Describe the structure and types of haemoglobin. Outline its synthesis and describe its fate after red cell destruction.

Definition and Normal Values

Structure

• Molecular weight 64,458
• Consists of haem (4%) + globin (96%)
• Haem = protoporphyrin IX + Fe2+ (ferrous). Iron in the ferrous state alone can bind O2
• Globin = 4 polypeptide chains, each bound to one haem
• One Hb molecule therefore binds 4 O2 molecules

Types of Haemoglobin

• HbF has higher O2 affinity (P50 19 mmHg) — it binds 2,3-BPG poorly → allows placental O2 extraction

Synthesis of Haem

Succinyl CoA + Glycine → ala synthase (rate-limiting; needs vit B6) → δ-aminolaevulinic acid → Porphobilinogen → Uroporphyrinogen → Coproporphyrinogen → Protoporphyrin IX → + Fe2+ (ferrochelatase) → haem

• Occurs in mitochondria and cytosol of the normoblast
• Haem inhibits ala synthase — negative feedback
• Lead inhibits ala dehydratase and ferrochelatase → basophilic stippling, ↑ ala in urine

Fate of Haemoglobin

RBC lives 120 days → Destroyed in res (spleen, liver, marrow) → Hb → haem + globin → Globin → amino acid pool → Haem → haem oxygenase → iron released (recycled) + biliverdin → Biliverdin reductase → Unconjugated bilirubin

• About 6 g of Hb is destroyed daily, yielding 300 mg of bilirubin
• Carbon monoxide is released — the body's only endogenous source
• Iron is conserved — only about 1 mg/day is lost

Functions of Haemoglobin

• Transport of O2 — 1 g Hb carries 1.34 mL O2; 97% of blood oxygen
• Transport of CO2 — as carbaminohaemoglobin (23% of total CO2)
• Buffering — the most important buffer of the blood after bicarbonate; reduced Hb is a better buffer than oxyhaemoglobin
• Contributes to blood viscosity

Iron Metabolism (in Brief)

• Total body iron 3–4 g; 65–70% in haemoglobin
• Absorbed in the duodenum as Fe2+; vitamin C aids absorption, phytates and tea hinder it
• Transported as transferrin; stored as ferritin and haemosiderin in liver, spleen and marrow
• Daily requirement — 1 mg male, 2–3 mg female, 3–4 mg in pregnancy
• Loss about 1 mg/day; there is no active excretory mechanism for iron

Abnormal Haemoglobins and Derivatives

Applied Aspects

• Thalassaemia — reduced synthesis of α or β chains; ↑ HbA2 and HbF in β-thalassaemia trait
• Sickle cell disease — abnormal structure; HbS polymerises when deoxygenated → sickling → vaso-occlusive crises
• Haemoglobinuria — when free plasma Hb exceeds the binding capacity of haptoglobin (about 100 mg/dL)
• Anaemia — graded by Hb: mild 10–12, moderate 7–10, severe < 7 g/dL
• Hb electrophoresis — the definitive test for thalassaemia and sickle cell disease
• HbA1c — glycated Hb; reflects the average blood glucose over the preceding 8–12 weeks
• Lead poisoning → blocks haem synthesis → basophilic stippling, ↑ urinary ala, microcytic anaemia