When should secondary polycythemia be considered in patients?

When to Consider Secondary Polycythemia

Secondary polycythemia should be considered in patients with elevated hemoglobin/hematocrit when there is evidence of hypoxia-driven or hypoxia-independent processes causing a true increase in red cell mass, after excluding relative polycythemia due to plasma volume depletion. 1

Classification and Etiology

Secondary polycythemia can be categorized into two main types:

Hypoxia-Driven Secondary Polycythemia

• Consider in patients with chronic lung disease, right-to-left cardiopulmonary shunts, high-altitude habitation, or hypoventilation syndromes including sleep apnea 1
• Smoker's polycythemia is a real condition caused by chronic carbon monoxide exposure, which resolves with smoking cessation 1, 2
• Carbon monoxide binds to hemoglobin with 200-250 times greater affinity than oxygen, creating a functional hypoxic state that triggers compensatory erythropoiesis 2
• Serum EPO levels are often initially elevated but may return to normal range once hemoglobin stabilizes at a higher level 1

Hypoxia-Independent Secondary Polycythemia

• Consider in patients with malignant or benign tumors (renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma) 1
• Congenital causes include abnormally elevated set point for EPO production and abnormal oxygen homeostasis (Chuvash polycythemia) 1
• Serum EPO levels are often elevated in these conditions 1

Other Causes of Secondary Polycythemia

• EPOR-mediated causes (some cases of autosomal-dominant congenital polycythemia) 1
• Exogenous administration of erythropoietic drugs (EPO, androgen preparations) 1
• Post-renal transplant erythrocytosis (PRTE) 1
• High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) 1

Diagnostic Approach

Initial Assessment

• Determine if polycythemia is true (increased red cell mass) or apparent (normal red cell mass with decreased plasma volume) 1
• Assess for clinical signs of plasma volume depletion (dehydration, diarrhea, vomiting, diuretic use, burns) 1
• Evaluate for hypoxemia through arterial blood gas analysis or pulse oximetry 1

Laboratory Evaluation

• Check serum EPO levels - may be elevated in hypoxia-driven and hypoxia-independent secondary polycythemia 1
• Consider red cell mass measurement in cases where the diagnosis remains unclear after initial evaluation 1
• Evaluate iron status, as iron deficiency can mask the degree of polycythemia in chronic hypoxic states 3

Imaging and Additional Testing

• Consider chest imaging to evaluate for pulmonary disease 4
• Abdominal imaging may be warranted to evaluate for renal or hepatic tumors in cases of unexplained polycythemia with elevated EPO levels 5
• Sleep study for suspected sleep apnea 1

Clinical Pearls and Pitfalls

Important Considerations

• Secondary polycythemia in COPD is associated with male sex, current smoking, impaired diffusing capacity for carbon monoxide (DLCO), and severe hypoxemia 4
• Even transient episodes of hypoxemia, such as during sleep or exercise, can stimulate EPO production and contribute to polycythemia 6
• Continuous or nocturnal oxygen therapy is associated with decreased risk of polycythemia in patients with chronic hypoxic conditions 4

Common Pitfalls

• Failing to distinguish between relative polycythemia (due to plasma volume depletion) and true polycythemia (increased red cell mass) 1
• Overlooking smoking as a cause of polycythemia - smoker's polycythemia is a real condition that resolves with smoking cessation 1, 2
• Misinterpreting normal EPO levels in chronic hypoxic states - levels may normalize after hemoglobin stabilizes at a higher level 1
• Performing unnecessary red cell mass measurements when the cause of polycythemia is clinically obvious 1

Management Implications

• Smoking cessation is the primary treatment for smoker's polycythemia, with risk reduction beginning within 1 year and return to baseline risk after 5 years 2
• Supplemental oxygen therapy can prevent or reverse secondary polycythemia in patients with chronic hypoxic conditions 4
• In severe cases with symptoms related to hyperviscosity, therapeutic phlebotomy may be considered 7