What is the likely diagnosis and recommended management for a patient with a 7‑year history of hemoglobin 15.8–17 g/dL, low erythropoietin, and otherwise normal complete blood count?

Likely Diagnosis: Idiopathic Erythrocytosis (Primary Polycythemia)

A patient with hemoglobin fluctuating between 15.8–17 g/dL, low erythropoietin, and otherwise normal blood counts for 7 years most likely has idiopathic erythrocytosis, and requires evaluation to exclude secondary causes of polycythemia and JAK2-negative myeloproliferative neoplasms. 1

Diagnostic Reasoning

Why Low EPO with Elevated Hemoglobin is Significant

• Normal erythropoietin levels range between 10-30 mU/mL in healthy adults 2
• The combination of elevated hemoglobin with suppressed (not elevated) EPO indicates autonomous red cell production independent of physiologic hypoxia signaling 1
• This pattern excludes secondary polycythemia, where EPO would be appropriately elevated in response to tissue hypoxia 1

Key Differential Diagnoses to Exclude

Polycythemia Vera (PV):

• Must test for JAK2 V617F mutation, JAK2 exon 12 mutations, and other myeloproliferative neoplasm markers 1
• Even with normal white blood cell and platelet counts, PV can present with isolated erythrocytosis initially
• The 7-year stable course makes aggressive malignancy less likely but does not exclude indolent myeloproliferative disease

Secondary Polycythemia with Autonomous EPO Production:

• Screen for renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma, and parathyroid carcinoma with appropriate imaging 1
• Evaluate for renal cysts, polycystic kidney disease, uterine leiomyomas, pheochromocytoma, and meningioma 1
• These conditions produce ectopic EPO but typically show elevated EPO levels, making them less likely here 1

Chuvash Polycythemia:

• Consider this congenital disorder of abnormal oxygen homeostasis, particularly in patients of Chuvash descent 1
• Genetic testing for VHL mutations may be warranted if family history suggests inherited polycythemia

Essential Diagnostic Workup

Immediate Laboratory Studies

• Complete blood count with reticulocyte count to assess bone marrow activity and confirm isolated erythrocytosis 2
• Peripheral blood smear to evaluate red cell morphology and exclude hemoglobinopathies 2
• JAK2 V617F mutation testing and JAK2 exon 12 mutations if V617F is negative 1
• Serum EPO level measurement to confirm the low reading and assess magnitude (if >500 mU/mL, this would indicate EPO resistance, though this seems unlikely given the clinical picture) 1
• Iron studies (serum iron, ferritin, total iron-binding capacity, transferrin saturation) to exclude iron deficiency masking higher hemoglobin 2
• Vitamin B12 and folate levels to exclude nutritional deficiencies 2

Evaluation for Secondary Causes

• Arterial blood gas and oxygen saturation to exclude occult hypoxemia 1
• Carboxyhemoglobin level if carbon monoxide exposure is possible 1
• Renal imaging (ultrasound or CT) to evaluate for renal masses, cysts, or renal artery stenosis 1
• Abdominal imaging to screen for hepatocellular carcinoma and other abdominal malignancies 1
• Brain MRI if cerebellar hemangioblastoma or meningioma is suspected 1

Assess for Hypoxic Conditions

• Echocardiogram to evaluate for right-to-left cardiopulmonary shunts 1
• Pulmonary function tests if hypoventilation syndrome is suspected 1
• Sleep study if obstructive sleep apnea with chronic hypoxemia is a consideration 1

Management Approach

Monitoring Without Intervention

• The 7-year stable course without symptoms suggests observation may be appropriate if malignancy and myeloproliferative neoplasm are excluded 1
• Monitor hemoglobin levels every 4-8 weeks initially, then extend intervals if stability continues 2
• Reassess complete blood count to detect evolution to overt myeloproliferative disease (rising white blood cells or platelets) 2

Therapeutic Phlebotomy Considerations

• Phlebotomy is NOT recommended in patients with stable hemoglobin M disease or high oxygen-affinity hemoglobinopathies, as higher erythrocyte mass compensates for impaired oxygen delivery 3
• If idiopathic erythrocytosis is confirmed and hemoglobin rises above 18 g/dL or symptoms develop, phlebotomy to maintain hemoglobin <16 g/dL in men may reduce thrombotic risk
• Target hematocrit <45% if phlebotomy is pursued, based on cardiovascular risk reduction data

Avoid Erythropoietin Therapy

• Exogenous EPO is contraindicated in this patient, as low endogenous EPO indicates the bone marrow is already producing red cells autonomously 2, 1
• ESAs increase thromboembolic risk by 67% (95% CI: 1.35-2.06) and would worsen polycythemia 1

Address Cardiovascular Risk

• Hemoglobin levels above 17 g/dL are associated with increased mortality in acute coronary syndromes (OR 1.79,95% CI 1.18-2.71) 4
• Optimize management of hypertension, hyperlipidemia, and other cardiovascular risk factors given the elevated hemoglobin
• Consider low-dose aspirin for thrombotic prophylaxis if no contraindications exist, particularly if JAK2 mutation is positive

Critical Pitfalls to Avoid

• Do not assume this is "normal" variation simply because other blood counts are normal—isolated erythrocytosis with low EPO requires thorough evaluation 1
• Do not initiate EPO therapy, as this would be physiologically inappropriate and potentially harmful 2, 1
• Do not overlook occult malignancy—ectopic EPO production from renal, hepatic, or cerebellar tumors must be excluded 1
• Do not dismiss the diagnosis without genetic testing for myeloproliferative neoplasms, as JAK2-negative PV exists and requires specific management 1
• Do not target hemoglobin >12 g/dL if any intervention is considered, as this significantly increases mortality and thrombotic risk 1