What are the secondary causes of polycythemia?

Secondary Causes of Polycythemia

Secondary polycythemia results from either hypoxia-driven mechanisms (chronic lung disease, cardiac shunts, high altitude, sleep apnea, carbon monoxide exposure) or hypoxia-independent mechanisms (EPO-producing tumors, congenital disorders, exogenous erythropoietin administration), with elevated or normal serum EPO levels distinguishing it from polycythemia vera. 1

Hypoxia-Driven Secondary Polycythemia

These conditions trigger compensatory erythropoiesis through tissue hypoxia and elevated EPO production:

Pulmonary and Cardiac Causes

• Chronic lung disease including COPD and pulmonary fibrosis causes chronic hypoxemia that stimulates EPO production 1, 2
• Right-to-left cardiopulmonary shunts create persistent hypoxia leading to compensatory erythrocytosis 1, 2
• Hypoventilation syndromes including obstructive sleep apnea cause chronic intermittent hypoxia 1, 2

Environmental and Toxic Exposures

• High-altitude habitation represents a physiologic adaptive response to reduced atmospheric oxygen 1, 2
• Smoker's polycythemia is caused by chronic carbon monoxide exposure, which binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia 1, 2
  • This condition resolves completely with smoking cessation 1
  • Carbon monoxide poisoning creates the same mechanism 2

Key Diagnostic Feature

• Serum EPO levels are often initially elevated but may return to normal range once hemoglobin stabilizes at a higher compensatory level 1
• Critical pitfall: Normal EPO in chronic hypoxic states can falsely suggest polycythemia vera rather than secondary polycythemia 1

Hypoxia-Independent Secondary Polycythemia

These conditions produce EPO autonomously, independent of tissue oxygen levels:

Malignant Tumors

• Renal cell carcinoma is the most common EPO-producing malignancy 1, 2
• Hepatocellular carcinoma produces EPO independently 1, 2
• Cerebellar hemangioblastoma 2
• Pheochromocytoma 1, 2
• Meningioma 1, 2
• Parathyroid carcinoma produces EPO autonomously through pathologic mechanisms 1

Benign Tumors

• Uterine leiomyomas (fibroids) can produce EPO 1, 2

Congenital Causes

• High oxygen-affinity hemoglobinopathy (autosomal-dominant inheritance) 1
• Chuvash polycythemia with abnormal oxygen homeostasis 1
• EPOR mutations causing abnormally elevated set point for EPO production 1
• 2,3-bisphosphoglycerate mutase deficiency 3
• Von Hippel-Lindau gene mutations 2

Iatrogenic and Exogenous Causes

• Exogenous erythropoietin administration for therapeutic purposes 1
• Androgen preparations stimulate erythropoiesis 1
• Post-renal transplant erythrocytosis (PRTE) 1
• Athletic doping with EPO or analogs 4, 3

Key Diagnostic Feature

• Serum EPO levels are typically elevated in hypoxia-independent secondary polycythemia 1

Diagnostic Algorithm for Secondary Polycythemia

Step 1: Confirm True Polycythemia

• Exclude apparent (relative) polycythemia from plasma volume depletion due to dehydration, vomiting, diarrhea, diuretic use, burns, or capillary leak syndrome 5, 2
• These conditions are clinically obvious and do not require red cell mass measurements 5

Step 2: Measure Serum EPO Level

• Low or inappropriately normal EPO → suggests polycythemia vera, not secondary polycythemia 1, 6
• Elevated EPO → proceed to evaluate for secondary causes 1, 6

Step 3: Assess for Hypoxia (if EPO elevated)

• Perform arterial blood gas analysis or pulse oximetry 1
• Obtain chest X-ray to evaluate for chronic lung disease 1
• Consider sleep study for suspected obstructive sleep apnea 1
• Assess smoking history and carbon monoxide exposure 1

Step 4: Evaluate for Tumors (if EPO elevated without hypoxia)

• Abdominal ultrasound or CT to screen for renal cell carcinoma, hepatocellular carcinoma, and other EPO-producing tumors 1, 2
• Consider brain imaging for cerebellar hemangioblastoma if clinically indicated 2

Step 5: Consider Congenital Causes (especially in young patients)

• Hemoglobin electrophoresis for high oxygen-affinity hemoglobinopathy 2
• Genetic testing for EPOR mutations, von Hippel-Lindau gene mutations, or 2,3-DPG mutase deficiency 2

Critical Pitfalls to Avoid

• Do not assume polycythemia vera without checking EPO levels, as elevated hemoglobin with a tumor or hypoxic condition requires EPO measurement to distinguish primary from secondary polycythemia 1
• Do not overlook smoking as a reversible cause—smoker's polycythemia is real and resolves with cessation 1, 2
• Do not misinterpret normal EPO in chronic hypoxic states—levels may normalize after hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera 1
• Do not perform unnecessary red cell mass measurements when plasma volume depletion is clinically obvious 5, 2