How to diagnose high-altitude polycythemia?

How to Diagnose High-Altitude Polycythemia

High-altitude polycythemia (HAPC) is diagnosed when hemoglobin is ≥190 g/L in females or ≥210 g/L in males in individuals living at high altitude (typically >4000 m), combined with clinical symptoms of chronic mountain sickness. 1, 2, 3

Diagnostic Criteria

Primary Hemoglobin Thresholds

• Males: Hemoglobin ≥210 g/L 1, 2, 3
• Females: Hemoglobin ≥190 g/L 1, 2, 3
• These thresholds are specifically defined for high-altitude populations and differ from polycythemia vera criteria 1

Associated Clinical Features

• Decreased arterial oxygen saturation despite elevated hemoglobin 4
• Symptoms of chronic mountain sickness including headache, dizziness, and sleep disturbances 3
• Residence at high altitude (typically >4000 m elevation) 2, 3

Critical Distinction: HAPC vs Polycythemia Vera

The most important diagnostic step is distinguishing HAPC from polycythemia vera (PV), as they require completely different therapeutic approaches. 1

Features Suggesting Polycythemia Vera Rather Than HAPC

• Leukocytosis and thrombocytosis (PV typically shows elevated white blood cells and platelets, while HAPC may show thrombocytopenia) 1, 5
• Hypochromic microcytic red blood cells with low mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) due to iron deficiency 1, 6
• Low serum erythropoietin (EPO) level (<2 U/L strongly favors PV) 7, 8
• JAK2 mutation positivity (present in >95% of PV cases) 7, 8

When to Test for Polycythemia Vera at High Altitude

Many patients with polycythemia at altitude are unnecessarily evaluated for PV if hemoglobin/hematocrit is the sole criterion. 1 Consider PV testing only when:

• Leukocytosis and/or thrombocytosis are present alongside polycythemia 1
• Microcytic hypochromic anemia pattern suggests iron deficiency (which is characteristic of PV, not typical HAPC) 1, 6
• Unusual thrombosis occurs (such as Budd-Chiari syndrome) 7
• Aquagenic pruritus or erythromelalgia are present 7

Diagnostic Algorithm for High-Altitude Polycythemia

Step 1: Confirm Elevated Hemoglobin

• Verify hemoglobin ≥210 g/L (males) or ≥190 g/L (females) 1, 2, 3
• Ensure adequate hydration to exclude relative polycythemia from dehydration 9
• Repeat complete blood count if initial values are borderline 9

Step 2: Assess Complete Blood Count Pattern

• If isolated erythrocytosis (normal white blood cells and platelets, normocytic red cells): likely HAPC 1
• If pancytosis (elevated white blood cells, platelets, and red cells) with microcytosis: consider PV and proceed to Step 3 1

Step 3: Measure Serum Erythropoietin (Only if PV Suspected)

• Low EPO (<2 U/L): strongly suggests PV, proceed to JAK2 testing 7, 8
• Normal or elevated EPO: consistent with HAPC (appropriate physiologic response to hypoxia) 7, 4

Step 4: JAK2 Mutation Testing (Only if PV Strongly Suspected)

• Positive JAK2V617F or exon 12 mutation confirms PV 8, 7
• Negative result does not completely exclude PV but makes HAPC more likely in high-altitude context 8

Additional Laboratory Findings in HAPC

Characteristic Blood Changes

• Significantly increased hematocrit values 2, 4
• Increased reticulocyte count (reflecting enhanced bone marrow erythropoiesis) 4
• Possible thrombocytopenia (unlike PV, which shows thrombocytosis) 5
• Increased 2,3-bisphosphoglycerate (2,3-BPG) levels facilitating oxygen release 4

Erythrocyte Morphology and Function

• Increased proportion of abnormal erythrocytes (vesicular erythrocytes and acanthocytes) 4
• Increased erythrocyte osmotic fragility 4
• Reduced erythrocyte apoptosis contributing to polycythemia 4

Common Diagnostic Pitfalls

Do Not Assume All High-Altitude Polycythemia is Secondary

• While most polycythemia at altitude is physiologic adaptation (HAPC), approximately 16.7% of cases evaluated may actually be PV 1
• The key is using the complete blood count pattern to guide selective testing rather than reflexively ordering JAK2 testing for all elevated hemoglobin at altitude 1

Do Not Overlook Iron Deficiency

• Iron deficiency with microcytosis in the context of polycythemia strongly suggests PV rather than HAPC 1, 6
• Low MCHC (<32%) indicates iron deficiency that can mask the true degree of erythrocytosis 6, 9

Do Not Rely on Red Cell Mass Measurement

• Red cell mass measurement is costly and not routinely needed for HAPC diagnosis 8, 9
• Normal red cell mass does not exclude polycythemia vera 8, 7