Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver

Abstract

Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is an autosomal-dominant disorder due to the half-normal activity of the heme biosynthetic enzyme, hydroxymethylbilane (HMB) synthase (1). Symptomatic heterozygotes, most (~90%) of which are women, experience episodic life-threatening acute neurovisceral attacks that typically begin with severe abdominal pain and may include hypertension, tachycardia, constipation, motor weakness and seizures. These attacks are precipitated by certain drugs, dieting and hormonal factors that increase the hepatic expression of 5-aminolevulinic acid synthase 1 (ALAS1) (1). When hepatic ALAS1 is induced, the half-normal activity of HMB synthase becomes ratelimiting, leading to decreased heme biosynthesis and depletion of the hepatic "free" heme pool. Depletion of the"free" heme pool leads to further induction of 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.

Recurrent attacks of acute hepatic porphyria: major role of the chronic inflammatory response in the liver

“… showed that during intravascular hemolysis leading to free haem excess, the liver is the most susceptible organ to haem overload, and when hemopexin capacity is exceeded, haem accumulates mainly in Küpffer cells. In line with our results, three well‐documented studies concerning recurrent AIP patients reported also that regular hemin infusions trigger variable liver iron overload .…”

“…The pathogenesis of the acute attacks is hypothesized to result from an overproduction of a hepatic neurotoxic metabolite, presumably d-aminolevulinic acid (ALA) [3,4]. This notion is consistent with the correction of the disease by liver transplantation in patients with severe AIP [5][6][7][8][9]. Moreover, when domino liver transplantations were performed, the recipients developed biological and clinical acute porphyric attacks [10].…”

Pathophysiology, Pharmacology and Treatment of Acute Intermittent Porphyria: A Patient Case Description and Recommendations from the Current Literature

“…1, 19 An analysis by Singal et al 1 reported that as of 2014, of the 14 known AIP liver transplant patients, bile leak was recorded for 1, renal dysfunction for 2, and hepatic artery thrombosis for 4. Yasuda et al 20 performed a review which showed that HAT was not seen at therapeutic levels of anticoagulation.…”

Acute hepatic porphyrias: Recommendations for evaluation and long‐term management

“…Because orthotopic liver transplantation is associated with morbidity and mortality, it is considered a treatment of last resort. In addition, patients who already have advanced neuropathy with quadriplegia and respiratory paralysis are considered poor candidates for transplantation …”