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Mechanistically, the symptomatology and disease progression of non-alcoholic fatty liver disease (NAFLD) remain poorly understood, which makes therapeutic progress difficult. In this review, we focus on the potential importance of decreased urea cycle activity as a pathogenic mechanism. Urea synthesis is an exclusive hepatic function and is the body's only on-demand and definitive pathway to remove toxic ammonia. The compromised urea cycle activity in NAFLD is likely caused by epigenetic damage to urea cycle enzyme genes and increased hepatocyte senescence. When the urea cycle is dysfunctional, ammonia accumulates in liver tissue and blood, as has been demonstrated in both animal models and patients with NAFLD. The problem may be augmented by parallel changes in the glutamine/glutamate system. In the liver, the accumulation of ammonia leads to inflammation, stellate cell activation and fibrogenesis, which is partially reversible. This may be an important mechanism for the transition of bland steatosis to steatohepatitis and further to cirrhosis and hepatocellular carcinoma. Systemic hyperammonaemia has widespread negative effects on other organs. Best known are the cerebral consequences that manifest as cognitive disturbances, which are prevalent in patients with NAFLD. Furthermore, high ammonia levels induce a negative muscle protein balance leading to sarcopenia, compromised immune function and increased risk of liver cancer. There is currently no rational way to reverse reduced urea cycle activity but there are promising animal and human reports of ammonia-lowering strategies correcting several of the mentioned untoward aspects of NAFLD. In conclusion, the ability of ammonia-lowering strategies to control the symptoms and prevent the progression of NAFLD should be explored in clinical trials., Competing Interests: Rajiv Jalan is the inventor of OPA, which has been patented by UCL and licensed to Mallinckrodt Pharma. He is also the founder of Yaqrit Discovery, a spin out company from University College London, Hepyx Limited and Cyberliver. He had research collaborations with Yaqrit Discovery. All other authors have nothing to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Background & Aims: Acute-on-chronic liver failure (ACLF) is characterised by high short-term mortality, systemic inflammation, and failure of hepatic regeneration. Its treatment is a major unmet medical need. This study was conducted to explore whether combining TAK-242, a Toll-like receptor-4 (TLR4) antagonist, with granulocyte-colony stimulating factor (G-CSF), could reduce inflammation whilst enhancing liver regeneration., Methods: Two mouse models of ACLF were investigated. Chronic liver injury was induced by carbon tetrachloride; lipopolysaccharide (LPS) or galactosamine (GalN) were then administered as extrahepatic or hepatic insults, respectively. G-CSF and/or TAK-242 were administered daily. Treatment durations were 24 hours and 5 days in the LPS model and 48 hours in the GalN model., Results: In a mouse model of LPS-induced ACLF, treatment with G-CSF was associated with significant mortality (66% after 48 hours vs. 0% without G-CSF). Addition of TAK-242 to G-CSF abrogated mortality (0%) and significantly reduced liver cell death, macrophage infiltration and inflammation. In the GalN model, both G-CSF and TAK-242, when used individually, reduced liver injury but their combination was significantly more effective. G-CSF treatment, with or without TAK-242, was associated with activation of the pro-regenerative and anti-apoptotic STAT3 pathway. LPS-driven ACLF was characterised by p21 overexpression, which is indicative of hepatic senescence and inhibition of hepatocyte regeneration. While TAK-242 treatment mitigated the effect on senescence, G-CSF, when co-administered with TAK-242, resulted in a significant increase in markers of hepatocyte regeneration., Conclusion: The combination of TAK-242 and G-CSF inhibits inflammation, promotes hepatic regeneration and prevents mortality in models of ACLF; thus, this combination could be a potential treatment option for ACLF., Lay Summary: Acute-on-chronic liver failure is associated with severe liver inflammation and poor short-term survival. Therefore, effective treatments are urgently needed. Herein, we have shown, using mouse models, that the combination of granulocyte-colony stimulating factor (which can promote liver regeneration) and TAK-242 (which inhibits a receptor that plays a key role in inflammation) could be effective for the treatment of acute-on-chronic liver failure., Competing Interests: Conflict of interest Rajiv Jalan has research collaborations with Yaqrit. Rajiv Jalan is the founder of Yaqrit Limited, which is developing UCL inventions for treatment of patients with cirrhosis. Rajiv Jalan is an inventor of ornithine phenylacetate, which was licensed by UCL to Mallinckrodt. He is also a Founder of Hepyx Ltd. and Cyberliver Ltd. Cornelius Engelmann has received advisory fees from Novartis and CSL Behring. He is shareholder of Hepyx Ltd. Fausto Andreola is shareholder of Hepyx Ltd. Rajiv Jalan, Cornelius Engelmann, Fausto Andreola and Thomas Berg are the named inventors on the patents surrounding the use of G-TAK in ACLF, which have been filed as a priority application. This patent has been licensed to Hepyx Ltd. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Hepatic encephalopathy (HE) is a severe complication of liver disease, describing a spectrum of neurological and psychiatric abnormalities ranging from subclinical alterations to coma. HE is the leading cause for hospital readmission, intensive care treatment, and mortality in patients with chronic liver disease. The complex and multifaceted pathogenesis is not yet fully understood, but hypotheses focus on ammonia and systemic inflammation, which are the main targets for currently available therapies in clinical practice. Nevertheless, the remaining high clinical relevance and healthcare burden of this syndrome underlines the emergence for further unraveling the full spectrum of pathomechanisms, as this provides the basis for the development of novel, highly targeted therapies. In this review, the most recent literature about current and future therapies for HE, relevant for intensive care management, will be discussed., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Vasopressin receptor-mediated vasoconstriction is considered to be involved in the pathogenesis of organ failure in acute-on-chronic liver failure (ACLF)., Patients and Methods: We studied the association between six single nucleotide polymorphisms (SNPs) of the vasopressin 1a receptor gene and the development of organ failure in 826 patients admitted for acute decompensation of liver cirrhosis (n=641) or ACLF (n=185)., Results: No associations were found for SNPs with the presence of circulatory or renal failure. A C>T mutation in SNP rs7308855 and a T>A mutation in SNP rs7298346 showed an association with the presence of coagulation failure in the entire population (n=61, P=0.024 and 0.060, respectively) and in the subgroup of patients with ACLF (n=44, P=0.081 and 0.056, respectively)., Conclusion: Genetic variation in the vasopressin 1a receptor was found not to be associated with circulatory or renal failure, but with the presence of coagulation failure in patients with acute decompensation of liver cirrhosis and ACLF.

The current primary prophylaxis for esophageal variceal bleeding in cirrhotic patients consists of nonselective β-blocker (NSBB) therapy. However, only approximately half of the patients achieve a sufficient hemodynamic response to NSBB therapy. Clinical application of hemodynamic response monitoring is still under debate. The aim of this meta-analysis is to assess the potential clinical value of monitoring the hemodynamic response to NSBB therapy using hepatic venous pressure gradient (HVPG) measurements in the primary prophylaxis for variceal bleeding. A systematic literature search was performed in PubMed, Embase, Web of Science, and the COCHRANE Library. Randomized-controlled trials and case series that included cirrhotic patients receiving primary prophylaxis for variceal bleeding with NSBBs and hemodynamic response monitoring using HVPG measurements were included for analysis. The primary outcome measure was variceal bleeding. A fixed-effect analysis was carried out using the Mantel-Haenszel method for relative risks. Six of the 1172 papers found were selected on the basis of stringent selection criteria. Hemodynamic response (HVPG ≤12 mmHg and/or a reduction of ≥20%, or ≥10% in one study, from baseline) to β-blocker therapy was associated significantly with a lower risk of variceal bleeding (relative risk=0.13, 95% confidence interval=0.06-0.29) compared with a nonresponse. Patients achieving a hemodynamic response to NSBB therapy have a lower risk of variceal bleeding than hemodynamic nonresponders. Hemodynamic monitoring in primary prophylaxis is of potential clinical value and requires further assessment in large cohort randomized-controlled trials.

Purpose: The aim of this study was to compare patient characteristics and midterm outcomes after RFA for unresectable Hepatocellular carcinoma (HCC) in Asian and European cohorts., Materials and Methods: The study was based on retrospective analysis of 279 patients (mean 64.8 ± 12.1 years; 208 males) treated with RFA for de novo HCC in tertiary referral centers in Singapore and the Netherlands, with median follow-up of 28.2 months (quartiles: 13.1-40.5 months). Cumulative incidence of recurrence and death were analyzed using a competing risk model., Results: Age was higher in the Asian group: 66.5 versus 60.1 years (p < 0.0001). The most common etiology was hepatitis B in the Asian group (48.0 %) and alcohol-induced cirrhosis in Europeans (54.4 %); p < 0.001. Asian patients had less advanced disease: 35.5, 55.0, and 3.0 %, respectively, had BCLC 0, A, and B versus 21.5, 58.2, and 15.2 % in the European group (p = 0.01). The cumulative incidences of recurrence in the Asian group at 1, 2, 3, and 5 years were 37.0, 56.4, 62.3, and 67.7 %, respectively, compared to 32.6, 47.2, 49.7, and 53.4 % in the European group (p = 0.474). At 1, 2, 3, and 5 years, the cumulative incidence rates of death in the Asian group were 2.0, 3.9, 4.9, and 4.9 %, respectively, corresponding to 7.7, 9.2, 14.1, and 21.0 % in the European group (p = 0.155)., Conclusion: Similar short-term treatment outcomes are achieved with RFA in HCC patients in the South-East Asian and Northern-European populations. Midterm recurrence and death rates differ between the groups as a result of differences in baseline patient characteristics and patient selection. Our study provides insight relevant to the design of future international studies., Competing Interests: The authors declare that they have no other conflicts of interest. Informed Consent For this type of study, formal consent is not required in our institutions.

Background & Aims: Research on vasopressin (AVP) in cirrhosis and its role in the assessment of prognosis has been hindered by the difficulty of measuring AVP levels accurately. Copeptin, a 39-aminoacid glycopeptide, is released from the neurohypophysis together with AVP. Copeptin could have a role as biomarker of prognosis in cirrhosis as it may reflect circulatory dysfunction. The aim of this study is to investigate the role of copeptin as biomarker of disease progression and prognosis in cirrhosis., Methods: This prospective study is divided in 2 study protocols including 321 consecutive patients. Plasma copeptin levels were measured in all patients at study inclusion. Protocol 1: to investigate the relationship of copeptin with kidney and circulatory function (56 patients). Protocol 2: to investigate the relationship between copeptin and prognosis, as assessed by the development of complications of cirrhosis or mortality at 3months (265 patients admitted to hospital for complications of cirrhosis)., Results: Patients with decompensated cirrhosis showed significantly higher plasma copeptin levels compared to those of patients with compensated cirrhosis. Copeptin levels had a significant positive correlation with model for end-satge liver disease (MELD) score, AVP, endogenous vasoconstrictor systems, and kidney function parameters. Patients developing complications of cirrhosis or mortality had significantly higher plasma copeptin levels compared to those of the remaining patients. Plasma copeptin levels were an independent predictive factor of both the development of complications and mortality at 3months. This was confirmed in a validation series of 120 patients., Conclusions: Copeptin is a novel biomarker of disease progression and prognosis in cirrhosis., Lay Summary: Copeptin is a fragment of the vasopressin precursor, a hormone that is known to be increased in patients with cirrhosis and that plays a role in the development of complications of the disease. Vasopressin is difficult to measure, but copeptin is a more stable molecule and is easier to measure in blood. Solà and Kerbert and colleagues have shown in a series of 361 patients that copeptin is markedly increased in patients with cirrhosis who develop complications during the following 3months, compared to those patients who do not develop complications. Moreover, copeptin correlates with prognosis., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Copeptin is a stable cleavage product of the arginine vasopressin (AVP) precursor and is equimolarly secreted with AVP. Copeptin is currently considered a reliable prognostic marker in a wide variety of diseases other than cirrhosis. We aimed to investigate the association between severity of cirrhosis and copeptin concentrations and to confirm whether copeptin is of prognostic significance in cirrhosis., Methods: One hundred and eighty-four cirrhotic patients hospitalized in two tertiary referral centres were studied. Serum copeptin was measured in samples obtained at hospital admission. Differences in serum copeptin between Child-Pugh classes were evaluated using the Kruskal-Wallis test. Cox proportional hazard regression and Kaplan-Meier analyses were performed to evaluate associations of copeptin and other possible prognostic factors with 6- and 12-month mortality., Results: Median serum copeptin (interquartile range) increased significantly through Child-Pugh classes A [5.4 (3.1-10.7) pmol/L], B [9.6 (6.0-17.3) pmol/L] and C [13.8 (5.8-34.1) pmol/L, P < 0.01]. Patients with serum copeptin >12.3 pmol/L displayed significantly higher mortality rates at 6 and 12 months as compared to those with serum copeptin ≤12.3 pmol/L (Log-rank test: P < 0.01). Serum copeptin >12.3 pmol/L was significantly associated with mortality, particularly at 6 months, independently of age, clinical parameters and Model for End stage Liver Disease (MELD), MELD-sodium and Child-Pugh score., Conclusions: Serum copeptin concentration increases significantly along with the severity of cirrhosis as defined by the Child-Pugh classification. A high serum copeptin concentration predicts survival, particularly at 6 months, independently of liver-specific scoring systems in a heterogeneous population of hospitalized cirrhotic patients., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Advanced liver cirrhosis is associated with systemic hemodynamic derangement leading to the development of severe complications associated with increased mortality. Copeptin is a stable cleavage product of the precursor of arginine vasopressin, a key-regulator in hemodynamic homeostasis. Copeptin is currently considered a reliable prognostic marker in a wide variety of diseases other than cirrhosis. The present study aimed to assess copeptin, both experimentally and clinically, as a potential biomarker of hemodynamic derangement and to evaluate its prognostic significance in cirrhosis., Materials and Methods: Two studies were executed: 1) in 18 thioacetamide-induced cirrhotic rats and 5 control rats, plasma copeptin and hemodynamic measurements were performed, 2) in 61 cirrhotic patients, serum copeptin concentration was measured in samples collected at time of registration at the waiting list for liver transplantation. In 46 patients, also a second copeptin measurement was performed during follow-up while registered at the waiting list for liver transplantation. To determine the association of serum copeptin and clinical data with outcome, Cox proportional hazard regression analysis and Kaplan Meier analysis were performed., Results: Plasma copeptin concentration was significantly higher in cirrhotic rats than in controls (1.6 ± 0.5 vs. 0.9 ± 0.1 pmol/L, p< 0.01) and was negatively correlated to the mean arterial blood pressure (r = -0.574, p = 0.013). In cirrhotic patients, serum copeptin concentration was high [11.0 (5.2-24.0) pmol/L] and increased significantly during the time of registration at the waiting list for liver transplantation. MELD and MELD-sodium score were significantly correlated to serum copeptin [MELD: (r = 0.33, p = 0.01), MELD-sodium: (r = 0.29, p = 0.02)], also at time of the second copeptin measurement [MELD and MELD-sodium: r = 0.39, p< 0.01]. In cirrhotic humans, serum copeptin concentration was significantly associated with outcome, independently of the MELD and MELD-sodium score. Patients with a low serum copeptin concentration at time of registration at the liver transplant waiting list had significantly better transplant-free survival rates at 3, 6 and 12 months of follow-up as compared to those with a high serum copeptin concentration (Log-rank: p< 0.01, p< 0.01 and p = 0.02 respectively)., Conclusions: Circulating copeptin levels are elevated in rats and humans with cirrhosis. Copeptin is independently associated with outcome in cirrhotic patients awaiting liver transplantation.