Microcytic Anemia

Definition

Pathophysiologic Framework

1. Iron (for heme)
2. Porphyrin/heme (the iron-containing ring)
3. Globin chains (protein scaffold)

"Defects in heme synthesis, in contrast to globin synthesis, are less common and may be acquired or inherited. Acquired abnormalities are usually associated with myelodysplasia, may lead to either a macro- or microcytic anemia, and are frequently associated with mitochondrial iron loading."

Etiology — The Four Major Causes

Iron Deficiency Anemia (Most Common)

1. Iron depletion — ferritin falls, no anemia yet
2. Iron-deficient erythropoiesis — low serum iron, high TIBC, reticulocyte production falls
3. Iron deficiency anemia — frank microcytic, hypochromic anemia

• Blood loss (most common in adults): GI bleeding (occult or overt), menorrhagia, parasitic infection (Hookworm)
• Inadequate intake: malnutrition, restrictive diets
• Malabsorption: celiac disease, H. pylori, post-gastrectomy, achlorhydria
• Increased demand: pregnancy, infancy, adolescence

Thalassemias

• β-Thalassemia: reduced/absent β-globin → excess α-chains precipitate and damage RBCs
• α-Thalassemia: gene deletions reduce α-chain output; severity depends on number of affected alleles (trait → HbH disease → hydrops fetalis)

Sideroblastic Anemia

• Myelodysplastic syndrome (MDS)
• Chronic alcohol use
• Drugs: isoniazid, chloramphenicol, linezolid
• Lead toxicity
• Copper deficiency

Diagnostic Approach Summary

Investigations to Rule Out Microcytic Anemia

First-Line: Complete Blood Count (CBC) with Indices

According to Harrison's (21st ed., p. 1751): "A routine complete blood count is required as part of the evaluation and includes the hemoglobin, hematocrit, and red cell indices: MCV, MCH, and MCHC."

Second-Line: Iron Studies

Per Harrison's (p. 2884): "By definition, marrow iron stores are absent when the serum ferritin level is <15 µg/L… Once the transferrin saturation falls to 15–20%, hemoglobin synthesis becomes impaired."

Third-Line: Peripheral Blood Smear

Fourth-Line: Reticulocyte Count & Reticulocyte Production Index (RPI)

• Reticulocyte count: Low (hypoproliferative) in IDA and ACD; elevated in hemolysis or after treatment
• RPI < 2: Hypoproliferative — suggests IDA, ACD, or thalassemia trait
• Hypochromic reticulocytes: Early sensitive marker of iron-deficient erythropoiesis

Hemoglobin Electrophoresis / HPLC

• To rule out thalassemia and hemoglobinopathies
• β-Thalassemia trait: ↑ HbA2 (>3.5%), ↑ HbF
• α-Thalassemia trait: often normal electrophoresis (requires DNA/PCR analysis)
• HbH disease: HbH (β4 tetramers) on electrophoresis

Additional Targeted Investigations

Diagnostic Algorithm at a Glance

Low MCV on CBC
       ↓
Iron studies + Ferritin
       ↓
 ┌─────────────────────────────────┐
 │                                 │
Low ferritin             Normal/High ferritin
(IDA)                         ↓
                    Hemoglobin Electrophoresis
                         ↓            ↓
                   Abnormal         Normal
                (Thalassemia)         ↓
                              CRP + ferritin pattern
                              ↓              ↓
                          High ferritin    ↑ Iron/Sat
                            + ↓ iron       Ring sideroblasts
                           (ACD)         (Sideroblastic)