Polycythemia differential diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Overview

Polycythemia manifests in a variety of clinical forms, differentiation must be established in accordance with the particular subtype. Primary and secondary polycythemia must be differentiated from each other. Primary polycythemia might be seen in patients with various mutations. Iatrogenic causes including medications, athletic drugs, and smoking might cause primary polycythemia. Secondary polycythemia must be differentiated in patients with chronic hypoxemia, erythropoietin producing tumors, or arteriovenous malformations.

Differential Diagnosis of Polycythemia

Polycythemia must be differentiated from a variety of other conditions.

Category	Disease	Etiology	Mutation	Clinical manifestations														Laboratory findings						Gold standard disgnosis	Associated findings
				Demography	Symptoms						Signs							CBC				EPO level	PBS
					Fatigue	Headache	Shortness of breath	Bleeding	Pain	Other symptoms	Appearance	SaO2	Fever	BP	Tenderness	Splenomegaly	Other signs	Hb	RBC	WBC	Plt
Mutational causes	Polycythemia vera (PV)	Autonomous erythrocyte production	JAK2 mutation (> 95%)	Mean age >60 years old	+	+	+	±	Erythromelagia Chest pain	Stroke-like symptoms Pruritis Dizziness Visual disturbance	Facial plethora	Nl	−	↑	Painful erythema	+	Lymphadenopathy	↑	↑ RBC mass	Nl to ↑	Nl to ↑	↓	Elevated normochromic, normocytic RBCs Thrombocytosis Rarely immature cells Leukoerythroblastic picture	WHO criteria for PV	Stroke Venous thrombosis Myelofibrosis Acute leukemia
	Chuvash polycythemia	Hypoxia-sensing disorder	VHL mutation	Russia, Italy <40 years old	+	+	+	±	Arthralgia	Pruritis Dizziness	Facial plethora	↓	−	↑	Painful erythema	+	Lymphadenopathy	↑	↑	Nl	Nl	↑	Elevated normochromic, normocytic RBCs	Molecular genetic testing	Multiple thrombotic events
	Hereditary methemoglobinemia	Cytochrome b5 reductase deficiency Hemoglobin M disease	Mutations in globin gene	Infants	±	±	±	−	−	−	Cyanosis	Inaccurately Nl	−	Nl	−	−	Altered mental status	↑	↑	Nl	Nl	Nl	NA	RBC enzyme activity + DNA analysis	Usually asymptomatic
	Primary familial and congenital polycythemia	Autosomal dominant inheritance	EPOR mutation	Very rare	+	+	±	−	−	−	Facial plethora	Nl	−	Nl to ↑	−	−	Altered mental status	↑	↑	Nl	Nl	Nl to ↓	NA	Isolated erythrocytosis + genetic testing	Mild manifestations of hyperviscosity
Category	Disease	Etiology	Mutation	Demography	Fatigue	Headache	Shortness of breath	Bleeding	Pain	Other symptoms	Appearance	SaO2	Fever	BP	Tenderness	Splenomegaly	Other signs	Hb	RBC	WBC	Plt	EPO level	PBS	Gold standard diagnosis	Associated findings
Iatrogenic causes	Smoking	Reduced plasma volume Accelerated erythropoiesis	−	Any	−	−	+	−	−	−	Cyanosis	↓	−	Nl	−	−	−	↑	Nl	Nl to ↑	Nl to ↑	Nl to ↓	NA	Clinical manifestation	NA
	Chronic exposure to carbon monoxide	Occupational exposure	−	Miners, fire fighters	+	+	+	−	−	Dizziness Altered cognition	Cyanosis, flushed cheeks	Nl	−	Nl	−	−	−	↑	↑	Nl	Nl	Nl to ↓	NA	Blood level of carboxyhemoglobin	Concomitant cyanide exposure
	Diuretics	Reduced plasma volume	−	Any	−	−	−	−	−	Dizziness	Nl	Nl	−	Nl to ↓	−	−	−	↑	Nl	Nl	Nl	Nl to ↓	NA	Clinical manifestation	NA
	Use of androgens or anabolic steroids	Reduced plasma volume Accelerated erythropoiesis	−	Athletes	−	+	+	−	−	−	Acne and hirsutism	Nl	−	Nl to ↑	−	−	Gynecomastia	↑	↑	Nl	Nl	↓	NA	Clinical manifestation	Hypogonadism Cardiac hypertrophy
	Self−injection of erythropoietin	Reduced plasma volume Accelerated erythropoiesis	−	Athletes	−	+	+	−	−	−	Muscular body	↓	−	↑	−	−	−	↑	↑	Nl	Nl	↑	NA	Erythropoietin level	MI Stroke Thromboembolic disease Antibody-mediated anemia
Secondary causes	Secondary polycythemia due to hypoxemia	Chronic lung disease Right-to-left cardiac shunts Sleep apnea High altitude	−	Depends on etiology	+	+	+	−	Depends on etiology	Shortness of breath	Cyanosis	↓	−	Nl to ↑	−	−	Crackles Tachypnea Tachycardia	↑	↑	Nl	Nl	↑	NA	Clinical manifestation + imaging	Variable manifestations given the diverse etiologies
	Secondary polycythemia due to erythropoietin producing tumor	Renal cell carcinoma Hepatocellular carcinoma Cerebellar hemangioblastoma Pheochromocytoma Uterine fibroids	−	Depends on etiology	+	−	−	−	Depends on etiology	Depends on etiology	Chronically ill	Nl	±	Nl to ↑	±	±	Hepatomegaly Bruising	↑/↓	↑/↓	Nl	↑	↑	NA	Clinical manifestation + biopsy	Variable manifestations given the diverse etiologies
	Hereditary hemorrhagic telangiectasia	Pulmonary arteriovenous malformations	ACVRL1, ENG, GDF2, SMAD4 mutation	Children	−	+	+	GI bleeding	−	Epistaxis Hemoptysis	Multiple telangiectasia on face, extremities, and body	Nl to ↓	−	Nl	−	−	−	↑/↓	↑/↓	Nl	Nl	↑/↓	NA	Clinical criteria + genomic testing	Autosomal dominant Pulmonary hypertension Cerebral AVMs
Category	Disease	Etiology	Mutation	Demography	Fatigue	Headache	Shortness of breath	Bleeding	Pain	Other symptoms	Appearance	SaO2	Fever	BP	Tenderness	Splenomegaly	Other signs	Hb	RBC	WBC	Plt	EPO level	PBS	Gold standard diagnosis	Associated findings