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

Mol Med 2015 Jun 5;21:487-95. Epub 2015 Jun 5.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.

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.

Download full-text PDF

Source
http://dx.doi.org/10.2119/molmed.2015.00099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607616PMC
June 2015
79 Reads

Publication Analysis

Top Keywords

hmb synthase
12
explanted liver
12
5-aminolevulinic acid
8
concentration elevated
8
biochemical pathologic
8
intermittent porphyria
8
synthase activity
8
ala pbg
8
liver transplantation
8
acute intermittent
8
liver
5
pbg
5
attacks olt
4
nodular regenerative
4
regenerative hyperplasia
4
hyperplasia reported
4
untreatable debilitating
4
debilitating chronic
4
chronic attacks
4
findings included
4

References

(Supplied by CrossRef)

KE Anderson et al.
2001

FS Dar et al.
Hepatobiliary Pancreat. Dis. Int. 2010

JK Dowman et al.
Liver Transpl. 2012

AK Seth et al.
Liver Transpl. 2007

ZF Soonawalla et al.
Lancet 2004

S Wahlin et al.
Transpl. Int. 2010

P Harper et al.
Expert Opin. Orphan Drugs 2014

JK Dowman et al.
Ann. Intern. Med. 2011

M Yasuda et al.
Proc. Natl. Acad. Sci. U. S. A. 2014

J Zhang et al.
J. Chromatogr. B Analyt. Technol Biomed. Life Sci. 2011

S Clavero et al.
Hum. Mol. Genet. 2010

Similar Publications