L12: Microcytic Anaemias – Iron

Microcytic anaemia is defined by a mean corpuscular volume (MCV) below 80 fL. The three main causes are iron deficiency anaemia, thalassaemia, and anaemia of chronic inflammation (also called anaemia of chronic disease). Each has distinct pathophysiology, iron indices, and management.

Iron is essential for haemoglobin synthesis: each haem group contains one iron atom in the ferrous (Fe²⁺) state. Iron absorption occurs in the duodenum and proximal jejunum. Ferric iron (Fe³⁺) in the intestinal lumen is reduced to Fe²⁺ by duodenal cytochrome B (Dcytb), then transported into enterocytes by divalent metal transporter 1 (DMT1). Within enterocytes, iron may be stored as ferritin or exported to plasma by ferroportin. Hephaestin (a ferroxidase) oxidises Fe²⁺ to Fe³⁺ for binding to transferrin in plasma. Transferrin, a glycoprotein synthesised by the liver, carries two Fe³⁺ ions and delivers iron to cells via transferrin receptor 1 (TfR1).

The key regulator of systemic iron homeostasis is hepcidin, a peptide hormone synthesised by hepatocytes. Hepcidin binds ferroportin and triggers its internalisation and degradation, reducing iron export from enterocytes, macrophages, and hepatocytes. Iron overload or inflammation increases hepcidin production; iron deficiency decreases it.

Iron stores are estimated by serum ferritin: each microgram per litre of ferritin reflects approximately 8–10 mg of stored iron. In New Zealand, a ferritin below 20 µg/L is classified as iron deficient; international guidelines typically use lower thresholds (e.g., <12–15 µg/L). However, ferritin is an acute phase protein — it rises in inflammation even when iron stores are genuinely depleted, potentially masking deficiency in patients with concurrent infection or inflammatory disease.

Transferrin saturation (serum iron ÷ total iron-binding capacity × 100%) reflects the proportion of transferrin carrying iron; reference interval is 16–50%. In iron deficiency, serum iron falls and TIBC rises (liver upregulates transferrin production), resulting in low saturation. In anaemia of inflammation, both serum iron and TIBC are low (transferrin production is suppressed by cytokines), with low saturation and high ferritin.

Iron deficiency anaemia is the world's most common nutritional deficiency. Causes include inadequate intake, poor absorption (coeliac disease, post-gastrectomy, achlorhydria), and chronic blood loss (gastrointestinal bleeding — especially colorectal cancer or ulcer — or menorrhagia in women). The blood film shows microcytic hypochromic red cells. Treatment is oral ferrous sulphate; intravenous iron (ferric carboxymaltose) is used when oral iron is not tolerated or absorbed.

Hereditary haemochromatosis is the most common autosomal recessive disorder in people of Northern European descent, caused by homozygous HFE gene C282Y mutation (~1 in 200 New Zealand Caucasians). HFE mutations reduce hepcidin expression, leading to unchecked iron absorption and progressive iron deposition in the liver (cirrhosis), heart (cardiomyopathy), pancreas (diabetes), joints (arthropathy), and skin (bronze discolouration). Treatment is regular venesection (phlebotomy), which removes iron as haemoglobin and corrects iron overload over months to years.