Clinical meaning
Acute intermittent porphyria (AIP) is the most common and most clinically significant of the acute hepatic porphyrias, a group of inherited metabolic disorders caused by defects in the heme biosynthesis pathway. AIP results from an autosomal dominant mutation in the gene encoding porphobilinogen deaminase (PBG deaminase, also called hydroxymethylbilane synthase or uroporphyrinogen I synthase), the third enzyme in the heme biosynthetic pathway. This enzyme normally catalyzes the conversion of porphobilinogen (PBG) to hydroxymethylbilane. When the enzyme is deficient, porphobilinogen and its precursor delta-aminolevulinic acid (ALA) accumulate to toxic levels during acute attacks, producing the characteristic neurovisceral symptoms.
The heme biosynthesis pathway consists of eight enzymatic steps, beginning with the condensation of glycine and succinyl-CoA to form delta-aminolevulinic acid (ALA) in the mitochondria (catalyzed by ALA synthase, the rate-limiting enzyme) and ending with the insertion of iron into protoporphyrin IX to form heme. Heme serves as the prosthetic group for hemoglobin, myoglobin, cytochrome P450 enzymes, and catalase. Under normal conditions, heme production is tightly regulated by negative feedback inhibition of ALA synthase -- when heme levels are adequate, ALA synthase activity is suppressed. In AIP, the partial deficiency of PBG deaminase (approximately 50% of normal activity) is usually compensated under basal conditions, and most carriers remain asymptomatic throughout life. Acute attacks are triggered when demand for hepatic heme production increases, upregulating ALA synthase (the rate-limiting enzyme) and flooding the pathway with ALA and PBG that cannot be adequately processed by the deficient PBG deaminase.
Common triggers for acute attacks include medications that induce hepatic cytochrome P450 enzymes (barbiturates, phenytoin, carbamazepine, sulfonamides, rifampin, oral contraceptives, progesterone), fasting or caloric restriction (which depletes hepatic heme stores used for glucose metabolism enzymes), hormonal fluctuations (attacks are more common in women of reproductive age, often premenstrual, due to progesterone's induction of ALA synthase), alcohol consumption, smoking, infection, stress, and surgery. The accumulated ALA and PBG are neurotoxic. ALA is structurally similar to gamma-aminobutyric acid (GABA) and may interfere with GABA-ergic neurotransmission. Both ALA and PBG cause oxidative damage to neurons and may impair axonal transport and myelin integrity. This neurotoxicity produces the three cardinal clinical manifestations of AIP.