The initial assessment of anaemia is guided by two complementary observations: red-cell size and the adequacy of the marrow response. The first asks whether the red cells were built correctly, and the mean cell volume answers it. The second asks whether the marrow is trying, and the reticulocyte production index answers that. Cell size reflects a race between cytoplasm and DNA. When haemoglobin cannot be assembled, the cytoplasm stays small and pale, and the cell is microcytic and hypochromic. When DNA synthesis stalls, nuclear division lags behind a swelling cytoplasm, and the cell emerges macrocytic. Normocytic anaemia usually means the cells were made properly but were lost or destroyed.
Iron deficiency, thalassaemia trait and anaemia of chronic disease all produce the small cell. Ferritin separates them cleanly, because it is the only marker that falls in iron deficiency alone. A ferritin below 30 micrograms per litre indicates depleted stores, whereas inflammation can raise it despite empty shelves. In true deficiency the liver compensates by synthesising more transferrin, so the total iron-binding capacity rises. In chronic inflammation, interleukin-6 drives hepcidin, which degrades ferroportin and locks iron inside macrophages. Consequently ferritin is normal or high, iron-binding capacity is low, and iron tablets achieve nothing.
Thalassaemia trait shares the small cell but not the empty store. Globin-chain imbalance leads the marrow to produce many small cells, so the red cell count is preserved and the distribution width stays narrow. The Mentzer index, mean cell volume divided by red cell count, falls below 13 in thalassaemia and rises above 13 in iron deficiency. Haemoglobin electrophoresis confirms beta-thalassaemia trait when haemoglobin A2 exceeds 3.5 per cent. However, iron deficiency itself lowers haemoglobin A2, so electrophoresis is deferred until the stores are replete. Iron given to a thalassaemic patient who is not deficient risks overload.
Iron deficiency is a finding, never a diagnosis, and the cause must always be pursued. Menstrual loss and a vegetarian diet commonly contribute in young women. Nevertheless, coeliac serology belongs in every work-up, because the inflamed duodenum is precisely where dietary iron is absorbed. Adults with coeliac disease frequently have no gastrointestinal symptoms at all. Gastroscopy with duodenal biopsies confirms the diagnosis, and gluten must continue until the biopsy is taken. In men and post-menopausal women, bidirectional endoscopy is required to exclude a bleeding lesion.
Oral ferrous sulphate on alternate days is absorbed more efficiently than daily dosing, because each dose raises hepcidin for about a day. The haemoglobin should rise by about 20 grams per litre within four weeks. Failure to respond suggests malabsorption, ongoing loss or the wrong diagnosis, and intravenous iron becomes appropriate. Replacement continues for about three months after the haemoglobin normalises, so that the stores, not merely the count, are refilled.
Macrocytosis carries its own trap. Hypersegmented neutrophils signal megaloblastic change from vitamin B12 or folate deficiency. Only B12 deficiency injures the dorsal columns and corticospinal tracts, producing subacute combined degeneration. Folic acid given alone repairs the blood picture while the cord continues to degenerate, so both vitamins are measured before either is prescribed.
All microcytic anaemias are first sorted by ferritin, because ferritin falls only in iron deficiency.
Is the red cell count preserved and the Mentzer index below 13? Suspect thalassaemia trait and defer electrophoresis until iron is replete.
On every iron-deficient adult, request coeliac serology, since the damaged duodenum absorbs the iron.
Lucid rule for macrocytosis: measure B12 and folate before treating, because folate alone masks cord degeneration.