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The increasing epidemic of obesity worldwide is linked to serious health effects, including increased prevalence of type 2 diabetes mellitus, cardiovascular disease and nonalcoholic fatty liver disease (NAFLD). NAFLD is the liver manifestation of the metabolic syndrome and includes the spectrum of liver steatosis (known as nonalcoholic fatty liver) and steatohepatitis (known as nonalcoholic steatohepatitis), which can evolve into progressive liver fibrosis and eventually cause cirrhosis. Although NAFLD is becoming the number one cause of chronic liver diseases, it is part of a systemic disease that affects many other parts of the body, including adipose tissue, pancreatic β-cells and the cardiovascular system. The pathomechanism of NAFLD is multifactorial across a spectrum of metabolic derangements and changes in the host microbiome that trigger low-grade inflammation in the liver and other organs. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear regulatory factors that provide fine tuning for key elements of glucose and fat metabolism and regulate inflammatory cell activation and fibrotic processes. This Review summarizes and discusses the current literature on NAFLD as the liver manifestation of the systemic metabolic syndrome and focuses on the role of PPARs in the pathomechanisms as well as in the potential targeting of disease. This Review describes the pathophysiological roles of peroxisome proliferator-activated receptors (PPARs) in nonalcoholic steatohepatitis and related metabolic diseases, and summarizes the preclinical and clinical data on the use of PPAR agonists to treat nonalcoholic steatohepatitis as part of a systemic metabolic disease. Key points Nonalcoholic steatohepatitis (NASH) is the fastest growing liver disease worldwide; however, it is often not recognized until advanced disease stages. The management and treatment of NASH, the liver manifestation of the metabolic syndrome, require a holistic approach. Peroxisome proliferator-activated receptors (PPARs) regulate metabolism, inflammation and fibrosis, all of which determine NASH progression. There is an urgent need for medical therapy for patients with NASH. Both PPARα-β/δ dual agonism as well as PPARγ agonism have shown beneficial effects on liver histology in phase IIb clinical trials for NASH. Single, dual and pan-PPAR agonists are under development for the pharmacological treatment of NASH.

Non-alcoholic steatohepatitis (NASH) is becoming a leading cause of cirrhosis with the burden of NASH-related complications projected to increase massively over the coming years. Several molecules with different mechanisms of action are currently in development to treat NASH, although reported efficacy to date has been limited. Given the complexity of the pathophysiology of NASH, it will take the engagement of several targets and pathways to improve the results of pharmacological intervention, which provides a rationale for combination therapies in the treatment of NASH. As the field is moving towards combination therapy, this article reviews the rationale for such combination therapies to treat NASH based on the current therapeutic landscape as well as the advantages and limitations of this approach.

Knowledge on SARS-CoV-2 infection and its resultant COVID-19 in liver diseases has rapidly increased during the pandemic. Hereby, we review COVID-19 liver manifestations and pathophysiological aspects related to SARS-CoV-2 infection in patients without liver disease as well as the impact of COVID-19 in patients with chronic liver disease (CLD), particularly cirrhosis and liver transplantation (LT). SARS-CoV-2 infection has been associated with overt proinflammatory cytokine profile, which probably contributes substantially to the observed early and late liver abnormalities. CLD, particularly decompensated cirrhosis, should be regarded as a risk factor for severe COVID-19 and death. LT was impacted during the pandemic, mainly due to concerns regarding donation and infection in recipients. However, LT did not represent a risk factor per se of worse outcome. Even though scarce, data regarding COVID-19 specific therapy in special populations such as LT recipients seem promising. COVID-19 vaccine-induced immunity seems impaired in CLD and LT recipients, advocating for a revised schedule of vaccine administration in this population.

Non-alcoholic steatohepatitis is becoming the most important aetiology for advanced liver disease. There has been important progress in the field in recent years and the complexity of the pathophysiology of NASH is better understood. Multiple non-invasive circulating and imaging biomarkers have been tested. The importance of lifestyle has been recognised and several drugs are being tested in clinical trials. This review addresses the challenges that healthcare professionals face in the management of NASH patients.

The metabolic dysfunction that characterizes obesity and type 2 diabetes mellitus affects not only the heart and kidneys, but also the liver. Although lifestyle modification remains the cornerstone in the management of metabolic liver diseases, the field has progressed this year, with a new definition, validation of non-invasive biomarkers and numerous clinical trials. Key advances Panels of non-invasive biomarkers have the potential to diagnose patients with NASH and those with NASH and fibrosis 4 . Panels of non-invasive biomarkers have predictive value for outcomes, especially those capturing the degree of fibrosis 6 . Drugs targeting new targets, such as thyroid hormone receptor-β and fibroblast growth factor 21, showed positive results in clinical trials 8 , 9 . There is a high degree of variability in the responses of the placebo groups in these trials 8 , 9 .

Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.

Hepatocellular carcinoma (HCC) ranks number three among the most frequent causes of death from solid tumors worldwide. With obesity and fatty liver diseases as risk factors on the rise, HCC represents an ever increasing challenge. While there is still no curative treatment for most patients numerous novel drugs have been proposed, but most ultimately failed in phase III trials. This manuscript targets therapeutic advances and most burning issues. Expert key point summaries and urgent research agenda are provided regarding risk factors, including microbiota, need for prognostic and predictive biomarkers and the equivocal role of liver biopsy. Therapeutic topics highlighted are locoregional techniques, combination therapies and the potential of immunotherapy. Finally the manuscript provides a critical evaluation of novel targets and strategies for personalized treatment of HCC.

We aimed to investigate the potential impact of metabolic risk factors and lifestyles on mortality in hepatocellular carcinoma (HCC) patients. From the Korean Central Cancer Registry database (2008–2016), 8,505 HCC patients were included in the analysis. Patients with 2 or more metabolic risk factors (n = 2384, 28.0%) showed significantly worse overall survival (OS, 29 months, 95% confidence interval [CI] 27–33) than patients with 0 (n = 2269 [26.7%]; 41 months, 95% CI 37–47), or 1 (n = 3852 [45.3%]; 42 months; 95% CI 38–46) metabolic risk factor. ( P  < 0.001) In the multivariable Cox analysis, patients with ≥ 2 metabolic risk factors had significantly elevated risk of overall mortality (adjusted hazards ratio (HR) = 1.14 [95% CI 1.06–1.23], P  < 0.001) and HCC-specific mortality (sub-distribution HR = 1.09 [95% CI 1.00–1.09], P  = 0.046), compared to those without. Alcohol and smoking were also independent risk factors for worse overall and HCC-specific mortality (all P  < 0.05). Metabolic comorbidities were associated with greater risk of mortality in a dose-dependent manner in HCC patients, regardless of tumor stage and liver function. Alcohol intake and smoking significantly increased mortality by themselves and even further with the presence of metabolic risk.

The prognosis of patients with hepatocellular carcinoma is dependent on the stage of tumor at diagnosis. The earlier the tumor is found, the higher the chances to offer a curative treatment. In order to diagnose hepatocellular carcinoma early, patients at risk should be enrolled in a surveillance program. The population at risk is usually defined as patients with cirrhosis. These patients should have twice a year a ultrasonographic examination of the liver. However, more and more patients will develop hepatocellular carcinoma in the context of nonalcoholic fatty liver disease which is tightly linked to obesity and diabetes. In these patients, this approach is jeopardized by the difficulty to perform a sonography of good quality due to the obesity and more importantly by the fact that hepatocellular carcinoma occurs frequently in the context of nonalcoholic fatty liver disease before the cirrhosis. This article reviews the impact of the changing epidemiology of hepatocellular carcinoma on its screening.

Chronic liver diseases pose a serious public health issue. Identifying patients at risk for advanced liver fibrosis is crucial for early intervention. The Fibrosis-4 score (FIB-4), a simple non-invasive test, classifies patients into three risk groups for advanced fibrosis. This study aimed to estimate the prevalence of patients at risk for advanced hepatic fibrosis at a Swiss tertiary care hospital by calculating the FIB-4 score in routine blood analysis. A retrospective study was conducted using data from 36,360 patients who visited outpatient clinics at eight main clinics of the University Hospital Bern in Switzerland. The data collection period ran from January 1st to December 31st, 2022. Patients attending the hepatology outpatient clinic were excluded. We then calculated the overall and clinic-specific prevalence of patients falling into the high risk category for advanced fibrosis according to FIB-4. Among the 36,360 patients, 26,245 (72.2%) had a low risk of advanced fibrosis (FIB-4 <1.3), whereas 3913 (10.8%) and 2597 (7.1%) patients were flagged to have a high risk of advanced fibrosis (FIB-4 >2.67 and FIB-4 >3.25 respectively). Geriatrics and Cardiology had the highest proportions of patients at risk for advanced fibrosis over all clinics. This study demonstrates a high prevalence of high FIB-4 score in a Swiss tertiary care hospital. The implementation of the automatically generated FIB-4 score in daily practice, not only in primary care, but also within tertiary care hospitals, could be crucial for early identification of outpatients at high risk of advanced liver fibrosis requiring further hepatological investigations.