What are the causes of elevated hemoglobin (polycythemia) and the initial work‑up?

Causes of Elevated Hemoglobin (Polycythemia)

Primary Classification Framework

Elevated hemoglobin results from three distinct mechanisms: apparent (relative) polycythemia due to plasma volume depletion, primary clonal disorders (polycythemia vera), or secondary polycythemia driven by either hypoxia-dependent or hypoxia-independent erythropoietin production. 1, 2

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Apparent (Relative) Polycythemia

These causes involve normal red cell mass with contracted plasma volume:

• Dehydration from severe fluid loss, diarrhea, vomiting, or diuretic use creates relative polycythemia that is clinically obvious and does not require specialized testing 1, 2
• Capillary leak syndrome reduces plasma volume while red cell mass remains normal 1
• Severe burns cause plasma volume contraction 1
• Chronic stress and sympathetic nervous system activation can cause primary vascular compartment contraction (reduced venous compliance), often associated with hypertension and psychological stress 3

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Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a JAK2-mutated myeloproliferative neoplasm characterized by clonal erythrocytosis:

• JAK2 V617F mutation is present in >95% of cases and is the definitive diagnostic marker 1, 2, 4
• Serum erythropoietin (EPO) levels are low or inappropriately normal with >90% specificity for polycythemia vera 1, 2
• Classic presentation includes erythrocytosis, leukocytosis (50% of cases), thrombocytosis (50% of cases), and splenomegaly 1, 5
• Characteristic symptoms include aquagenic pruritus, erythromelalgia, and unusual thrombosis 1
• Bone marrow examination shows panmyelosis with trilineage hyperplasia and pleomorphic megakaryocytes 1, 4
• Microcytosis (low MCV) may be present due to iron deficiency from increased utilization or phlebotomy, and can mask the true hemoglobin elevation 1

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Secondary Polycythemia: Hypoxia-Driven Causes

These conditions stimulate compensatory erythropoietin production through tissue hypoxia:

Pulmonary Causes

• Chronic obstructive pulmonary disease (COPD) and pulmonary fibrosis cause chronic hypoxemia 1, 2
• Obstructive sleep apnea creates chronic intermittent hypoxia; strongly consider in obese patients with unexplained fatigue 1, 2, 4
• Other hypoventilation syndromes lead to compensatory erythrocytosis 1, 2

Cardiac Causes

• Right-to-left cardiopulmonary shunts (cyanotic congenital heart disease) cause hypoxia-mediated polycythemia 1, 2
• Low systemic arterial oxygen saturation (<92%) stimulates renal EPO release 1

Environmental & Toxic Causes

• High-altitude habitation represents physiologic adaptation to reduced atmospheric oxygen 1, 2
• Chronic carbon monoxide exposure (smoker's polycythemia) is the most common cause of secondary polycythemia; carbon monoxide binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia that resolves with smoking cessation 1, 2, 6

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Secondary Polycythemia: Hypoxia-Independent Causes

These conditions produce erythropoietin autonomously, independent of tissue oxygen levels:

Malignant Tumors

• Renal cell carcinoma is the most common EPO-producing malignancy 1, 2
• Hepatocellular carcinoma produces autonomous EPO 1, 2
• Parathyroid carcinoma produces EPO pathologically 1

Benign Tumors

• Cerebellar hemangioblastoma (often associated with von Hippel-Lindau syndrome) 2
• Uterine leiomyomas (fibroids) can produce EPO 1, 2
• Pheochromocytoma may produce EPO 1, 2
• Meningioma can produce EPO 1, 2

Other Causes

• Post-renal transplant erythrocytosis (PRTE) occurs in transplant recipients 1, 2
• Exogenous erythropoietin or testosterone therapy causes iatrogenic polycythemia 1, 2
• High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) impairs oxygen release to tissues 1, 2
• Congenital EPOR mutations (autosomal-dominant) cause receptor-mediated polycythemia 1, 2
• Chuvash polycythemia (abnormal oxygen homeostasis) represents congenital abnormal EPO set point 1

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Initial Diagnostic Work-Up Algorithm

Step 1: Confirm True Polycythemia

• Repeat hemoglobin/hematocrit to verify sustained elevation beyond sex- and age-adjusted norms 1, 2
• Assess for plasma volume depletion by evaluating for dehydration, diuretic use, vomiting, diarrhea, or burns 1, 2
• Males with hematocrit >60% and females >55% always have absolute polycythemia 6

Step 2: Order JAK2 Mutation and Serum EPO Simultaneously

This is the single most important diagnostic step:

• JAK2 V617F mutation testing should be performed immediately, as it is present in >95% of polycythemia vera cases 1, 2, 4
• Serum EPO level serves as the key discriminator:
  • Low or inappropriately normal EPO (specificity >90%) strongly suggests polycythemia vera 1, 2
  • Elevated EPO points toward secondary polycythemia 1, 2
  • Normal EPO does not exclude polycythemia vera (sensitivity only 64-70%); proceed with JAK2 testing regardless 1

Step 3: Evaluate for Secondary Causes Based on EPO Level

If EPO is elevated or high-normal:

Screen for Hypoxia-Driven Causes

• Obtain detailed smoking history and measure carboxyhemoglobin levels, as smoking is the most frequent secondary cause 1, 2, 6
• Arterial blood gas or pulse oximetry to document hypoxemia 1, 2, 4
• Chest X-ray to evaluate for chronic lung disease 1, 2
• Sleep study (polysomnography) for suspected obstructive sleep apnea, especially in obese patients with fatigue 1, 4
• Echocardiography if arterial oxygen saturation <92% to identify right-to-left shunts 1

Screen for Hypoxia-Independent Causes (if no hypoxia identified)

• Abdominal ultrasound or CT to screen for renal cell carcinoma, hepatocellular carcinoma, or other EPO-producing tumors 1, 2
• Review medication history for exogenous EPO or testosterone use 1, 2
• Renal function tests to evaluate for post-renal transplant erythrocytosis 1
• Consider hemoglobin electrophoresis in young patients for high oxygen-affinity hemoglobinopathy 2

Step 4: Complete Blood Count with Differential

• Evaluate for thrombocytosis, leukocytosis, or microcytosis (low MCV), which strongly suggest polycythemia vera even with borderline hemoglobin 1
• Check serum ferritin, iron, and transferrin saturation because iron deficiency can mask true polycythemia vera by suppressing hemoglobin elevation 1

Step 5: Bone Marrow Examination (if JAK2 positive or diagnosis unclear)

• Bone marrow biopsy shows hypercellularity with trilineage growth and pleomorphic megakaryocytes in polycythemia vera 1, 4
• WHO 2016 criteria require either: (1) all three major criteria (elevated hemoglobin/hematocrit, JAK2 mutation, characteristic bone marrow morphology), or (2) first two major criteria plus subnormal EPO 1

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Critical Diagnostic Pitfalls to Avoid

• Do not assume normal EPO excludes polycythemia vera—EPO sensitivity is only 64-70%; always perform JAK2 testing when polycythemia is confirmed 1
• Do not overlook smoking as a cause—smoker's polycythemia is real and resolves with cessation; risk reduction begins within 1 year 1, 2, 6
• Beware of iron deficiency masking polycythemia vera—microcytosis with borderline hemoglobin plus thrombocytosis, leukocytosis, or splenomegaly mandates immediate JAK2 testing 1
• Do not perform aggressive phlebotomy in secondary polycythemia—this depletes iron, reduces oxygen-carrying capacity, and paradoxically increases stroke risk 1
• In cyanotic heart disease, phlebotomy is only indicated when hemoglobin >20 g/dL and hematocrit >65% with hyperviscosity symptoms after excluding dehydration 1
• EPO levels may normalize in chronic hypoxic states after hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera 1
• Hemoglobin stable for ≥8 years without progressive rise makes polycythemia vera very unlikely, as untreated PV shows continual increase over time 1