What is the differential diagnosis for a patient presenting with elevated hemoglobin (hgb)?

Differential Diagnosis for Elevated Hemoglobin

The differential diagnosis for elevated hemoglobin divides into primary (clonal) causes—most importantly polycythemia vera—and secondary (reactive) causes including hypoxia-related conditions, renal disease, and exogenous erythropoietin exposure. 1, 2

Primary (Clonal) Causes

Polycythemia Vera (PV)

• PV is the most critical primary cause to identify, characterized by JAK2 mutations in >95% of cases (JAK2 V617F in most, JAK2 exon 12 in rare cases) 2, 3
• Diagnostic criteria require hemoglobin >16.5 g/dL in men or >16.0 g/dL in women, though masked PV can present with normal hemoglobin/hematocrit due to blood dilution or coincidental blood loss 2, 4
• Associated features include thrombocytosis (53%), leukocytosis (49%), splenomegaly (36%), pruritus (33%), and erythromelalgia (5.3%) 2
• Low or normal serum erythropoietin (EPO) level is highly suggestive (specificity >90%), though sensitivity is only ~70% 1
• Thrombosis risk is substantial: 16% arterial and 7% venous events at or before diagnosis, including unusual sites like splanchnic veins 2, 4, 5

Other Myeloproliferative Neoplasms

• Chronic myeloid leukemia (CML) can present with elevated hemoglobin and requires BCR/ABL1 fusion testing 3
• Essential thrombocythemia may have low EPO levels similar to PV 1

Congenital Polycythemias

• Activating mutations of the erythropoietin receptor (EPOR) cause low EPO levels mimicking PV 1
• NADH cytochrome b5 reductase deficiency (CYB5R3 gene mutations) causes hereditary methemoglobinemia with compensatory erythrocytosis 1

Secondary (Reactive) Causes

Hypoxia-Related

• Chronic obstructive pulmonary disease and chronic lung disease are common causes 2, 6
• Sleep apnea with chronic hypoxemia 2
• Cyanotic congenital heart disease 7
• High altitude residence 6
• Heavy tobacco smoking (carbon monoxide-induced tissue hypoxia) 2, 6

Renal Causes

• Renal cell carcinoma (inappropriate EPO production) 6
• Renal artery stenosis 6
• Polycystic kidney disease 6
• Post-renal transplantation 6

Exogenous Erythropoietin

• Erythropoietin administration (performance enhancement, chronic kidney disease treatment) 1
• Androgen therapy 6

Hemoglobin Variants

• Hemoglobin M variants (HBA1, HBA2, HBB, HBG1, HBG2 mutations) cause methemoglobinemia with compensatory erythrocytosis, presenting with cyanosis but typically asymptomatic otherwise 1
• High oxygen-affinity hemoglobin variants 1

Diagnostic Algorithm

Step 1: Confirm true erythrocytosis

• Hemoglobin >16.5 g/dL (men) or >16.0 g/dL (women), or documented increase above individual baseline 1, 2
• Look for PV-related features: thrombocytosis, leukocytosis, microcytosis from iron deficiency, splenomegaly, aquagenic pruritus, unusual thrombosis, erythromelalgia 1

Step 2: Measure serum EPO level

• Low EPO strongly suggests PV (specificity >90%) and warrants bone marrow examination 1
• Normal EPO does not exclude PV (sensitivity ~70%) and still requires further workup if clinical suspicion exists 1
• High EPO suggests secondary causes—investigate for hypoxia, renal disease, or exogenous sources 1

Step 3: JAK2 mutation testing

• Test for JAK2 V617F mutation (present in >95% of PV cases) 2, 3
• If negative, test for JAK2 exon 12 mutations 2, 3
• JAK2-negative patients with thrombosis in unusual sites still require bone marrow examination to exclude masked PV 4

Step 4: Bone marrow examination (when indicated)

• Perform when EPO is low or normal with clinical suspicion for PV 1
• Look for hypercellularity, increased megakaryocytes with clustering, giant megakaryocytes, pleomorphism, mild reticulin fibrosis, and decreased iron stores 1
• Include cytogenetic studies (abnormalities in 13-18% at diagnosis) 1

Step 5: Evaluate for secondary causes

• Arterial blood gas and oxygen saturation (rule out hypoxia) 1, 6
• Chest imaging for pulmonary disease 6
• Sleep study if sleep apnea suspected 2
• Renal imaging and function tests 6
• Smoking history and carboxyhemoglobin level 2, 6

Step 6: Consider specialized testing in equivocal cases

• Co-oximetry to measure methemoglobin levels if cyanosis present 1, 8
• Hemoglobin electrophoresis or HPLC for hemoglobin variants 9
• CYB5R3 enzyme activity and genetic testing if hereditary methemoglobinemia suspected 1, 7
• Red cell mass measurement rarely needed (costly and adds limited value when hematocrit >60% without obvious hemoconcentration) 1

Critical Pitfalls to Avoid

• Do not dismiss normal hemoglobin/hematocrit in patients with thrombosis in unusual sites—masked PV can present this way and requires JAK2 testing and bone marrow examination 4
• Do not rely solely on elevated hemoglobin threshold—documented increase above individual baseline warrants investigation even within reference range 1
• Do not overlook additional mutations in JAK2-positive patients—TET2 (19%), DNMT3A (3.4%), and ASXL1 (3.4%) mutations occur in 34.5% of PV patients and affect prognosis 3
• Do not forget BCR/ABL1 testing—CML can present with erythrocytosis and must be excluded 3
• Do not misinterpret pulse oximetry in cyanotic patients—methemoglobinemia causes falsely reassuring readings and requires co-oximetry for diagnosis 8