From the Guidelines
Polycythemia with normal erythropoietin (Epo) levels can be caused by several conditions, including polycythemia vera (PV), congenital disorders, high-affinity hemoglobinopathies, and medication effects. The most common cause is polycythemia vera (PV), a myeloproliferative neoplasm characterized by JAK2 mutations that lead to autonomous red cell production despite normal or low Epo levels 1. Other causes include:
- Congenital disorders like Chuvash polycythemia (caused by VHL gene mutations) and other rare genetic conditions involving the oxygen-sensing pathway
- High-affinity hemoglobinopathies that bind oxygen too tightly, creating a functional hypoxia that stimulates erythropoiesis despite normal oxygen saturation
- Medications, particularly testosterone and anabolic steroids, that can stimulate erythropoiesis independently of Epo
- Rarely, ectopic erythropoietin receptor expression on tumor cells can cause polycythemia through non-Epo ligand activation When evaluating a patient with polycythemia and normal Epo levels, JAK2 mutation testing is essential to rule out polycythemia vera, followed by consideration of medication effects, hemoglobinopathies, and genetic testing for rare congenital causes if clinically indicated 1. It is also important to note that a normal serum EPO level does not exclude the possibility of PV, and a low serum EPO level is highly suggestive but not diagnostic of PV 1. Bone marrow examination with cytogenetic studies and specialized tests such as c-mpl immunohistochemistry and PRV-1 expression may be necessary to confirm the diagnosis in equivocal cases 1. In terms of management, the approach depends on the underlying cause, and judicious phlebotomy to a hematocrit level of 60% is reasonable in some cases, such as cyanotic congenital heart disease and high oxygen-affinity hemoglobinopathy 1. Additionally, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor inhibitors may be effective in lowering hematocrit levels in post-renal transplant erythrocytosis 1. Overall, a comprehensive evaluation and individualized management approach are necessary to address the underlying cause of polycythemia with normal Epo levels and improve patient outcomes.
From the Research
Causes of Polycythemia with Normal Erythropoietin (Epo) Levels
- Primary polycythemias are the result of intrinsic abnormalities of the hematopoietic progenitors that lead to constitutive overproduction of red cells accompanied by low erythropoietin (EPO) levels 2.
- However, some cases of polycythemia vera (PV) may present with normal or high serum EPO levels, making the diagnosis more complex 3, 4, 5.
- The presence of a JAK2 mutation is a key factor in the diagnosis of PV, and its absence, combined with normal or increased serum EPO level, makes the diagnosis unlikely 4, 5.
- Secondary causes of polycythemia should be ruled out before labeling a patient as having PV, and serum EPO level helps distinguish primary and secondary polycythemia 3.
Diagnostic Considerations
- The World Health Organization (WHO) consensus criteria for diagnosing PV demand the presence of two major criteria and one minor criterion or the presence of the first major criterion and two minor criteria 3.
- A low EPO is considered a minor WHO criterion for PV diagnosis, but a normal or high EPO level does not exclude the diagnosis 3, 4, 5.
- Further diagnostic tests, such as the JAK2 gene mutation test, are usually required to confirm the final diagnosis 3, 4, 5.
Risk Stratification and Management
- Current risk stratification in PV is designed to estimate the likelihood of thrombotic complications, and patients are categorized as high-risk or low-risk based on age and thrombosis history 6, 4, 5.
- The main goal of therapy in PV is to prevent thrombohemorrhagic complications, and treatment options include phlebotomy, aspirin, and cytoreductive therapy 6, 4, 5.