What are the causes of elevated hemoglobin (high red blood cell count) levels?

Causes of Elevated Hemoglobin

Elevated hemoglobin results from either true polycythemia (increased red blood cell mass) or relative polycythemia (plasma volume depletion), with causes ranging from primary bone marrow disorders like polycythemia vera to secondary hypoxia-driven conditions and physiological adaptations.

Primary Polycythemia (Bone Marrow Disorders)

• Polycythemia vera is the most important primary cause, characterized by JAK2 mutations (present in up to 97% of cases) that drive autonomous red blood cell production independent of erythropoietin levels 1
• Rare genetic disorders include high-oxygen-affinity hemoglobin variants, erythropoietin receptor mutations, and Chuvash polycythemia (von Hippel-Lindau gene mutation) 1

Secondary Polycythemia: Hypoxia-Driven Causes

Chronic Lung Disease and Sleep Disorders

• Chronic obstructive pulmonary disease (COPD) causes chronic tissue hypoxia that stimulates erythropoietin production, with the prevalence of polycythemia increasing significantly when combined with obstructive sleep apnea (6.4% in overlap syndrome vs 2.9% in COPD alone) 1, 2
• Obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production, with percentage of total sleep time with oxygen saturation <90% being an independent predictor of polycythemia (OR 1.030 per 1% increase) 1, 2

Cardiac Causes

• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport—this is a physiological adaptation, not a pathological condition requiring treatment 1

Environmental and Lifestyle Factors

• Smoking leads to "smoker's polycythemia" due to chronic carbon monoxide exposure, which causes tissue hypoxia and stimulates erythropoietin production; this resolves with smoking cessation 1
• High altitude residence causes physiological increases in hemoglobin that vary by elevation: +0.2 g/dL at 1,000 meters up to +4.5 g/dL at 4,500 meters, with regional variations (most pronounced in East Africans and South Americans, least in South/Southeast Asians) 1, 3

Secondary Polycythemia: Non-Hypoxic Causes

• Erythropoietin-producing tumors including renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can cause autonomous erythropoietin production 1
• Testosterone therapy (prescribed or unprescribed) is a common iatrogenic cause in young adults and should always be considered in the differential diagnosis 1
• Exogenous erythropoietin therapy directly stimulates red blood cell production, with expected hemoglobin increases of 0.3 g/dL per week 1

Relative Polycythemia (Plasma Volume Depletion)

• Dehydration causes hemoconcentration and is the most common cause of acute hemoglobin elevation—this must be excluded before pursuing extensive workup 1, 4
• Diuretic use chronically reduces plasma volume, leading to elevated hemoglobin and hematocrit concentrations 1
• Stress polycythemia (Gaisböck syndrome) involves chronic plasma volume contraction without true increase in red blood cell mass 1
• Burns cause significant plasma volume loss through capillary leak 1

Physiological Variations (Not Pathological)

• Sex differences emerge at puberty due to testosterone and estrogen effects: adult males have hemoglobin 15.5 ± 2.0 g/dL versus menstruating females 14.0 ± 2.0 g/dL 1
• Age-related changes occur, though anemia is not a normal consequence of aging 1
• Altitude adaptation in children shows lower hemoglobin increases per kilometer elevation compared to adults across all world regions 3

Critical Diagnostic Thresholds

• True erythrocytosis is defined as 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
• These thresholds must be adjusted for altitude of residence, as standard cutoffs do not apply at high elevations 1
• Hemoglobin is more reliable than hematocrit for diagnosis because hematocrit can falsely increase by 2-4% with sample storage and is affected by hyperglycemia, while hemoglobin remains stable 1

Important Clinical Pitfalls

• Iron deficiency can coexist with erythrocytosis, particularly in cyanotic heart disease or polycythemia vera, causing microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin—mean corpuscular volume (MCV) is unreliable for screening iron deficiency in this context 1
• Methemoglobinemia can present with apparent "polycythemia" on co-oximetry but represents functional anemia with impaired oxygen delivery, not true erythrocytosis—pulse oximetry will be falsely reassuring 5
• Single measurements are unreliable—always confirm with repeated testing before initiating extensive workup or treatment 1