What is the workup for a patient with decreased hemoglobin (Hb) and ferritin of unknown cause?

Workup of Decreased Hemoglobin and Ferritin of Unknown Cause

The comprehensive workup for a patient with decreased hemoglobin and ferritin of unknown cause should include complete blood count with indices, reticulocyte count, iron studies (transferrin saturation, serum ferritin), inflammatory markers, and specific testing for vitamin deficiencies. 1

Initial Laboratory Assessment

Minimum Required Testing

• Complete blood count (CBC) with:
  • Hemoglobin level
  • Red cell indices (MCV, MCH, MCHC)
  • Red cell distribution width (RDW)
  • White blood cell count and differential
  • Platelet count
• Reticulocyte count
• Iron studies:
  • Serum ferritin
  • Transferrin saturation (TSAT)
  • Serum iron
  • Total iron binding capacity (TIBC)
• C-reactive protein (CRP) or other inflammatory markers 1

Additional First-Line Testing

• Vitamin B12 and folate levels
• Renal function tests (creatinine, BUN)
• Liver function tests 1

Interpretation of Initial Results

Evaluating Iron Deficiency

• Low ferritin (<30 μg/L in women, <100 μg/L in men) is the most specific indicator of iron deficiency 1, 2
• However, ferritin is an acute phase reactant and may be falsely elevated in inflammatory conditions
• When ferritin is low with normal or high TSAT (>20%), consider iron deficiency anemia
• When ferritin is high (>300 μg/L) with low TSAT (<20%), consider anemia of inflammation 1

Red Cell Indices Analysis

• Microcytosis (MCV <80 fL) suggests iron deficiency or thalassemia
• Macrocytosis (MCV >100 fL) suggests vitamin B12/folate deficiency or medication effects
• High RDW indicates iron deficiency even when MCV is normal 1, 3
• Reticulocyte count helps distinguish between production problems (low count) versus blood loss or hemolysis (high count) 1

Advanced Testing for Unclear Cases

Additional Laboratory Testing

• Reticulocyte hemoglobin content (CHr) - values <26 pg strongly suggest iron deficiency 4, 5
• Percentage of hypochromic red cells
• Soluble transferrin receptor (when available)
• Hepcidin levels (when available) 1
• Hemoglobin electrophoresis (if thalassemia suspected)

Specialized Testing Based on Clinical Suspicion

• Bone marrow examination with iron staining (when diagnosis remains unclear after non-invasive testing) 4
• Endoscopic evaluation (if GI blood loss suspected)
• Hemolysis panel (if hemolytic anemia suspected):
  • Haptoglobin
  • Lactate dehydrogenase
  • Bilirubin 1

Diagnostic Algorithm

1. Confirm true anemia: Compare hemoglobin to WHO thresholds (<13 g/dL for men, <12 g/dL for non-pregnant women) 1

2. Assess iron status:

   • If ferritin <30 μg/L (women) or <100 μg/L (men) with low TSAT (<20%): Iron deficiency confirmed
   • If ferritin 100-300 μg/L with low TSAT (<20%): Consider functional iron deficiency or anemia of inflammation
   • If ferritin >300 μg/L with low TSAT (<20%): Likely anemia of inflammation 1

3. Evaluate reticulocyte response:

   • Low/normal reticulocytes: Production problem (iron deficiency, chronic disease)
   • High reticulocytes: Blood loss or hemolysis 1

4. Consider specific etiologies based on pattern:

   • Microcytic, low ferritin: Classic iron deficiency (investigate source of blood loss)
   • Normocytic, low/normal ferritin with inflammation: Anemia of chronic disease
   • Macrocytic: Check B12/folate, medication review, alcohol history
   • Pancytopenia: Consider bone marrow disorders 1

Common Pitfalls and Considerations

1. Ferritin interpretation: Ferritin is an acute phase reactant and may be falsely elevated in inflammatory conditions. In patients with inflammation, iron deficiency may be present despite "normal" ferritin values (up to 100 μg/L) 1

2. Mixed anemias: Multiple causes of anemia can coexist (e.g., iron deficiency plus B12 deficiency), which may result in normal MCV despite significant abnormalities 1

3. Chronic kidney disease: Patients with CKD may have complex anemia with multiple contributing factors including iron deficiency, reduced erythropoietin production, and inflammation 1

4. Heart failure: Consider iron deficiency even with normal hemoglobin in heart failure patients, as iron deficiency alone can worsen exercise capacity and outcomes 1

5. Hemochromatosis: In patients with unexpectedly high ferritin, consider genetic hemochromatosis and check transferrin saturation (typically >45%) 1

By following this systematic approach to the workup of decreased hemoglobin and ferritin, clinicians can efficiently diagnose the underlying cause and initiate appropriate treatment to improve patient outcomes.