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)

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

“…Importantly, ECM is highly dynamic as shown in HIV patients receiving antiretroviral treatment, which led to attenuation of remodelling of collagen type IV and elastin, but not collagen type III and biglycan . Recently, collagen type III deposition was shown to be boosted in AD and ACLF . The present study suggests that the levels of collagen type IV remodelling markers do not accumulate with impaired renal function.…”

“…AD of cirrhosis might progress to multiple organ failure, defining acute‐on‐chronic liver failure (ACLF) with poor survival . Interestingly, AD might boost the net deposition of collagen type III, a major component of the interstitial matrix, suggesting a new role of ECM in decompensated cirrhosis …”

“…In the natural course of chronic liver disease, remodelling of extracellular matrix (ECM) leads to progressive fibrosis. [1][2][3][4][5][6] Matrix metalloproteinases (MMPs) cleave ECM molecules and generate small peptide fragments, known as neo-epitopes. These neo-epitopes are released into the circulation, and they can be measured with the Protein Fingerprint Technology using specific antibodies.…”

“…15,16 Interestingly, AD might boost the net deposition of collagen type III, a major component of the interstitial matrix, suggesting a new role of ECM in decompensated cirrhosis. 3 The ECM can be subdivided in two compartments; the basement membrane and the underlying interstitial matrix. The basement membrane provides structural support and polarity to epithelial cells, controls growth, cell migration and epithelialization during tissue repair.…”

Collagen biology and non‐invasive biomarkers of liver fibrosis

“…In both studies, significant changes in PRO‐C3 level from baseline were observed as a result of therapy . There are limited studies regarding the predictive value of PRO‐C3; however, studies have shown that PRO‐C3 has the ability to predict decompensation and mortality in patients with liver disease, and to predict transplant‐free survival in patients with PSC . However, further investigation regarding the predictive and prognostic value of PRO‐C3 is required, as well as its relationship to clinical outcomes.…”