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Aim: Investigating the effect of finerenone on liver function, cardiovascular and kidney composite outcomes in patients with chronic kidney disease and type 2 diabetes, stratified by their risk of liver steatosis, inflammation and fibrosis. Materials and Methods: Post hoc analysis stratified patients (N = 13 026) by liver fibrosis and enzymes: high risk of steatosis (hepatic steatosis index >36); elevated transaminases [alanine transaminase (ALT) >33 (males) and >25 IU/L (females)]; and fibrosis‐4 (FIB‐4) index scores >3.25, >2.67 and >1.30. Liver enzymes were assessed by changes in ALT, aspartate aminotransferase and gamma‐glutamyl transferase. Composite kidney outcome was defined as onset of kidney failure, sustained estimated glomerular filtration rate decline ≥57% from baseline over ≥4 weeks or kidney death. Composite cardiovascular outcome was defined as cardiovascular death, non‐fatal myocardial infarction, non‐fatal stroke or hospitalization for heart failure. Results: ALT, aspartate aminotransferase and gamma‐glutamyl transferase levels were consistent between treatment groups and remained stable throughout. Finerenone consistently reduced the risk of composite kidney outcome, irrespective of altered liver tests. Higher FIB‐4 score was associated with higher incidence rates of composite cardiovascular outcome. Finerenone reduced the risk of composite cardiovascular outcome versus placebo in FIB‐4 subgroups by 52% (>3.25), 39% (>2.67) and 24% (>1.30) (p values for interaction =.01,.13 and.03, respectively). Conclusions: Finerenone has neutral effects on liver parameters in patients with chronic kidney disease and type 2 diabetes. Finerenone showed robust and consistent kidney benefits in patients with altered liver tests, and profound cardiovascular benefits even in patients with higher FIB‐4 scores who were at high risk of developing cardiovascular complications. [ABSTRACT FROM AUTHOR]

Summary: Non‐alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive accumulation of fat in the liver that can progress to liver inflammation (non‐alcoholic steatohepatitis [NASH]), liver fibrosis, and cirrhosis. Although most efforts for drug development are focusing on the treatment of the latest stages of NAFLD, where significant fibrosis and NASH are present, findings from studies suggest that the amount of liver fat may be an important independent risk factor and/or predictor of development and progression of NAFLD and metabolic diseases. In this review, we first describe the current tools available for quantification of liver fat in humans and then present the clinical and pathophysiological evidence that link liver fat with NAFLD progression as well as with cardiometabolic diseases. Finally, we discuss current pharmacological and non‐pharmacological approaches to reduce liver fat and present open questions that have to be addressed in future studies. [ABSTRACT FROM AUTHOR]

Alcohol‐associated liver disease is the primary cause of liver‐related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic hepatitis represents the most acute and severe manifestation of alcohol‐associated liver disease and is characterized by a rapid onset of jaundice with progressive inflammatory liver injury, worsening of portal hypertension, and an increased risk for multiorgan failure in patients with excessive alcohol consumption. Severe alcoholic hepatitis is associated with a poor prognosis and high short‐term mortality. During the COVID‐19 pandemic, rates of alcohol‐associated hepatitis have increased significantly, underscoring that it is a serious and growing health problem. However, adequate management of alcohol‐associated hepatitis and its complications in everyday clinical practice remains a major challenge. Currently, pharmacotherapy is limited to corticosteroids, although these have only a moderate effect on reducing short‐term mortality. In recent years, translational studies deciphering key mechanisms of disease development and progression have led to important advances in the understanding of the pathogenesis of alcoholic hepatitis. Emerging pathophysiology‐based therapeutic approaches include anti‐inflammatory agents, modifications of the gut‐liver axis and intestinal dysbiosis, epigenetic modulation, antioxidants, and drugs targeting liver regeneration. Concurrently, evidence is increasing that early liver transplantation is a safe treatment option with important survival benefits in selected patients with severe alcoholic hepatitis not responding to medical treatment. This narrative review describes current pathophysiology and management concepts of alcoholic hepatitis, provides an update on emerging treatment options, and focuses on the need for holistic and patient‐centred treatment approaches to improve prognosis. [ABSTRACT FROM AUTHOR]

Summary: Background and Aims: Phase III trials have established atezolizumab plus bevacizumab as the novel standard of care for patients with unresectable hepatocellular carcinoma (HCC). However, these trials raised concerns regarding treatment efficacy in non‐viral HCC, and it remains unclear whether combination immunotherapy is safe and effective in patients with advanced cirrhosis. Methods: One hundred patients with unresectable HCC initiated therapy with atezolizumab plus bevacizumab at our centre between January 2020 and March 2022. The control cohort consisted of 80 patients with advanced HCC who received either sorafenib (n = 43) or lenvatinib (n = 37) as systemic treatment. Results: Overall survival (OS) and progression‐free survival (PFS) were significantly longer within the atezolizumab/bevacizumab group and comparable to phase III data. The benefits in terms of increased objective response rate (ORR), OS and PFS were consistent across subgroups, including non‐viral HCC (58%). The ROC‐optimised neutrophil‐to‐lymphocyte ratio (NLR) cut‐off of 3.20 was the strongest independent predictor of ORR and PFS. In patients with advanced cirrhosis Child–Pugh B, liver function was significantly better preserved with immunotherapy. Patients with Child–Pugh B cirrhosis showed similar ORR but shorter OS and PFS compared to patients with preserved liver function. Conclusions: Atezolizumab plus bevacizumab showed good efficacy and safety in patients with unresectable HCC and partially advanced liver cirrhosis in a real‐world setting. Moreover, the NLR was able to predict response to atezolizumab/bevacizumab treatment and may guide patient selection. [ABSTRACT FROM AUTHOR]

The circadian clock comprises a cellular endogenous timing system coordinating the alignment of physiological processes with geophysical time. Disruption of circadian rhythms has been associated with several metabolic diseases. In this review, we focus on liver as a major metabolic tissue and one of the most well‐studied organs with regard to circadian regulation. We summarize current knowledge about the role of local and systemic clocks and rhythms in regulating biological functions of the liver. We discuss how the disruption of circadian rhythms influences the development of non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH). We also critically evaluate whether NAFLD/NASH may in turn result in chronodisruption. The last chapter focuses on potential roles of the clock system in prevention and treatment of NAFLD/NASH and the interaction of current NASH drug candidates with liver circadian rhythms and clocks. It becomes increasingly clear that paying attention to circadian timing may open new avenues for the optimization of NAFLD/NASH therapies and provide interesting targets for prevention and treatment of these increasingly prevalent disorders. [ABSTRACT FROM AUTHOR]

In July 2020, the entry inhibitor bulevirtide was approved in the European Union for the treatment of chronic hepatitis delta virus (HDV) infection. We describe the first 48 weeks of bulevirtide therapy in eight patients (n = 7 male, n = 1 female; n = 3 compensated cirrhosis) treated at our centre. Median ALT values declined from 82 to 34 U/L after 48 weeks. Median HDV RNA dropped from 13 380 000 to 3135 copies/ml. One patient showed no significant response and was discontinued at week 16. Overall, we observed a favourable safety profile and a marked biochemical and virological response in the majority of our patients. [ABSTRACT FROM AUTHOR]

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity. [ABSTRACT FROM AUTHOR]

Background: Liver disease and depression are known to be closely associated. Non-invasive tests (NIT), such as the FIB-4 score, have been recommended by different guidelines to rule out advanced fibrosis and to stratify the risk of liver-related outcomes in patients with chronic liver diseases. However, the predictive value of an elevated FIB-4 score regarding the development of depression and/or anxiety disorders among the general population is unknown. Methods: By using the Disease Analyzer database (IQVIA), which compiles diagnoses and laboratory values as well as basic medical and demographic data of patients followed in general practices in Germany, we identified 370,756 patients with available lab values for FIB-4 score calculation between 2005 and 2019. Patients with an FIB-4 score < 2 were matched 1:1 to patients with an FIB-4 index ≥ 2 by age, sex and yearly consultation frequency. Results: In regression analysis, the incidence rate ratio (IRR) of depression was significantly higher among patients with an FIB-4 score ≥ 2.0 compared to patients with a lower FIB-4 score <2.0 (IRR: 1.12, p < 0.001). This association was significant for both female (IRR: 1.10, p = 0.004) and male (IRR: 1.15, p < 0.001) patients and strongest in the age groups ≤50 years (IRR: 1.42, p < 0.001) and 51-60 years (IRR: 1.34, p < 0.001). There was no significant association between an elevated FIB-4 score ≥ 2.0 and the incidence of depression among patients aged 60 years and older. There was no significant increase in the IRR of anxiety disorders for patients with high or low FIB-4 scores. Conclusion: Our study suggests a previously unknown association between an elevated FIB-4 score and an increased incidence of depression. This finding suggests that the FIB-4 score is not only a valuable tool for the prediction of liver-specific endpoints but also may be of relevance for the prediction of extrahepatic comorbidities, which in turn may argue for clinical screening programs in patients with an elevated FIB-4. [ABSTRACT FROM AUTHOR]

Studies investigating the gut-liver axis have largely focused on bacteria, whereas little is known about commensal fungi. We characterized fecal fungi in patients with non-alcoholic fatty liver disease (NAFLD) and investigated their role in a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis. We performed fungal internal transcribed spacer 2 sequencing using fecal samples from 78 patients with NAFLD, 16 controls and 73 patients with alcohol use disorder. Anti- Candida albicans (C. albicans) IgG was measured in blood samples from 17 controls and 79 patients with NAFLD. Songbird, a novel multinominal regression tool, was used to investigate mycobiome changes. Germ-free mice were colonized with feces from patients with non-alcoholic steatohepatitis (NASH), fed a Western diet for 20 weeks and treated with the antifungal amphotericin B. The presence of non-obese NASH or F2-F4 fibrosis was associated with a distinct fecal mycobiome signature. Changes were characterized by an increased log-ratio for Mucor sp./ Saccharomyces cerevisiae (S. cerevisiae) in patients with NASH and F2-F4 fibrosis. The C. albicans/S. cerevisiae log-ratio was significantly higher in non-obese patients with NASH when compared with non-obese patients with NAFL or controls. We observed a different fecal mycobiome composition in patients with NAFLD and advanced fibrosis compared to those with alcohol use disorder and advanced fibrosis. Plasma anti- C. albicans IgG was increased in patients with NAFLD and advanced fibrosis. Gnotobiotic mice, colonized with human NASH feces and treated with amphotericin B were protected from Western diet-induced steatohepatitis. Non-obese patients with NAFLD and more advanced disease have a different fecal mycobiome composition to those with mild disease. Antifungal treatment ameliorates diet-induced steatohepatitis in mice. Intestinal fungi could be an attractive target to attenuate NASH. Non-alcoholic fatty liver disease is one of the most common chronic liver diseases and is associated with changes in the fecal bacterial microbiome. We show that patients with non-alcoholic fatty liver disease and more severe disease stages have a specific composition of fecal fungi and an increased systemic immune response to Candida albicans. In a fecal microbiome-humanized mouse model of Western diet-induced steatohepatitis, we show that treatment with antifungals reduces liver damage. [Display omitted] • More advanced disease severity in non-alcoholic fatty liver disease is associated with a specific composition of fecal fungi. • Changes are particularly present in non-obese patients. • Systemic antibodies against Candida albicans are increased in patients with non-alcoholic fatty liver disease and advanced fibrosis. • Antifungals protect germ-free fecal microbiome-humanized mice from Western diet-induced steatohepatitis. [ABSTRACT FROM AUTHOR]