What are the diagnostic criteria for high altitude polycythemia?

Diagnostic Criteria for 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 above 2500 meters altitude for more than 10 years, after excluding polycythemia vera through JAK2 mutation testing. 1, 2, 3

Defining Characteristics

HAPC represents a distinct clinical entity from polycythemia vera (PV), characterized by:

• Excessive erythrocytosis with hemoglobin ≥190 g/L in females or ≥210 g/L in males 1, 2, 3
• Residence requirement of living above 2500-4000 meters altitude for at least 10 years 3
• Decreased arterial oxygen saturation as the underlying physiologic driver 4

The key distinction is that HAPC represents a maladaptive response to chronic hypoxia, whereas PV is a clonal myeloproliferative disorder 5.

Diagnostic Algorithm

Step 1: Confirm Elevated Hemoglobin/Hematocrit

• Measure hemoglobin and hematocrit, adjusting thresholds for altitude of residence 6
• At altitudes above 4000 meters, hemoglobin levels can physiologically increase by 3.5-4.5 g/dL above sea level values 6
• Repeat measurements to confirm persistent elevation rather than transient changes 6

Step 2: Exclude Polycythemia Vera

This is the critical step that distinguishes HAPC from PV. Many patients with polycythemia at altitude may be unnecessarily evaluated for PV if hemoglobin/hematocrit is the sole criterion 5.

• Order JAK2 mutation testing (both V617F and exon 12 mutations) to exclude PV 6, 7, 5
• In a high-altitude study, only 16.7% of patients with polycythemia actually had PV confirmed by JAK2 mutation 5
• PV patients exhibit distinct CBC patterns including leukocytosis, thrombocytosis, and hypochromic microcytic RBCs related to iron deficiency 5

Step 3: Complete Blood Count Analysis

Examine the complete blood count for patterns that distinguish HAPC from PV:

• HAPC typically shows: isolated erythrocytosis without significant leukocytosis or thrombocytosis 5
• PV typically shows: pancytosis with elevated WBC (>12 × 10⁹/L), platelets (>400 × 10⁹/L), and microcytic RBCs from iron deficiency 8, 5
• Assess for iron deficiency, which commonly coexists with both conditions but is more characteristic of PV 5

Step 4: Assess for Secondary Causes

Even at altitude, evaluate for other secondary causes of erythrocytosis:

• Smoking history and carbon monoxide exposure, which stimulates erythropoietin production 6
• Obstructive sleep apnea, which produces nocturnal hypoxemia driving erythropoietin production 6
• Chronic lung disease (COPD) causing additional hypoxic stimulus 6
• Testosterone use, either prescribed or unprescribed 6

Step 5: Measure Serum Erythropoietin

• Low or normal EPO levels suggest HAPC as a physiologic response to chronic hypoxia 8
• Elevated EPO levels would be unusual and suggest investigating for EPO-producing tumors (renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma) 6
• Note that EPO levels have limited diagnostic specificity (>90%) but reduced sensitivity (<70%) for distinguishing PV from secondary causes 8

Common Diagnostic Pitfalls

Pitfall 1: Applying Sea-Level Diagnostic Thresholds

• Do not use standard PV diagnostic thresholds (Hb >18.5 g/dL men, >16.5 g/dL women) at high altitude without adjustment 8, 7
• Physiologic adaptation to altitude can increase hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters) 6
• The WHO criteria for PV specifically state thresholds should be adjusted for "altitude of residence" 8, 7

Pitfall 2: Unnecessary JAK2 Testing

• Avoid reflexive JAK2 testing in all patients with elevated hemoglobin at altitude 5
• First assess the CBC pattern: isolated erythrocytosis suggests HAPC, while pancytosis with microcytic RBCs suggests PV 5
• This approach reduces unnecessary workups and healthcare costs 5

Pitfall 3: Overlooking Iron Deficiency

• Iron deficiency can coexist with HAPC and mask the true degree of erythrocytosis 6, 5
• Check serum ferritin, transferrin saturation, and iron levels 6
• Mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis 6

Clinical Manifestations Supporting HAPC Diagnosis

Beyond laboratory criteria, clinical features help distinguish HAPC:

• Symptoms of hyperviscosity: headache, dizziness, fatigue, dyspnea 1
• Absence of PV-related features: no splenomegaly, aquagenic pruritus, erythromelalgia, or unusual thrombosis (Budd-Chiari syndrome) 8, 6
• Chronic mountain sickness symptoms: persistent arterial hypoxia and ventilatory impairment 2

When to Refer to Hematology

Immediate hematology referral is warranted if:

• JAK2 mutation is positive, confirming PV rather than HAPC 6
• Hemoglobin >200 g/L with symptoms of hyperviscosity 6
• Unexplained splenomegaly is present 6
• Diagnosis remains unclear after initial workup 6

Monitoring and Follow-Up

Once HAPC is diagnosed:

• Serial hemoglobin/hematocrit monitoring every 3-6 months 6
• Assess for end-organ complications, particularly kidney disease (proteinuria, hypertension, hyperuricemia) 3
• Evaluate for progression to chronic mountain sickness with worsening symptoms 2