Porphyrias
Also known as: porphyria
The porphyrias are a group of disorders caused by enzyme defects in the heme synthesis pathway. Intermediates accumulate upstream of the blocked step, producing either neurovisceral attacks or blistering photosensitivity depending on which enzyme is affected.
Heme is built in an eight-step pathway that begins in the mitochondrion, moves to the cytosol, and returns to the mitochondrion. The rate-limiting first step is catalyzed by ALA synthase, which condenses glycine and succinyl-CoA into δ-aminolevulinic acid; heme itself feeds back to inhibit this enzyme. When a downstream enzyme is deficient, the pathway backs up and the intermediates immediately before the block accumulate in tissue, blood, and urine.
The clinical picture depends on which intermediates build up. Early intermediates such as ALA and porphobilinogen are neurotoxic and cause acute attacks; later intermediates are true porphyrin rings that absorb light and generate reactive oxygen species in the skin, causing photosensitivity. Acute intermittent porphyria, from porphobilinogen deaminase deficiency, therefore presents with painful abdominal attacks, peripheral neuropathy, psychiatric disturbance, and port-wine colored urine, without skin findings. Porphyria cutanea tarda, from uroporphyrinogen decarboxylase deficiency, is the most common porphyria and presents with blistering and fragility of sun-exposed skin.
Acute attacks are typically provoked rather than spontaneous. Anything that induces hepatic cytochrome P450 raises demand for heme, which de-represses ALA synthase and drives more substrate into the blocked pathway — commonly certain drugs, alcohol, smoking, fasting, and hormonal fluctuations. Treatment of an acute attack targets that mechanism: glucose loading and intravenous hemin both suppress ALA synthase. Porphyria cutanea tarda is associated with hepatitis C, alcohol use, and iron overload, and is managed with sun protection, phlebotomy, and low-dose hydroxychloroquine.
Lead poisoning is tested alongside the porphyrias because lead inhibits two enzymes in the same pathway, ALA dehydratase and ferrochelatase, causing microcytic sideroblastic anemia with basophilic stippling and elevated protoporphyrin. On USMLE Step 1, expect vignettes that ask you to name the deficient enzyme from a pattern of accumulated intermediates, or to distinguish an acute neurovisceral porphyria from a cutaneous one.
Key takeaways
- Porphyrias result from enzyme deficiencies in heme synthesis, with intermediates accumulating before the block.
- ALA synthase is the rate-limiting enzyme and is feedback-inhibited by heme.
- Acute intermittent porphyria causes abdominal pain, neuropathy, and psychiatric symptoms without photosensitivity.
- Porphyria cutanea tarda is the most common porphyria and causes blistering of sun-exposed skin.
- Lead inhibits ALA dehydratase and ferrochelatase, producing sideroblastic anemia with basophilic stippling.