What is the approach to diagnose erythrocytosis in a male?

Diagnostic Approach to Erythrocytosis in Males

The diagnosis of erythrocytosis in males requires a systematic approach starting with confirmation of elevated hemoglobin (>16.5 g/dL) or hematocrit (>49%), followed by determination of whether the condition is primary (clonal) or secondary (reactive). 1

Initial Diagnostic Criteria

• Confirm erythrocytosis:
  • Hemoglobin >16.5 g/dL in men
  • OR Hematocrit >49% in men
  • OR Increased red cell mass (RCM) 1

Diagnostic Algorithm

Step 1: Confirm True Erythrocytosis

• Rule out relative erythrocytosis (plasma volume contraction) due to dehydration
• Consider red cell mass measurement in borderline cases

Step 2: JAK2 Mutation Testing

• Test for JAK2 V617F mutation (present in ~97% of polycythemia vera cases)
• If negative but strong suspicion of PV, test for JAK2 exon 12 mutations 1

Step 3: Measure Serum Erythropoietin (EPO) Level

• Low EPO: Suggests primary erythrocytosis (polycythemia vera)
• Normal/High EPO: Suggests secondary erythrocytosis 1, 2

Step 4: Bone Marrow Biopsy

• Indicated when PV is suspected
• Look for: hypercellularity with trilineage growth (panmyelosis), prominent erythroid, granulocytic, and megakaryocytic proliferation 1

Diagnostic Criteria for Polycythemia Vera (PV)

According to the 2016 WHO criteria, diagnosis requires meeting either:

• All 3 major criteria, OR
• First 2 major criteria plus the minor criterion

Major criteria:

1. Elevated hemoglobin/hematocrit/RCM as defined above
2. Bone marrow biopsy showing hypercellularity with trilineage growth
3. Presence of JAK2 V617F or JAK2 exon 12 mutation

Minor criterion:

• Subnormal serum EPO level 1

Evaluation of Secondary Erythrocytosis

If JAK2 mutation is negative and EPO is normal or elevated, investigate causes of secondary erythrocytosis:

Hypoxia-driven causes:

• Chronic lung disease (perform pulmonary function tests)
• Sleep apnea (consider sleep study)
• Smoking (carboxyhemoglobinemia)
• High altitude residence
• Congenital heart disease with right-to-left shunting (echocardiogram) 1

Non-hypoxic causes:

• Medications:

  • Testosterone/androgens (up to 66.7% of users develop erythrocytosis) 3
  • SGLT-2 inhibitors (2.1-22% develop erythrocytosis) 3
  • Anti-angiogenic tyrosine kinase inhibitors 3
  • Erythropoiesis-stimulating agents

• Renal causes:

  • Renal cell carcinoma (renal ultrasound/CT)
  • Renal cysts
  • Post-renal transplant erythrocytosis 4
  • Renal artery stenosis

• Congenital causes (if lifelong erythrocytosis):

  • High-oxygen-affinity hemoglobinopathy (hemoglobin electrophoresis, P50 measurement)
  • EPO receptor mutations
  • VHL gene mutations 2

Important Clinical Considerations

• Iron deficiency can mask erythrocytosis in PV; check iron studies 1
• Therapeutic phlebotomy should be reserved for symptomatic patients with hematocrit >65% and hemoglobin >20 g/dL, with volume replacement to prevent dehydration 1
• Repeated routine phlebotomies are not recommended due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke 1
• For testosterone-induced erythrocytosis, consider changing from injectable to topical formulations, as transdermal preparations have lower risk of erythrocytosis (2.8-17.9% vs. 43.8% with injectables) 5

By following this systematic approach, clinicians can effectively diagnose the cause of erythrocytosis in male patients and implement appropriate management strategies to reduce morbidity and mortality.