title: Liver Transplantation for Acute Intermittent Porphyria: Biochemical and Pathologic Studies of the Explanted Liver.
abstract: 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.
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yasuda
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Angelika L
authors.initials: AL
authors.lastname: Erwin
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Lawrence U
authors.initials: LU
authors.lastname: Liu
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Manisha
authors.initials: M
authors.lastname: Balwani
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Brenden
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Senkottuvelan
authors.initials: S
authors.lastname: Kadirvel
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Lin
authors.initials: L
authors.lastname: Gan
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Fiel
authors.affiliation: Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Gordon
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Chunli
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Sonia
authors.initials: S
authors.lastname: Clavero
authors.affiliation: Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Antonios
authors.initials: A
authors.lastname: Arvelakis
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Hetanshi
authors.initials: H
authors.lastname: Naik
authors.affiliation: Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: L David
authors.initials: LD
authors.lastname: Martin
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
authors.forename: John D
authors.initials: JD
authors.lastname: Phillips
authors.affiliation: Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Karl E
authors.initials: KE
authors.lastname: Anderson
authors.affiliation: Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Vaithamanithi M
authors.initials: VM
authors.lastname: Sadagoparamanujam
authors.affiliation: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.|Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Sander S
authors.initials: SS
authors.lastname: Florman
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis / Q000235:genetics*; D000328:Adult; D000622:Aminolevulinic Acid / Q000097:blood / Q000652:urine; D005260:Female; D006418:Heme / Q000378:metabolism; D006801:Humans; D011163:Hydroxymethylbilane Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D016031:Liver Transplantation; D011162:Porphobilinogen / Q000097:blood / Q000652:urine; D017118:Porphyria, Acute Intermittent / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D014578:Uroporphyrins / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D014578:Uroporphyrins; C022181:uroporphyrin III; D006418:Heme; D011162:Porphobilinogen; D000622:Aminolevulinic Acid; D000624:5-Aminolevulinate Synthetase; D011163:Hydroxymethylbilane Synthase