Begins and ends in the mitochondrion, with ALA synthase rate limiting
Expansion
Pathway: glycine plus succinyl-CoA, via ALA synthase (the rate-limiting enzyme, requiring vitamin B6), through several steps to haem. It starts in the mitochondrion, moves to the cytoplasm, then returns.
Regulation: haem inhibits ALA synthase by negative feedback. Anything that consumes haem, notably cytochrome P450 induction, therefore derepresses the pathway and precipitates attacks.
Acute intermittent porphyria (porphobilinogen deaminase deficiency)
- Neurovisceral attacks: severe abdominal pain with no abdominal signs, neuropathy, psychiatric disturbance, seizures, hyponatraemia from SIADH
- No photosensitivity, since the accumulating precursors are not photoactive
- Urine darkens on standing
- Precipitated by drugs (barbiturates, sulphonamides, oestrogens, alcohol), fasting, infection and the menstrual cycle. Treated with carbohydrate and haem arginate
Porphyria cutanea tarda, the commonest, causes photosensitivity with blistering and skin fragility, associated with hepatitis C, alcohol and iron overload.
Lead inhibits ALA dehydratase and ferrochelatase, causing microcytic anaemia with basophilic stippling, abdominal colic and neuropathy.