Haem and porphyrias

Haem synthesis

• About 85% of haem is made in the marrow, most of the rest in the liver (for cytochromes).
• B6 deficiency (isoniazid), alcohol, lead and X-linked ALA synthase mutations cause sideroblastic anaemia: iron cannot be used, so it accumulates in mitochondria (ring sideroblasts); microcytic anaemia with high iron and ferritin.

Porphyrias and lead

Haemoglobin and myoglobin

• Adult HbA is alpha2 beta2 (about 97%), HbA2 alpha2 delta2 (about 2.5%), HbF alpha2 gamma2.
• Sickle cell disease: a missense mutation replaces glutamic acid with valine at position 6 of beta-globin. Deoxygenated HbS polymerises and sickles cells. After repeated transfusion, the blood contains both HbS and the donor HbA.
• Haemoglobin has four subunits; binding of one oxygen changes the shape of the others and raises their affinity (cooperativity), giving a sigmoid curve suited to unloading oxygen in tissues. Myoglobin is a single chain with one haem and no cooperativity, so its curve is hyperbolic with very high affinity: it stores oxygen in muscle.
• Right shift (lower affinity, easier unloading): raised CO2, H+ (Bohr effect), temperature and 2,3-BPG. A P50 above the normal 27 mmHg (for example 37 mmHg in chronic hypoxic COPD with raised 2,3-BPG and acidosis) indicates a right shift. HbF binds 2,3-BPG poorly and is left-shifted.
• In the first minutes of myocardial ischaemia, oxygen lack stops oxidative phosphorylation, so the heart switches to anaerobic glycolysis and produces lactate; ATP and creatine phosphate fall.

Carbon monoxide and methaemoglobin

• CO binds haemoglobin about 240 times more strongly than oxygen, reduces carrying capacity and shifts the curve left. Standard pulse oximeters read carboxyhaemoglobin as oxyhaemoglobin, so saturation shows a falsely normal value (for example 98%). Treat with 100% oxygen, which cuts the half-life from about 4–6 hours to about 1 hour; consider hyperbaric oxygen in severe cases.
• Methaemoglobin contains ferric (Fe3+) iron that cannot carry oxygen. Causes: nitrites, dapsone, prilocaine and benzocaine, congenital cytochrome b5 reductase deficiency. Chocolate-brown blood, cyanosis with normal PaO2. Treat with methylene blue (not in G6PD deficiency).
• HbA1c (glycated haemoglobin) reflects average glucose over about 2–3 months.

Haem breakdown and bilirubin

• Red cells live about 120 days and are removed by splenic macrophages. Haem oxygenase opens haem to biliverdin, releasing iron and CO; biliverdin reductase forms unconjugated bilirubin.
• Unconjugated bilirubin is water-insoluble, travels on albumin and is not filtered into urine. The liver conjugates it with glucuronic acid (UDP-glucuronyltransferase, UGT1A1) and excretes it in bile. Gut bacteria form urobilinogen (some reabsorbed and excreted in urine) and stercobilin (brown stool).

Iron absorption and transport

• Body iron is about 3–4 g, two-thirds in haemoglobin. Absorption, about 1–2 mg a day, occurs in the duodenum and upper jejunum.
• Non-haem Fe3+ is reduced to Fe2+ by duodenal cytochrome b, helped by vitamin C and gastric acid, then enters enterocytes by DMT1. Iron is stored as ferritin or exported by ferroportin, oxidised by hephaestin and carried on transferrin. Haem iron (meat) is absorbed better than non-haem iron (vegetables).
• Inhibitors: tannins in tea, phytates, calcium, antacids and PPIs. For a woman with iron deficiency who drinks tea with meals, advise taking vitamin C-rich food with meals and avoiding tea around mealtimes.
• Hepcidin, made by the liver, degrades ferroportin, cutting absorption and trapping iron in macrophages. It rises in inflammation (anaemia of chronic disease) and is low in iron deficiency and hereditary haemochromatosis.
• Storage: ferritin (soluble) and haemosiderin (insoluble, Prussian blue). There is no regulated excretion.

Iron deficiency, chronic disease and overload

• Iron deficiency gives a microcytic hypochromic film with pencil cells, plus glossitis, angular cheilitis, koilonychia and, with an oesophageal web, dysphagia (Plummer–Vinson). Ferritin is an acute-phase protein, so a "normal" ferritin during fever or inflammation does not exclude iron deficiency.
• To separate iron deficiency from beta-thalassaemia trait, check ferritin and HbA2 (raised above 3.5% in thalassaemia trait).
• Hereditary haemochromatosis (HFE C282Y, autosomal recessive): low hepcidin, excess absorption; diabetes, bronze skin, arthropathy of the 2nd and 3rd MCP joints, cirrhosis, cardiomyopathy, hypogonadism. First-line treatment is regular venesection; desferrioxamine is for transfusional overload.

Remember ALA synthase with B6 starts haem; lead blocks ALA dehydratase and ferrochelatase; hepcidin shuts ferroportin.

Exam trap Pulse oximetry is falsely normal in carbon monoxide poisoning; give 100% oxygen.

Exam trap Myoglobin's curve is hyperbolic because it is a single chain with no cooperativity.

How FCPS asks about this

• Rate-limiting enzyme of haem synthesis and its cofactor: ALA synthase; pyridoxal phosphate (B6).
• Sickle cell substitution at position 6: glutamic acid replaced by valine.
• Myoglobin hyperbolic versus haemoglobin sigmoid curve: single chain, no cooperativity.
• Tea with every meal in iron deficiency: vitamin C with meals, avoid tea.
• Diabetes, bronze skin, MCP arthropathy, high saturation: haemochromatosis; regular venesection.
• Family drowsy near a gas heater with 98% oximetry: carboxyhaemoglobin read as oxyhaemoglobin; 100% oxygen.
• First minutes of myocardial ischaemia: anaerobic glycolysis producing lactate.