Diagnostic Workup and Management of Microcytic Anemia
Initial Diagnostic Approach
Serum ferritin is the single most powerful first-line test for microcytic anemia, with a cut-off of 45 μg/L providing optimal sensitivity and specificity in clinical practice. 1
Primary Laboratory Tests
Order serum ferritin, transferrin saturation (TSAT), and C-reactive protein (CRP) together as the initial diagnostic panel to distinguish iron deficiency from other causes of microcytosis 1
Ferritin <15 μg/L confirms absent iron stores with 99% specificity for iron deficiency anemia 1
Ferritin <30 μg/L indicates depleted iron stores consistent with iron deficiency 1
Ferritin >150 μg/L makes absolute iron deficiency unlikely even when inflammation is present 1
TSAT <16–20% confirms iron deficiency, particularly when ferritin may be falsely elevated by inflammation 1
Interpreting Results in the Context of Inflammation
When CRP is elevated, ferritin up to 100 μg/L may still represent iron deficiency because ferritin behaves as an acute-phase reactant 1
Add TSAT when ferritin appears falsely normal due to inflammation; TSAT <20% with ferritin >100 μg/L indicates anemia of chronic disease rather than true iron deficiency 1
Red Cell Indices for Differential Diagnosis
Low MCV with RDW >14% strongly suggests iron deficiency anemia, reflecting a mixed population of older normal-sized cells and newer microcytic cells 1
Low MCV with RDW ≤14% suggests thalassemia minor, where red cells are uniformly small 1
Mean corpuscular hemoglobin (MCH) is more reliable than MCV for detecting iron deficiency because it is less affected by specimen storage conditions 1
Investigation of Underlying Cause
Once iron deficiency is confirmed, a systematic search for the source of iron loss is mandatory rather than simply treating with iron supplementation alone. 1
Gastrointestinal Evaluation
Adult males with hemoglobin <110 g/L should receive fast-track gastrointestinal referral for both upper endoscopy and colonoscopy 1
Non-menstruating women with hemoglobin <100 g/L warrant fast-track GI referral 1
Investigation should be considered at any level of anemia with confirmed iron deficiency, especially with more severe degrees 1
Upper endoscopy with duodenal biopsies is mandatory to exclude celiac disease, which accounts for 2–3% of iron deficiency anemia cases 1
Colonoscopy is particularly high-yield in older adults for detecting colonic carcinoma, adenomatous polyps, and angiodysplasia 1
Do not accept upper GI findings (esophagitis, erosions, peptic ulcer) as the sole cause without also examining the lower GI tract, because dual pathology is present in approximately 10–15% of patients 1
Additional Causes to Evaluate
In premenopausal women, heavy menstrual bleeding is the most common cause, but gastrointestinal evaluation is still required unless menstrual loss fully accounts for the anemia 1
Screen for celiac disease serologically before endoscopic evaluation 1
Assess dietary history for inadequate iron intake, particularly vegetarian or vegan diets in adolescents 2
Review medications carefully for NSAIDs, which are a common cause of occult gastrointestinal blood loss 2
Treatment Protocol
First-Line Oral Iron Therapy
The first-line treatment is oral iron supplementation with ferrous sulfate 200 mg three times daily for at least three months after correction of anemia to replenish iron stores. 1
Alternative formulations include ferrous gluconate and ferrous fumarate if ferrous sulfate is not tolerated 1
Ascorbic acid can be added to enhance iron absorption 1
A hemoglobin rise ≥10 g/L within 2 weeks confirms iron deficiency even when iron studies are equivocal 1
Expected hemoglobin increase is at least 2 g/dL within 4 weeks of starting treatment 1
Monitoring Response
Monitor hemoglobin concentration and red cell indices at three-monthly intervals for one year, then after a further year 1
Provide additional oral iron if hemoglobin or MCV falls below normal 1
Management of Treatment Failure
If the patient fails to respond to oral iron therapy within 2–4 weeks, consider non-compliance, ongoing blood loss, malabsorption, or rare genetic disorders. 1
Indications for Intravenous Iron
Consider intravenous iron if malabsorption is present (e.g., celiac disease, inflammatory bowel disease, post-gastrectomy) 1
IV iron formulations include iron sucrose or ferric carboxymaltose, with expected hemoglobin increase of at least 2 g/dL within 4 weeks 1
When to Order Hemoglobin Electrophoresis
Order hemoglobin electrophoresis only after iron studies are normal or borderline, or when the MCV is disproportionately low relative to the degree of anemia, or when the patient belongs to a high-risk ethnic group (African, Mediterranean, or Southeast Asian ancestry). 1
Failure of anemia to improve after 4 weeks of adequate oral iron therapy despite good compliance warrants hemoglobin electrophoresis to evaluate for thalassemia or other hemoglobinopathies 1
Patients with beta-thalassemia trait usually have elevated levels of hemoglobin A2 3
Rare Genetic Disorders to Consider
Iron-refractory iron deficiency anemia (IRIDA) presents with remarkably low TSAT, low-to-normal ferritin, and failure to respond to oral iron but may respond to IV iron 1
X-linked sideroblastic anemia (ALAS2 defects) should be treated initially with pyridoxine (vitamin B6) 50–200 mg daily, then 10–100 mg daily lifelong if responsive 1
Genetic testing for disorders like SLC11A2, STEAP3, SLC25A38, ALAS2, or ABCB7 should be considered if extreme microcytosis (MCV <70) or family history of refractory anemia is present 1
Critical Pitfalls to Avoid
Do not assume all microcytic anemia is iron deficiency; anemia of chronic disease, thalassemia, and sideroblastic anemia require different management 1
Do not rely on ferritin alone in inflammatory states; add TSAT to accurately diagnose iron deficiency 1
Do not overlook combined deficiencies; iron deficiency can coexist with B12 or folate deficiency, recognizable by elevated RDW 1
Do not use hemoglobin electrophoresis as a first-line investigation; it is costly and unnecessary when iron studies are abnormal 1
Do not attribute severe iron deficiency anemia in the elderly solely to dietary insufficiency; mandatory GI evaluation is essential 1
In elderly patients on anticoagulants, do not attribute melena solely to oral iron supplementation, as this delays recognition of life-threatening GI bleeding 1
Do not give iron therapy empirically when ferritin is markedly elevated (e.g., in sideroblastic anemia), because hepcidin-mediated sequestration prevents utilization and may cause iron overload 1