What is the workup for borderline high hemoglobin (elevated hemoglobin)?

Diagnostic Workup for Borderline High Hemoglobin

The diagnostic workup for borderline high hemoglobin should begin with a systematic approach to differentiate between relative and absolute erythrocytosis, with particular focus on ruling out polycythemia vera as the most serious underlying cause.

Initial Evaluation

Step 1: Confirm True Elevation

• Verify that hemoglobin is truly elevated based on sex-specific thresholds:
  • Men: >16.5 g/dL
  • Women: >16.0 g/dL
• Repeat measurement to rule out laboratory error or transient elevation
• Consider dehydration as a potential cause of relative erythrocytosis

Step 2: Basic Laboratory Workup

• Complete blood count with differential
• Peripheral blood smear examination
• Comprehensive metabolic panel
• Serum erythropoietin (EPO) level 1
  • Low EPO suggests primary erythrocytosis (polycythemia vera)
  • Normal/high EPO suggests secondary erythrocytosis

Step 3: Differentiate Primary vs. Secondary Causes

For Low EPO (Suspicious for Polycythemia Vera):

• Bone marrow examination with cytogenetic studies 1
• JAK2 V617F mutation testing
• If JAK2 V617F negative, test for JAK2 exon 12, CALR, and MPL mutations
• Consider red cell mass measurement in borderline cases

For Normal/High EPO (Secondary Causes):

• Arterial blood gas analysis to assess oxygenation
• Pulmonary function tests
• Sleep study to rule out obstructive sleep apnea
• Abdominal imaging (CT or ultrasound) to evaluate kidneys and liver
• Hemoglobin electrophoresis to identify high-oxygen-affinity hemoglobin variants 2
• P50 testing (oxygen-hemoglobin dissociation curve) 2
• Consider sequencing of HBA1, HBA2, and HBB genes if high-oxygen-affinity hemoglobin is suspected 2

Special Considerations

Medications and Substances

• Review all medications that may affect hemoglobin levels
• Assess for anabolic steroid use
• Screen for tobacco use (increases carboxyhemoglobin)
• Evaluate alcohol consumption 3

Methemoglobinemia Assessment

• Consider methemoglobinemia if cyanosis is present despite normal oxygen saturation
• Measure methemoglobin levels using co-oximetry 1, 4
• Screen for G6PD deficiency before administering methylene blue if methemoglobinemia is present 4

Other Important Tests

• Glucose-6-phosphate dehydrogenase (G6PD) level 1
• Evaluation for common drug causes of hemolysis 1
• Assessment of iron status (ferritin, transferrin saturation)
• Renal function tests

Common Pitfalls and Caveats

1. Failure to distinguish relative from absolute erythrocytosis

   • Relative erythrocytosis (plasma volume contraction) may be due to dehydration, diuretics, or stress polycythemia
   • Absolute erythrocytosis represents true increase in red cell mass

2. Overlooking high-oxygen-affinity hemoglobin variants

   • Normal venous P50 does not completely rule out high-oxygen-affinity hemoglobin 2
   • Consider genetic testing even with normal P50 in idiopathic erythrocytosis

3. Missing secondary causes in young adults

   • Young adults with erythrocytosis often have secondary causes such as smoking, obesity, or recreational drug use 3
   • Secondary erythrocytosis due to hypoxia is the most common etiology in young adults 3

4. Antiretroviral therapy effect

   • Some antiretroviral drugs (particularly zidovudine and stavudine) can affect hemoglobin values 5
   • Consider this factor when evaluating HIV-positive patients

5. Inadequate follow-up

   • Studies show frequent lack of follow-up after initial investigations 3
   • Establish a clear follow-up plan for patients with unexplained erythrocytosis

By following this systematic approach, clinicians can effectively evaluate borderline high hemoglobin levels and identify underlying causes that may require specific management to reduce morbidity and mortality.