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There is growing evidence that glucose metabolism in the liver is in part under the control of the endocannabinoid system (ECS) which is also supported by its presence in this organ. The ECS consists of its cannabinoid receptors (CBRs) and enzymes that are responsible for endocannabinoid production and metabolism. ECS is known to be differentially influenced by the hepatic glucose metabolism and insulin resistance, e.g., cannabinoid receptor type 1(CB1) antagonist can improve the glucose tolerance and insulin resistance. Interestingly, our own study shows that expression patterns of CBRs are influenced by the light/dark cycle, which is of significant physiological and clinical interest. The ECS system is highly upregulated during chronic liver disease and a growing number of studies suggest a mechanistic and therapeutic impact of ECS on the development of liver fibrosis, especially putting its receptors into focus. An opposing effect of the CBRs was exerted via the CB1 or CB2 receptor stimulation. An activation of CB1 promoted fibrogenesis, while CB2 activation improved antifibrogenic responses. However, underlying mechanisms are not yet clear. In the context of liver diseases, the ECS is considered as a possible mediator, which seems to be involved in the synthesis of fibrotic tissue, increase of intrahepatic vascular resistance and subsequently development of portal hypertension. Portal hypertension is the main event that leads to complications of the disease. The main complication is the development of variceal bleeding and ascites, which have prognostic relevance for the patients. The present review summarizes the current understanding and impact of the ECS on glucose metabolism in the liver, in association with the development of liver cirrhosis and hemodynamics in cirrhosis and its complication, to give perspectives for development of new therapeutic strategies.

Liver failure is a life-threatening complication of infections restricting the host's response to infection. The pivotal role of the liver in metabolic, synthetic, and immunological pathways enforces limits the host's ability to control the immune response appropriately, making it vulnerable to ineffective pathogen resistance and tissue damage. Deregulated networks of liver diseases are gradually uncovered by high-throughput, single-cell resolved OMICS technologies visualizing an astonishing diversity of cell types and regulatory interaction driving tolerogenic signaling in health and inflammation in disease. Therefore, this review elucidates the effects of the dysregulated host response on the liver, consequences for the immune response, and possible avenues for personalized therapeutics.

Organ dysfunction or overt failure is a commonplace event in the critically ill affecting up to 70% of patients during their stay in the ICU. The outcome depends on the resolution of impaired organ function, while a domino-like deterioration of organs other than the primarily affected ones paves the way for increased mortality. “Acute Liver Failure” was defined in the 1970s as a rare and potentially reversible severe liver injury in the absence of prior liver disease with hepatic encephalopathy occurring within 8 weeks. Dysfunction of the liver in general reflects a critical event in “Multiple Organ Dysfunction Syndrome” due to immunologic, regulatory and metabolic functions of liver parenchymal and non-parenchymal cells. Dysregulation of the inflammatory response, persistent microcirculatory (hypoxic) impairment or drug-induced liver injury are leading problems that result in “secondary liver failure,” i.e., acquired liver injury without underlying liver disease or deterioration of preexisting (chronic) liver disease (“Acute-on-Chronic Liver Failure”). Conventional laboratory markers, such as transaminases or bilirubin, are limited to provide insight into the complex facets of metabolic and immunologic liver dysfunction. Furthermore, inhomogeneous definitions of these entities lead to widely ranging estimates of incidence. In the present work, we review the different definitions to improve the understanding of liver dysfunction as a perpetrator (and therapeutic target) of multiple organ dysfunction syndrome in critical care. Graphic Abstract

The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high risk and to pave the way for personalized screening approaches. In this study, data of patients recruited at 10 centers across Europe and the United States were analyzed. Only patients without clinical signs of hepatic encephalopathy were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤-4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed. In total, 1,868 patients with cirrhosis with a median model for end-stage liver disease (MELD) of 11 were analyzed (Child-Pugh [CP] stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 patients (35%). After excluding patients with a history of overt hepatic encephalopathy, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), whereas it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (Spearman ρ = -0.16, P < 0.001). The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches.

Preclinical, epidemiological, and small clinical studies suggest that green tea extract (GTE) and its major active component epigallocatechingallate (EGCG) exhibit antineoplastic effects in the colorectum. A randomized, double-blind trial of GTE standardized to 150 mg of EGCG b.i.d. vs placebo over 3 years was conducted to prevent colorectal adenomas (n = 1,001 with colon adenomas enrolled, 40 German centers). Randomization (1:1, n = 879) was performed after a 4-week run-in with GTE for safety assessment. The primary end point was the presence of adenoma/colorectal cancer at the follow-up colonoscopy 3 years after randomization. The safety profile of GTE was favorable with no major differences in adverse events between the 2 well-balanced groups. Adenoma rate in the modified intention-to-treat set (all randomized participants [intention-to-treat population] and a follow-up colonoscopy 26-44 months after randomization; n = 632) was 55.7% in the placebo and 51.1% in the GTE groups. This 4.6% difference was not statistically significant (adjusted relative risk 0.905; P = 0.1613). The respective figures for the per-protocol population were 54.3% (151/278) in the placebo group and 48.3% (129/267) in the GTE group, indicating a slightly lower adenoma rate in the GTE group, which was not significant (adjusted relative risk 0.883; P = 0.1169). GTE was well tolerated, but there was no statistically significant difference in the adenoma rate between the GTE and the placebo groups in the whole study population.

Background Recent studies suggest a contribution of intrahepatic mineralocorticoid receptor (MR) activation to the development of cirrhosis. As MR blockade abrogates the development of cirrhosis and hypoxia, common during the development of cirrhosis, can activate MR in hepatocytes. But, the impact of non-physiological hepatic MR activation is unknown. In this study, we investigate the impact of hypoxia-induced hepatocyte MR activation as a relevant factor in cirrhosis. Methods RNA sequencing followed by gene ontology term enrichment analysis was performed on liver samples from rats treated for 12 weeks with or without CCl 4 and for the last four weeks with or without eplerenone (MR antagonist). We investigated if these changes can be mimicked by hypoxia in a human hepatocyte cell line (HepG2 cells) and in primary rat hepatocytes (pRH). In order to evaluate the functional cellular importance, hepatocyte lipid accumulation, glucose consumption, lactate production and mitochondrial function were analyzed. Results In cirrhotic liver tissue genes annotated to the GOterm “Monocarboxylic acid metabolic process” (PPARα, PDK4, AMACR, ABCC2, Lipin1) are downregulated. This effect is reversed by the MR antagonist eplerenone in vivo. The alterations are partially mimicked by hypoxia in rat and human hepatocytes in tissue culture. Furthermore, the reduction of mRNA and protein expression of PPARα, PDK4, AMACR, ABCC2 and Lipin1 during hypoxia is prevented by eplerenone in rat and human hepatocytes. Aldosterone, the endogenous MR agonist, did not affect the expression of those proteins in hepatocytes. As those proteins are key regulators of hepatocyte energy homeostasis, we analyzed if hypoxia affected glucose consumption, lactate production and lipid accumulation in HepG2 cells in a MR-mediated manner. All three parameters were affected by hypoxia and were partially normalized by eplerenone. Conclusion Our findings suggest that non-physiological MR activation plays a role in the dysregulation of glucose and lipid metabolism in hepatocytes. This leads to an increase in apoptosis, probably resulting in a proinflammatory micromilieu of the hepatic tissue. The enhanced deposition of extracellular matrix contributes to the development of cirrhosis. Therefore, MR antagonists may have therapeutic potential in the treatment of early stages of liver disease due to their direct action in the liver.

Background Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis, primarily due to failed early detection. HCC screening is recommended among individuals with cirrhosis using biannual abdominal ultrasound, for earlier tumor detection, administration of curative treatment, and improved survival. Surveillance by imaging with or without biomarkers such as alpha-fetoprotein (AFP) remains suboptimal for early stage HCC detection. Here we report on the development and assessment of methylation biomarkers from liquid biopsies for HCC surveillance in cirrhotic patients. Methods DNA methylation markers including the HCCBloodTest (Epigenomics AG) and a DNA-methylation panel established by next generation sequencing (NGS) were assessed using a training/testing design. The NGS panel algorithm was established in a training study (41 HCC patients; 46 cirrhotic non-HCC controls). For testing, plasma samples were obtained from cirrhotic patients (Child class A or B) with (60) or without (103) early stage HCC (BCLC stage 0, A, B). The assays were then tested using blinded sample sets and analyzed by preset algorithms. Results The HCCBloodTest and the NGS panel exhibited 76.7% and 57% sensitivities at 64.1% and 97% specificity, respectively. In a post-hoc analysis, a combination of the NGS panel with AFP (20 ng/mL) achieved 68% sensitivity at 97% specificity (AUC = 0.9). Conclusions Methylation biomarkers in cell free plasma DNA provide a new alternative for HCC surveillance. Multiomic panels comprising DNA methylation markers with other biological markers, such as AFP, provide an option to further increase the overall clinical performance of surveillance via minimally invasive blood samples. Trial Registration : Test set study—ClinicalTrials.gov (NCT03804593) January 11, 2019, retrospectively registered.

Background Patients with cirrhosis and ascites (and portal hypertension) are at risk of developing acute kidney injury (AKI). Although many etiologies exist, hepatorenal AKI (HRS-AKI) remains a frequent and difficult-to-treat cause, with a very high mortality when left untreated. The standard of care is the use of terlipressin and albumin. This can lead to reversal of AKI, which is associated to survival. Nevertheless, only approximately half of the patients achieve this reversal and even after reversal patients remains at risk for new episodes of HRS-AKI. TIPS is accepted for use in patients with variceal bleeding and refractory ascites, which leads to a reduction in portal pressure. Although preliminary data suggest it may be useful in HRS-AKI, its use in this setting is controversial and caution is recommended given the fact that HRS-AKI is associated to cardiac alterations and acute-on-chronic liver failure (ACLF) which represent relative contraindications for transjugular intrahepatic portosystemic shunt (TIPS). In the last decades, with the new definition of renal failure in patients with cirrhosis, patients are identified at an earlier stage. These patients are less sick and therefore more likely to not have contraindications for TIPS. We hypothesize that TIPS could be superior to the standard of care in patients with HRS-AKI. Methods This study is a prospective, multicenter, open, 1:1-randomized, controlled parallel-group trial. The main end-point is to compare the 12-month liver transplant-free survival in patients assigned to TIPS compared to the standard of care (terlipressin and albumin). Secondary end-point include reversal of HRS-AKI, health-related Quality of Life (HrQoL), and incidence of further decompensation among others. Once patients are diagnosed with HRS-AKI, they will be randomized to TIPS or Standard of Care (SOC). TIPS should be placed within 72 h. Until TIPS placement, TIPS patients will be treated with terlipressin and albumin. Once TIPS is placed, terlipressin and albumin should be weaned off according to the attending physician. Discussion If the trial were to show a survival advantage for patients who undergo TIPS placement, this could be incorporated in routine clinical practice in the management of patients with HRS-AKI. Trial registration Clinicaltrials.gov NCT05346393 . Released to the public on 01 April 2022.

High concentrations of methylglyoxal (MGO) cause cytotoxiticy via formation of advanced glycation endproducts (AGEs) and inflammation. MGO is detoxificated enzymatically by glyoxalase-I (Glo-I). The aim of this study was to analyze the role of Glo-I during the development of cirrhosis. In primary hepatocytes, hepatic stellate cells (pHSC) and sinusoidal endothelial cells (pLSEC) from rats with early (CCl4 8wk) and advanced cirrhosis (CCl4 12wk) expression and activity of Glo-I were determined and compared to control. LPS stimulation (24h; 100ng/ml) of HSC was conducted in absence or presence of the partial Glo-I inhibitor ethyl pyruvate (EP) and the specific Glo-I inhibitor BrBzGSHCp2. MGO, inflammatory and fibrotic markers were measured by ELISA and Western blot. Additional rats were treated with CCl4 ± EP 40mg/kg b.w. i.p. from wk 8-12 and analyzed with sirius red staining and Western blot. Expression of Glo-I was significantly reduced in cirrhosis in whole liver and primary liver cells accompanied by elevated levels of MGO. Activity of Glo-I was reduced in cirrhotic pHSC and pLSEC. LPS induced increases of TNF-α, Nrf2, collagen-I, α-SMA, NF-kB and pERK of HSC were blunted by EP and BrBzGSHCp2. Treatment with EP during development of cirrhosis significantly decreased the amount of fibrosis (12wk CCl4: 33.3±7.3%; EP wk 8-12: 20.7±6.2%; p<0.001) as well as levels of α-SMA, TGF-β and NF-κB in vivo. Our results show the importance of Glo-I as major detoxifying enzyme for MGO in cirrhosis. The reduced expression of Glo-I in cirrhosis demonstrates a possible explanation for increased inflammatory injury and suggests a \"vicious circle\" in liver disease. Blunting of the Glo-I activity decrease the amount of fibrosis in established cirrhosis and constitutes a novel target for antifibrotic therapy.