Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of
hydroxymethylbilane (HMB) synthase. Symptomatic individuals experience life-threatening acute neurovisceral attacks that are precipitated by factors that induce the hepatic expression of 5-aminolevulinic
acid synthase 1 (ALAS1), resulting in the marked accumulation of the putative neurotoxic
porphyrin precursors 5-aminolevulinic
acid (ALA) and
porphobilinogen (PBG). Here, we provide the first detailed description of the biochemical and pathologic alterations in the explanted liver of an AIP patient who underwent orthotopic
liver transplantation (OLT) due to untreatable and debilitating chronic attacks. After OLT, the recipient's plasma and urinary ALA and PBG rapidly normalized, and her attacks immediately stopped. In the explanted liver, (a) ALAS1
mRNA and activity were elevated approximately ~3- and 5-fold, and ALA and PBG concentrations were increased ~3- and 1,760-fold, respectively; (b)
uroporphyrin III concentration was elevated; (c) microsomal
heme content was sufficient, and representative
cytochrome P450 activities were essentially normal; (d) HMB synthase activity was approximately half-normal (~42%); (e)
iron concentration was slightly elevated; and (f)
heme oxygenase I
mRNA was increased approximately three-fold. Notable pathologic findings included nodular regenerative
hyperplasia, previously not reported in AIP livers, and minimal
iron deposition, despite the large number of
hemin infusions received before OLT. These findings suggest that the neurovisceral symptoms of AIP are not associated with generalized hepatic
heme deficiency and support the neurotoxicity of ALA and/or PBG. Additionally, they indicate that substrate inhibition of hepatic HMB synthase activity by PBG is not a pathogenic mechanism in acute attacks.