What are the causes of elevated hemoglobin levels in a patient?

Causes of Elevated Hemoglobin

Elevated hemoglobin results from either increased red blood cell production (absolute erythrocytosis) or decreased plasma volume (relative polycythemia), with primary causes including polycythemia vera, secondary causes including chronic hypoxia and erythropoietin-producing tumors, and relative causes including dehydration and diuretic use. 1

Primary Erythrocytosis (Polycythemia Vera)

• Polycythemia vera is caused by JAK2 mutations (found in up to 97% of cases) leading to uncontrolled red blood cell production. 1
• Diagnosis requires either both major criteria (elevated hemoglobin >18.5 g/dL in men or >16.5 g/dL in women AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria. 1
• Minor criteria include bone marrow hypercellularity with trilineage growth, subnormal serum erythropoietin level, and endogenous erythroid colony formation. 1
• Rare genetic causes include high-oxygen-affinity hemoglobin variants, erythropoietin receptor mutations, and Chuvash polycythemia (von Hippel-Lindau gene mutation). 1

Secondary Erythrocytosis: Hypoxia-Driven Causes

Chronic Lung Disease

• Chronic obstructive pulmonary disease causes persistent hypoxemia leading to compensatory erythropoietin production and increased red blood cell mass. 1, 2
• Obstructive sleep apnea produces nocturnal hypoxemia that stimulates erythropoietin production and can cause progressive erythrocytosis over months. 1, 2
• The correlation between serum erythropoietin and lung function indices is negative, while blood hemoglobin correlates positively with lung function impairment. 3

Smoking

• "Smoker's polycythemia" results from chronic carbon monoxide exposure, which creates tissue hypoxia and drives erythropoietin production; this resolves with smoking cessation. 1, 2
• Carbon monoxide from smoking binds hemoglobin, reducing oxygen-carrying capacity and triggering compensatory erythrocytosis. 1

High Altitude Adaptation

• Altitude adaptation causes physiological increases in hemoglobin, with the magnitude varying by ethnicity: Andean populations show the highest increase (1 g/dL per 1000 m), while other populations show smaller increases (0.6 g/dL per 1000 m). 1, 4
• Chronic mountain sickness represents maladaptation with excessive erythrocytosis: hemoglobin can reach 22.1 g/dL compared to 17.1 g/dL in healthy high-altitude residents. 5
• In chronic mountain sickness, increased hemoglobin mass contributes approximately 65% to elevated hemoglobin concentration, while decreased plasma volume contributes 35%. 5
• Frequent altitude changes (common in South American and Asian countries) cause oscillating hemoglobin, hematocrit, and plasma erythropoietin concentrations with each hypoxic-normoxic cycle. 6

Cyanotic Congenital Heart Disease

• Right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport. 1, 2
• This represents an appropriate physiological response rather than pathological overproduction. 1

Secondary Erythrocytosis: Hypoxia-Independent Causes

Erythropoietin-Producing Tumors

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

Exogenous Erythropoietin and Testosterone

• Erythropoietin therapy directly stimulates red blood cell production and can cause elevated hemoglobin levels. 1
• Testosterone use (prescribed or unprescribed) causes erythrocytosis and should be considered in the differential diagnosis, particularly in young adults. 1
• Patients on testosterone therapy should have hematocrit closely monitored, with dose adjustment or temporary discontinuation if levels continue rising. 1

Relative Polycythemia (Plasma Volume Depletion)

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause relative polycythemia through plasma volume depletion without true increase in red blood cell mass. 1
• This represents hemoconcentration rather than increased erythropoiesis. 1

Physiological Variations

Sex Differences

• Males typically have higher hemoglobin levels than females (15.5 ± 2.0 g/dL versus 14.0 ± 2.0 g/dL), with these differences emerging at puberty due to testosterone and estrogen effects. 1
• Post-menopausal females have hemoglobin levels similar to males. 1

Age Considerations

• Hemoglobin levels may vary with age, though anemia is not a normal consequence of aging and reflects poor health when present. 7

Critical Diagnostic Approach

Initial Laboratory Workup

• Complete blood count with red cell indices, reticulocyte count, differential blood cell count, serum ferritin, transferrin saturation, and C-reactive protein 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 is essential to assess red cell morphology and identify abnormalities. 1

Testing for Polycythemia Vera

• JAK2 mutation testing (both exon 14 and exon 12) should be performed when hemoglobin exceeds 18.5 g/dL in men or 16.5 g/dL in women. 1
• Bone marrow biopsy is required if JAK2 mutation is positive to confirm diagnosis and assess for trilineage myeloproliferation. 1

Evaluation for Secondary Causes

• Sleep study should be performed if nocturnal hypoxemia is suspected. 1
• Pulmonary function tests and chest imaging for chronic lung disease evaluation. 1
• Medication review for testosterone, erythropoietin, or other causative agents. 1
• Serum erythropoietin levels help differentiate primary (low/normal) from secondary (elevated) causes. 1

Common Pitfalls to Avoid

• Do not perform therapeutic phlebotomy unless hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with symptoms of hyperviscosity, as routine phlebotomy causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 1, 2
• Do not use standard polycythemia vera diagnostic thresholds at high altitude without adjustment for altitude of residence. 1
• Do not overlook coexisting iron deficiency in patients with erythrocytosis, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 1, 2
• Do not assume a single elevated measurement represents true erythrocytosis; confirm with repeated measurements. 1
• Mean corpuscular volume is unreliable for screening iron deficiency in erythrocytosis; serum ferritin, transferrin saturation, and iron levels are required. 1