What are the causes of polycythemia in adults over 40?

Causes of Polycythemia in Adults Over 40

Polycythemia in adults over 40 results from either primary clonal stem cell disorders (polycythemia vera) or secondary causes driven by hypoxia, inappropriate erythropoietin production, or plasma volume depletion. 1, 2

Classification Framework

Polycythemia is categorized into three main types 3, 1:

• True polycythemia: Real increase in red blood cell mass, either clonal (polycythemia vera) or non-clonal (secondary polycythemia) 3
• Apparent polycythemia: Normal red cell mass with reduced plasma volume (relative polycythemia) 3
• Inapparent polycythemia: True increase in red cell mass masked by concomitant plasma volume expansion 3

Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a clonal myeloproliferative neoplasm caused by acquired JAK2 mutations present in >95% of cases. 2, 4

Key Features:

• Erythropoietin levels are characteristically low or inappropriately normal (specificity >90%, sensitivity 64-70%) 1, 5
• Leukocytosis occurs in 49% and thrombocytosis in 53% of cases 2, 5
• Autonomous erythropoiesis independent of EPO regulation 1
• Increased risk of thrombosis, bleeding, and transformation to myelofibrosis (12.7%) or acute myeloid leukemia (6.8%) 4

Secondary Polycythemia: Hypoxia-Driven Causes

Chronic Lung Disease

• Chronic obstructive pulmonary disease (COPD) causes persistent hypoxemia leading to compensatory erythrocytosis 2
• Chronic lung diseases trigger EPO production in response to tissue hypoxia 1

Obstructive Sleep Apnea

• Produces chronic intermittent hypoxia leading to compensatory erythrocytosis, particularly in obese patients 2
• Treatment with CPAP resolves polycythemia by eliminating nocturnal hypoxemia 5

Smoking (Smoker's Polycythemia)

• Carbon monoxide binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia that triggers compensatory erythropoiesis 1
• This is a real condition causing true polycythemia, not just relative polycythemia 1, 5
• Resolves with smoking cessation, with risk reduction beginning within 1 year and return to baseline after 5 years 1

Cyanotic Congenital Heart Disease

• Right-to-left intracardiac or extracardiac shunts result in hypoxemia and compensatory erythrocytosis 1
• Low systemic arterial oxygen saturation prompts kidneys to release erythropoietin 1

High-Altitude Habitation

• Chronic exposure to reduced atmospheric oxygen triggers compensatory erythropoiesis 1

Hypoventilation Syndromes

• Various conditions causing chronic hypoventilation lead to hypoxia-driven polycythemia 1

Secondary Polycythemia: Hypoxia-Independent Causes

EPO-Producing Tumors

Consider malignant or benign tumors that produce erythropoietin autonomously: 1

• Renal cell carcinoma
• Hepatocellular carcinoma
• Uterine leiomyomas
• Pheochromocytoma
• Meningioma
• Parathyroid carcinoma (produces EPO autonomously, independent of tissue oxygen levels) 1

Post-Renal Transplant Erythrocytosis (PRTE)

• Occurs from inappropriate EPO production following renal transplantation 1, 2

Exogenous Erythropoietic Agents

• Exogenous administration of erythropoietin or androgen preparations causes secondary polycythemia 1
• Doping in athletes can induce artificial erythrocytosis 6

Congenital Causes

• High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) 1
• Chuvash polycythemia (abnormal oxygen homeostasis) 1
• EPOR-mediated causes (autosomal-dominant congenital polycythemia from EPO receptor mutations) 1, 6
• 2,3-bisphosphoglycerate mutase deficiency 6
• Abnormally elevated set point for EPO production 1

Post-Splenectomy or Functional Hyposplenism

• Can elevate red cell parameters 2

Apparent (Relative) Polycythemia

Results from plasma volume depletion with normal red cell mass: 3, 1

• Severe dehydration
• Diarrhea and vomiting
• Diuretic use
• Capillary leak syndrome
• Severe burns

Gaisböck syndrome (relative polycythemia with hypertension and nephropathy) and stress polycythemia are poorly understood entities with little foundation 3

Critical Diagnostic Distinctions

EPO Levels as Key Discriminator:

• Low or inappropriately normal EPO → Strongly suggests polycythemia vera (specificity >90%) 1, 2, 5
• Elevated EPO → Suggests secondary polycythemia (hypoxia-driven or tumor-related) 1, 2
• Normal EPO in chronic hypoxic states: Beware that EPO may normalize after hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera 1

JAK2 Mutation Testing:

• Present in >95% of polycythemia vera cases but absent in secondary causes 2, 7, 4
• Essential for distinguishing primary from secondary polycythemia 1, 5

Common Pitfalls to Avoid

• Failing to distinguish relative polycythemia from true polycythemia leads to misdiagnosis 1
• Overlooking smoking as a cause - smoker's polycythemia is real and resolves with cessation 1
• Misinterpreting normal EPO levels in chronic hypoxic states - levels may normalize after hemoglobin stabilizes 1
• Assuming normal EPO excludes polycythemia vera - EPO sensitivity for PV is only 64-70%; normal EPO with elevated hemoglobin still requires JAK2 testing 1
• Performing unnecessary red cell mass measurements when the cause is clinically obvious (dehydration, diuretics, burns) 3, 1
• Missing the distinction between primary and secondary polycythemia could lead to inappropriate treatment with phlebotomy or cytoreductive therapy when the underlying cause is tumor-related EPO production 1