A 32-year-old woman presents with recurrent episodes of severe abdominal pain, ascending motor neuropathy, dark urine, and confusion. Episodes are precipitated by oral contraceptive pills. Urinary ALA and PBG are markedly elevated. This is most consistent with acute intermittent porphyria (AIP). The molecular rationale for OCP being a trigger is:
- A Oestrogens inhibit haem oxygenase, causing haem accumulation that inhibits ALA synthase
- B OCPs directly inhibit PBG deaminase (HMBS) enzyme causing porphobilinogen accumulation
- C Oestrogen metabolites are CYP450 substrates; increased CYP450 synthesis depletes hepatic haem, de-represses ALAS1, and drives excess ALA/PBG production in a haploinsufficient PBG deaminase background ✓
- D Progesterone in OCPs inhibits uroporphyrinogen decarboxylase causing ALA buildup
Explanation
Acute intermittent porphyria is caused by haploinsufficiency of porphobilinogen deaminase (PBGD/HMBS), reducing its activity to ~50% of normal. Triggers like OCPs, certain drugs, fasting, and infections increase the demand for cytochrome P450 enzymes. CYP450 synthesis requires haem as a prosthetic group. When hepatic haem is consumed for CYP450 production, free haem levels fall, de-repressing ALAS1 (ALA synthase 1, the rate-limiting enzyme, normally feedback-inhibited by free haem). ALAS1 upregulation drives excess ALA and PBG production. In the haploinsufficient state, PBGD cannot process the excess PBG efficiently, causing accumulation and overflow of neurotoxic ALA. Oestrogen metabolites are themselves CYP450 inducers via PXR/CYP3A4. Haem arginate treatment (providing exogenous haem) suppresses ALAS1 and terminates acute attacks.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.