What are the potential causes of mild elevations in Red Blood Cell (RBC) count, hemoglobin, and hematocrit in an adult patient, possibly with a history of smoking or living at high altitude?

Causes of Mild Elevations in RBC, Hemoglobin, and Hematocrit

Primary Diagnostic Framework

For mild elevations in RBC count, hemoglobin, and hematocrit, the most common causes are secondary polycythemia from chronic hypoxia (smoking, high altitude, sleep apnea), relative polycythemia from dehydration or diuretic use, and less commonly, polycythemia vera or other myeloproliferative disorders. 1

Secondary Causes: Hypoxia-Driven Erythrocytosis

Smoking-Related Polycythemia

• Chronic smoking causes "smoker's polycythemia" through carbon monoxide exposure, which creates tissue hypoxia and stimulates erythropoietin production. 1 This resolves with smoking cessation. 1
• Carbon monoxide from smoking binds hemoglobin, reducing oxygen delivery and triggering compensatory erythrocytosis. 1

High Altitude Adaptation

• Altitude increases hemoglobin predictably: +0.2 g/dL at 1,000m, +0.5 g/dL at 1,500m, +0.8 g/dL at 2,000m, +1.3 g/dL at 2,500m, +1.9 g/dL at 3,000m, and +3.5 g/dL at 4,000m above sea level. 1
• This physiological adaptation maintains adequate oxygen delivery despite lower atmospheric oxygen pressure. 2
• Failure to adjust diagnostic thresholds for altitude leads to overdiagnosis of polycythemia and underdiagnosis of anemia. 2

Obstructive Sleep Apnea

• Nocturnal hypoxemia from sleep apnea drives erythropoietin production, causing secondary erythrocytosis. 1
• A sleep study should be performed if nocturnal hypoxemia is suspected based on symptoms like snoring, witnessed apneas, or daytime somnolence. 1

Chronic Lung Disease

• Chronic obstructive pulmonary disease (COPD) and other pulmonary conditions causing chronic hypoxemia stimulate compensatory erythrocytosis. 1
• Pulmonary function tests and chest imaging help identify these causes. 1

Cyanotic Congenital Heart Disease

• Right-to-left cardiac shunting causes arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport. 1

Secondary Causes: Hypoxia-Independent Erythrocytosis

Testosterone Therapy

• Testosterone use (prescribed or unprescribed) commonly causes erythrocytosis and must be considered in the differential diagnosis. 1
• Hematocrit should be monitored closely in patients on testosterone, with dose reduction or temporary discontinuation if levels rise excessively. 1

Erythropoietin-Producing Tumors

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently. 1
• Renal imaging (ultrasound or CT) should be performed to exclude renal masses, hydronephrosis, or cystic disease. 1

Exogenous Erythropoietin

• Erythropoietin therapy directly increases hemoglobin and hematocrit levels. 1

Relative Polycythemia (Plasma Volume Depletion)

Dehydration and Volume Contraction

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause relative polycythemia through plasma volume depletion without true increase in red cell mass. 1
• Confirm adequate hydration status before pursuing extensive workup. 1

Primary Polycythemia

Polycythemia Vera

• Polycythemia vera is characterized by JAK2 mutation (present in up to 97% of cases) and autonomous red cell production independent of erythropoietin. 1
• Diagnostic thresholds: hemoglobin >18.5 g/dL in men or >16.5 g/dL in women, and hematocrit >55% in men or >49.5% in women. 1
• JAK2 mutation testing (both exon 14 and exon 12) should be performed when polycythemia vera is suspected. 1

Rare Genetic Disorders

• High-oxygen-affinity hemoglobin variants, erythropoietin receptor mutations, and Chuvash polycythemia (von Hippel-Lindau gene mutation) are uncommon causes. 1

Initial Diagnostic Workup

Essential Laboratory Tests

• Complete blood count with red cell indices, reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation, and C-reactive protein (CRP) should be obtained. 1
• Hemoglobin is more accurate than hematocrit for assessment because it remains stable during sample storage, while hematocrit can falsely increase by 2-4% with prolonged storage. 1
• Peripheral blood smear review identifies abnormal red cell morphology. 1

Secondary Testing Based on Initial Results

• If absolute erythrocytosis is confirmed, measure erythropoietin levels to differentiate primary from secondary causes. 1
• Low or inappropriately normal erythropoietin suggests polycythemia vera; elevated levels suggest secondary causes. 1
• High RDW with normal or low MCV suggests coexisting iron deficiency with erythrocytosis. 1

Critical Management Pitfalls to Avoid

Phlebotomy Considerations

• Therapeutic phlebotomy is indicated ONLY when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with symptoms of hyperviscosity, after excluding dehydration. 1
• Repeated routine phlebotomies are contraindicated in secondary polycythemia due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 1
• When phlebotomy is necessary, replace with equal volume of dextrose or saline to prevent hemoconcentration. 1

Iron Deficiency Recognition

• Iron deficiency can coexist with erythrocytosis, causing microcytic polycythemia with elevated RBC count but reduced hemoglobin. 1
• MCV is unreliable for screening iron deficiency in erythrocytosis; serum ferritin and transferrin saturation are required. 1
• If iron deficiency is confirmed (transferrin saturation <20%), cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur. 1

Polycythemia Vera-Specific Management

• For confirmed polycythemia vera, maintain hematocrit strictly below 45% through phlebotomy to reduce thrombotic risk. 1
• Low-dose aspirin (81-100 mg daily) is the second cornerstone of therapy for thrombosis prevention. 1
• Refer immediately to hematology if JAK2 mutation is positive or diagnosis remains unclear. 1