What are the causes of polycythemia?

Causes of Polycythemia

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

Apparent (Relative) Polycythemia

Apparent polycythemia represents a false elevation without true increase in red cell mass:

• Plasma volume depletion from severe dehydration, diarrhea, vomiting, diuretic use, capillary leak syndrome, or severe burns causes relative polycythemia that is clinically obvious and does not require specialized testing 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, 3
• Extreme "high-normal" values that exceed the 95th percentile of reference intervals can be misinterpreted as pathologic polycythemia 1

Common pitfall: Gaisböck syndrome (relative polycythemia with hypertension) and stress polycythemia are poorly understood entities with little foundation; Mayo Clinic data found no patients with true relative polycythemia in 109 consecutive measurements 1

Primary Polycythemia

Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm with clonal erythrocytosis, characterized by low or inappropriately normal serum EPO levels 2

• JAK2 V617F mutation is present in up to 97% of PV cases and should be tested when EPO is low or normal 2, 3
• PV patients typically present with leukocytosis, thrombocytosis, and hypochromic microcytic RBCs related to iron deficiency 4
• Bone marrow examination showing characteristic morphologic features remains the cornerstone for confirming PV diagnosis 2

Familial polycythemia with autosomal-dominant inheritance involves activating mutations of the EPO receptor (EPOR) gene, resulting in a C-terminal–truncated receptor with enhanced signal transduction 1, 2

• Serum EPO levels are usually low in EPOR-mutated patients 1
• However, EPOR mutations are not found in most patients with autosomal-dominant congenital polycythemia 1

Secondary Polycythemia: Hypoxia-Driven Causes

Central hypoxic processes:

• Chronic lung disease (COPD, pulmonary fibrosis) triggers compensatory erythropoiesis through tissue hypoxia 1, 2, 5
• Right-to-left cardiopulmonary vascular shunts cause secondary polycythemia due to hypoxia 1, 2
• High-altitude habitation leads to physiologic polycythemia as an adaptive response to reduced atmospheric oxygen 1, 2, 5
• Carbon monoxide poisoning and chronic exposure in smokers creates functional hypoxia 1
• Hypoventilation syndromes including obstructive sleep apnea cause chronic intermittent hypoxia leading to compensatory erythrocytosis 1, 2, 6, 7

Peripheral hypoxic processes:

• Renal artery stenosis causes localized renal hypoxia 1
• High oxygen-affinity hemoglobinopathy (congenital; autosomal-dominant) prevents adequate oxygen release to tissues 1, 3
• 2,3-Diphosphoglycerate mutase deficiency (congenital; autosomal-recessive) impairs oxygen delivery 1

Critical diagnostic point: In hypoxia-driven secondary polycythemia, serum EPO levels are often initially elevated but may return to within the normal reference range once hemoglobin has stabilized at a higher level 1, 3

Secondary Polycythemia: Hypoxia-Independent Causes

Malignant tumors producing pathologic EPO:

• Renal cell carcinoma produces EPO independently of hypoxia 1, 2, 3
• Hepatocellular carcinoma produces EPO independently of hypoxia 1, 2, 3
• Cerebellar hemangioblastoma produces EPO independently of hypoxia 1, 2, 3
• Parathyroid carcinoma can produce pathologic EPO 1

Nonmalignant conditions:

• Uterine leiomyomas (benign tumors) can produce EPO 1, 3
• Pheochromocytoma can produce EPO 1, 3
• Meningioma can produce EPO 1, 3
• Renal cysts (polycystic kidney disease) can produce EPO 1

Congenital causes:

• Chuvash polycythemia results from abnormal oxygen homeostasis, with mutations in the von Hippel-Lindau gene on chromosome 3 (or chromosome 11 per other studies); endemic in Russia 1, 3
• Abnormally elevated set point for EPO production (congenital) 1, 3

Drug-associated causes:

• Exogenous EPO administration (EPO doping) induces polycythemia 1, 3, 5, 8
• Androgen preparations stimulate erythropoiesis 1, 3

Unknown mechanisms:

• Post-renal transplant erythrocytosis (PRTE) may involve EPO hypersensitivity of erythroid progenitor cells, possibly related to increased IGF-1 and its binding proteins 1, 3
• Serum EPO levels may be either elevated or normal in PRTE 1

Diagnostic Algorithm

Step 1: Distinguish apparent from true polycythemia

• Assess for clinically obvious plasma volume depletion (dehydration, diarrhea, vomiting, diuretics, burns) 1, 3
• Verify hemoglobin/hematocrit values are truly elevated beyond sex- and race-adjusted normal values 1
• Red cell mass measurement is inappropriate when clinical context is obvious 1, 2

Step 2: Measure serum EPO level as the key discriminator

• Low or inappropriately normal EPO: suggests polycythemia vera; proceed to JAK2 V617F mutation testing 2, 3
• Elevated EPO: suggests secondary polycythemia; evaluate for hypoxia-driven versus hypoxia-independent causes 2, 3

Step 3: Evaluate for hypoxia if EPO is elevated

• Arterial blood gas analysis or pulse oximetry to document hypoxemia 3, 5
• Chest X-ray to evaluate for chronic lung disease 3
• Sleep study for suspected obstructive sleep apnea, especially in obese patients with fatigue 3, 6, 7
• Assess for high-altitude habitation or carbon monoxide exposure 1, 2, 5

Step 4: If EPO elevated without hypoxia, evaluate for tumors

• Abdominal ultrasound or CT to screen for renal cell carcinoma, hepatocellular carcinoma, or other EPO-producing tumors 3
• Consider imaging for cerebellar hemangioblastoma, pheochromocytoma, or meningioma based on clinical presentation 1, 2, 3

Step 5: Consider congenital causes in young patients

• Hemoglobin electrophoresis for high oxygen-affinity hemoglobinopathy 8
• Genetic testing for EPOR mutations, von Hippel-Lindau gene mutations, or 2,3-DPG mutase deficiency 1, 8

Critical Pitfalls to Avoid

• Do not assume "adequate sleep" rules out sleep apnea: patients with OSA are typically unaware of their sleep fragmentation and nocturnal arousals 6
• Do not rush to diagnose polycythemia vera without excluding secondary causes: especially in obese patients with fatigue or those with obvious hypoxic conditions 6, 4
• Do not misinterpret normal EPO levels in chronic hypoxic states: levels may normalize after hemoglobin stabilizes at a higher baseline 1, 3
• Do not overlook smoking as a cause: smoker's polycythemia is real and resolves with cessation, with risk reduction beginning within 1 year 1, 2, 3
• Do not perform unnecessary red cell mass measurements: when the cause of plasma volume depletion is clinically obvious or when hematocrit exceeds 60% without hemoconcentration 1, 2, 3