What are the potential causes of a chronic mildly elevated red blood cell count?

Potential Causes of Chronic Mildly Elevated Red Blood Cell Count

Chronic mildly elevated red blood cell counts result from either true polycythemia (increased red cell mass) or apparent polycythemia (normal red cell mass with reduced plasma volume or extreme normal variation), with the most common causes being polycythemia vera, secondary polycythemia from hypoxia or tumors, and relative polycythemia from plasma volume contraction. 1

Primary Classification Framework

The differential diagnosis must distinguish between true polycythemia (actual increase in red blood cell mass) and apparent polycythemia (elevated hematocrit without increased red cell mass). 1

True Polycythemia Causes

Polycythemia Vera (Primary Polycythemia)

• A clonal myeloproliferative disorder where abnormal hematopoietic stem cells overproduce red cells, typically accompanied by increased granulocytes and platelets 1
• More than 95% of patients have a JAK2 gene variant, which distinguishes it from secondary causes 2
• Often presents with splenomegaly (36%), pruritus (33%), and thrombocytosis (53%) or leukocytosis (49%) 2
• Median survival ranges from 14.1 to 27.6 years from diagnosis 2

Secondary Polycythemia - Hypoxia-Driven (EPO-Mediated)

Central hypoxic processes: 1

• Chronic lung disease (COPD, pulmonary fibrosis)
• Right-to-left cardiopulmonary shunts
• High-altitude habitation
• Hypoventilation syndromes including obstructive sleep apnea
• Carbon monoxide poisoning, particularly smoker's polycythemia from chronic tobacco exposure 1

Peripheral hypoxic processes: 1

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

Cyanotic congenital heart disease: 1

• Right-to-left shunting causes arterial oxygen saturation <75%, triggering compensatory erythrocytosis
• Results in decompensated erythrocytosis when erythropoietin levels remain persistently elevated

Secondary Polycythemia - Hypoxia-Independent (Pathologic EPO Production)

Malignant tumors producing EPO: 1

• Renal cell carcinoma
• Hepatocellular carcinoma
• Cerebellar hemangioblastoma
• Parathyroid carcinoma

Benign conditions producing EPO: 1

• Uterine leiomyomas
• Renal cysts and polycystic kidney disease
• Pheochromocytoma
• Meningioma

Congenital EPO dysregulation: 1

• Chuvash polycythemia (abnormal oxygen homeostasis, von Hippel-Lindau gene mutations)
• Abnormally elevated set point for EPO production

EPO Receptor-Mediated Polycythemia

• Activating mutations of the EPO receptor causing C-terminal truncation and enhanced signal transduction 1
• Some cases of autosomal-dominant congenital polycythemia 1

Drug-Associated Polycythemia

• Exogenous EPO administration (EPO doping) 1
• Androgen preparations 1

Post-Renal Transplant Erythrocytosis

• May involve EPO hypersensitivity of erythroid progenitor cells, possibly related to increased IGF-1 and binding proteins 1

Apparent Polycythemia Causes

Relative Polycythemia (Reduced Plasma Volume)

Acute causes (clinically obvious): 1

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

Chronic causes (controversial): 1

• Gaisböck syndrome (relative polycythemia with hypertension and nephropathy) - poorly understood with little foundation
• Stress polycythemia (associated with emotional stress) - poorly understood
• Note: In a Mayo Clinic series of 109 consecutive measurements, no patients with true relative polycythemia were identified 1

Extreme Normal Variation

• Hemoglobin/hematocrit values exceeding the 95th percentile of reference intervals without true disease 1
• More common in males and varies by race 1
• PCV values up to 0.60 may represent apparent polycythemia, with only 18% having truly reduced plasma volume 3

Clinical Associations and Risk Factors

Factors associated with apparent polycythemia: 3

• Male sex
• Obesity
• Smoking (causes true smoker's polycythemia from carbon monoxide)
• Hypertension
• Alcohol consumption
• Arterial oxygen desaturation
• Renal disease
• Increased catecholamine levels

Critical Diagnostic Pitfalls

Iron deficiency masking polycythemia: 1

• Pathologic red cell mass may be lowered to within normal range by superimposed iron deficiency or bleeding
• Can create microcytic polycythemia that mimics thalassemia minor 4
• In secondary polycythemia with iron deficiency, iron supplementation causes RBC count to remain elevated while MCV normalizes 4

Inapparent polycythemia: 1

• True increase in red cell mass masked by concomitant increase in plasma volume, resulting in normal hemoglobin/hematocrit

Comorbid conditions: 1

• A patient can have both polycythemia vera and an unrelated hypoxic condition (e.g., PV plus chronic lung disease)