Cargando…

Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation

Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating...

Descripción completa

Detalles Bibliográficos
Autores principales: Laurain, Audrey, Rubera, Isabelle, Razzouk-Cadet, Micheline, Bonnafous, Stéphanie, Albuquerque, Miguel, Paradis, Valérie, Patouraux, Stéphanie, Duranton, Christophe, Lesaux, Olivier, Lefthériotis, Georges, Tran, Albert, Anty, Rodolphe, Gual, Philippe, Iannelli, Antonio, Favre, Guillaume
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312703/
https://www.ncbi.nlm.nih.gov/pubmed/35884801
http://dx.doi.org/10.3390/biomedicines10071496
_version_ 1784753899687641088
author Laurain, Audrey
Rubera, Isabelle
Razzouk-Cadet, Micheline
Bonnafous, Stéphanie
Albuquerque, Miguel
Paradis, Valérie
Patouraux, Stéphanie
Duranton, Christophe
Lesaux, Olivier
Lefthériotis, Georges
Tran, Albert
Anty, Rodolphe
Gual, Philippe
Iannelli, Antonio
Favre, Guillaume
author_facet Laurain, Audrey
Rubera, Isabelle
Razzouk-Cadet, Micheline
Bonnafous, Stéphanie
Albuquerque, Miguel
Paradis, Valérie
Patouraux, Stéphanie
Duranton, Christophe
Lesaux, Olivier
Lefthériotis, Georges
Tran, Albert
Anty, Rodolphe
Gual, Philippe
Iannelli, Antonio
Favre, Guillaume
author_sort Laurain, Audrey
collection PubMed
description Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT. We also assessed the expression of four key regulators of PPi in liver tissues and established correlations between AC, and scores of liver fibrosis and liver failure in these patients. LT candidates with various liver diseases were included. AC scores were assessed in coronary arteries, abdominal aorta, and aortic valves. Liver fibrosis was evaluated on liver biopsies and from non-invasive tests (FIB-4 and APRI scores). Liver functions were assessed by measuring serum albumin, ALBI, MELD, and Pugh–Child scores. An enzymatic assay was used to dose [PPi]pl. A group of patients without liver alterations from a previous cohort provided a control group. Gene expression assays were performed with mRNA extracted from liver biopsies and compared between LT recipients and the control individuals. [PPi]pl negatively correlated with APRI (r = −0.57, p = 0.001, n = 29) and FIB-4 (r = −0.47, p = 0.006, n = 29) but not with interstitial fibrosis index from liver biopsies (r = 0.07, p = 0.40, n = 16). Serum albumin positively correlated with [PPi]pl (r = 0.71; p < 0.0001, n = 20). ALBI, MELD, and Pugh–Child scores correlated negatively with [PPi]pl (r = −0.60, p = 0.0005; r = −0.56, p = 0.002; r = −0.41, p = 0.02, respectively, with n = 20). Liver fibrosis assessed on liver biopsies by FIB-4 and by APRI positively correlated with coronary AC (r = 0.51, p = 0.02, n = 16; r = 0.58, p = 0.009, n = 20; r = 0.41, p = 0.04, n = 20, respectively) and with abdominal aorta AC (r = 0.50, p = 0.02, n = 16; r = 0.67, p = 0.002, n = 20; r = 0.61, p = 0.04, n = 20, respectively). FIB-4 also positively correlated with aortic valve calcification (r = 0.40, p = 0.046, n = 20). The key regulator genes of PPi production in liver were lower in patients undergoing liver transplantation as compared to controls. Three months after surgery, serum albumin levels were restored to physiological levels (40 [37–44] vs. 35 [30–40], p = 0.009) and [PPi]pl was normalized (1.40 [1.07–1.86] vs. 0.68 [0.53–0.80] µmol/L, p = 0.0005, n = 12). Liver failure and/or fibrosis correlated with AC in several arterial beds and were associated with low plasma PPi and dysregulation of key proteins involved in PPi homeostasis. Liver transplantation normalized these parameters.
format Online
Article
Text
id pubmed-9312703
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-93127032022-07-26 Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation Laurain, Audrey Rubera, Isabelle Razzouk-Cadet, Micheline Bonnafous, Stéphanie Albuquerque, Miguel Paradis, Valérie Patouraux, Stéphanie Duranton, Christophe Lesaux, Olivier Lefthériotis, Georges Tran, Albert Anty, Rodolphe Gual, Philippe Iannelli, Antonio Favre, Guillaume Biomedicines Article Liver fibrosis is associated with arterial calcification (AC). Since the liver is a source of inorganic pyrophosphate (PPi), an anti-calcifying compound, we investigated the relationship between plasma PPi ([PPi]pl), liver fibrosis, liver function, AC, and the hepatic expression of genes regulating PPi homeostasis. To that aim, we compared [PPi]pl before liver transplantation (LT) and 3 months after LT. We also assessed the expression of four key regulators of PPi in liver tissues and established correlations between AC, and scores of liver fibrosis and liver failure in these patients. LT candidates with various liver diseases were included. AC scores were assessed in coronary arteries, abdominal aorta, and aortic valves. Liver fibrosis was evaluated on liver biopsies and from non-invasive tests (FIB-4 and APRI scores). Liver functions were assessed by measuring serum albumin, ALBI, MELD, and Pugh–Child scores. An enzymatic assay was used to dose [PPi]pl. A group of patients without liver alterations from a previous cohort provided a control group. Gene expression assays were performed with mRNA extracted from liver biopsies and compared between LT recipients and the control individuals. [PPi]pl negatively correlated with APRI (r = −0.57, p = 0.001, n = 29) and FIB-4 (r = −0.47, p = 0.006, n = 29) but not with interstitial fibrosis index from liver biopsies (r = 0.07, p = 0.40, n = 16). Serum albumin positively correlated with [PPi]pl (r = 0.71; p < 0.0001, n = 20). ALBI, MELD, and Pugh–Child scores correlated negatively with [PPi]pl (r = −0.60, p = 0.0005; r = −0.56, p = 0.002; r = −0.41, p = 0.02, respectively, with n = 20). Liver fibrosis assessed on liver biopsies by FIB-4 and by APRI positively correlated with coronary AC (r = 0.51, p = 0.02, n = 16; r = 0.58, p = 0.009, n = 20; r = 0.41, p = 0.04, n = 20, respectively) and with abdominal aorta AC (r = 0.50, p = 0.02, n = 16; r = 0.67, p = 0.002, n = 20; r = 0.61, p = 0.04, n = 20, respectively). FIB-4 also positively correlated with aortic valve calcification (r = 0.40, p = 0.046, n = 20). The key regulator genes of PPi production in liver were lower in patients undergoing liver transplantation as compared to controls. Three months after surgery, serum albumin levels were restored to physiological levels (40 [37–44] vs. 35 [30–40], p = 0.009) and [PPi]pl was normalized (1.40 [1.07–1.86] vs. 0.68 [0.53–0.80] µmol/L, p = 0.0005, n = 12). Liver failure and/or fibrosis correlated with AC in several arterial beds and were associated with low plasma PPi and dysregulation of key proteins involved in PPi homeostasis. Liver transplantation normalized these parameters. MDPI 2022-06-24 /pmc/articles/PMC9312703/ /pubmed/35884801 http://dx.doi.org/10.3390/biomedicines10071496 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Laurain, Audrey
Rubera, Isabelle
Razzouk-Cadet, Micheline
Bonnafous, Stéphanie
Albuquerque, Miguel
Paradis, Valérie
Patouraux, Stéphanie
Duranton, Christophe
Lesaux, Olivier
Lefthériotis, Georges
Tran, Albert
Anty, Rodolphe
Gual, Philippe
Iannelli, Antonio
Favre, Guillaume
Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation
title Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation
title_full Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation
title_fullStr Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation
title_full_unstemmed Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation
title_short Arterial Calcifications in Patients with Liver Cirrhosis Are Linked to Hepatic Deficiency of Pyrophosphate Production Restored by Liver Transplantation
title_sort arterial calcifications in patients with liver cirrhosis are linked to hepatic deficiency of pyrophosphate production restored by liver transplantation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9312703/
https://www.ncbi.nlm.nih.gov/pubmed/35884801
http://dx.doi.org/10.3390/biomedicines10071496
work_keys_str_mv AT laurainaudrey arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT ruberaisabelle arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT razzoukcadetmicheline arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT bonnafousstephanie arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT albuquerquemiguel arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT paradisvalerie arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT patourauxstephanie arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT durantonchristophe arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT lesauxolivier arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT leftheriotisgeorges arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT tranalbert arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT antyrodolphe arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT gualphilippe arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT iannelliantonio arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation
AT favreguillaume arterialcalcificationsinpatientswithlivercirrhosisarelinkedtohepaticdeficiencyofpyrophosphateproductionrestoredbylivertransplantation