Increased apoptotic activity is associated with hospital mortality and disruption in lipid homeostasis in acute-on-chronic liver failure.

Mark McPhail; Evangelos Triantafyllou; Debbie Shawcross; Charalambos G. Antoniades; Mattew R. Lewis; Elizabeth Want; Vishal C. Patel; Yasmin Pasha; (Robin) Daniel Abeles; William Bernal; Elaine Holmes; Julia Wendon; Simon D. Taylor-Robinson

Increased apoptotic activity is associated with hospital mortality and disruption in lipid homeostasis in acute-on-chronic liver failure.

Mark McPhail, Evangelos Triantafyllou, Debbie Shawcross, Charalambos G. Antoniades, Mattew R. Lewis, Elizabeth Want, Vishal C. Patel, Yasmin Pasha, (Robin) Daniel Abeles, William Bernal, Elaine Holmes, Julia Wendon, Simon D. Taylor-Robinson

Research output: Contribution to journal › Meeting abstract › peer-review

Abstract

Background Apoptosis is an important mechanism of hepatocyte cell death in acetaminophen acute liver failure (AALF), sepsis and by lipoapoptosis in non-alcoholic steatohepatitis (NASH). In AALF and NASH peripheral blood levels of apoptotic and necrotic markers (total and caspase cleaved cytokeratin-18) reflect underlying severity of disease. Acute-on-chronic liver failure (ACLF) is associated with reduction in high and low density lipoprotein (HDL,LDL) and phosphocholine (PC) concentrations but whether this reflects increased apoptotic activity is not known. Methods Fifty nine patients with cirrhosis (33 ACLF(12 died; 21 survived); 26 compensated (CLD)) and 7 healthy controls (HC) were studied. Median age was 55(23-65) years with 41 male, 18 female. The aetiology of cirrhosis was alcohol(32), viral(6) , NASH (7) , autoimmune(10) and other(4). Peripheral blood plasma was tested on admission for levels of total and caspase-cleaved cytokeratin 18 (M30,M65). Global metabolic and lipid of plasma was performed by 1H nuclear magnetic resonance spectroscopy (NMR) and reverse phase ultra performance liquid chromatography mass spectrometry (UPLCMS). Multivariate analysis was performed by orthogonal projection to least squares (OPLS) and univariate analysis by Spearman rank correlation and Kruskall-Wallis test. Results Levels of M30 were elevated in both CLD and ACLF compared with HC (p<0.01 HC v CLD; p<0001 HC v ACLF). Similarly the plasma levels of M65 were also highest in ACLF patients compared with CLD and HC (p<0.0001 ACLF v HC; p<0.01 CLD v HC). M30/M65 ratios were lowest in DC compared to other groups (p<0.0001 HC v CLD; p<0.001 HC v ACLF). M30 and M65 were correlated with MELD score (M30 v MELD r=0.40, p=0.002; M65 v MELD r=0.39, p=0.004). On OPLS modelling M65 (but not M30) levels correlated negatively with the LDL (p(corr)=-0.87,p<0.001) and PC(p(corr)=-0.79,p<0.001) resonances on 1H NMR. Of the identified lipids on UPLCMS LPC(16:0) at 520 m/z was negatively correlated with M30 (r=-0.30,p=0.010) and M65 (r=-0.39,p=0.002) levels and also predicted hospital survival (AUROC 0.76 (95%CI 0.66-0.84),p<0.001). M65 levels performed less well at outcome prediction (AUROC 0.66 (95%CI 0.54-0.76), p=0.02). M30 and M30/M65 ratio were not independently associated with outcome. Conclusion ACLF is associated with an increase in levels of both total and caspase cleaved cytokeratin-18 which correlates with increasing MELD score and reduced LDL and LPC levels in peripheral blood. This suggests that hepatocyte death mediated by lipo-apoptotic mechanisms is an important component in the progression of severe disease and poor outcome in ACLF.

Original language	English
Article number	1324
Pages (from-to)	851A-852A
Number of pages	2
Journal	Hepatology
Volume	58
Publication status	Published - Oct 2013
Event	64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases - Washington, United Kingdom Duration: 1 Nov 2013 → 5 Nov 2013

Cite this

McPhail, M., Triantafyllou, E., Shawcross, D., Antoniades, C. G., Lewis, M. R., Want, E., Patel, V. C., Pasha, Y., Abeles, D., Bernal, W., Holmes, E., Wendon, J., & Taylor-Robinson, S. D. (2013). Increased apoptotic activity is associated with hospital mortality and disruption in lipid homeostasis in acute-on-chronic liver failure. Hepatology, 58, 851A-852A. Article 1324.

@article{9f2a69b54bb24aba8c030a1e73602c4b,

title = "Increased apoptotic activity is associated with hospital mortality and disruption in lipid homeostasis in acute-on-chronic liver failure.",

abstract = "Background Apoptosis is an important mechanism of hepatocyte cell death in acetaminophen acute liver failure (AALF), sepsis and by lipoapoptosis in non-alcoholic steatohepatitis (NASH). In AALF and NASH peripheral blood levels of apoptotic and necrotic markers (total and caspase cleaved cytokeratin-18) reflect underlying severity of disease. Acute-on-chronic liver failure (ACLF) is associated with reduction in high and low density lipoprotein (HDL,LDL) and phosphocholine (PC) concentrations but whether this reflects increased apoptotic activity is not known. Methods Fifty nine patients with cirrhosis (33 ACLF(12 died; 21 survived); 26 compensated (CLD)) and 7 healthy controls (HC) were studied. Median age was 55(23-65) years with 41 male, 18 female. The aetiology of cirrhosis was alcohol(32), viral(6) , NASH (7) , autoimmune(10) and other(4). Peripheral blood plasma was tested on admission for levels of total and caspase-cleaved cytokeratin 18 (M30,M65). Global metabolic and lipid of plasma was performed by 1H nuclear magnetic resonance spectroscopy (NMR) and reverse phase ultra performance liquid chromatography mass spectrometry (UPLCMS). Multivariate analysis was performed by orthogonal projection to least squares (OPLS) and univariate analysis by Spearman rank correlation and Kruskall-Wallis test. Results Levels of M30 were elevated in both CLD and ACLF compared with HC (p<0.01 HC v CLD; p<0001 HC v ACLF). Similarly the plasma levels of M65 were also highest in ACLF patients compared with CLD and HC (p<0.0001 ACLF v HC; p<0.01 CLD v HC). M30/M65 ratios were lowest in DC compared to other groups (p<0.0001 HC v CLD; p<0.001 HC v ACLF). M30 and M65 were correlated with MELD score (M30 v MELD r=0.40, p=0.002; M65 v MELD r=0.39, p=0.004). On OPLS modelling M65 (but not M30) levels correlated negatively with the LDL (p(corr)=-0.87,p<0.001) and PC(p(corr)=-0.79,p<0.001) resonances on 1H NMR. Of the identified lipids on UPLCMS LPC(16:0) at 520 m/z was negatively correlated with M30 (r=-0.30,p=0.010) and M65 (r=-0.39,p=0.002) levels and also predicted hospital survival (AUROC 0.76 (95%CI 0.66-0.84),p<0.001). M65 levels performed less well at outcome prediction (AUROC 0.66 (95%CI 0.54-0.76), p=0.02). M30 and M30/M65 ratio were not independently associated with outcome. Conclusion ACLF is associated with an increase in levels of both total and caspase cleaved cytokeratin-18 which correlates with increasing MELD score and reduced LDL and LPC levels in peripheral blood. This suggests that hepatocyte death mediated by lipo-apoptotic mechanisms is an important component in the progression of severe disease and poor outcome in ACLF. ",

author = "Mark McPhail and Evangelos Triantafyllou and Debbie Shawcross and Antoniades, {Charalambos G.} and Lewis, {Mattew R.} and Elizabeth Want and Patel, {Vishal C.} and Yasmin Pasha and Abeles, {(Robin) Daniel} and William Bernal and Elaine Holmes and Julia Wendon and Taylor-Robinson, {Simon D.}",

note = "Publisher: WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA Accession Number: WOS:000330252204107 ISSN: 0270-9139 eISSN: 1527-3350; 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases ; Conference date: 01-11-2013 Through 05-11-2013",

year = "2013",

month = oct,

language = "English",

volume = "58",

pages = "851A--852A",

journal = "Hepatology",

issn = "0270-9139",

publisher = "Wolters Kluwer Health",

}

TY - JOUR

T1 - Increased apoptotic activity is associated with hospital mortality and disruption in lipid homeostasis in acute-on-chronic liver failure.

AU - McPhail, Mark

AU - Triantafyllou, Evangelos

AU - Shawcross, Debbie

AU - Antoniades, Charalambos G.

AU - Lewis, Mattew R.

AU - Want, Elizabeth

AU - Patel, Vishal C.

AU - Pasha, Yasmin

AU - Abeles, (Robin) Daniel

AU - Bernal, William

AU - Holmes, Elaine

AU - Wendon, Julia

AU - Taylor-Robinson, Simon D.

N1 - Publisher: WILEY-BLACKWELL, 111 RIVER ST, HOBOKEN 07030-5774, NJ USA Accession Number: WOS:000330252204107 ISSN: 0270-9139 eISSN: 1527-3350

PY - 2013/10

Y1 - 2013/10

N2 - Background Apoptosis is an important mechanism of hepatocyte cell death in acetaminophen acute liver failure (AALF), sepsis and by lipoapoptosis in non-alcoholic steatohepatitis (NASH). In AALF and NASH peripheral blood levels of apoptotic and necrotic markers (total and caspase cleaved cytokeratin-18) reflect underlying severity of disease. Acute-on-chronic liver failure (ACLF) is associated with reduction in high and low density lipoprotein (HDL,LDL) and phosphocholine (PC) concentrations but whether this reflects increased apoptotic activity is not known. Methods Fifty nine patients with cirrhosis (33 ACLF(12 died; 21 survived); 26 compensated (CLD)) and 7 healthy controls (HC) were studied. Median age was 55(23-65) years with 41 male, 18 female. The aetiology of cirrhosis was alcohol(32), viral(6) , NASH (7) , autoimmune(10) and other(4). Peripheral blood plasma was tested on admission for levels of total and caspase-cleaved cytokeratin 18 (M30,M65). Global metabolic and lipid of plasma was performed by 1H nuclear magnetic resonance spectroscopy (NMR) and reverse phase ultra performance liquid chromatography mass spectrometry (UPLCMS). Multivariate analysis was performed by orthogonal projection to least squares (OPLS) and univariate analysis by Spearman rank correlation and Kruskall-Wallis test. Results Levels of M30 were elevated in both CLD and ACLF compared with HC (p<0.01 HC v CLD; p<0001 HC v ACLF). Similarly the plasma levels of M65 were also highest in ACLF patients compared with CLD and HC (p<0.0001 ACLF v HC; p<0.01 CLD v HC). M30/M65 ratios were lowest in DC compared to other groups (p<0.0001 HC v CLD; p<0.001 HC v ACLF). M30 and M65 were correlated with MELD score (M30 v MELD r=0.40, p=0.002; M65 v MELD r=0.39, p=0.004). On OPLS modelling M65 (but not M30) levels correlated negatively with the LDL (p(corr)=-0.87,p<0.001) and PC(p(corr)=-0.79,p<0.001) resonances on 1H NMR. Of the identified lipids on UPLCMS LPC(16:0) at 520 m/z was negatively correlated with M30 (r=-0.30,p=0.010) and M65 (r=-0.39,p=0.002) levels and also predicted hospital survival (AUROC 0.76 (95%CI 0.66-0.84),p<0.001). M65 levels performed less well at outcome prediction (AUROC 0.66 (95%CI 0.54-0.76), p=0.02). M30 and M30/M65 ratio were not independently associated with outcome. Conclusion ACLF is associated with an increase in levels of both total and caspase cleaved cytokeratin-18 which correlates with increasing MELD score and reduced LDL and LPC levels in peripheral blood. This suggests that hepatocyte death mediated by lipo-apoptotic mechanisms is an important component in the progression of severe disease and poor outcome in ACLF.

AB - Background Apoptosis is an important mechanism of hepatocyte cell death in acetaminophen acute liver failure (AALF), sepsis and by lipoapoptosis in non-alcoholic steatohepatitis (NASH). In AALF and NASH peripheral blood levels of apoptotic and necrotic markers (total and caspase cleaved cytokeratin-18) reflect underlying severity of disease. Acute-on-chronic liver failure (ACLF) is associated with reduction in high and low density lipoprotein (HDL,LDL) and phosphocholine (PC) concentrations but whether this reflects increased apoptotic activity is not known. Methods Fifty nine patients with cirrhosis (33 ACLF(12 died; 21 survived); 26 compensated (CLD)) and 7 healthy controls (HC) were studied. Median age was 55(23-65) years with 41 male, 18 female. The aetiology of cirrhosis was alcohol(32), viral(6) , NASH (7) , autoimmune(10) and other(4). Peripheral blood plasma was tested on admission for levels of total and caspase-cleaved cytokeratin 18 (M30,M65). Global metabolic and lipid of plasma was performed by 1H nuclear magnetic resonance spectroscopy (NMR) and reverse phase ultra performance liquid chromatography mass spectrometry (UPLCMS). Multivariate analysis was performed by orthogonal projection to least squares (OPLS) and univariate analysis by Spearman rank correlation and Kruskall-Wallis test. Results Levels of M30 were elevated in both CLD and ACLF compared with HC (p<0.01 HC v CLD; p<0001 HC v ACLF). Similarly the plasma levels of M65 were also highest in ACLF patients compared with CLD and HC (p<0.0001 ACLF v HC; p<0.01 CLD v HC). M30/M65 ratios were lowest in DC compared to other groups (p<0.0001 HC v CLD; p<0.001 HC v ACLF). M30 and M65 were correlated with MELD score (M30 v MELD r=0.40, p=0.002; M65 v MELD r=0.39, p=0.004). On OPLS modelling M65 (but not M30) levels correlated negatively with the LDL (p(corr)=-0.87,p<0.001) and PC(p(corr)=-0.79,p<0.001) resonances on 1H NMR. Of the identified lipids on UPLCMS LPC(16:0) at 520 m/z was negatively correlated with M30 (r=-0.30,p=0.010) and M65 (r=-0.39,p=0.002) levels and also predicted hospital survival (AUROC 0.76 (95%CI 0.66-0.84),p<0.001). M65 levels performed less well at outcome prediction (AUROC 0.66 (95%CI 0.54-0.76), p=0.02). M30 and M30/M65 ratio were not independently associated with outcome. Conclusion ACLF is associated with an increase in levels of both total and caspase cleaved cytokeratin-18 which correlates with increasing MELD score and reduced LDL and LPC levels in peripheral blood. This suggests that hepatocyte death mediated by lipo-apoptotic mechanisms is an important component in the progression of severe disease and poor outcome in ACLF.

M3 - Meeting abstract

SN - 0270-9139

VL - 58

SP - 851A-852A

JO - Hepatology

JF - Hepatology

M1 - 1324

T2 - 64th Annual Meeting and Postgraduate Course of the American-Association-for-the-Study-of-Liver-Diseases

Y2 - 1 November 2013 through 5 November 2013

ER -

Increased apoptotic activity is associated with hospital mortality and disruption in lipid homeostasis in acute-on-chronic liver failure.

Abstract

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