Microcytic & Macrocytic Anemias

Classifying anemia by MCV and RDW

MCV bins. After confirming true anemia with hemoglobin and hematocrit, the mean corpuscular volume sorts it: microcytic under 80 fL, normocytic 80–100 fL, macrocytic over 100 fL. The red cell distribution width (RDW) measures size variation (anisocytosis) and refines the workup.

Microcytic = TAILS. Thalassemia, Anemia of chronic disease, Iron deficiency, Lead poisoning and Sideroblastic anemia all reflect defective hemoglobin production: too little globin, too little iron delivered, or failed heme synthesis. With too little hemoglobin, precursors undergo extra divisions and end up small.

RDW and the Mentzer index. Iron deficiency gives a HIGH RDW (older normal-sized cells mixed with newer small ones), whereas thalassemia gives a NORMAL RDW (uniformly small cells); high RDW plus low MCV strongly suggests iron deficiency. The Mentzer index (MCV ÷ RBC count) under 13 favors thalassemia, whose RBC count is relatively high, and over 13 favors iron deficiency.

Iron deficiency and anemia of chronic disease

Iron handling. Iron is absorbed as Fe²⁺ in the duodenum, exits enterocytes and macrophages through ferroportin, travels on transferrin, and is stored as ferritin. Hepcidin, made by the liver, degrades ferroportin and so is the master switch: it blocks both gut absorption and macrophage iron release.

Iron deficiency anemia (IDA). The most common anemia worldwide. Ferritin falls first as stores empty; serum iron and transferrin saturation then fall while TIBC (transferrin) rises. RDW rises early, and the anemia becomes microcytic and hypochromic. Low ferritin is the most specific marker of depleted stores unless inflammation raises it. Causes are chronic blood loss (menorrhagia, GI bleeding, hookworm worldwide), increased demand (pregnancy, growth), and malabsorption (celiac disease, gastrectomy).

In adult men and postmenopausal women, IDA is colorectal cancer until proven otherwise; in premenopausal women, think menorrhagia.

Clinical clues. Fatigue, pica (ice craving = pagophagia), koilonychia (spoon nails), glossitis and restless legs. Plummer-Vinson syndrome is the triad of iron deficiency, esophageal webs and dysphagia and raises the risk of esophageal squamous cell carcinoma.

Anemia of chronic disease (ACD). Chronic infection, autoimmune disease or cancer raises hepcidin (driven by IL-6), which degrades ferroportin and traps iron in macrophages and enterocytes: iron is present but unavailable. Serum iron is low, TIBC low, ferritin (an acute-phase reactant) high or normal, and saturation normal to low. The anemia is usually normocytic but can become microcytic. High ferritin with low iron and low TIBC means ACD, not IDA.

Thalassemia, sideroblastic anemia and lead

Thalassemias. These inherited defects of globin-chain synthesis have NORMAL iron studies and target cells. α-Thalassemia (chromosome 16) usually results from gene deletions; β-thalassemia (chromosome 11) from point mutations. Microcytosis is out of proportion to the mild anemia, and the RDW is often normal because the cells are uniformly small.

β-Thalassemia. Reduced β chains shift production toward δ chains, so HbA₂ (α₂δ₂) rises above 3.5% in the minor form. The major form appears after about 6 months as HbF falls: marrow expansion widens the skull and facial bones, extramedullary hematopoiesis enlarges the liver and spleen, and transfusions plus increased gut absorption cause secondary iron overload.

Sideroblastic anemia. Defective heme synthesis strands iron in the mitochondria that ring the nucleus of erythroid precursors, forming ringed sideroblasts on marrow Prussian blue stain. Iron studies mimic overload: high iron, high ferritin, high saturation, low-normal TIBC. Causes are lead, alcohol, isoniazid (B6 depletion), myelodysplasia and the X-linked ALAS2 defect. Pyridoxine (B6) is the ALA synthase cofactor, so isoniazid-induced sideroblastic anemia responds to B6.

Lead poisoning. Lead inhibits ALA dehydratase and ferrochelatase, blocking heme synthesis and raising protoporphyrin; the smear shows basophilic stippling (aggregated ribosomes), with a sideroblastic picture in the marrow. Adults are exposed through batteries and ammunition and develop wrist or foot drop; children eating old paint chips develop encephalopathy, Burton gum lines and abdominal colic. Treat with chelation: succimer in children, or EDTA plus dimercaprol for severe poisoning.

Macrocytic anemias

Megaloblastic anemia. Impaired DNA synthesis lets the cytoplasm mature faster than the nucleus, producing large marrow megaloblasts, macro-ovalocytes, hypersegmented neutrophils (over 5 lobes) and often mild pancytopenia. Many precursors die in the marrow (ineffective erythropoiesis), raising LDH and indirect bilirubin. B12 or folate deficiency is the usual cause; drugs that impair DNA synthesis (methotrexate, hydroxyurea, 5-FU, phenytoin, zidovudine) produce the same macrocytosis.

Why MMA separates B12 from folate. Folate supplies one-carbon units for thymidine synthesis, and B12-dependent methionine synthase regenerates folate while converting homocysteine to methionine, so both deficiencies raise homocysteine. B12 is also the cofactor for methylmalonyl-CoA mutase, so only B12 deficiency raises methylmalonic acid (MMA).

B12 deficiency and the spinal cord. B12 deficiency causes subacute combined degeneration of the dorsal columns (lost vibration and proprioception), lateral corticospinal tracts (weakness, upgoing toes) and spinocerebellar tracts (ataxia), plus peripheral neuropathy. Causes are pernicious anemia (antibodies to intrinsic factor and parietal cells), terminal ileum disease or resection, Diphyllobothrium latum, and a strict vegan diet. Folate deficiency (poor diet, alcoholism, pregnancy, methotrexate) spares the nervous system.

Never give folate alone to a B12-deficient patient: it corrects the anemia but lets the neuropathy progress.

Non-megaloblastic macrocytosis. DNA synthesis is normal and there are NO hypersegmented neutrophils; that absence is the tip-off. Causes are chronic alcohol use (direct marrow toxicity), liver disease, hypothyroidism, and reticulocytosis (young RBCs are large).