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Published in: Digestive Diseases and Sciences 11/2015

01-11-2015 | Original Article

Circulating Elastin Fragments Are Not Affected by Hepatic, Renal and Hemodynamic Changes, But Reflect Survival in Cirrhosis with TIPS

Authors: M. J. Nielsen, J. Lehmann, D. J. Leeming, R. Schierwagen, S. Klein, C. Jansen, C. P. Strassburg, F. Bendtsen, S. Møller, T. Sauerbruch, M. A. Karsdal, A. Krag, J. Trebicka

Published in: Digestive Diseases and Sciences | Issue 11/2015

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Abstract

Background and Aims

Progressive fibrosis increases hepatic resistance and causes portal hypertension with complications. During progressive fibrosis remodeling and deposition of collagens and elastin occur. Elastin remodeling is crucially involved in fibrosis progression in animal models and human data. This study investigated the association of circulating elastin with the clinical outcome in cirrhotic patients with severe portal hypertension receiving transjugular intrahepatic porto-systemic shunt (TIPS).

Methods

We analyzed portal and hepatic venous samples of 110 cirrhotic patients obtained at TIPS insertion and 2 weeks later. The circulating levels of elastin fragments (ELM) were determined using specific monoclonal ELISA. The relationship of ELM with clinical short-time follow-up and long-term outcome was investigated.

Results

Circulating levels of ELM showed a gradient across the liver before TIPS with higher levels in the hepatic vein. Interestingly, the circulating ELM levels remained unchanged after TIPS. The circulating levels of ELM in portal and hepatic veins correlated with platelet counts and inversely with serum sodium. Hepatic venous levels of ELM were higher in CHILD C compared to CHILD A and B and were associated with the presence of ascites. Patients with high levels of ELM in the hepatic veins before TIPS showed poorer survival. In multivariate analysis ELM levels in the hepatic veins and MELD were independent predictors of mortality in these patients.

Conclusion

This study demonstrated that circulating levels of ELM are not associated with hemodynamic changes, but might reflect fibrosis remodeling and predict survival in patients with severe portal hypertension receiving TIPS independently of MELD.
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Literature
1.
2.
go back to reference Boyer TD, Haskal ZJ, American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology. 2010;51:306.CrossRefPubMed Boyer TD, Haskal ZJ, American Association for the Study of Liver Diseases. The role of transjugular intrahepatic portosystemic shunt (TIPS) in the management of portal hypertension: update 2009. Hepatology. 2010;51:306.CrossRefPubMed
3.
go back to reference Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology. 2007;133:825–834.CrossRefPubMed Salerno F, Camma C, Enea M, Rossle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta-analysis of individual patient data. Gastroenterology. 2007;133:825–834.CrossRefPubMed
4.
go back to reference Garcia-Pagan JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362:2370–2379.CrossRefPubMed Garcia-Pagan JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362:2370–2379.CrossRefPubMed
5.
go back to reference Trebicka J, Krag A, Gansweid S, et al. Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt. Eur J Gastroenterol Hepatol. 2011;23:1218–1225.CrossRefPubMed Trebicka J, Krag A, Gansweid S, et al. Endotoxin and tumor necrosis factor-receptor levels in portal and hepatic vein of patients with alcoholic liver cirrhosis receiving elective transjugular intrahepatic portosystemic shunt. Eur J Gastroenterol Hepatol. 2011;23:1218–1225.CrossRefPubMed
6.
go back to reference Trebicka J, Krag A, Gansweid S, et al. Soluble TNF-alpha-receptors I are prognostic markers in TIPS-treated patients with cirrhosis and portal hypertension. PLoS One. 2013;8:e83341.PubMedCentralCrossRefPubMed Trebicka J, Krag A, Gansweid S, et al. Soluble TNF-alpha-receptors I are prognostic markers in TIPS-treated patients with cirrhosis and portal hypertension. PLoS One. 2013;8:e83341.PubMedCentralCrossRefPubMed
7.
go back to reference Berres Marie-Luise, Asmacher Sonja, Lehmann Jennifer, et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Hepatol. 2015;62:332–339.CrossRefPubMed Berres Marie-Luise, Asmacher Sonja, Lehmann Jennifer, et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Hepatol. 2015;62:332–339.CrossRefPubMed
10.
11.
go back to reference Karsdal MA, Nielsen MJ, Sand JM, et al. Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure. Assay Drug Dev Technol. 2013;11:70–92.PubMedCentralCrossRefPubMed Karsdal MA, Nielsen MJ, Sand JM, et al. Extracellular matrix remodeling: the common denominator in connective tissue diseases. Possibilities for evaluation and current understanding of the matrix as more than a passive architecture, but a key player in tissue failure. Assay Drug Dev Technol. 2013;11:70–92.PubMedCentralCrossRefPubMed
12.
go back to reference Leeming DJ, Nielsen MJ, Dai Y, et al. Enzyme-linked immunosorbent serum assay specific for the 7S domain of Collagen Type IV (P4NP 7S): a marker related to the extracellular matrix remodeling during liver fibrogenesis. Hepatol Res. 2012;42:482–493.CrossRefPubMed Leeming DJ, Nielsen MJ, Dai Y, et al. Enzyme-linked immunosorbent serum assay specific for the 7S domain of Collagen Type IV (P4NP 7S): a marker related to the extracellular matrix remodeling during liver fibrogenesis. Hepatol Res. 2012;42:482–493.CrossRefPubMed
13.
go back to reference Leeming DJ, Karsdal MA, Byrjalsen I, et al. Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension. Aliment Pharmacol Ther. 2013;38:1086–1096.PubMedCentralCrossRefPubMed Leeming DJ, Karsdal MA, Byrjalsen I, et al. Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension. Aliment Pharmacol Ther. 2013;38:1086–1096.PubMedCentralCrossRefPubMed
14.
go back to reference Veidal SS, Karsdal MA, Nawrocki A, et al. Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis. Fibrogenesis Tissue Repair. 2011;4:22.PubMedCentralCrossRefPubMed Veidal SS, Karsdal MA, Nawrocki A, et al. Assessment of proteolytic degradation of the basement membrane: a fragment of type IV collagen as a biochemical marker for liver fibrosis. Fibrogenesis Tissue Repair. 2011;4:22.PubMedCentralCrossRefPubMed
15.
go back to reference Jansen C, Leeming DJ, Mandorfer M, et al. PRO-C3-levels in patients with HIV/HCV-Co-infection reflect fibrosis stage and degree of portal hypertension. PLoS One. 2014;9:e108544.PubMedCentralCrossRefPubMed Jansen C, Leeming DJ, Mandorfer M, et al. PRO-C3-levels in patients with HIV/HCV-Co-infection reflect fibrosis stage and degree of portal hypertension. PLoS One. 2014;9:e108544.PubMedCentralCrossRefPubMed
16.
go back to reference Schierwagen R, Leeming DJ, Klein S, et al. Serum markers of the extracellular matrix remodeling reflect antifibrotic therapy in bile-duct ligated rats. Front Physiol. 2013;4:195.PubMedCentralCrossRefPubMed Schierwagen R, Leeming DJ, Klein S, et al. Serum markers of the extracellular matrix remodeling reflect antifibrotic therapy in bile-duct ligated rats. Front Physiol. 2013;4:195.PubMedCentralCrossRefPubMed
17.
go back to reference Leeming DJ, Anadol E, Schierwagen R, et al. Combined antiretroviral therapy attenuates hepatic extracellular matrix remodeling in HIV patients assessed by novel protein fingerprint markers. Aids. 2014;28:2081–2090.CrossRefPubMed Leeming DJ, Anadol E, Schierwagen R, et al. Combined antiretroviral therapy attenuates hepatic extracellular matrix remodeling in HIV patients assessed by novel protein fingerprint markers. Aids. 2014;28:2081–2090.CrossRefPubMed
18.
go back to reference Hennenberg M, Trebicka J, Sauerbruch T, Heller J. Mechanisms of extrahepatic vasodilation in portal hypertension. Gut. 2008;57:1300–1314.CrossRefPubMed Hennenberg M, Trebicka J, Sauerbruch T, Heller J. Mechanisms of extrahepatic vasodilation in portal hypertension. Gut. 2008;57:1300–1314.CrossRefPubMed
19.
go back to reference Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis—current status and future directions. J Hepatol. 2014;61:912–924.PubMedCentralCrossRefPubMed Iwakiri Y, Shah V, Rockey DC. Vascular pathobiology in chronic liver disease and cirrhosis—current status and future directions. J Hepatol. 2014;61:912–924.PubMedCentralCrossRefPubMed
20.
go back to reference Pellicoro A, Aucott RL, Ramachandran P, et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology. 2012;55:1965–1975.CrossRefPubMed Pellicoro A, Aucott RL, Ramachandran P, et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology. 2012;55:1965–1975.CrossRefPubMed
21.
go back to reference Ehling J, Bartneck M, Fech V, et al. Elastin-based molecular MRI of liver fibrosis. Hepatology. 2013;58:1517–1518.CrossRefPubMed Ehling J, Bartneck M, Fech V, et al. Elastin-based molecular MRI of liver fibrosis. Hepatology. 2013;58:1517–1518.CrossRefPubMed
22.
go back to reference Brensing KA, Horsch M, Textor J, et al. Hemodynamic effects of propranolol and nitrates in cirrhotics with transjugular intrahepatic portosystemic stent-shunt. Scand J Gastroenterol. 2002;37:1070–1076.CrossRefPubMed Brensing KA, Horsch M, Textor J, et al. Hemodynamic effects of propranolol and nitrates in cirrhotics with transjugular intrahepatic portosystemic stent-shunt. Scand J Gastroenterol. 2002;37:1070–1076.CrossRefPubMed
23.
go back to reference Brensing KA, Textor J, Perz J, et al. Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut. 2000;47:288–295.PubMedCentralCrossRefPubMed Brensing KA, Textor J, Perz J, et al. Long term outcome after transjugular intrahepatic portosystemic stent-shunt in non-transplant cirrhotics with hepatorenal syndrome: a phase II study. Gut. 2000;47:288–295.PubMedCentralCrossRefPubMed
24.
go back to reference Jansen C, Eischeid H, Goertzen J, et al. The role of miRNA-34a as a prognostic biomarker for cirrhotic patients with portal hypertension receiving TIPS. PLoS One. 2014;9:e103779.PubMedCentralCrossRefPubMed Jansen C, Eischeid H, Goertzen J, et al. The role of miRNA-34a as a prognostic biomarker for cirrhotic patients with portal hypertension receiving TIPS. PLoS One. 2014;9:e103779.PubMedCentralCrossRefPubMed
25.
go back to reference Skjot-Arkil H, Clausen RE, Nguyen QH, et al. Measurement of MMP-9 and -12 degraded elastin (ELM) provides unique information on lung tissue degradation. BMC Pulm Med. 2012;12:34.PubMedCentralCrossRefPubMed Skjot-Arkil H, Clausen RE, Nguyen QH, et al. Measurement of MMP-9 and -12 degraded elastin (ELM) provides unique information on lung tissue degradation. BMC Pulm Med. 2012;12:34.PubMedCentralCrossRefPubMed
26.
go back to reference Arthur MJ. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology. 2002;122:1525–1528.CrossRefPubMed Arthur MJ. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology. 2002;122:1525–1528.CrossRefPubMed
27.
go back to reference Petersen E, Gineitis A, Wagberg F, Angquist KA. Serum levels of elastin-derived peptides in patients with ruptured and asymptomatic abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2001;22:48–52.CrossRefPubMed Petersen E, Gineitis A, Wagberg F, Angquist KA. Serum levels of elastin-derived peptides in patients with ruptured and asymptomatic abdominal aortic aneurysms. Eur J Vasc Endovasc Surg. 2001;22:48–52.CrossRefPubMed
28.
go back to reference D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology. 2006;131:1611–1624.CrossRefPubMed D’Amico G, Garcia-Pagan JC, Luca A, Bosch J. Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review. Gastroenterology. 2006;131:1611–1624.CrossRefPubMed
29.
go back to reference Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–1437, 37.e1-9. Moreau R, Jalan R, Gines P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144:1426–1437, 37.e1-9.
30.
31.
go back to reference Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, Ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000;31:864–871.CrossRefPubMed Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, Ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology. 2000;31:864–871.CrossRefPubMed
32.
go back to reference Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359:1018–1026.PubMedCentralCrossRefPubMed Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med. 2008;359:1018–1026.PubMedCentralCrossRefPubMed
33.
go back to reference Londono MC, Cardenas A, Guevara M, et al. MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut. 2007;56:1283–1290.PubMedCentralCrossRefPubMed Londono MC, Cardenas A, Guevara M, et al. MELD score and serum sodium in the prediction of survival of patients with cirrhosis awaiting liver transplantation. Gut. 2007;56:1283–1290.PubMedCentralCrossRefPubMed
34.
go back to reference Londono MC, Guevara M, Rimola A, et al. Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation. Gastroenterology. 2006;130:1135–1143.CrossRefPubMed Londono MC, Guevara M, Rimola A, et al. Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation. Gastroenterology. 2006;130:1135–1143.CrossRefPubMed
35.
go back to reference Serste T, Gustot T, Rautou PE, et al. Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites. J Hepatol. 2012;57:274–280.CrossRefPubMed Serste T, Gustot T, Rautou PE, et al. Severe hyponatremia is a better predictor of mortality than MELDNa in patients with cirrhosis and refractory ascites. J Hepatol. 2012;57:274–280.CrossRefPubMed
Metadata
Title
Circulating Elastin Fragments Are Not Affected by Hepatic, Renal and Hemodynamic Changes, But Reflect Survival in Cirrhosis with TIPS
Authors
M. J. Nielsen
J. Lehmann
D. J. Leeming
R. Schierwagen
S. Klein
C. Jansen
C. P. Strassburg
F. Bendtsen
S. Møller
T. Sauerbruch
M. A. Karsdal
A. Krag
J. Trebicka
Publication date
01-11-2015
Publisher
Springer US
Published in
Digestive Diseases and Sciences / Issue 11/2015
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI
https://doi.org/10.1007/s10620-015-3783-9

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