Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation

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.

EXPERIMENTAL CIRRHOSIS: LIVER MORPHOLOGY AND FUNCTION

The aim was to establish the morphofunctional changes of liver in the experimental cirrhosis. Materials and methods: The research was conducted on 24 white male Wistar rats. Experimental cirrhosis of the liver was simulated by oral administration of CCl4 2 g/kg 2 times weekly for three months. From the selected fragments of the liver, histological specimens were done according to the conventional method and examined by light microscopy. The activity of the enzymes of cytolysis and cholestasis (ALT, AST, alkaline phosphatase), the content of components of bile (cholesterol, bilirubin and bile acids) were determined in the serum. In the blood and liver were determined the content of the final products of metabolism of nitric oxide: NO2 - and NO3 -; in the blood – the content of ceruloplasmin, lactate, pyruvate, middle molecular-weight protein MWP1 and MWP2. In the liver – the activity of succinate dehydrogenase (SDG) and cytochrome oxidase (CHO), N-demethylase and p-hydroxylase microsomal activity. The state of the system of prooxidants-antioxidants was judged by the content in the liver of thiobarbituric acid reactive substance (TBARS), lipid hydroperoxide (LHP), concentration of sulfhydril group (GSH), catalase activities (CAT), superoxide dismutase (SOD). The content of endothelial (eNOS) and inducible (iNOS) NO synthases, the concentration of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α were determined by the enzyme immunoassay. Results: Cirrhosis of the liver, which is morphologically confirmed by the presence of prominent sclerosis in the periportal zones and the formation of umbel, is accompanied by the development of cytolysis and cholestasis processes with an increase in the content of components of bile in the blood (cholesterol, bilirubin and bile acids). An increase in the content of lipoperoxidation products and disturbance of the state of the enzymatic and non-enzymatic units of the antioxidant system, decrease in the activity of mitochondrial (succinate dehydrogenase and cytochrome oxidase) enzymes have been established. The activity of the detoxification processes decreases, namely the inhibition of N-demethylase and p-hydroxylase activity of the liver microsomes, so the manifestations of endotoxicosis increase. This is accompanied with decreased content of endothelial and an increased content inducible NO synthase, a concentration of a stable metabolite of nitric oxide nitrite anion in the blood increase and a decrease in the liver. Сonclusions: Experimental CCl4 cirrhosis is characterized morphologically by sclerosis in the periportal zones and the formation of umbao. The metabolic and functional cirrhoticliver is characterized by cytolysis and cholestasis activation, inhibition of detoxication, prooxidant-antooxidant, including nitrooxidative, disbalance.