Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

Michael Praktiknjo; Jennifer Lehmann; Mette J Nielsen; Robert Schierwagen; Frank E Uschner; Carsten Meyer; Daniel Thomas; Christian P Strassburg; Flemming Bendtsen; Søren Møller; Aleksander Krag; Morten A Karsdal; Diana J Leeming; Jonel Trebicka

doi:10.1002/hep4.1135

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

Michael Praktiknjo, Jennifer Lehmann, Mette J Nielsen, Robert Schierwagen, Frank E Uschner, Carsten Meyer, Daniel Thomas, Christian P Strassburg, Flemming Bendtsen, Søren Møller, Aleksander Krag, Morten A Karsdal, Diana J Leeming, Jonel Trebicka

Department of Clinical Medicine

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Abstract

Patients with end-stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute-on-chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III plays a role in the acceleration of liver cirrhosis after AD and analyzed its formation (Pro-C3) and degradation (matrix metalloproteinase-degraded type III collagen [C3M]) markers in animal models and human disease. Bile duct ligation induced different stages of liver fibrosis in rats. Fibrosis development (hydroxyprolin content, sirius red staining, α-smooth muscle actin immunohistochemistry, messenger RNA of profibrotic cytokines), necroinflammation (aminotransferases levels), fibrolysis (matrix metalloproteinase 2 expression and activity, C1M, C4M), and Pro-C3 and C3M were analyzed 2, 3, 4, 5, and 6 weeks after bile duct ligation (n = 5 each group). In 110 patients with decompensated liver cirrhosis who underwent a transjugular intrahepatic portosystemic shunt procedure for AD, clinical and laboratory parameters as well as Pro-C3 and C3M were measured in blood samples from portal and hepatic veins and were collected just before the transjugular intrahepatic portosystemic shunt placement and 1-3 weeks later. Animal studies showed increased markers of collagen type III deposition with fibrosis, necroinflammation, and decompensation of liver cirrhosis, defined as ascites development. Higher Pro-C3 levels were associated with injury, disease severity scores (Model for End-Stage Liver Disease, Child-Pugh, chronic liver failure-C AD), ACLF development, and mortality. C3M decreased with AD and the chronic liver failure-C AD score. Collagen type III deposition ratio increased with the risk of ACLF development and mortality. Conclusion: We show for the first time that AD boosts collagen type III deposition in experimental and human cirrhosis, possibly contributing to the worsened outcome in patients with decompensated cirrhosis. (Hepatology Communications 2018;2:211-222).

Original language	English
Journal	Hepatology Research
Volume	2
Issue number	2
Pages (from-to)	211-222
Number of pages	12
ISSN	1386-6346
DOIs	https://doi.org/10.1002/hep4.1135
Publication status	Published - 2018

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Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosisFinal published version, 564 KBLicence: CC BY-NC-ND

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Praktiknjo, M., Lehmann, J., Nielsen, M. J., Schierwagen, R., Uschner, F. E., Meyer, C., Thomas, D., Strassburg, C. P., Bendtsen, F., Møller, S., Krag, A., Karsdal, M. A., Leeming, D. J., & Trebicka, J. (2018). Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis. Hepatology Research, 2(2), 211-222. https://doi.org/10.1002/hep4.1135

Praktiknjo, M, Lehmann, J, Nielsen, MJ, Schierwagen, R, Uschner, FE, Meyer, C, Thomas, D, Strassburg, CP, Bendtsen, F , Møller, S, Krag, A, Karsdal, MA, Leeming, DJ & Trebicka, J 2018, 'Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis', Hepatology Research, vol. 2, no. 2, pp. 211-222. https://doi.org/10.1002/hep4.1135

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title = "Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis",

abstract = "Patients with end-stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute-on-chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III plays a role in the acceleration of liver cirrhosis after AD and analyzed its formation (Pro-C3) and degradation (matrix metalloproteinase-degraded type III collagen [C3M]) markers in animal models and human disease. Bile duct ligation induced different stages of liver fibrosis in rats. Fibrosis development (hydroxyprolin content, sirius red staining, α-smooth muscle actin immunohistochemistry, messenger RNA of profibrotic cytokines), necroinflammation (aminotransferases levels), fibrolysis (matrix metalloproteinase 2 expression and activity, C1M, C4M), and Pro-C3 and C3M were analyzed 2, 3, 4, 5, and 6 weeks after bile duct ligation (n = 5 each group). In 110 patients with decompensated liver cirrhosis who underwent a transjugular intrahepatic portosystemic shunt procedure for AD, clinical and laboratory parameters as well as Pro-C3 and C3M were measured in blood samples from portal and hepatic veins and were collected just before the transjugular intrahepatic portosystemic shunt placement and 1-3 weeks later. Animal studies showed increased markers of collagen type III deposition with fibrosis, necroinflammation, and decompensation of liver cirrhosis, defined as ascites development. Higher Pro-C3 levels were associated with injury, disease severity scores (Model for End-Stage Liver Disease, Child-Pugh, chronic liver failure-C AD), ACLF development, and mortality. C3M decreased with AD and the chronic liver failure-C AD score. Collagen type III deposition ratio increased with the risk of ACLF development and mortality. Conclusion: We show for the first time that AD boosts collagen type III deposition in experimental and human cirrhosis, possibly contributing to the worsened outcome in patients with decompensated cirrhosis. (Hepatology Communications 2018;2:211-222).",

author = "Michael Praktiknjo and Jennifer Lehmann and Nielsen, {Mette J} and Robert Schierwagen and Uschner, {Frank E} and Carsten Meyer and Daniel Thomas and Strassburg, {Christian P} and Flemming Bendtsen and S{\o}ren M{\o}ller and Aleksander Krag and Karsdal, {Morten A} and Leeming, {Diana J} and Jonel Trebicka",

year = "2018",

doi = "10.1002/hep4.1135",

language = "English",

volume = "2",

pages = "211--222",

journal = "Hepatology Research",

issn = "1386-6346",

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T1 - Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

AU - Praktiknjo, Michael

AU - Lehmann, Jennifer

AU - Nielsen, Mette J

AU - Schierwagen, Robert

AU - Uschner, Frank E

AU - Meyer, Carsten

AU - Thomas, Daniel

AU - Strassburg, Christian P

AU - Bendtsen, Flemming

AU - Møller, Søren

AU - Krag, Aleksander

AU - Karsdal, Morten A

AU - Leeming, Diana J

AU - Trebicka, Jonel

PY - 2018

Y1 - 2018

N2 - Patients with end-stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute-on-chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III plays a role in the acceleration of liver cirrhosis after AD and analyzed its formation (Pro-C3) and degradation (matrix metalloproteinase-degraded type III collagen [C3M]) markers in animal models and human disease. Bile duct ligation induced different stages of liver fibrosis in rats. Fibrosis development (hydroxyprolin content, sirius red staining, α-smooth muscle actin immunohistochemistry, messenger RNA of profibrotic cytokines), necroinflammation (aminotransferases levels), fibrolysis (matrix metalloproteinase 2 expression and activity, C1M, C4M), and Pro-C3 and C3M were analyzed 2, 3, 4, 5, and 6 weeks after bile duct ligation (n = 5 each group). In 110 patients with decompensated liver cirrhosis who underwent a transjugular intrahepatic portosystemic shunt procedure for AD, clinical and laboratory parameters as well as Pro-C3 and C3M were measured in blood samples from portal and hepatic veins and were collected just before the transjugular intrahepatic portosystemic shunt placement and 1-3 weeks later. Animal studies showed increased markers of collagen type III deposition with fibrosis, necroinflammation, and decompensation of liver cirrhosis, defined as ascites development. Higher Pro-C3 levels were associated with injury, disease severity scores (Model for End-Stage Liver Disease, Child-Pugh, chronic liver failure-C AD), ACLF development, and mortality. C3M decreased with AD and the chronic liver failure-C AD score. Collagen type III deposition ratio increased with the risk of ACLF development and mortality. Conclusion: We show for the first time that AD boosts collagen type III deposition in experimental and human cirrhosis, possibly contributing to the worsened outcome in patients with decompensated cirrhosis. (Hepatology Communications 2018;2:211-222).

AB - Patients with end-stage liver disease develop acute decompensation (AD) episodes, which become more frequent and might develop into acute-on-chronic liver failure (ACLF). However, it remains unknown how AD induces acceleration of liver disease. We hypothesized that remodeling of collagen type III plays a role in the acceleration of liver cirrhosis after AD and analyzed its formation (Pro-C3) and degradation (matrix metalloproteinase-degraded type III collagen [C3M]) markers in animal models and human disease. Bile duct ligation induced different stages of liver fibrosis in rats. Fibrosis development (hydroxyprolin content, sirius red staining, α-smooth muscle actin immunohistochemistry, messenger RNA of profibrotic cytokines), necroinflammation (aminotransferases levels), fibrolysis (matrix metalloproteinase 2 expression and activity, C1M, C4M), and Pro-C3 and C3M were analyzed 2, 3, 4, 5, and 6 weeks after bile duct ligation (n = 5 each group). In 110 patients with decompensated liver cirrhosis who underwent a transjugular intrahepatic portosystemic shunt procedure for AD, clinical and laboratory parameters as well as Pro-C3 and C3M were measured in blood samples from portal and hepatic veins and were collected just before the transjugular intrahepatic portosystemic shunt placement and 1-3 weeks later. Animal studies showed increased markers of collagen type III deposition with fibrosis, necroinflammation, and decompensation of liver cirrhosis, defined as ascites development. Higher Pro-C3 levels were associated with injury, disease severity scores (Model for End-Stage Liver Disease, Child-Pugh, chronic liver failure-C AD), ACLF development, and mortality. C3M decreased with AD and the chronic liver failure-C AD score. Collagen type III deposition ratio increased with the risk of ACLF development and mortality. Conclusion: We show for the first time that AD boosts collagen type III deposition in experimental and human cirrhosis, possibly contributing to the worsened outcome in patients with decompensated cirrhosis. (Hepatology Communications 2018;2:211-222).

U2 - 10.1002/hep4.1135

DO - 10.1002/hep4.1135

M3 - Journal article

C2 - 29404528

SN - 1386-6346

VL - 2

SP - 211

EP - 222

JO - Hepatology Research

JF - Hepatology Research

IS - 2

ER -

Acute decompensation boosts hepatic collagen type III deposition and deteriorates experimental and human cirrhosis

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