What causes elevated hemoglobin levels?

Causes of Elevated Hemoglobin

Elevated hemoglobin levels can result from various pathological conditions including polycythemia vera, secondary polycythemia due to hypoxia, and relative polycythemia from plasma volume depletion, with each requiring specific diagnostic approaches to determine the underlying cause. 1, 2

Primary Causes

• Polycythemia Vera (PV): A chronic myeloproliferative disorder characterized by increased red blood cell mass due to clonal proliferation of hematopoietic stem cells, typically involving JAK2 mutations 2, 3
• Congenital erythrocytosis: Rare genetic disorders causing elevated hemoglobin levels, including:
  • High-oxygen-affinity hemoglobin variants 1
  • Erythropoietin receptor mutations 1
  • Chuvash polycythemia (mutation in von Hippel-Lindau gene) 1

Secondary Causes (Hypoxia-Driven)

• High altitude exposure: Living at elevations above 1,000 meters causes a compensatory increase in hemoglobin concentration, with the magnitude varying by region (0.6-1.0 g/dL per 1,000m) 4, 5
• Chronic pulmonary diseases: Conditions causing chronic hypoxemia 1, 3
• Cyanotic heart disease: Compensatory erythrocytosis develops to improve oxygen transport 2
• Sleep apnea: Intermittent nocturnal hypoxemia stimulates erythropoietin production 2
• Smoking: Carbon monoxide exposure from smoking leads to "smoker's polycythemia" due to chronic tissue hypoxia 1

Secondary Causes (Hypoxia-Independent)

• Tumor-associated: Certain malignancies can produce erythropoietin independently:
  • Renal cell carcinoma 1
  • Hepatocellular carcinoma 1
  • Pheochromocytoma 1
  • Uterine leiomyoma 1
  • Meningioma 1
• Medication-induced:
  • Testosterone and androgenic steroids 2
  • Erythropoietin therapy 1

Relative Polycythemia (Plasma Volume Depletion)

• Dehydration: Severe fluid loss from various causes 1, 6
  • Diarrhea 1
  • Vomiting 1
  • Excessive sweating 1
• Diuretic use: Causing contraction of plasma volume 1
• Burns: Significant fluid shifts can cause hemoconcentration 1
• Stress polycythemia (Gaisböck syndrome): Controversial condition associated with hypertension, though poorly understood 1

Physiological Variations

• Sex differences: Males typically have higher hemoglobin levels than females 1
• Age-related changes: Hemoglobin levels may vary with age, though anemia is not a normal consequence of aging 1
• Altitude adaptation: Normal hemoglobin increases with altitude exposure, with specific adjustments needed for altitude (see table below) 1, 6

Table: Normal Increase in Hemoglobin Levels with Altitude

Altitude (meters)	Increase in Hb (g/dL)
<1,000	0
1,000	+0.2
1,500	+0.5
2,000	+0.8
2,500	+1.3
3,000	+1.9
3,500	+2.7
4,000	+3.5
4,500	+4.5
[1]

Diagnostic Approach

• Confirm true erythrocytosis with elevated hemoglobin (>18.5 g/dL in men, >16.5 g/dL in women) or hematocrit (>55% in men, >49.5% in women) 2
• Evaluate for relative polycythemia by assessing hydration status 1
• Test for JAK2 mutations when polycythemia vera is suspected 2, 7
• Consider sleep study if nocturnal hypoxemia is suspected 2
• Measure erythropoietin levels to differentiate between primary and secondary causes 1, 7
• Assess for smoking history and carbon monoxide exposure 1

Clinical Pearls and Pitfalls

• Avoid unnecessary red cell mass measurements in cases where the cause of elevated hemoglobin is clinically obvious (e.g., severe dehydration) 1
• Don't overlook the possibility of coexisting iron deficiency in patients with erythrocytosis 2
• Therapeutic phlebotomy should only be considered when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with associated symptoms of hyperviscosity 2
• Regional differences exist in the magnitude of hemoglobin increase with altitude, with Andean populations showing the highest increase (1 g/dL/1000m) compared to other regions (0.6 g/dL/1000m) 4, 5
• Children show less pronounced hemoglobin increases with altitude compared to adults 5