What are the causes of secondary polycythemia in adults, particularly in older adults with chronic conditions such as chronic obstructive pulmonary disease (COPD), sleep apnea, or cardiac conditions like cyanotic heart disease?

Causes of Secondary Polycythemia

Overview

Secondary polycythemia results from either hypoxia-driven compensatory erythropoiesis or hypoxia-independent pathologic erythropoietin (EPO) production, with chronic lung disease, sleep apnea, cyanotic heart disease, and EPO-producing tumors being the most clinically significant causes. 1, 2

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Hypoxia-Driven Causes

Pulmonary Conditions

• Chronic obstructive pulmonary disease (COPD) is one of the most common causes of secondary polycythemia in adults, with prevalence ranging from 3.5% in females to 9.2% in males with moderate to very severe disease 3
• Chronic lung diseases including pulmonary fibrosis trigger compensatory erythropoiesis through sustained tissue hypoxia 1, 2
• Obstructive sleep apnea (OSA) causes chronic intermittent hypoxia leading to compensatory erythrocytosis, particularly in obese patients 1, 4

Cardiac Conditions

• Cyanotic congenital heart disease with right-to-left intracardiac or extracardiac shunts results in hypoxemia and compensatory erythrocytosis 5
• Right-to-left cardiopulmonary vascular shunts cause secondary polycythemia due to chronic hypoxia 1, 2
• Aortic oxygen saturations <75% may be the critical threshold below which decompensated erythrocytosis occurs in cyanotic heart disease 5

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
• This condition resolves with smoking cessation, with risk reduction beginning within 1 year and return to baseline after 5 years 1

Hypoventilation Syndromes

• Hypoventilation syndromes including sleep apnea cause chronic intermittent hypoxia leading to compensatory erythrocytosis 1, 2
• Hypoventilation caused by insufficient respiratory pump (presenting with hypercapnea and hypoxemia) induces compensatory polycythemia 6

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Hypoxia-Independent Causes

Malignant Tumors

• Renal cell carcinoma produces EPO autonomously, independent of tissue oxygen levels 1, 2
• Hepatocellular carcinoma produces EPO independently of hypoxia 1, 2
• Cerebellar hemangioblastoma produces EPO independently of hypoxia 1, 2
• Parathyroid carcinoma produces EPO autonomously through pathologic production 1

Benign Tumors

• Uterine leiomyomas (benign tumors) can produce EPO 1, 2
• Pheochromocytoma can produce EPO 1, 2
• Meningioma can produce EPO 1, 2

Congenital and Genetic Causes

• High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) leads to secondary polycythemia 1
• Chuvash polycythemia results from abnormal oxygen homeostasis with abnormally elevated set point for EPO production 1
• EPOR-mediated causes (some cases of autosomal-dominant congenital polycythemia) can lead to secondary polycythemia 1

Iatrogenic Causes

• Exogenous administration of erythropoietic drugs (EPO, androgen preparations) causes secondary polycythemia 1
• Post-renal transplant erythrocytosis (PRTE) is a recognized cause of secondary polycythemia 1

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Pathophysiology by Mechanism

Compensatory Erythropoiesis in Hypoxia

• Right-to-left shunting results in low systemic arterial oxygen saturation, prompting kidneys to release erythropoietin to stimulate bone marrow red cell production 5
• The increase in red blood cell mass is a compensatory response to improve oxygen transport in chronic hypoxemia 5
• Serum EPO levels are often initially elevated but may return to normal range once hemoglobin stabilizes at a higher compensatory level 1

Iron Deficiency Complications

• Increasing red cell mass is accompanied by increased iron requirements, and in the absence of adequate iron, iron deficiency occurs 5
• Iron-deficient red cells become microcytic hypochromic with decreased oxygen-carrying capacity and reduced deformability in capillaries 5

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Clinical Pearls and Common Pitfalls

Diagnostic Considerations

• Do not overlook smoking as a cause - smoker's polycythemia is a real condition that resolves with smoking cessation 1, 2
• Beware of "normal" EPO levels in chronic hypoxic states - EPO may normalize after hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera 1
• Distinguish true from relative polycythemia - failing to assess for plasma volume depletion (dehydration, diuretics, burns) can lead to misdiagnosis 1, 2

Risk Factors in COPD

• In COPD patients, male sex, current smoking, impaired DLCO, and severe hypoxemia are associated with increased risk for secondary polycythemia 3
• Continuous or nocturnal supplemental oxygen use are associated with decreased risk for polycythemia in COPD 3

Management Cautions

• Avoid aggressive or repeated routine phlebotomies - this risks iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 5, 1
• Most cyanotic patients have compensated erythrocytosis with stable hemoglobin that requires no intervention 5
• Therapeutic phlebotomy is indicated only for hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity (headache, increasing fatigue) in the absence of dehydration 5