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

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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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Abbreviations

TIPS:

Transjugular intrahepatic portosystemic shunt

ECM:

Extracellular matrix

MMPs:

Matrix metalloproteinases

PSPG:

Portal systemic pressure gradient

ELM:

MMP-degraded elastin

TMB:

Tetramethyl benzinidine

AUC:

Area under the curve

MELD:

Model for end-stage liver disease

CI:

Confidence interval

BUN:

Blood urea nitrogen

References

  1. Bosch J. Complications of cirrhosis. I. Portal hypertension. J Hepatol. 2000;32:141–156.

    Article  CAS  PubMed  Google Scholar 

  2. 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.

    Article  PubMed  Google Scholar 

  3. 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.

    Article  CAS  PubMed  Google Scholar 

  4. 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.

    Article  CAS  PubMed  Google Scholar 

  5. 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.

    Article  CAS  PubMed  Google Scholar 

  6. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  7. 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.

    Article  CAS  PubMed  Google Scholar 

  8. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–1669.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Bataller R, Brenner DA. Liver fibrosis. J Clin Investig. 2005;115:209–218.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Iredale JP. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J Clin Investig. 2007;117:539–548.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. 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.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  16. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  17. 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.

    Article  CAS  PubMed  Google Scholar 

  18. Hennenberg M, Trebicka J, Sauerbruch T, Heller J. Mechanisms of extrahepatic vasodilation in portal hypertension. Gut. 2008;57:1300–1314.

    Article  CAS  PubMed  Google Scholar 

  19. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  PubMed  Google Scholar 

  21. Ehling J, Bartneck M, Fech V, et al. Elastin-based molecular MRI of liver fibrosis. Hepatology. 2013;58:1517–1518.

    Article  PubMed  Google Scholar 

  22. 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.

    Article  CAS  PubMed  Google Scholar 

  23. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  25. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Arthur MJ. Reversibility of liver fibrosis and cirrhosis following treatment for hepatitis C. Gastroenterology. 2002;122:1525–1528.

    Article  PubMed  Google Scholar 

  27. 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.

    Article  CAS  PubMed  Google Scholar 

  28. 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.

    Article  PubMed  Google Scholar 

  29. 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. Sethasine S, Jain D, Groszmann RJ, Garcia-Tsao G. Quantitative histological-hemodynamic correlations in cirrhosis. Hepatology. 2012;55:1146–1153.

    Article  PubMed Central  PubMed  Google Scholar 

  31. 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.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. 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.

    Article  PubMed  Google Scholar 

  35. 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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors thank G. Hack, S. Bellinghausen, D. Bammer, L. Larsen, and HT. Nguyen for excellent technical assistance. Furthermore, we thank our statistician Inger Byrjalsen for statistical guidance. The study was supported by grants of Deutsche Forschungsgemeinschaft (SFB TRR57 to P18), grants of H. J. & W. Hector Foundation (M60.2), grants of the Danish Agency for Science Technology and Innovation, and grants of the Danish Research Foundation.

Conflict of interest

Mette Juul Nielsen, Diana J. Leeming, and Morten A. Karsdal are employees of Nordic Bioscience, a company engaged in the development of biochemical markers. Morten A Karsdal holds stocks in Nordic Bioscience.

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    Authors and Affiliations

    1. Nordic Bioscience, Fibrosis Biology and Biomarkers, Herlev, Denmark

      M. J. Nielsen, D. J. Leeming & M. A. Karsdal

    2. Department of Gastroenterology, Odense Hospital, University of Southern Denmark, Odense, Denmark

      M. J. Nielsen & A. Krag

    3. Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany

      J. Lehmann, R. Schierwagen, S. Klein, C. Jansen, C. P. Strassburg, T. Sauerbruch & J. Trebicka

    4. Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark

      F. Bendtsen

    5. Department of Clinical Physiology and Nuclear Medicine, 239 Center for Functional and Diagnostic Imaging and Research, Faculty of Health Sciences Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark

      S. Møller

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    1. M. J. Nielsen
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    Correspondence to J. Trebicka.

    Additional information

    M. J. Nielsen and J. Lehmann have contributed equally to this work.

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    Nielsen, M.J., Lehmann, J., Leeming, D.J. et al. Circulating Elastin Fragments Are Not Affected by Hepatic, Renal and Hemodynamic Changes, But Reflect Survival in Cirrhosis with TIPS. Dig Dis Sci 60, 3456–3464 (2015). https://doi.org/10.1007/s10620-015-3783-9

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