Liver transplantation for acute intermittent porphyria

Biochemical and pathologic studies of the explanted liver

Makiko Yasuda, Angelika L. Erwin, Lawrence U. Liu, Manisha Balwani, Brenden Chen, Senkottuvelan Kadirvel, Lin Gan, M. Isabel Fie, Ronald E. Gordon, Chunli Yu, Sonia Clavero, Antonios Arvelakis, Hetanshi Naik, L. David Martin, John D. Phillips, Karl Anderson, V-M Ramanujam, Sander S. Florman, Robert J. Desnick

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydrox-ymethylbilane (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.

Original languageEnglish (US)
Pages (from-to)487-495
Number of pages9
JournalMolecular Medicine
Volume21
DOIs
StatePublished - Jun 5 2015

Fingerprint

Acute Intermittent Porphyria
Aminolevulinic Acid
Liver Transplantation
Porphobilinogen
Liver
Heme
Iron
Porphobilinogen Synthase
Heme Oxygenase (Decyclizing)
Messenger RNA
Hemin
Life Change Events
Porphyrins
Cytochrome P-450 Enzyme System
Hyperplasia

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Molecular Medicine
  • Genetics(clinical)

Cite this

Yasuda, M., Erwin, A. L., Liu, L. U., Balwani, M., Chen, B., Kadirvel, S., ... Desnick, R. J. (2015). Liver transplantation for acute intermittent porphyria: Biochemical and pathologic studies of the explanted liver. Molecular Medicine, 21, 487-495. https://doi.org/10.2119/molmed.2015.00099

Liver transplantation for acute intermittent porphyria : Biochemical and pathologic studies of the explanted liver. / Yasuda, Makiko; Erwin, Angelika L.; Liu, Lawrence U.; Balwani, Manisha; Chen, Brenden; Kadirvel, Senkottuvelan; Gan, Lin; Fie, M. Isabel; Gordon, Ronald E.; Yu, Chunli; Clavero, Sonia; Arvelakis, Antonios; Naik, Hetanshi; Martin, L. David; Phillips, John D.; Anderson, Karl; Ramanujam, V-M; Florman, Sander S.; Desnick, Robert J.

In: Molecular Medicine, Vol. 21, 05.06.2015, p. 487-495.

Research output: Contribution to journalArticle

Yasuda, M, Erwin, AL, Liu, LU, Balwani, M, Chen, B, Kadirvel, S, Gan, L, Fie, MI, Gordon, RE, Yu, C, Clavero, S, Arvelakis, A, Naik, H, Martin, LD, Phillips, JD, Anderson, K, Ramanujam, V-M, Florman, SS & Desnick, RJ 2015, 'Liver transplantation for acute intermittent porphyria: Biochemical and pathologic studies of the explanted liver', Molecular Medicine, vol. 21, pp. 487-495. https://doi.org/10.2119/molmed.2015.00099
Yasuda, Makiko ; Erwin, Angelika L. ; Liu, Lawrence U. ; Balwani, Manisha ; Chen, Brenden ; Kadirvel, Senkottuvelan ; Gan, Lin ; Fie, M. Isabel ; Gordon, Ronald E. ; Yu, Chunli ; Clavero, Sonia ; Arvelakis, Antonios ; Naik, Hetanshi ; Martin, L. David ; Phillips, John D. ; Anderson, Karl ; Ramanujam, V-M ; Florman, Sander S. ; Desnick, Robert J. / Liver transplantation for acute intermittent porphyria : Biochemical and pathologic studies of the explanted liver. In: Molecular Medicine. 2015 ; Vol. 21. pp. 487-495.
@article{a7428a4f51c047d89f73b754a884a546,
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 hydrox-ymethylbilane (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.",
author = "Makiko Yasuda and Erwin, {Angelika L.} and Liu, {Lawrence U.} and Manisha Balwani and Brenden Chen and Senkottuvelan Kadirvel and Lin Gan and Fie, {M. Isabel} and Gordon, {Ronald E.} and Chunli Yu and Sonia Clavero and Antonios Arvelakis and Hetanshi Naik and Martin, {L. David} and Phillips, {John D.} and Karl Anderson and V-M Ramanujam and Florman, {Sander S.} and Desnick, {Robert J.}",
year = "2015",
month = "6",
day = "5",
doi = "10.2119/molmed.2015.00099",
language = "English (US)",
volume = "21",
pages = "487--495",
journal = "Molecular Medicine",
issn = "1076-1551",
publisher = "Feinstein Institute for Medical Research",

}

TY - JOUR

T1 - Liver transplantation for acute intermittent porphyria

T2 - Biochemical and pathologic studies of the explanted liver

AU - Yasuda, Makiko

AU - Erwin, Angelika L.

AU - Liu, Lawrence U.

AU - Balwani, Manisha

AU - Chen, Brenden

AU - Kadirvel, Senkottuvelan

AU - Gan, Lin

AU - Fie, M. Isabel

AU - Gordon, Ronald E.

AU - Yu, Chunli

AU - Clavero, Sonia

AU - Arvelakis, Antonios

AU - Naik, Hetanshi

AU - Martin, L. David

AU - Phillips, John D.

AU - Anderson, Karl

AU - Ramanujam, V-M

AU - Florman, Sander S.

AU - Desnick, Robert J.

PY - 2015/6/5

Y1 - 2015/6/5

N2 - Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydrox-ymethylbilane (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.

AB - Acute intermittent porphyria (AIP) is an autosomal-dominant hepatic disorder caused by the half-normal activity of hydrox-ymethylbilane (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.

UR - http://www.scopus.com/inward/record.url?scp=84941926229&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941926229&partnerID=8YFLogxK

U2 - 10.2119/molmed.2015.00099

DO - 10.2119/molmed.2015.00099

M3 - Article

VL - 21

SP - 487

EP - 495

JO - Molecular Medicine

JF - Molecular Medicine

SN - 1076-1551

ER -