What are the causes of isolated polycythemia?

Causes of Isolated Polycythemia

Isolated polycythemia can be categorized into primary (polycythemia vera) and secondary causes, with secondary polycythemia being further divided into hypoxia-driven and non-hypoxia-driven etiologies. 1

Primary Polycythemia

Polycythemia Vera (PV)

• Myeloproliferative neoplasm characterized by clonal erythrocytosis
• Associated with JAK2 gene mutations (>95% of cases)
  • JAK2 V617F mutation (most common)
  • JAK2 exon 12 mutations (in JAK2 V617F-negative cases) 1, 2
• Often accompanied by:
  • Leukocytosis (49%)
  • Thrombocytosis (53%)
  • Splenomegaly (36%) 2

Secondary Polycythemia

Hypoxia-Driven (EPO levels initially elevated, may normalize)

1. Respiratory Causes:

   • Chronic pulmonary disease (COPD)
   • Hypoventilation syndromes
   • Sleep apnea
   • Smoker's polycythemia 1

2. Cardiovascular Causes:

   • Right-to-left cardiopulmonary shunts
   • Cyanotic congenital heart disease 1

3. Environmental Causes:

   • High-altitude residence
   • Carbon monoxide poisoning 1

Non-Hypoxia-Driven (EPO levels typically elevated)

1. Neoplastic Causes:

   • EPO-producing tumors:
     • Renal cell carcinoma
     • Hepatocellular carcinoma
     • Cerebellar hemangioblastoma
     • Pheochromocytoma 1

2. Renal Causes:

   • Post-renal transplant erythrocytosis
   • Renal artery stenosis
   • Hydronephrosis 1

3. Endocrine Causes:

   • Cushing's syndrome
   • Androgen excess (exogenous testosterone/anabolic steroids) 1

4. Iatrogenic Causes:

   • Exogenous erythropoietin administration
   • Androgen preparations 1

5. Congenital Causes:

   • Chuvash polycythemia (VHL gene mutation)
   • High-oxygen-affinity hemoglobinopathies 1

Diagnostic Approach

1. Initial Assessment:

   • Confirm true polycythemia: hemoglobin/hematocrit above the 95th percentile adjusted for sex and race
   • Rule out relative polycythemia (decreased plasma volume) 1

2. Key Diagnostic Tests:

   • Serum erythropoietin level
     • Low: suggests primary polycythemia (PV)
     • Normal/elevated: suggests secondary causes 1
   • JAK2 mutation testing (sensitivity >95% for PV) 1, 3
   • Bone marrow biopsy (if clinical suspicion remains high) 1

Clinical Pearls and Pitfalls

• Important Distinction: Polycythemia vera involves increased production of all three cell lines, while isolated erythrocytosis only affects red blood cells 1, 4

• Diagnostic Pitfall: Patients with PV may present with thrombosis (16% arterial, 7% venous) at or before diagnosis, often at unusual sites like splanchnic veins 2, 3

• Treatment Consideration: All patients with confirmed PV require phlebotomy to maintain hematocrit <45% and low-dose aspirin to prevent thrombotic complications 1, 2, 3

• Monitoring Recommendation: Regular monitoring of hematological parameters is essential for all patients with polycythemia, regardless of etiology 1

• Secondary Polycythemia Management: Treat the underlying cause when possible; for example, ACE inhibitors for post-renal transplant erythrocytosis or CPAP for sleep apnea 1, 5