porphobilinogen

Heme synthesis begins with glycine + succinyl-CoA forming ALA via ALA synthase (rate-limiting step, feedback inhibited by heme). ALA dehydratase (porphobilinogen synthase) then combines two ALA molecules to form porphobilinogen. PBG deaminase (hydroxymethylbilane synthase) converts PBG to hydroxymethylbilane, which is later converted to uroporphyrinogen III and subsequent intermediates leading to heme.

In Acute Intermittent Porphyria (AIP), there is a deficiency of PBG deaminase (autosomal dominant, partial enzyme deficiency). This leads to accumulation of ALA and PBG proximal to the block. Clinically, AIP presents with the classic triad of abdominal pain, neuropsychiatric symptoms (anxiety, psychosis, confusion), and autonomic dysfunction (tachycardia, hypertension), often precipitated by drugs that induce cytochrome P450 (e.g., barbiturates, sulfonamides), alcohol, fasting, or hormonal changes (e.g., menstrual cycle). Symptoms are due to neurotoxic accumulation of ALA and PBG, not heme deficiency itself.

Diagnosis: Urine PBG is markedly elevated during acute attacks and is the best initial screening test (Watson-Schwartz test or quantitative PBG). Urine may turn dark/port-wine colored upon exposure to light and air due to oxidation of porphobilinogen to porphobilin and uroporphyrin.

Treatment: IV heme (hematin) and glucose (both suppress ALA synthase activity), avoidance of triggering drugs.

Contrast with ALA dehydratase deficiency porphyria (rare) - elevated ALA but normal PBG, and lead poisoning, which inhibits ALA dehydratase and ferrochelatase, causing elevated ALA but not PBG - mimicking AIP clinically but distinguished by normal PBG and characteristic findings (basophilic stippling, abdominal pain, neuropathy).