What are the causes of a hemoglobin level of 20.3 g/dL, indicating polycythemia?

Causes of Hemoglobin 20.3 g/dL

A hemoglobin of 20.3 g/dL represents severe erythrocytosis that requires immediate evaluation for polycythemia vera (primary cause) versus secondary causes including chronic hypoxia, smoking, sleep apnea, renal tumors, or other erythropoietin-driven conditions. 1, 2

Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a clonal myeloproliferative neoplasm caused by JAK2 mutations in >95% of cases. 2 This represents a primary bone marrow disorder where red blood cell production is unregulated and independent of normal erythropoietin control. 3, 2

• JAK2V617F mutation (exon 14) is present in the vast majority of PV cases, with JAK2 exon 12 mutations accounting for most remaining cases. 1, 4
• Diagnosis requires hemoglobin ≥18.5 g/dL in men or ≥16.5 g/dL in women, plus JAK2 mutation, plus either bone marrow hypercellularity with trilineage growth OR subnormal serum erythropoietin levels. 4, 2
• Associated findings often include thrombocytosis (53% of patients), leukocytosis (49%), splenomegaly (36%), and pruritus (33%). 2

Secondary Polycythemia (Hypoxia-Driven)

Chronic tissue hypoxia stimulates erythropoietin production, leading to compensatory erythrocytosis. 1, 5

Pulmonary and Cardiac Causes

• Chronic obstructive pulmonary disease (COPD) and chronic hypoxemia from any lung disease cause secondary erythrocytosis. 1
• Obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production. 1, 2
• Cyanotic congenital heart disease with right-to-left shunting results in compensatory erythrocytosis to improve oxygen transport. 6
• In Eisenmenger syndrome specifically, erythrocytosis is an adaptive response and most patients maintain stable hemoglobin levels without intervention. 6

Smoking-Related

• "Smoker's polycythemia" results from chronic carbon monoxide exposure, which causes tissue hypoxia and stimulates erythropoietin production. 6, 1
• This resolves with smoking cessation. 6

High Altitude

• Altitude adaptation causes physiologically normal increases in hemoglobin (e.g., +1.9 g/dL at 3,000 meters, +3.5 g/dL at 4,000 meters). 1

Secondary Polycythemia (Erythropoietin-Driven, Non-Hypoxic)

Certain conditions produce erythropoietin independently of tissue oxygenation. 1, 7

• Renal cell carcinoma is a classic paraneoplastic cause, producing erythropoietin autonomously. 1, 7
• Other erythropoietin-secreting tumors include hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma. 1
• Exogenous erythropoietin therapy or testosterone use can cause iatrogenic erythrocytosis. 1
• Testosterone therapy specifically should be considered in younger adults with unexplained erythrocytosis. 1

Relative Polycythemia (Plasma Volume Depletion)

Dehydration is the most common cause of falsely elevated hemoglobin/hematocrit and must be excluded before pursuing extensive workup. 1, 4

• Severe dehydration, diarrhea, vomiting, diuretic use, capillary leak syndrome, and severe burns all cause plasma volume contraction. 6
• Verifying adequate hydration status is crucial before proceeding with polycythemia vera workup. 4
• Gaisböck syndrome (stress polycythemia) and chronic plasma volume contraction remain controversial entities with little foundation. 6

Rare Genetic Causes

Inherited disorders affecting oxygen sensing or hemoglobin function can cause familial erythrocytosis. 1, 5

• High-oxygen-affinity hemoglobin variants decrease oxygen delivery to tissues, triggering compensatory erythrocytosis. 1, 5
• Erythropoietin receptor mutations cause primary familial polycythemia. 1, 5
• Chuvash polycythemia (von Hippel-Lindau gene mutation) disrupts hypoxia sensing. 1, 5
• 2,3-BPG deficiency alters hemoglobin-oxygen affinity. 5

Diagnostic Approach for Hemoglobin 20.3 g/dL

First, confirm true polycythemia by excluding dehydration and verifying the elevated value on repeat testing. 1, 4

Initial Laboratory Workup

• Complete blood count with differential, reticulocyte count, serum ferritin, transferrin saturation, and C-reactive protein. 1
• Check for iron deficiency (low MCHC <32%, low ferritin) which can mask true erythrocytosis. 4
• Hemoglobin is more accurate than hematocrit for assessment because hematocrit can increase 2-4% with storage due to MCV changes. 1

Distinguishing Primary from Secondary Causes

• JAK2V617F mutation testing (exon 14) is first-line; if negative, proceed to JAK2 exon 12 testing. 1, 4, 2
• Serum erythropoietin level: low EPO has >90% specificity for PV, while high EPO suggests secondary polycythemia. 1, 4
• Normal EPO does not exclude PV. 4

Evaluation for Secondary Causes

• Assess smoking history and carbon monoxide exposure. 1
• Consider sleep study if nocturnal hypoxemia suspected. 1
• Evaluate for COPD or other chronic lung disease. 1
• Screen for renal cell carcinoma and other erythropoietin-secreting tumors with imaging if clinically indicated. 1, 7
• Review medication history for testosterone or erythropoietin use. 1

Bone Marrow Examination

• Bone marrow biopsy is recommended when PV is suspected, particularly before initiating cytoreductive therapy. 4
• Look for hypercellularity for age with trilineage growth (panmyelosis). 4

Critical Management Considerations at This Hemoglobin Level

At hemoglobin 20.3 g/dL, therapeutic phlebotomy is indicated ONLY if hematocrit exceeds 65% AND the patient has symptoms of hyperviscosity (headache, fatigue, poor concentration) AND dehydration has been excluded. 6, 1

Phlebotomy Guidelines

• When phlebotomy is performed, always replace with equal volume of dextrose or saline to prevent further hemoconcentration. 6
• Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke. 6, 1
• Remove only 1 unit of blood per session. 6

Iron Management

• Iron deficiency should be avoided even in the presence of erythrocytosis because iron-deficient red blood cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 6
• If iron deficiency is confirmed, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur. 6, 1
• Discontinue iron once ferritin and transferrin saturation normalize. 6

Specific Context: Cyanotic Heart Disease

• In patients with cyanotic congenital heart disease, most maintain compensated erythrocytosis with stable hemoglobin requiring no intervention. 6
• Alterations in hemoglobin tend to indicate intercurrent issues (dehydration, iron deficiency, infection) requiring their own correction rather than phlebotomy. 6

Common Pitfalls to Avoid

• Do not perform aggressive phlebotomy without confirming hyperviscosity symptoms and excluding dehydration. 6
• Do not overlook coexisting iron deficiency, which paradoxically increases thrombotic risk despite elevated hemoglobin. 6, 4
• Do not assume relative polycythemia without proper evaluation—most cases of sustained hemoglobin 20.3 g/dL represent true erythrocytosis. 6
• Do not delay JAK2 testing in patients with sustained erythrocytosis, as early PV diagnosis impacts thrombosis prevention strategies. 2