Haem and Porphyrin Metabolism
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Direct answer
Haem is built in eight steps that begin and end in the mitochondrion, with glycine and succinyl-CoA condensed by ALA synthase — the rate-limiting enzyme, requiring pyridoxal phosphate — into δ-aminolaevulinic acid. Two downstream enzymes, ALA dehydratase and ferrochelatase, are zinc-containing sulfhydryl enzymes, which is why lead poisons both and produces sideroblastic anaemia with basophilic stippling. The porphyrias split cleanly for the exam into acute neuropsychiatric syndromes — acute intermittent porphyria the prototype, with raised urine ALA and porphobilinogen and no photosensitivity — and photosensitive blistering syndromes, led by porphyria cutanea tarda, the commonest of all; haem degradation then runs through biliverdin to bilirubin, whose unbound fraction causes kernicterus.
What you must remember
- ALA synthase is mitochondrial, rate-limiting, pyridoxal phosphate-dependent and repressed by haem — the feedback loop every porphyria question turns on.
- Lead inhibits ALA dehydratase and ferrochelatase, so ALA rises while porphobilinogen stays normal; the clinical set is sideroblastic anaemia with basophilic stippling, Burton's line on the gums, abdominal colic and wrist drop.
- Acute intermittent porphyria: porphobilinogen deaminase (hydroxymethylbilane synthase) deficiency, autosomal dominant; severe abdominal pain, tachycardia and hypertension, motor polyneuropathy, psychiatric features and hyponatraemia; photosensitivity is absent, and urine darkens to port-wine on standing.
- Precipitants of an acute attack — barbiturates (the classic anaesthetic trap), sulphonamides, alcohol, oestrogens, fasting — all induce cytochrome P450, consuming hepatic haem and derepressing ALA synthase.
- Treatment of an acute attack: generous carbohydrate (glucose loading) and intravenous haem arginate, with the precipitating drug withdrawn; morphine is among the safer analgesics, barbiturates absolutely are not.
- Porphyria cutanea tarda: uroporphyrinogen decarboxylase deficiency, the commonest porphyria; fragile blisters on sun-exposed dorsal hands, hypertrichosis, tea-coloured urine with pink fluorescence; associated with alcohol, hepatitis C, iron overload and oestrogens; treated by phlebotomy.
- Erythropoietic protoporphyria (ferrochelatase) gives immediate burning pain on sun exposure with little blistering; congenital erythropoietic porphyria (Gunther disease) gives extreme photosensitivity, erythrodontia — red teeth fluorescing under Wood's lamp — and hirsutism.
- Haem degradation: microsomal haem oxygenase opens the ring to biliverdin, releasing carbon monoxide and iron; biliverdin reductase yields bilirubin, which is glucuronidated by the liver and reduced by gut bacteria to urobilinogen and stercobilin.
A worked case: abdominal pain after wisdom-tooth anaesthesia
A 22-year-old woman returns three days after wisdom-tooth extraction under general anaesthesia with unbearable colicky abdominal pain, a pulse of 128, blood pressure 165/95, and crying spells labelled as hysteria; one examination finding reorders everything — wrist drop from a motor polyneuropathy. Add the laboratory thread: sodium 126 mmol/L from an ADH-like effect, and urine that darkens to the colour of port wine after standing in daylight. Reason the derepression chain: the anaesthetic's barbiturate induced cytochrome P450 in the liver, consuming the free haem pool; the fall in haem releases feedback on ALA synthase, which floods the pathway to the blocked step, accumulating ALA and porphobilinogen — the latter oxidising to the dark pigment in the collecting bag. A Watson–Schwarz screen on the urine confirms porphobilinogen, and quantitation secures acute intermittent porphyria. Treatment is glucose loading and haem arginate, withdrawal of precipitant drugs, and an anaesthetic card for life: propofol-type agents are considered safe; barbiturates and sulphonamides are not. Family screening follows: the defect is autosomal dominant with variable penetrance.
Where students slip
Photosensitivity is wrongly granted to acute intermittent porphyria; its absence alongside abdominal pain is the single most tested discriminator. Second, the darkening urine is read as haematuria — porphobilinogen oxidises on exposure to air and light, and a dipstick shows no red cells. Third, lead poisoning and acute porphyria are conflated; lead raises ALA with normal porphobilinogen, porphobilinogen deaminase deficiency raises both. Fourth, the barbiturate link is memorised as a pharmacology footnote, then the same drug is prescribed in the case stem — the exam rewards seeing the trap. Fifth, porphyria cutanea tarda's associations (hepatitis C and iron) are forgotten, though screening for them is standard the day the diagnosis is made. Finally, when ferrochelatase fails in lead poisoning or protoporphyria, free protoporphyrin accumulates instead of haem.
Frequently asked questions
Which enzyme is rate-limiting in haem synthesis and what cofactor does it need?
ALA synthase, condensing glycine with succinyl-CoA in mitochondria; pyridoxal phosphate (vitamin B6) is its cofactor.
Which two enzymes of the pathway does lead inhibit?
ALA dehydratase and ferrochelatase, both zinc-dependent sulfhydryl enzymes, causing raised ALA and sideroblastic anaemia.
Which porphyria causes abdominal pain without photosensitivity?
Acute intermittent porphyria, from porphobilinogen deaminase deficiency, with raised urine ALA and porphobilinogen and urine that darkens on standing.
How is an acute porphyric attack treated?
Carbohydrate loading with intravenous glucose, haem arginate to repress ALA synthase, withdrawal of precipitant drugs, and analgesia with safer agents such as opioids.
Which enzyme is deficient in porphyria cutanea tarda, and what is the treatment?
Uroporphyrinogen decarboxylase; phlebotomy to deplete iron, plus alcohol cessation and hepatitis C treatment.
Which products of haem breakdown colour the stool and urine?
Gut bacteria reduce bilirubin to urobilinogen, oxidised to stercobilin for the brown stool; some urobilinogen is reabsorbed and excreted in urine.