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Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma

Hyperammonemic encephalopathy is a potentially fatal condition associated with fibrolamellar hepatocellular carcinoma. The mechanism involved in hyperammonemia in patients with fibrolamellar carcinoma was unclear until a possible physiopathological pathway was recently proposed. An ornithine transca...

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Autores principales: Surjan, Rodrigo Cañada T, de Lima, Thais M, de Souza, Heraldo P, Machado, Marcel Cerqueira C, Ardengh, José C
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cureus 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922532/
https://www.ncbi.nlm.nih.gov/pubmed/36788919
http://dx.doi.org/10.7759/cureus.33750
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author Surjan, Rodrigo Cañada T
de Lima, Thais M
de Souza, Heraldo P
Machado, Marcel Cerqueira C
Ardengh, José C
author_facet Surjan, Rodrigo Cañada T
de Lima, Thais M
de Souza, Heraldo P
Machado, Marcel Cerqueira C
Ardengh, José C
author_sort Surjan, Rodrigo Cañada T
collection PubMed
description Hyperammonemic encephalopathy is a potentially fatal condition associated with fibrolamellar hepatocellular carcinoma. The mechanism involved in hyperammonemia in patients with fibrolamellar carcinoma was unclear until a possible physiopathological pathway was recently proposed. An ornithine transcarboxylase dysfunction was suggested as a result of increased ornithine decarboxylase activity induced by c-Myc overexpression. This c-Myc overexpression resulted from Aurora kinase A overexpression derived from the activity of a chimeric kinase that is the final transcript of a deletion in chromosome 19, common to all fibrolamellar carcinomas. We performed the analysis of the expression of all enzymes involved and tested for the mutation in chromosome 19 in fresh frozen samples of fibrolamellar hepatocellular carcinoma, non-tumor liver, and hepatic adenomatosis. The specific DNAJB-PRKACA fusion protein that results from the recurrent mutation on chromosome 19 common to all fibrolamellar carcinoma was detected only in the fibrolamellar carcinoma sample. Fibrolamellar carcinoma and adenomyomatosis samples presented increased expression of Aurora kinase A, c-MYC, and ornithine decarboxylase when compared to normal liver, while ornithine transcarbamylase was decreased. The proposed physiopathological pathway is correct and that overexpression of c-Myc may also be responsible for hyperammonemia in patients with other types of rapidly growing hepatomas. This gives further evidence to apply new and adequate treatment to this severe complication.
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spelling pubmed-99225322023-02-13 Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma Surjan, Rodrigo Cañada T de Lima, Thais M de Souza, Heraldo P Machado, Marcel Cerqueira C Ardengh, José C Cureus Pathology Hyperammonemic encephalopathy is a potentially fatal condition associated with fibrolamellar hepatocellular carcinoma. The mechanism involved in hyperammonemia in patients with fibrolamellar carcinoma was unclear until a possible physiopathological pathway was recently proposed. An ornithine transcarboxylase dysfunction was suggested as a result of increased ornithine decarboxylase activity induced by c-Myc overexpression. This c-Myc overexpression resulted from Aurora kinase A overexpression derived from the activity of a chimeric kinase that is the final transcript of a deletion in chromosome 19, common to all fibrolamellar carcinomas. We performed the analysis of the expression of all enzymes involved and tested for the mutation in chromosome 19 in fresh frozen samples of fibrolamellar hepatocellular carcinoma, non-tumor liver, and hepatic adenomatosis. The specific DNAJB-PRKACA fusion protein that results from the recurrent mutation on chromosome 19 common to all fibrolamellar carcinoma was detected only in the fibrolamellar carcinoma sample. Fibrolamellar carcinoma and adenomyomatosis samples presented increased expression of Aurora kinase A, c-MYC, and ornithine decarboxylase when compared to normal liver, while ornithine transcarbamylase was decreased. The proposed physiopathological pathway is correct and that overexpression of c-Myc may also be responsible for hyperammonemia in patients with other types of rapidly growing hepatomas. This gives further evidence to apply new and adequate treatment to this severe complication. Cureus 2023-01-13 /pmc/articles/PMC9922532/ /pubmed/36788919 http://dx.doi.org/10.7759/cureus.33750 Text en Copyright © 2023, Surjan et al. https://creativecommons.org/licenses/by/3.0/This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Pathology
Surjan, Rodrigo Cañada T
de Lima, Thais M
de Souza, Heraldo P
Machado, Marcel Cerqueira C
Ardengh, José C
Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma
title Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma
title_full Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma
title_fullStr Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma
title_full_unstemmed Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma
title_short Molecular Basis of Hyperammonemic Encephalopathy in Fibrolamellar Hepatocellular Carcinoma
title_sort molecular basis of hyperammonemic encephalopathy in fibrolamellar hepatocellular carcinoma
topic Pathology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9922532/
https://www.ncbi.nlm.nih.gov/pubmed/36788919
http://dx.doi.org/10.7759/cureus.33750
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