scholarly journals Different inflammasome activation predisposes for acute-on-chronic liver failure depending on hepatic compensation in human and experimental liver cirrhosis

2020 ◽  
Vol 73 ◽  
pp. S207-S208
Author(s):  
Sofia Monteiro ◽  
Josephine Grandt ◽  
Frank Uschner ◽  
Nina Kimer ◽  
Jan Lysgaard Madsen ◽  
...  
2020 ◽  
Vol 73 ◽  
pp. S504
Author(s):  
Tammo Lambert Tergast ◽  
Abdul-Rahman Kabbani ◽  
Marie Schultalbers ◽  
Michael P. Manns ◽  
Markus Cornberg ◽  
...  

2021 ◽  
Vol 11 ◽  
Author(s):  
Sabrina Rueschenbaum ◽  
Sandra Ciesek ◽  
Alexander Queck ◽  
Marek Widera ◽  
Katharina Schwarzkopf ◽  
...  

IntroductionAcute-on-chronic liver failure (ACLF) is characterized by high levels of systemic inflammation and parallel suppression of innate immunity, whereas little is known about adaptive immune immunity in ACLF. We therefore aimed to characterize the development of the adaptive immune system during the progression of liver cirrhosis to ACLF. Patients with compensated/stable decompensated liver cirrhosis, acute decompensation of liver cirrhosis, or ACLF were recruited from a prospective cohort study. Comprehensive immunophenotyping was performed using high dimensional flow cytometry. Replication of Torque teno (TT) virus was quantified as a marker of immunosuppression. High frequencies of detectable TT virus were observed already in patients with compensated/stable decompensated liver cirrhosis compared to healthy controls (>50% vs. 19%), suggesting relatively early occurrence of immunosuppression in cirrhosis. In line, profoundly reduced numbers of distinct innate and adaptive immune cell populations were observed before ACLF development. These changes were accompanied by parallel upregulation of co-stimulatory (e.g. CD40L, OX40, CD69, GITR, TIM-1) and inhibitory immune checkpoints (e.g. PDPN, PROCR, 2B4, TIGIT) on CD4+ and CD8+ T cells, which again preceded the development of ACLF. On a functional basis, the capacity of CD4+ and CD8+ T cells to produce pro-inflammatory cytokines upon stimulation was strongly diminished in patients with acute decompensation of liver cirrhosis and ACLF.ConclusionImpaired innate and—in particular—adaptive cellular immunity occurs relatively early in the pathogenesis of liver cirrhosis and precedes ACLF. This may contribute to the development of ACLF by increasing the risk of infections in patients with liver cirrhosis.


Gut ◽  
2020 ◽  
pp. gutjnl-2019-320170 ◽  
Author(s):  
Sofia Monteiro ◽  
Josephine Grandt ◽  
Frank Erhard Uschner ◽  
Nina Kimer ◽  
Jan Lysgård Madsen ◽  
...  

ObjectiveSystemic 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 ACLF development in compensated and recompensated patients.Design249 patients with cirrhosis, divided into compensated and recompensated (previous AD), were followed prospectively for fatal ACLF development. Two external cohorts (n=327) (recompensation, AD and ACLF) were included. Inflammasome-driving interleukins (ILs), IL-1α (caspase-4/11-dependent) and IL-1β (caspase-1-dependent), were measured. In rats, bile duct ligation-induced 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.ResultsPatients developing ACLF showed higher baseline levels of ILs. Recompensated patients and patients with detectable ILs had higher rates of ACLF 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 ACLF 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 ACLF and higher IL-1α and IL-1β detection rates in patients with ACLF were confirmed in the two external cohorts.ConclusionPrevious AD is an important risk factor for fatal ACLF development and possibly linked with inflammasome activation. Animal models confirmed the results showing a link between ACLF development and IL-1α in compensated cirrhosis and IL-1β in recompensated cirrhosis.


Critical Care ◽  
2017 ◽  
Vol 21 (1) ◽  
Author(s):  
Annarein J. C. Kerbert ◽  
◽  
Hein W. Verspaget ◽  
Àlex Amorós Navarro ◽  
Rajiv Jalan ◽  
...  

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