What are the differential diagnoses for polycythemia?

Differential Diagnoses for Polycythemia

Polycythemia must be classified into three major categories: apparent (relative) polycythemia due to plasma volume depletion, primary polycythemia (polycythemia vera), and secondary polycythemia driven by either hypoxia-dependent or hypoxia-independent mechanisms. 1, 2

Apparent (Relative) Polycythemia

This represents a false elevation in hemoglobin/hematocrit without true increase in red cell mass:

• Plasma volume depletion from dehydration, severe diarrhea, vomiting, diuretic use, burns, or capillary leak syndrome 2, 3
• Smoker's polycythemia caused by chronic carbon monoxide exposure, which binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia 2, 4

Primary Polycythemia

• Polycythemia vera (PV): A JAK2-mutated myeloproliferative neoplasm with clonal erythrocytosis, characterized by low or inappropriately normal serum EPO levels 1, 5
• Familial polycythemia: Autosomal-dominant condition with activating mutations of the EPO receptor (EPOR) 1, 3

Secondary Polycythemia: Hypoxia-Driven

These conditions trigger compensatory erythropoiesis through tissue hypoxia:

Central Hypoxic Processes

• Chronic lung disease (COPD, pulmonary fibrosis) 1, 2
• Right-to-left cardiopulmonary shunts 1, 2
• High-altitude habitation 1, 3
• Hypoventilation syndromes including obstructive sleep apnea 1, 2

Peripheral Hypoxic Processes

• Renal artery stenosis causing localized renal hypoxia 1
• High oxygen-affinity hemoglobinopathies (congenital, autosomal-dominant) 1, 2
• 2,3-diphosphoglycerate mutase deficiency (congenital, autosomal-recessive) 1, 3

Secondary Polycythemia: Hypoxia-Independent

These conditions involve pathologic EPO production without true tissue hypoxia:

Malignant Tumors

• Renal cell carcinoma 1, 2
• Hepatocellular carcinoma 1, 2
• Cerebellar hemangioblastoma 1, 3
• Parathyroid carcinoma 1

Benign Conditions

• Uterine leiomyomas 1, 2
• Renal cysts and polycystic kidney disease 1, 2
• Pheochromocytoma 1, 2
• Meningioma 1, 2

Congenital Disorders

• Chuvash polycythemia with abnormal oxygen homeostasis and elevated EPO set point 1, 2

Drug-Associated

• EPO doping with exogenous erythropoietin administration 1, 2
• Androgen preparations 1, 2

Other Mechanisms

• Post-renal transplant erythrocytosis 1, 2
• Autosomal-dominant or autosomal-recessive congenital polycythemia of unknown mechanism 1

Critical Diagnostic Distinctions

The first step is determining whether polycythemia is true (increased red cell mass) or apparent (normal red cell mass with decreased plasma volume). 1, 2

• Serum EPO levels are the key discriminator: low or inappropriately normal in PV, elevated in most secondary causes, though EPO may normalize after hemoglobin stabilizes in chronic hypoxic states 1, 2
• JAK2 V617F mutation is present in up to 97% of PV cases and should be tested when EPO is low or normal 2, 5
• Bone marrow examination remains the cornerstone for confirming PV diagnosis, showing characteristic morphologic features 1, 5

Common Pitfalls to Avoid

• Failing to distinguish relative from true polycythemia leads to unnecessary workup and misdiagnosis 2
• Overlooking smoking as a cause—smoker's polycythemia resolves with cessation, with risk reduction beginning within 1 year 2, 4
• Misinterpreting normal EPO levels in chronic hypoxic states where levels may have normalized after compensatory hemoglobin elevation 2
• Assuming low EPO always means PV—rare cases of PV can present with elevated EPO levels, requiring JAK2 testing and bone marrow examination for confirmation 6
• Performing unnecessary red cell mass measurements when clinical context is obvious (e.g., hematocrit >60% without hemoconcentration) 1