Prevalence of Low Erythropoietin in Idiopathic Erythrocytosis
Approximately 27-40% of patients with idiopathic erythrocytosis have low serum erythropoietin levels, which creates significant diagnostic overlap with polycythemia vera and challenges the reliability of low EPO as a distinguishing criterion.
Key Prevalence Data
The prevalence of low EPO in idiopathic erythrocytosis varies substantially depending on patient selection:
In JAK2-negative erythrocytosis patients with low-to-normal EPO levels specifically selected for study, 27% (8/30) harbored JAK2 exon 12 mutations, representing a subset of what would otherwise be classified as idiopathic erythrocytosis 1
In a broader cohort of JAK2-negative erythrocytosis patients (non-neoplastic erythrocytosis), approximately 40% had EPO levels below the lower range of normal, despite lacking any JAK2 mutations and not meeting criteria for polycythemia vera 2
Among mixed erythrocytosis cohorts including apparent and idiopathic erythrocytosis, low EPO values occurred in "a few" patients, particularly at higher hemoglobin values (>16 g/dL) 3
Clinical Implications of These Findings
Diagnostic Challenges
Low EPO is not specific for polycythemia vera when found in JAK2-negative patients. The finding that 40% of confirmed non-neoplastic erythrocytosis patients have low EPO levels fundamentally challenges the WHO minor criterion that uses subnormal EPO to support a PV diagnosis 2. This creates a diagnostic dilemma where patients fulfill one minor criterion for PV but lack the molecular hallmark of the disease.
When Low EPO Matters Most
Low EPO has its highest diagnostic value (>90% specificity) for polycythemia vera only when JAK2 mutations are present or when hemoglobin is clearly elevated 4, 5. In the absence of JAK2 mutations:
- Specificity drops substantially because a significant minority of idiopathic erythrocytosis patients will have inappropriately low EPO 2
- The positive predictive value for PV diagnosis becomes unreliable without molecular confirmation 1
Practical Diagnostic Algorithm
When encountering low EPO in erythrocytosis:
First, perform JAK2 V617F mutation testing - if positive, low EPO supports PV diagnosis with >97% specificity 5, 6
If JAK2 V617F negative, proceed to JAK2 exon 12 testing - this captures an additional 27% of patients with low EPO who have a clonal disorder 1
If both JAK2 tests are negative despite low EPO, test for EPO-independent erythroid colony formation - this occurred exclusively in JAK2 exon 12-positive patients in one cohort 1
Consider bone marrow biopsy - look for hypercellularity with panmyelosis, clustered pleomorphic megakaryocytes, and depleted iron stores that would support PV even without typical molecular markers 6, 7
Common Pitfalls
Do not diagnose polycythemia vera based on low EPO alone in JAK2-negative patients. The 40% prevalence of low EPO in confirmed non-neoplastic erythrocytosis means that approximately 2 in 5 patients with idiopathic erythrocytosis will have this finding, leading to potential misdiagnosis if molecular testing is not performed 2.
Recognize that "idiopathic erythrocytosis" may be a heterogeneous category. Some patients with low EPO and negative standard JAK2 testing may harbor rare mutations or represent early/masked PV that will declare itself over time 1, 7.
Iron deficiency can mask the true hemoglobin level - ensure iron studies show ferritin >100 µg/dL and transferrin saturation >20% before concluding EPO is inappropriately low for the degree of erythrocytosis 7.