflammation

Systematic Diagnostic Algorithm

Step 1: Evaluate the Polycythemia First

Obtain complete blood count with differential, comprehensive metabolic panel (including creatinine and liver function), and arterial oxygen saturation. 1 The elevated hemoglobin requires evaluation for:

• Primary polycythemia vera: Check JAK2 mutation, serum erythropoietin level 1
• Secondary polycythemia: Assess for chronic hypoxia (COPD, sleep apnea, high altitude), renal disease, or malignancy 1
• Relative polycythemia: Evaluate volume status and diuretic use 1

Step 2: Characterize the ESR Elevation

ESR 74 mm/h represents a markedly elevated value (>50 mm/h), which significantly increases the likelihood of underlying disease. 1 At this level, the most common associations are:

Infection (40% of cases with ESR >100): 2, 3

• Pulmonary infections account for 58% of infectious causes 4
• Chronic osteomyelitis, particularly in patients with diabetes or recent trauma 1
• Obtain blood cultures if fever, chills, or constitutional symptoms present 1

Malignancy (36% of cases): 3

• Hematologic malignancies (lymphoma, multiple myeloma) are particularly associated with extreme ESR elevations 4
• Solid tumors, especially with metastatic disease 2
• Chest radiography to exclude pulmonary malignancy 1

Autoimmune/Rheumatologic disease (38% of cases): 3

• Giant cell arteritis if age >50 years: ESR >40 mm/h has 93.2% sensitivity; requires urgent evaluation for new headache, jaw claudication, or visual symptoms 1
• Polymyalgia rheumatica: bilateral shoulder/hip pain, morning stiffness >45 minutes 1
• Adult-onset Still's disease: fever, rash, arthralgia with markedly elevated ferritin 5

Step 3: Essential Laboratory Workup

Order the following tests immediately: 1

• C-reactive protein (CRP): More sensitive for acute inflammation; rises within 12-24 hours and normalizes faster than ESR 1, 5
• Complete metabolic panel: Assess for azotemia (which artificially elevates ESR) and renal disease 1
• Serum ferritin: Extremely elevated in Still's disease, malignancy, and infection 1
• Rheumatoid factor and anti-CCP antibodies if joint symptoms present 1
• Serum protein electrophoresis: Screen for multiple myeloma if age >50 years 4

Step 4: Age-Specific Considerations

If age >50 years with new headache, visual symptoms, or jaw claudication: 1

• Urgent ophthalmology and rheumatology referral same-day for temporal artery biopsy
• Do not delay corticosteroids if high clinical suspicion

If age >45 years with back pain: 6

• Urgent MRI of spine to exclude vertebral osteomyelitis, spinal malignancy, or compression fractures
• Blood cultures if any fever present

Step 5: Monitoring Strategy

Repeat ESR and CRP in 2-4 weeks if no diagnosis established after initial workup. 1 ESR remains elevated longer than CRP after inflammation resolves, so discordance between the two can guide interpretation. 5

• If CRP normalizes but ESR remains elevated: suggests resolving inflammation 5
• If both remain elevated: pursue additional serological testing (ANA, ANCA, tuberculosis testing) only if clinical signs suggest specific conditions 1

Critical Clinical Pitfalls

Do not attribute the elevated ESR solely to the polycythemia. 1 While polycythemia should theoretically lower ESR, an ESR of 74 mm/h indicates significant pathology requiring investigation.

ESR >70 mm/h is an independent prognostic factor for mortality (HR 1.89), warranting close follow-up even if initial workup is unrevealing. 7

Almost all patients with extreme ESR elevations have an identifiable etiology, with infection being the most common. 3 A "wait and see" approach is inappropriate at this level of elevation.

The combination of elevated hemoglobin with elevated ESR may indicate:

• Hypernephroma (renal cell carcinoma) producing erythropoietin 1
• Polycythemia vera with concurrent infection or inflammatory complication 4
• Chronic lung disease with secondary polycythemia and superimposed infection 5