Acute intermittent porphyria (AIP) results from porphobilinogen deaminase (PBGD) deficiency. Acute attacks are precipitated by drugs (barbiturates, griseofulvin), fasting, and infections. Which mechanism links these precipitants to the acute attack?

• A Barbiturates directly inhibit PBGD, worsening the enzymatic block
• B All precipitants induce hepatic ALA synthase (ALAS1) via nuclear receptors (e.g., PXR), overwhelming the reduced PBGD capacity and causing ALA and PBG accumulation, which are neurotoxic ✓
• C Fasting reduces heme levels, disinhibiting PBGD by removing heme feedback
• D Infections generate reactive oxygen species that oxidize porphyrin precursors to neurotoxic electrophiles

Explanation

Hepatic ALA synthase-1 (ALAS1) is the rate-limiting step of heme synthesis and is feedback-inhibited by free heme. Precipitants of AIP (barbiturates, phenytoin, griseofulvin, alcohol, fasting, hormonal fluctuations) induce cytochrome P450 enzymes via nuclear receptors (PXR, AHR), consuming heme. Heme depletion removes feedback inhibition on ALAS1, dramatically upregulating ALA production. Since PBGD activity is already ~50% reduced (heterozygous deficiency), the increased substrate (ALA, PBG) exceeds the enzymatic capacity, causing accumulation of ALA and PBG. ALA is neurotoxic (structurally similar to GABA), causing autonomic neuropathy, psychiatric symptoms, and the classic triad.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.