Monteiro, S;
Grandt, J;
Uschner, FE;
Kimer, N;
Madsen, JL;
Schierwagen, R;
Klein, S;
... Trebicka, J; + view all
(2020)
Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.
Gut
10.1136/gutjnl-2019-320170.
(In press).
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Abstract
OBJECTIVE Systemic inflammation predisposes acutely decompensated (AD) cirrhosis to the development of acute-on-chronic liver failure (ACLF). Supportive treatment can improve AD patients, becoming recompensated. Little is known about the outcome of patients recompensated after AD. We hypothesise that different inflammasome activation is involved in ACL F development in compensated and recompensated patients. DESIGN 249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACL F development. Two external cohorts (n=327) (recompensation, AD and ACL F) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1- dependent), were measured. In rats, bile duct ligationinduced cirrhosis and lipopolysaccharide exposition were used to induce AD and subsequent recompensation. IL-1α and IL-1β levels and upstream/downstream gene expression were measured. RESULTS Patients developing ACL F showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACL F development than compensated patients. Baseline CLIF-C (European Foundation for the study of chronic liver failure consortium) AD, albumin and IL-1α were independent predictors of ACL F development in compensated and CLIF-C AD and IL-1β in recompensated patients. Compensated rats showed higher IL-1α gene expression and recompensated rats higher IL-1β levels with higher hepatic gene expression. Higher IL-1β detection rates in recompensated patients developing ACL F and higher IL-1α and IL-1β detection rates in patients with ACL F were confirmed in the two external cohorts. CONCLUSION Previous AD is an important risk factor for fatal ACL F development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACL F development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis
| Type: | Article |
|---|---|
| Title: | Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1136/gutjnl-2019-320170 |
| Publisher version: | https://doi.org/10.1136/gutjnl-2019-320170 |
| Language: | English |
| Additional information: | This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10094883 |
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