Collagen type IV remodelling gender-specifically predicts mortality in decompensated cirrhosis

Jennifer Lehmann, Michael Praktiknjo, Mette Juul Nielsen, Robert Schierwagen, Carsten Meyer, Daniel Thomas, Francesco Violi, Christian P Strassburg, Flemming Bendtsen, Søren Møller, Aleksander Krag, Morten Asser Karsdal, Diana Julie Leeming, Jonel Trebicka, Jennifer Lehmann, Michael Praktiknjo, Mette Juul Nielsen, Robert Schierwagen, Carsten Meyer, Daniel Thomas, Francesco Violi, Christian P Strassburg, Flemming Bendtsen, Søren Møller, Aleksander Krag, Morten Asser Karsdal, Diana Julie Leeming, Jonel Trebicka

Abstract

Background & aims: Remodelling of extracellular matrix is crucial in progressive liver fibrosis. Collagen type III desposition has been shown in acute decompensation. Extratracellular matrix is compiled of deposition of various components. The role of basement membrane collagen type IV in advanced cirrhosis and acute decompensation is unclear and investigated in this study.

Methods: Patients with decompensated cirrhosis from the prospective NEPTUN cohort (ClinicalTrials.gov Identifier: NCT03628807), who underwent transjugular intrahepatic portosystemic shunt procedure were included. Clinical and laboratory parameters, PRO-C4 and C4M levels were measured in blood samples from portal and hepatic veins just before transjugular intrahepatic portosystemic shunt placement.

Results: Levels of C4M and PRO-C4 are significantly lower in patients with massive ascites and impaired renal sodium excretion. C4M and PRO-C4 show gender-specific profiles with significantly lower levels in females compared to males. Females with higher C4M levels show higher mortality. By contrast, males with higher C4M levels show lower mortality. In multivariate Cox regression analysis, C4M is an independent predictor of survival in female patients.

Conclusion: This study shows that markers of collagen type IV remodelling do not accumulate in severe renal dysfunction. Although collagen type IV degradation markers derive from the liver, portal venous C4M levels are relevant for survival. Moreover, it demonstrates that circulating C4M shows gender-specific profiles, which can independently predict survival in female patients with decompensated cirrhosis.

Keywords: ACLF; acute decompensation; acute-on-chronic liver failure; cirrhosis; collagen type IV; extracellular matrix remodelling; gender; liver; portal hypertension; transjugular intrahepatic portosystemic shunt.

Conflict of interest statement

The authors do not have any disclosures to report.

© 2019 The Authors. Liver International published by John Wiley & Sons Ltd.

Figures

Figure 1
Figure 1
(A) shows levels of C4M and P4NP7S stratified by gender in hepatic and portal vein. Levels in females are significantly lower. (B) shows levels of C4M in portal and hepatic vein. Levels in hepatic vein are significantly higher. (C) shows levels of P4NP7S in portal and hepatic vein. Levels in hepatic vein are significantly higher. (C) shows that before TIPS procedure, the levels of C3M and P4NP7S in portal and hepatic vein stratified for indication for TIPS. Levels of patients with refractory ascites are significantly lower. (E) shows levels of P4NP7S stratified for severity of ascites in portal and hepatic vein. Levels in patients with severe ascites are significantly lower. (F) shows levels of P4NP7S and C4M stratified for sodium excretion in 24 h urine. Levels of P4NP7S are significantly higher in patients with higher than median sodium excretion. Levels of C4M are significantly higher in patients with higher than median sodium excretion. *P < 0.05, **P < 0.01, ***P < 0.001, ns not significant
Figure 2
Figure 2
(A) Kaplan‐Meier survival curve of the whole cohort stratified for C4M in hepatic vein. (B) Kaplan‐Meier survival curve of the whole cohort stratified for C4M in portal vein. (C) Kaplan‐Meier survival curve of female patients stratified for C4M in hepatic vein. (D) Kaplan‐Meier survival curve of female patients stratified for C4M in portal vein. (E) Kaplan‐Meier survival curve of male patients stratified for C4M in hepatic vein

References

    1. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655‐1669.
    1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209‐218.
    1. Praktiknjo M, Lehmann J, Nielsen MJ, et al. Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis. Hepatol Commun. 2018;2(2):211‐222.
    1. 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(9):e108544.
    1. 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 Lond Engl. 2014;28(14):2081‐2090.
    1. 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(2):70‐92.
    1. 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 Off J Jpn Soc Hepatol. 2012;42(5):482‐493.
    1. 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;5(4):22.
    1. 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(9):1086‐1096.
    1. 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.
    1. Salerno F, Cammà C, Enea M, Rössle M, Wong F. Transjugular intrahepatic portosystemic shunt for refractory ascites: a meta‐analysis of individual patient data. Gastroenterology. 2007;133(3):825‐834.
    1. García‐Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362(25):2370‐2379.
    1. Trebicka J. Emergency TIPS in a Child‐Pugh B patient: When does the window of opportunity open and close? J Hepatol. 2017;66(2):442‐450.
    1. Bureau C, Thabut D, Oberti F, et al. Transjugular intrahepatic portosystemic shunts with covered stents increase transplant‐free survival of patients with cirrhosis and recurrent ascites. Gastroenterology. 2017;152(1):157‐163.
    1. Moreau R, Jalan R, Gines P, et al. Acute‐on‐chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology. 2013;144(7):1426‐1437, 1437.e1‐9.
    1. Wong F. Acute kidney injury in liver cirrhosis: new definition and application. Clin Mol Hepatol. 2016;22(4):415‐422.
    1. Mak KM, Mei R. Basement membrane type IV collagen and laminin: An overview of their biology and value as fibrosis biomarkers of liver disease. Anat Rec Hoboken NJ 2007. 2017;300(8):1371‐1390.
    1. Zeisberg M, Kramer K, Sindhi N, Sarkar P, Upton M, Kalluri R. De‐differentiation of primary human hepatocytes depends on the composition of specialized liver basement membrane. Mol Cell Biochem. 2006;283(1‐2):181‐189.
    1. Rojkind M, Ponce‐Noyola P. The extracellular matrix of the liver. Coll Relat Res. 1982;2(2):151‐175.
    1. Trebicka J. Predisposing factors in acute‐on‐chronic liver failure. Semin Liver Dis. 2016;36(2):167‐173.
    1. Chen W, Rock JB, Yearsley MM, Ferrell LD, Frankel WL. Different collagen types show distinct rates of increase from early to late stages of hepatitis C‐related liver fibrosis. Hum Pathol. 2014;45(1):160‐165.
    1. Brensing KA, Hörsch M, Textor J, et al. Hemodynamic effects of propranolol and nitrates in cirrhotics with transjugular intrahepatic portosystemic stent‐shunt. Scand J Gastroenterol. 2002;37(9):1070‐1076.
    1. 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(2):288‐295.
    1. 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(12):1218‐1225.
    1. Berres M‐L, Asmacher S, Lehmann J, et al. CXCL9 is a prognostic marker in patients with liver cirrhosis receiving transjugular intrahepatic portosystemic shunt. J Hepatol. 2015;62(2):332‐339.
    1. Lehmann JM, Claus K, Jansen C, et al. Circulating CXCL10 in cirrhotic portal hypertension might reflect systemic inflammation and predict ACLF and mortality. Liver Int Off J Int Assoc Study Liver. 2018;38(5):875‐884.
    1. Berres M‐L, Lehmann J, Jansen C, et al. Chemokine (C‐X‐C motif) ligand 11 levels predict survival in cirrhotic patients with transjugular intrahepatic portosystemic shunt. Liver Int Off J Int Assoc Study Liver. 2016;36(3):386‐394.
    1. Nielsen MJ, Karsdal MA, Kazankov K, et al. Fibrosis is not just fibrosis ‐ basement membrane modelling and collagen metabolism differs between hepatitis B‐ and C‐induced injury. Aliment Pharmacol Ther. 2016;44(11‐12):1242‐1252.
    1. Liedtke C, Luedde T, Sauerbruch T, et al. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair. 2013;6(1):19.
    1. Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther. 2010;31(3):366‐374.
    1. Mehal W, To U. New approaches for fibrosis regression in alcoholic cirrhosis. Hepatol Int. 2016;10(5):773‐778.
    1. Buck M, Garcia‐Tsao G, Groszmann RJ, et al. Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients. Hepatol Baltim Md. 2014;59(3):1052‐1059.
    1. Ricard‐Blum S, Ruggiero F. The collagen superfamily: from the extracellular matrix to the cell membrane. Pathol Biol (Paris). 2005;53(7):430‐442.
    1. Miner JH. Glomerular basement membrane composition and the filtration barrier. Pediatr Nephrol Berl Ger. 2011;26(9):1413‐1417.
    1. Wells RG. Cellular sources of extracellular matrix in hepatic fibrosis. Clin Liver Dis. 2008;12(4):759‐768, viii.
    1. Bahramsoltani M, Slosarek I, De Spiegelaere W, Plendl J. Angiogenesis and collagen type IV expression in different endothelial cell culture systems. Anat Histol Embryol. 2014;43(2):103‐115.
    1. Barnabas O, Wang H, Gao X‐M. Role of estrogen in angiogenesis in cardiovascular diseases. J Geriatr Cardiol. 2013;10(4):377‐382.
    1. Trenti A, Tedesco S, Boscaro C, et al. Immunity and cell metabolism: Solving the puzzle. Int J Mol Sci. 2018;19(3).
    1. Zhang B, Zhang C‐G, Ji L‐H, Zhao G, Wu Z‐Y. Estrogen receptor β selective agonist ameliorates liver cirrhosis in rats by inhibiting the activation and proliferation of hepatic stellate cells. J Gastroenterol Hepatol. 2018;33(3):747‐755.
    1. Zhang B, Wu Z‐Y. Estrogen derivatives: novel therapeutic agents for liver cirrhosis and portal hypertension. Eur J Gastroenterol Hepatol. 2013;25(3):263‐270.
    1. Cengiz M, Ozenirler S, Yılmaz G. Estrogen receptor alpha expression and liver fibrosis in chronic hepatitis C virus genotype 1b: a clinicopathological study. Hepat Mon. 2014;14(9):e21885.
    1. Zdunek M, Silbiger S, Lei J, Neugarten J. Protein kinase CK2 mediates TGF‐beta1‐stimulated type IV collagen gene transcription and its reversal by estradiol. Kidney Int. 2001;60(6):2097‐2108.
    1. Pozzi A, Yurchenco PD, Iozzo RV. The nature and biology of basement membranes. Matrix Biol J Int Soc Matrix Biol. 2017;57–58:885‐11.
    1. Vllasaliu D, Falcone FH, Stolnik S, Garnett M. Basement membrane influences intestinal epithelial cell growth and presents a barrier to the movement of macromolecules. Exp Cell Res. 2014;323(1):218‐231.
    1. Mantaj J, Abu‐Shams T, Enlo‐Scott Z, Swedrowska M, Vllasaliu D. Role of the basement membrane as an intestinal barrier to absorption of macromolecules and nanoparticles. Mol Pharm. 2018.
    1. Biancheri P, Di Sabatino A, Corazza GR, MacDonald TT. Proteases and the gut barrier. Cell Tissue Res. 2013;351(2):269‐280.

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