What is the appropriate workup for suspected iron‑deficiency anemia?

Iron Deficiency Anemia Workup

The minimum workup for suspected iron‑deficiency anemia includes complete blood count with red‑cell indices (MCV, RDW), reticulocyte count, serum ferritin, transferrin saturation, and C‑reactive protein. 1

Initial Laboratory Assessment

Core Tests (Minimum Workup)

• Order a complete blood count with mean corpuscular volume (MCV) and red‑cell distribution width (RDW) to identify microcytosis and assess red‑cell size variability. 1
• Measure serum ferritin, which is the most powerful single test for iron deficiency; ferritin <30 μg/L confirms absolute iron deficiency in the absence of inflammation. 1
• Obtain transferrin saturation (calculated from serum iron and total iron‑binding capacity); values <20% indicate iron‑restricted erythropoiesis. 1
• Check C‑reactive protein (CRP) to detect inflammation, because ferritin behaves as an acute‑phase reactant and may be falsely elevated when inflammation is present. 1
• Measure reticulocyte count to distinguish inadequate bone‑marrow response (low or normal reticulocytes) from hemolysis or acute blood loss (elevated reticulocytes). 1

Interpreting Ferritin in the Presence of Inflammation

• When CRP is elevated or clinical inflammation is present, use ferritin <100 μg/L combined with transferrin saturation <20% to diagnose iron deficiency, because inflammation raises ferritin independently of iron stores. 1
• Ferritin 30–100 μg/L with low transferrin saturation suggests mixed iron‑deficiency anemia and anemia of chronic disease. 1

Extended Workup (When Initial Tests Are Equivocal or Anemia Persists)

• Measure vitamin B12 and folate levels if macrocytosis is present (MCV >100 fL) or if the patient has risk factors such as extensive small‑bowel resection, ileal Crohn's disease, or strict vegan diet. 1
• Order haptoglobin, lactate dehydrogenase, and indirect bilirubin if reticulocyte count is elevated, to evaluate for hemolysis. 1
• Consider soluble transferrin receptor measurement when ferritin is 30–100 μg/L and inflammation is present, to distinguish true iron deficiency from anemia of chronic disease. 1
• Check percentage of hypochromic red cells and reticulocyte hemoglobin content if available, as these are sensitive markers of functional iron deficiency. 1
• Measure creatinine and urea to assess renal function, because chronic kidney disease alters iron metabolism and anemia management. 1

Screening for Malabsorption

• Perform celiac disease screening with tissue transglutaminase IgA antibody and total IgA measurement in all patients with confirmed iron deficiency, because celiac disease is present in 2–5% of cases and can cause treatment failure if missed. 1, 2, 3
• Test for Helicobacter pylori infection using stool antigen or urea breath test, especially in patients with recurrent iron deficiency after initial correction. 1, 3

Hemoglobin Electrophoresis

• Order hemoglobin electrophoresis in patients of African, Mediterranean, or Southeast Asian ancestry who have microcytosis and hypochromia, to exclude thalassemia trait before pursuing extensive gastrointestinal investigation. 1

Red‑Cell Distribution Width (RDW)

• An elevated RDW (>15%) indicates a wide size range of red cells and is a sensitive marker of iron deficiency, particularly useful when microcytosis and macrocytosis coexist and neutralize each other to produce a normal MCV. 1

Gastrointestinal Investigation

Indications for Endoscopy

• Perform bidirectional endoscopy (upper endoscopy with duodenal biopsies and colonoscopy) in all adult men and postmenopausal women with confirmed iron‑deficiency anemia, because gastrointestinal malignancy may present solely with iron deficiency. 1, 3
• In premenopausal women, first assess menstrual blood loss and screen for celiac disease; reserve endoscopy for those ≥50 years, those with gastrointestinal symptoms (dyspepsia, altered bowel habits, rectal bleeding), alarm features, or a family history of colorectal cancer. 1, 3
• Colonoscopy is preferred over CT colonography for lower gastrointestinal investigation because it allows biopsy and polypectomy; either is acceptable and both are superior to barium enema. 1
• Only the presence of advanced gastric cancer or confirmed celiac disease on upper endoscopy should deter subsequent lower gastrointestinal investigation. 1

Small‑Bowel Investigation

• Further direct visualization of the small bowel with video capsule endoscopy or CT/MRI enterography is not necessary unless there are symptoms suggestive of small‑bowel disease (abdominal pain, weight loss, elevated CRP) or if hemoglobin cannot be restored or maintained with iron therapy despite normal upper and lower endoscopy. 1, 3

Faecal Occult Blood Testing

• Do not use faecal occult blood testing in the investigation of iron‑deficiency anemia, because it has no diagnostic benefit and does not replace the need for endoscopy. 1

Common Pitfalls to Avoid

• Do not rely on hemoglobin alone to define anemia severity; any level of anemia should be investigated when iron deficiency is present, because the lower the hemoglobin, the more likely there is serious underlying pathology. 1
• Do not use general‑population ferritin cut‑offs in patients with chronic inflammatory conditions (inflammatory bowel disease, chronic kidney disease, rheumatoid arthritis); apply higher thresholds (ferritin <100 μg/L) to avoid missing iron deficiency. 1
• Do not overlook vitamin B12 or folate deficiency in patients with extensive small‑bowel disease, because combined deficiencies blunt the hemoglobin response to iron therapy. 1
• Do not miss celiac disease screening; its prevalence of 2–5% in iron‑deficiency cases means failure to screen can lead to persistent anemia despite iron supplementation. 1, 2, 3
• Do not delay endoscopic evaluation in high‑risk patients (age ≥50, alarm symptoms, or treatment failure), as gastrointestinal malignancy may present solely with iron deficiency. 1, 3

Algorithmic Approach to Workup

1. Confirm anemia using WHO criteria: hemoglobin <12 g/dL in women, <13 g/dL in men. 1
2. Confirm iron deficiency: ferritin <30 μg/L (or <100 μg/L if inflammation present) and transferrin saturation <20%. 1
3. Check reticulocyte count: low/normal suggests deficiency or bone‑marrow disease; elevated suggests hemolysis or acute blood loss. 1
4. Screen for celiac disease with tissue transglutaminase IgA and total IgA in all patients. 1, 3
5. Assess MCV: microcytosis (MCV <80 fL) supports iron deficiency; macrocytosis (MCV >100 fL) prompts B12/folate testing; normal MCV with high RDW suggests coexisting deficiencies. 1
6. Perform bidirectional endoscopy in men and postmenopausal women; in premenopausal women, first evaluate menstrual loss and reserve endoscopy for those with risk factors. 1, 3
7. Consider small‑bowel investigation only if symptoms suggest small‑bowel disease or if anemia persists despite normal upper and lower endoscopy and adequate iron therapy. 1, 3

When to Seek Hematology Consultation

• Consult a hematologist if the cause of anemia remains unclear after completing the extended workup, including bidirectional endoscopy and celiac screening. 1
• Seek hematology input if anemia does not resolve within 6 months of appropriate iron therapy and treatment of the underlying cause. 1