Can Idiopathic Erythrocytosis Present with Low Serum Erythropoietin Levels?
Yes, idiopathic erythrocytosis can present with low serum erythropoietin (EPO) levels, occurring in a minority of cases, though this finding should prompt aggressive investigation for JAK2 mutations that may reclassify the diagnosis as polycythemia vera. 1, 2
Frequency and Clinical Significance of Low EPO in Idiopathic Erythrocytosis
Low EPO levels (below the reference range) occur in a subset of idiopathic erythrocytosis patients, though the exact frequency varies by study. 3, 4
In a large British cohort, low EPO values were documented in some patients with idiopathic erythrocytosis, particularly when hemoglobin exceeded 16 g/dL, suggesting that higher red cell mass can suppress EPO production even in non-clonal conditions. 3
The specificity of low EPO for polycythemia vera is 92-97% when hemoglobin is elevated, but this specificity decreases when hemoglobin is only borderline-high or when apparent erythrocytosis (plasma volume contraction) is present. 3, 4
Critical Diagnostic Imperative: Rule Out Occult Polycythemia Vera
When idiopathic erythrocytosis presents with low EPO, JAK2 mutation testing becomes mandatory because this combination strongly suggests undiagnosed polycythemia vera rather than true idiopathic disease. 1, 2
JAK2 Exon 12 Mutations in Low-EPO Idiopathic Erythrocytosis
In a cohort of 58 idiopathic erythrocytosis patients with low-to-normal serum EPO levels, 27% harbored JAK2 exon 12 mutations, reclassifying them as polycythemia vera variants. 5
All patients with JAK2 exon 12 mutations demonstrated EPO-independent (hypersensitive) erythroid progenitor growth in vitro, a hallmark of clonal myeloproliferative disease (p=0.0002). 5
JAK2 exon 12 mutations occur in approximately 3% of V617F-negative polycythemia vera cases, capturing patients who would otherwise be misdiagnosed as idiopathic erythrocytosis. 1
Recommended Testing Algorithm for Low-EPO Idiopathic Erythrocytosis
| Step | Test | Rationale |
|---|---|---|
| 1 | JAK2 V617F mutation (exon 14) | Present in >95% of polycythemia vera; low EPO + positive JAK2 V617F = definitive PV diagnosis [1,2] |
| 2 | JAK2 exon 12 mutation testing (if V617F negative) | Identifies an additional 27% of low-EPO idiopathic erythrocytosis as occult PV [5] |
| 3 | Bone marrow biopsy with morphology | Hypercellularity, erythroid hyperplasia, megakaryocyte clustering/atypia support PV over idiopathic erythrocytosis [1,5] |
| 4 | Endogenous erythroid colony assay (if available) | EPO-independent growth is 100% specific for JAK2 exon 12-mutated cases [5] |
Distinguishing True Idiopathic Erythrocytosis from Polycythemia Vera
Idiopathic erythrocytosis patients typically have higher serum EPO levels than polycythemia vera patients, though overlap exists. 6
In a comparative study of 78 idiopathic erythrocytosis versus 136 polycythemia vera patients, idiopathic erythrocytosis had significantly higher serum EPO levels (p<0.001), lower white blood cell counts, lower platelet counts, less frequent splenomegaly, and fewer thrombotic events. 6
Normal platelet count, normal spleen size, and absence of thrombosis at diagnosis argue strongly against polycythemia vera, particularly in men. 6
Phlebotomy-induced platelet count increase occurs in 70% of polycythemia vera patients but not in idiopathic erythrocytosis, providing a functional test to distinguish the two when molecular testing is equivocal. 6
Clinical Pitfalls to Avoid
Do not assume idiopathic erythrocytosis is the final diagnosis when EPO is low—this combination mandates comprehensive JAK2 testing (V617F + exon 12) because up to 27% will have occult polycythemia vera. 5
Raised EPO values can occur in idiopathic erythrocytosis, mainly at normal or borderline hemoglobin levels (<16 g/dL), creating diagnostic confusion with secondary polycythemia. 3
Low EPO specificity for polycythemia vera decreases when hemoglobin is not significantly elevated, so borderline cases require bone marrow examination and JAK2 testing rather than relying on EPO alone. 3
Apparent erythrocytosis (plasma volume contraction) can produce low EPO values in the absence of true red cell mass expansion, so clinical assessment for dehydration, diuretic use, or capillary leak is essential. 2, 7
Implications for Indian Adult Males
No ethnic-specific variation in EPO patterns or JAK2 mutation frequency has been documented for Indian populations, so the same diagnostic algorithm applies. 1, 2
The 27% prevalence of JAK2 exon 12 mutations in low-EPO idiopathic erythrocytosis is derived from international cohorts and should be assumed to apply universally until population-specific data emerge. 5
Smoking-related polycythemia is the most common secondary cause globally and must be excluded first through detailed smoking history and carboxyhemoglobin measurement. 2, 7