Is a baseline hemoglobin of 16 g/dL normal in an adult male with persistently low serum erythropoietin?

Is a Baseline Hemoglobin of 16 g/dL Normal in an Adult Male?

A baseline hemoglobin of 16 g/dL in an adult male is within the normal reference range (13–17 g/dL), but when persistently low serum erythropoietin is present, this combination is physiologically inappropriate and mandates immediate evaluation for polycythemia vera (PV), as suppressed EPO with normal-range hemoglobin represents masked or early-stage disease. 1, 2

Understanding Normal Hemoglobin Values

• The normal hemoglobin reference range for adult males is 13.0–17.0 g/dL (130–170 g/L), with the 97.5th percentile extending to approximately 18.0 g/dL in population studies. 3, 4
• A hemoglobin of 16 g/dL falls comfortably within this range and would not trigger an anemia work-up, which is only initiated when hemoglobin drops below 12 g/dL in adult males. 5
• Individual baseline hemoglobin varies considerably; many individuals have physiologically normal values for them that differ from population means. 5

The Critical Red Flag: Low Erythropoietin with Normal Hemoglobin

This is the key diagnostic concern that transforms an otherwise normal finding into a pathologic one:

• Suppressed serum erythropoietin (below the normal reference range of 10–30 mU/mL) is >90% specific for polycythemia vera, even when hemoglobin has not yet reached the WHO diagnostic threshold of ≥16.5 g/dL. 1
• Low EPO in the presence of normal hemoglobin represents physiologically inappropriate erythropoiesis—the bone marrow is producing red cells autonomously without appropriate EPO stimulation, the hallmark of a myeloproliferative neoplasm. 1, 2
• This discordance should never be dismissed simply because hemoglobin appears "normal"; it indicates masked or early PV that requires full diagnostic work-up. 1

Immediate Diagnostic Algorithm for This Patient

Step 1: Confirm Iron Status (Rule Out Masked PV)

• Order serum ferritin (target >100 µg/dL) and transferrin saturation (target >20%) to exclude iron deficiency that could be concealing a higher hemoglobin. 1
• Iron deficiency can mask PV by preventing hemoglobin from rising to diagnostic thresholds; once iron is repleted, hemoglobin may surge and unmask the disease. 1, 2

Step 2: Molecular Testing

• Order JAK2 V617F mutation testing (exon 14) as the first-line molecular assay, which detects >90% of PV cases. 5, 2
• If JAK2 V617F is negative, proceed to JAK2 exon 12 mutation testing, which accounts for most remaining PV cases. 5, 2

Step 3: Bone Marrow Biopsy (If JAK2 Positive)

• A positive JAK2 mutation combined with low EPO and adequate iron stores warrants bone marrow biopsy to document:
  • Hypercellularity with trilineage growth (panmyelosis)
  • Increased, clustered, pleomorphic megakaryocytes
  • Depleted iron stores
  • Possible mild reticulin fibrosis (present in ~12% of cases) 1, 2

Step 4: Apply WHO Diagnostic Criteria

• Major criteria for PV:
  1. Hemoglobin >16.5 g/dL in men (or sustained increase ≥2 g/dL from baseline, even if below absolute threshold)
  2. Bone marrow biopsy showing hypercellularity with trilineage growth
  3. Presence of JAK2 V617F or JAK2 exon 12 mutation 5, 2
• Minor criterion:
  • Subnormal serum EPO level 5, 1
• Diagnosis requires all 3 major criteria OR the first 2 major criteria plus the minor criterion. 5, 2

Management Even Before Formal Diagnosis

• Initiate aspirin 81 mg daily for thrombosis prophylaxis if JAK2 mutation is positive, even if hemoglobin remains within normal limits, as thrombotic risk is present in masked PV. 1
• Monitor hemoglobin closely (every 3–6 months); if it rises above 16.5 g/dL, initiate therapeutic phlebotomy to maintain target levels and reduce hyperviscosity-related thrombotic risk. 1

Common Pitfalls to Avoid

• Do not reassure the patient that "everything is normal" based solely on hemoglobin being 16 g/dL; the low EPO makes this a pathologic finding requiring full PV work-up. 1
• Do not order red-cell-mass measurement unless hemoglobin is borderline and clinical features strongly suggest PV, as it adds cost without altering management in most cases. 1
• Do not assume iron deficiency excludes PV; rather, recognize that iron replacement can unmask higher hemoglobin and potentially precipitate hyperviscosity. 1
• Do not delay JAK2 testing while waiting for hemoglobin to rise further; early molecular diagnosis allows for risk stratification and thrombosis prevention. 2

Why This Matters for Morbidity and Mortality

• Undiagnosed or untreated PV carries significant thrombotic risk (arterial and venous), which is the leading cause of morbidity and mortality in these patients. 2
• Early identification of masked PV allows initiation of aspirin and phlebotomy before hemoglobin rises to dangerous levels, directly reducing stroke, myocardial infarction, and deep vein thrombosis. 1, 2
• Patients with JAK2-positive disease benefit from thromboprophylaxis even when hemoglobin is still in the "normal" range, underscoring the importance of not dismissing low EPO findings. 1