7.1 Approach to Anemia & the Microcytic Anemias

Anemia is defined as a reduction in circulating red blood cell (RBC) mass, clinically quantified by a hemoglobin (Hb) < 13.0 g/dL in adult men or < 12.0 g/dL in non-pregnant adult women. A rigorous, algorithmic approach rooted in bone marrow kinetics and erythrocyte morphology is essential for accurate diagnosis and management on the ABIM Internal Medicine board exam.

1. Initial Diagnostic Algorithm & Reticulocyte Kinetics

The initial evaluation of anemia begins with two fundamental parameters:

1. The Reticulocyte Production Index (RPI / Reticulocyte Index [RI]): Assesses bone marrow erythropoietic response.
2. The Mean Corpuscular Volume (MCV): Classifies anemia into microcytic (< 80 fL), normocytic (80–100 fL), or macrocytic (> 100 fL).

Calculating the Reticulocyte Index (RI)

Because the raw reticulocyte percentage can be misleading in anemic patients, it must be corrected for the patient's degree of anemia and the premature release of "shift reticulocytes" from the marrow:

$\text{Corrected Reticulocyte \%} = \text{Reticulocyte \%} \times \left( \frac{\text{Patient's Hematocrit}}{45} \right)$

$\text{Reticulocyte Index (RI)} = \frac{\text{Corrected Reticulocyte \%}}{\text{Maturation Factor (Shift Factor)}}$

• RI < 2.0% (Hypoproliferative / Ineffective Erythropoiesis): Bone marrow failure, nutrient deficiencies (iron, B12, folate), anemia of chronic disease/inflammation, renal failure (erythropoietin deficiency), or myelodysplasia.
• RI ≥ 2.0% (Hyperproliferative Response): Active hemolysis or recovery from acute blood loss (with adequate iron and nutrient stores).

2. Microcytic Anemias (MCV < 80 fL)

Microcytosis reflects a defect in hemoglobin synthesis: heme synthesis defects (iron deficiency, sideroblastic anemia) or globin chain synthesis defects (thalassemias).

Iron Deficiency Anemia (IDA)

• Etiology & Mandatory Clinical Workup: In adult men of any age and postmenopausal women, IDA is considered gastrointestinal bleeding from an occult malignancy (colorectal adenocarcinoma, gastric cancer) until proven otherwise. Perform bidirectional endoscopy (esophagogastroduodenoscopy [EGD] and colonoscopy) promptly. In premenopausal women, evaluate for menorrhagia, celiac disease (anti-tissue transglutaminase IgA), or pregnancy.
• Treatment:
  • Oral Iron: Ferrous sulfate 325 mg (65 mg elemental iron) administered every other day or once daily. Alternate-day dosing reduces serum hepcidin spikes, maximizing fractional intestinal iron absorption and significantly minimizing GI side effects (constipation, nausea).
  • Intravenous (IV) Iron (Ferric carboxymaltose, Iron sucrose, Ferumoxytol): First-line for oral iron intolerance/failure, active inflammatory bowel disease (IBD), celiac disease/malabsorption, chronic kidney disease (CKD on hemodialysis or erythropoiesis-stimulating agents [ESAs]), second/third trimester pregnancy with severe anemia, and heart failure with reduced ejection fraction (HFrEF with ferritin < 100 or ferritin 100–299 with TSAT < 20% to improve functional capacity).

Thalassemia Syndromes

• Beta-Thalassemia Trait (Minor): Point mutations in the HBB gene on chromosome 11. Characterized by profound microcytosis (MCV often 55–70 fL) with mild anemia and elevated RBC count. Hemoglobin Electrophoresis: Diagnostic hallmark is elevated Hemoglobin A2 (HbA2 > 3.5%) and variably elevated HbF (1–5%).
• Alpha-Thalassemia Trait: Deletions of 1 or 2 of the 4 alpha-globin genes (HBA1/HBA2) on chromosome 16. Two-gene deletion (α-thal trait / minor: α-/α- [trans, common in African descent] or --/αα [cis, common in Southeast Asian descent with risk of Hb Barts hydrops fetalis in offspring]). Hemoglobin electrophoresis in adults is completely normal; diagnosis is confirmed via alpha-globin genetic DNA deletion testing.

Anemia of Chronic Disease / Inflammation

• Pathophysiology: Driven by inflammatory cytokines (principally Interleukin-6 [IL-6]), which stimulate hepatic synthesis of Hepcidin. Hepcidin binds and degrades the iron exporter Ferroportin-1 on enterocytes and macrophages, trapping iron inside reticuloendothelial stores, reducing intestinal iron absorption, and blunting erythropoietin response.

Sideroblastic Anemia

• Pathophysiology: Impaired heme synthesis leading to mitochondrial iron accumulation around the erythrocyte nucleus, visualized as ring sideroblasts on bone marrow aspirate with Prussian blue stain.
• Causes: Hereditary (X-linked ALAS2 mutation), acquired clonal (Myelodysplastic Syndrome with ring sideroblasts [MDS-RS, SF3B1 mutation]), or secondary to toxins/medications: lead poisoning (coarse basophilic stippling, lead lines on gingiva, wrist drop; treat with EDTA/Dimercaprol or Succimer), alcohol abuse, isoniazid (INH) toxicity (inhibits pyridoxine phosphokinase; treat/prevent with Pyridoxine / Vitamin B6), and copper deficiency / zinc toxicity.