Acute decompensation (AD) of cirrhosis is defined by the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination of these, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF), while their absence defines AD. We designed the PREDICT study, a European, prospective, observational study, to characterize the clinical course of AD and predict ACLF. A total of 1071 patients with AD were enrolled to collect detailed pre-specified information on the 3-month period prior to enrollment, and clinical and laboratory data at enrollment. Patients were then closely followed-up for 3 months. The 12-month outcomes (liver transplantation, and death) were also recorded. Three groups of patients were identified: Pre-ACLF patients (n=218), who developed ACLF and had 3-month and 1-year mortality rates of 53.7% and 67.4%, respectively. Unstable decompensated cirrhosis (UDC) patients (n = 233) required ≥1 readmission but not developing ACLF and had 21.0% and 35.6% mortality rates. Stable decompensated cirrhosis (SDC) patients (n = 620) who were neither readmitted, nor developed ACLF and showed a 1-year mortality of only 9.5%. The 3 groups differed significantly in the grade and course of systemic inflammation (high-grade at enrollment with aggravation during follow-up in pre-ACLF; low-grade at enrollment with subsequent steady-course in UDC; and low-grade at enrollment with subsequent improvement in the SDC) and prevalence of surrogates of severe portal hypertension throughout the study (high in UDC versus low in pre-ACLF and SDC). Acute decompensation without ACLF is a heterogeneous condition with three different clinical courses and two major pathophysiological mechanisms: systemic inflammation and portal hypertension. Prediction of ACLF development remains a major future task.

Chronic liver diseases, primarily metabolic dysfunction-associated steatotic liver disease (MASLD), harmful use of alcohol, or viral hepatitis, may result in liver fibrosis, cirrhosis, and cancer. Hepatic fibrogenesis is a complex process with interactions between different resident and non-resident heterogeneous liver cell populations, ultimately leading to deposition of extracellular matrix and organ failure. Shifts in cell phenotypes and functions involve pronounced transcriptional and protein synthesis changes that require metabolic adaptations in cellular substrate metabolism, including glucose and lipid metabolism, resembling changes associated with the Warburg effect in cancer cells. Cell activation and metabolic changes are regulated by metabolic stress responses, including the unfolded protein response, endoplasmic reticulum stress, autophagy, ferroptosis, and nuclear receptor signaling. These metabolic adaptations are crucial for inflammatory and fibrogenic activation of macrophages, lymphoid cells, and hepatic stellate cells. Modulation of these pathways, therefore, offers opportunities for novel therapeutic approaches to halt or even reverse liver fibrosis progression.

Objective: Adipose tissue-derived factors link non-alcoholic fatty liver disease (NAFLD) with obesity, which has also been reported for circulating chemerin. On the other hand, hepatic chemerin and chemokine-like receptor 1 (CMKLR1) mRNA expression has not yet been studied in an extensively characterized patient collective.Design: This study was cross-sectional and experimental in design.Methods: Liver tissue samples were harvested from 47 subjects and histologically examined according to the NAFLD activity score (NAS). The concentrations of chemerin and CMKLR1 were measured using semi-quantitative real-time PCR, and the concentration of serum chemerin was measured using ELISA. To evaluate potential effects of chemerin and CMKLR1, cultured primary human hepatocytes (PHHs) were exposed to selected metabolites known to play a role in NAFLD (insulin, glucagon, palmitoic acid, and interleukin-6 (IL6)).Results: Chemerin andCMKLR1mRNA levels were elevated in the human liver. Their expression was correlated with the NAS (R²=0.543;P<0.001 andR²=0.355;P=0.014 respectively) and was significantly elevated in patients with definite non-alcoholic steatohepatitis (NASH) (P<0.05 respectively). Linear regression analysis confirmed an independent association of liver fibrosis, steatosis, inflammation, and hepatocyte ballooning with hepatic chemerin mRNA expression (P<0.05 respectively). The expression of hepatic chemerin and CMKLR1 was correlated with the measures of obesity (P0.05). None of the other metabolites showed an influence (P>0.05).Conclusion: This is the first study to show that chemerin mRNA expression is significantly elevated in the liver of NASH patients and that CMKLR1 expression is upregulated in liver inflammation, whereby IL6 could play a causal role.

The new European clinical practice guidelines from three scientific societies (European Association for the Study of the Liver, European Association for the Study of Diabetes and European Association for the Study of Obesity) on the management of metabolic dysfunction-associated steatotic liver disease (MASLD) provide detailed recommendations on diagnosis, risk stratification, monitoring strategies, treatment and prevention. Lifestyle interventions (eg, weight reduction, Mediterranean diet, exercise, alcohol abstinence) and the treatment of cardiometabolic risk factors continue to be the mainstay of treatment and prevention of the disease. Incretin mimetics that are approved to treat obesity and/or type 2 diabetes such as semaglutide and tirzepatide have benefits for ameliorating metabolic dysfunction-associated steatohepatitis (MASH). Novel developments include adapted strategies for screening (case finding) using non-invasive tests (NITs) with a focus on detecting fibrosis or cirrhosis, risk-adjusted monitoring of MASLD by NITs as well as the recommendation to use, if locally approved, the thyroid hormone receptor β-agonist resmetirom in patients with non-cirrhotic MASH fibrosis (≥F2 stage).

Background: Stress hyperglycaemia (SHG) is a common complication in sepsis associated with poor outcome. Chemerin is an adipocytokine associated with inflammation and impaired glucose homeostasis in metabolic diseases such as type 2 diabetes (T2D). We aimed to investigate how alterations of circulating chemerin levels and corresponding visceral adipose tissue (VAT) expression are linked to glucose metabolism and prognosis in sepsis. Methods: Clinical data and tissue samples were taken from a cross-sectional study including control, T2D and sepsis patients, all undergoing laparotomy. A second independent patient cohort of patients with sepsis was included to evaluate associations with prognosis. This was complemented by a murine model of peritoneal infection and a high-fat diet. We analysed circulating chemerin by enzyme-linked immunosorbent assay and VAT messenger RNA (mRNA) expression by real-time polymerase chain reaction. Results: Circulating chemerin was increased in sepsis 1.69-fold compared with controls (p = 0.012) and 1.47-fold compared with T2D (p = 0.03). Otherwise, chemerin VAT mRNA expression was decreased in patients with sepsis (p = 0.006) and in septic diabetic animals (p = 0.009). Circulating chemerin correlated significantly with intra-operative glucose (r = 0.662; p = 0.01) and in trend with fasting glucose (r = 0.528; p = 0.052). After adjusting for body mass index or haemoglobin A1c, chemerin correlated in trend with insulin resistance evaluated using the logarithmised homeostasis model assessment of insulin resistance (r = 0.539, p = 0.071; r = 0.553, p = 0.062). Chemerin was positively associated with Acute Physiology and Chronic Health Evaluation II score in patients with sepsis (p = 0.036) and with clinical severity in septic mice (p = 0.031). In an independent study population, we confirmed association of chemerin with glucose levels in multivariate linear regression analysis (β = 0.556, p = 0.013). In patients with sepsis with SHG, non-survivors had significantly lower chemerin levels than survivors (0.38-fold, p = 0.006), while in patients without SHG, non-survivors had higher chemerin levels, not reaching significance (1.64-fold, p = 0.089). No difference was apparent in patients with pre-existing T2D (p = 0.44). Conclusions: We show, for the first time to our knowledge, that chemerin is increased in sepsis and that it associates with impaired glucose metabolism and survival in these patients. It could be further evaluated as a biomarker to stratify mortality risk of patients with SHG.