What are the causes of secondary polycythemia?

Causes of Secondary Polycythemia

Secondary polycythemia results from either hypoxia-driven compensatory erythropoiesis or hypoxia-independent pathologic EPO production, with chronic lung disease, sleep apnea, and smoking being the most common causes in clinical practice. 1

Hypoxia-Driven Causes

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

Pulmonary Causes

• Chronic lung disease (COPD, pulmonary fibrosis) is among the most common causes of secondary polycythemia in clinical practice 1, 2
• Obstructive sleep apnea causes chronic intermittent hypoxia leading to compensatory erythrocytosis, particularly in obese patients 1, 3
• Hypoventilation syndromes including obesity hypoventilation syndrome produce chronic hypoxemia 1, 2

Cardiovascular Causes

• Right-to-left cardiopulmonary shunts cause persistent hypoxemia and secondary erythrocytosis 1, 2

Environmental and Toxic Causes

• High-altitude habitation leads to physiologic polycythemia as an adaptive response to reduced atmospheric oxygen 1, 2
• Smoker's polycythemia is a real condition caused by chronic carbon monoxide exposure, which binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia 1, 2
• Carbon monoxide poisoning creates the same functional hypoxic state 1, 2

Key Clinical Pearl

• EPO levels are often initially elevated in hypoxia-driven causes but may return to normal range once hemoglobin stabilizes at a higher compensatory level, potentially causing diagnostic confusion 1
• Smoker's polycythemia resolves with smoking cessation, with risk reduction beginning within 1 year and return to baseline after 5 years 1

Hypoxia-Independent Causes

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

Malignant Tumors

• Renal cell carcinoma is the most common tumor causing pathologic EPO production 1, 2
• Hepatocellular carcinoma produces EPO independently of hypoxia 1, 2
• Cerebellar hemangioblastoma is a classic EPO-producing tumor 2
• Pheochromocytoma can produce EPO 1, 2
• Meningioma can produce EPO 1, 2
• Parathyroid carcinoma produces EPO autonomously through pathologic mechanisms 1

Benign Tumors

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

Post-Transplant

• Post-renal transplant erythrocytosis (PRTE) is a recognized cause of secondary polycythemia 1

Iatrogenic Causes

• Exogenous erythropoietic drugs (EPO, androgen preparations) cause secondary polycythemia 1
• Doping with EPO or analogs is increasingly recognized in athletes 4, 5

Congenital Causes

These are rare genetic conditions presenting in younger patients:

• High oxygen-affinity hemoglobinopathy (autosomal-dominant) causes tissue hypoxia despite normal oxygen saturation 1, 2
• Chuvash polycythemia results from abnormal oxygen homeostasis with elevated EPO set point 1
• EPOR mutations causing autosomal-dominant congenital polycythemia 1, 5
• 2,3-DPG mutase deficiency impairs oxygen delivery to tissues 2, 5
• Von Hippel-Lindau gene mutations affect oxygen sensing mechanisms 2

Diagnostic Algorithm

Step 1: Exclude apparent (relative) polycythemia by assessing for plasma volume depletion from dehydration, diarrhea, vomiting, diuretic use, or burns 1, 2

Step 2: Measure serum EPO level as the key discriminator—elevated EPO suggests secondary polycythemia, while low or inappropriately normal EPO suggests polycythemia vera 1, 2

Step 3: If EPO is elevated, evaluate for hypoxia using arterial blood gas or pulse oximetry, and obtain chest X-ray to assess for chronic lung disease 1, 2

Step 4: Consider sleep study (polysomnography) if obese, fatigued, or other clinical features suggest sleep apnea 1, 3

Step 5: If EPO elevated without hypoxia, obtain abdominal imaging (ultrasound or CT) to screen for renal cell carcinoma, hepatocellular carcinoma, or other EPO-producing tumors 1, 2

Step 6: In young patients without obvious secondary cause, consider hemoglobin electrophoresis for high oxygen-affinity variants and genetic testing for congenital causes 2

Critical Pitfalls to Avoid

• Do not overlook smoking as a cause—smoker's polycythemia is a real condition that resolves with cessation, not just a relative polycythemia 1, 2
• Do not misinterpret normal EPO levels in chronic hypoxic states—levels may normalize after hemoglobin stabilizes at a higher compensatory level, mimicking polycythemia vera 1
• Do not assume "adequate sleep" rules out sleep apnea—patients with OSA are typically unaware of their sleep fragmentation and nocturnal hypoxemia 3
• Do not rush to diagnose polycythemia vera without first excluding secondary causes, especially in patients with obesity, lung disease, or smoking history 3