What is the diagnostic approach for iron deficiency anemia?

Diagnostic Approach for Iron Deficiency Anemia

Initial Laboratory Confirmation

Diagnose iron deficiency anemia by confirming both anemia (hemoglobin below laboratory-specific normal range) and iron deficiency through serum ferritin measurement, with interpretation dependent on inflammatory status. 1

Step 1: Confirm Anemia

• Use hemoglobin concentration below the lower limit of normal for your laboratory's reference range 1
• Hemoglobin is preferred over hematocrit due to better reproducibility across laboratories 2
• Any level of anemia warrants investigation when iron deficiency is present—severity does not determine need for workup 1

Step 2: Essential Initial Blood Tests

Obtain the following minimum workup 2:

• Complete blood count with red cell indices (MCV, MCH, RDW) 1, 2
• Serum ferritin (most powerful single test for iron deficiency) 1
• Transferrin saturation 1, 2
• Inflammatory markers (C-reactive protein) 1, 2

Step 3: Interpret Iron Studies Based on Inflammatory State

Without inflammation present:

• Serum ferritin <30 μg/L is diagnostic of iron deficiency 1, 2
• Transferrin saturation <16% supports the diagnosis 1, 2

With inflammation or chronic disease:

• Serum ferritin up to 100 μg/L may still indicate iron deficiency 1, 2
• If ferritin is 30-100 μg/L with transferrin saturation <20%, suspect combined iron deficiency and anemia of chronic disease 1
• Ferritin >100 μg/L with transferrin saturation <20% suggests anemia of chronic disease 1

Step 4: Evaluate Red Cell Indices

• Microcytosis (low MCV) is characteristic of iron deficiency but may be absent in combined deficiencies 1, 2
• Elevated red cell distribution width (RDW) indicates iron deficiency even when MCV appears normal due to coexisting micro- and macrocytosis 1, 2
• Consider hemoglobin electrophoresis in appropriate ethnic populations to exclude thalassemia before pursuing gastrointestinal investigation 1

Extended Workup When Diagnosis Remains Unclear

If initial testing is equivocal, obtain 2:

• Vitamin B12 and folate levels
• Haptoglobin and lactate dehydrogenase
• Soluble transferrin receptor (sTfR)—elevated levels indicate true iron deficiency and help differentiate from anemia of chronic disease 2
• Percentage of hypochromic red cells or reticulocyte hemoglobin content 2

Confirming Iron Deficiency Through Therapeutic Trial

A hemoglobin rise ≥10 g/L within 2 weeks of iron therapy is highly suggestive of absolute iron deficiency, even if iron studies are equivocal. 1

Mandatory Gastrointestinal Investigation

All postmenopausal women and all men with confirmed iron deficiency anemia require upper and lower gastrointestinal investigation unless there is obvious non-gastrointestinal blood loss. 1

Celiac Disease Screening

• All patients must be screened for celiac disease with tissue transglutaminase antibody (IgA type) and total IgA level 1, 3
• Obtain duodenal biopsies during upper endoscopy as 2-3% of iron deficiency anemia patients have celiac disease 1

Bidirectional Endoscopy

• Perform both upper endoscopy (esophagogastroduodenoscopy) and colonoscopy 1, 3
• Upper endoscopy reveals a cause in 30-50% of patients 1
• Only advanced gastric cancer or celiac disease found on upper endoscopy should deter lower gastrointestinal investigation 1
• Colonoscopy is preferred over CT colonography, though either is acceptable and both are superior to barium enema 1

Premenopausal Women

• Screen for celiac disease in all premenopausal women 1
• Consider bidirectional endoscopy based on clinical judgment, particularly if age >40 years, marked anemia, or significant family history of colorectal carcinoma 1

Further Investigation for Refractory Cases

Small bowel investigation (capsule endoscopy, CT or MRI enterography) is indicated only when 1, 3:

• Symptoms suggest small bowel disease
• Hemoglobin cannot be restored or maintained with iron therapy
• Red flags present (involuntary weight loss, abdominal pain, elevated CRP) 3

Special Considerations

Chronic Inflammatory Conditions

In patients with inflammatory bowel disease, chronic kidney disease, heart failure, or cancer, use ferritin <100 μg/L as the diagnostic threshold and consider functional iron deficiency 1, 2

Common Pitfalls to Avoid

• Do not rely on hemoglobin and hematocrit alone—they decrease only with severe iron depletion and can miss early iron deficiency 4
• Do not perform fecal occult blood testing—it provides no benefit in iron deficiency anemia investigation 1
• Do not assume dietary insufficiency or NSAID use as the sole cause without completing gastrointestinal investigation 1
• In patients with negative bidirectional endoscopy and recurrent iron deficiency anemia, test for and eradicate Helicobacter pylori if present 1