What are the causes of polycythemia in adults?

Causes of Polycythemia

Polycythemia results from three major categories: apparent (relative) polycythemia due to plasma volume depletion, primary clonal disorders (polycythemia vera), or secondary causes driven by either hypoxia-dependent or hypoxia-independent mechanisms. 1

Apparent (Relative) Polycythemia

This is not true polycythemia but rather a decrease in plasma volume that concentrates red blood cells:

• Severe dehydration from diarrhea, vomiting, or diuretic use causes relative polycythemia that is clinically obvious and does not require specialized testing 1
• Capillary leak syndrome and severe burns also cause plasma volume depletion 1
• 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; this resolves with smoking cessation 1, 2

Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a JAK2-mutated myeloproliferative neoplasm with clonal erythrocytosis, characterized by low or inappropriately normal serum EPO levels:

• JAK2 V617F mutation is present in up to 97% of PV cases and should be tested when EPO is low or normal 1, 3
• PV often presents with leukocytosis (49%), thrombocytosis (53%), and panmyeloid hyperplasia of the bone marrow 1, 3
• Bone marrow examination showing characteristic morphologic features remains the cornerstone for confirming PV diagnosis 1
• Risks include progression to myelofibrosis (12.7%) or acute leukemia (6.8%) 3

Secondary Polycythemia: Hypoxia-Driven Causes

These conditions trigger compensatory erythropoiesis through tissue hypoxia:

Pulmonary Causes

• Chronic lung disease (COPD, pulmonary fibrosis) triggers compensatory erythropoiesis through tissue hypoxia 1, 4
• Hypoventilation syndromes including obstructive sleep apnea cause chronic intermittent hypoxia leading to compensatory erythrocytosis 1, 5

Cardiac Causes

• Right-to-left cardiopulmonary vascular shunts cause secondary polycythemia due to hypoxia 1
• Cyanotic congenital heart disease with right-to-left intracardiac or extracardiac shunts results in hypoxemia and compensatory erythrocytosis 2

Environmental and Toxic Causes

• High-altitude habitation leads to physiologic polycythemia as an adaptive response to reduced atmospheric oxygen 1, 4
• Carbon monoxide poisoning and chronic exposure in smokers creates functional hypoxia 1, 2

Secondary Polycythemia: Hypoxia-Independent Causes

These conditions produce EPO independently of hypoxia:

Malignant Tumors

• Renal cell carcinoma produces EPO independently of hypoxia 1, 2
• Hepatocellular carcinoma produces EPO independently of hypoxia 1, 2
• Parathyroid carcinoma produces EPO autonomously, independent of tissue oxygen levels 2

Benign Tumors

• Cerebellar hemangioblastoma produces EPO independently of hypoxia 1
• Uterine leiomyomas (benign tumors) can produce EPO 1, 2
• Pheochromocytoma can produce EPO 1, 2
• Meningioma can produce EPO 1, 2

Congenital Causes

• High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) can lead to secondary polycythemia 2, 6
• EPOR mutations (some cases of autosomal-dominant congenital polycythemia) can lead to secondary polycythemia 2, 6
• Chuvash polycythemia (abnormal oxygen homeostasis with abnormally elevated set point for EPO production) 2, 6
• 2,3-bisphosphoglycerate mutase deficiency 1, 6
• Von Hippel-Lindau gene mutations 1

Iatrogenic Causes

• Exogenous administration of erythropoietic drugs (EPO, androgen preparations) can cause secondary polycythemia 2
• Post-renal transplant erythrocytosis (PRTE) is a potential cause of secondary polycythemia 2

Critical Diagnostic Pitfalls

Failing to distinguish between relative polycythemia (due to plasma volume depletion) and true polycythemia (increased red cell mass) can lead to misdiagnosis 2

• Overlooking smoking as a cause of polycythemia—smoker's polycythemia is a real condition that resolves with smoking cessation 2
• Misinterpreting normal EPO levels in chronic hypoxic states—levels may normalize after hemoglobin stabilizes at a higher level 2
• Do not assume normal EPO excludes PV; EPO sensitivity for PV is only 64-70%; normal EPO with elevated hemoglobin still requires JAK2 testing 2