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Observational Study
. 2019 May;39(5):885-893.
doi: 10.1111/liv.14070. Epub 2019 Mar 7.

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

Jennifer Lehmann  1 , Michael Praktiknjo  1 , Mette Juul Nielsen  2   3 , Robert Schierwagen  1   4 , Carsten Meyer  5 , Daniel Thomas  5 , Francesco Violi  6 , Christian P Strassburg  1 , Flemming Bendtsen  7 , Søren Møller  8 , Aleksander Krag  3 , Morten Asser Karsdal  2 , Diana Julie Leeming  2 , Jonel Trebicka  1   3   4   9   10
Affiliations
Observational Study

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

Jennifer Lehmann et al. Liver Int. 2019 May.

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.

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Conflict of interest statement

The authors do not have any disclosures to report.

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
See this image and copyright information in PMC

References

    1. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134(6):1655‐1669. - PMC - PubMed
    1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209‐218. - PMC - PubMed
    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. - PMC - PubMed
    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. - PMC - PubMed
    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. - PubMed

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