Non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat within the cytoplasm of hepatocytes (exceeding 5% of liver weight) in individuals without significant alcohol consumption, has rapidly evolved into a pressing global health issue, affecting approximately 25% of the world population. This condition, closely associated with obesity, type 2 diabetes, and the metabolic syndrome, encompasses a spectrum of liver disorders ranging from simple steatosis without inflammation to non-alcoholic steatohepatitis (NASH) and cirrhotic liver disease. Recent research has illuminated the complex interplay between metabolic and immune responses in the pathogenesis of NASH, underscoring the critical role played by T and B lymphocytes. These immune cells not only contribute to necroinflammatory changes in hepatic lobules but may also drive the onset and progression of liver fibrosis. This narrative review aims to provide a comprehensive exploration of the effector mechanisms employed by T cells, B cells, and their respective subpopulations in the pathogenesis of NASH. Understanding the immunological complexity of NASH holds profound implications for the development of targeted immunotherapeutic strategies to combat this increasingly prevalent and burdensome metabolic liver disease.

UNASSIGNED: Non-alcoholic steatohepatitis (NASH), an escalating global health concern, is a primary factor behind cirrhosis, liver transplantation, and hepatocellular carcinoma. Effective treatments remain elusive. Danggui-Shaoyao-San (DGSY), a classic famous prescription employed in treating NASH, could hold promise, although its molecular underpinnings are still under investigation. This study undertakes an exploration of the impacts of DGSY on NASH and seeks to illuminate the mechanisms at play.
UNASSIGNED: UHPLC-Q-Orbitrap HRMS was employed to identify compounds within DGSY. Mice underwent a 25-week regimen of HFHC diet and high-sugar water, with 4 weeks of DGSY treatment for efficacy and pathogenic mechanism exploration in vivo. L02 cells were cultured with 0.2 mM FFA for 24 h, exposed to DGSY at 1 mg/ml and 2 mg/ml for efficacy and pathogenic mechanism exploration in vitro. Using online databases, we sought potential targets for NASH treatment, and through PPI networks, identified key targets. Expression levels of genes and proteins were examined by western blotting, RT-PCR, and immunofluorescence staining.
UNASSIGNED: Thirty-four compounds were identified within DGSY. DGSY brought about marked reductions in biochemical indicators and yielded significant improvements in NASH mice histological features. Additionally, it mitigated hepatic steatosis and inflammation both in vivo and in vitro. The top 10 targets from two network pharmacology analyses, one focusing on structural prediction and the other on literature mining, identified APOE and APP as potential therapeutic targets for DGSY in NASH treatment. PCR validation confirmed that DGSY reduced APP expression after treatment, and further investigation revealed that DGSY significantly suppressed hepatic APP and Aβ expression, indicating its effectiveness in treating NASH. Furthermore, it inhibited Aβ-induced Cathepsin B lysosomal release, reducing hepatic inflammation.
UNASSIGNED: Danggui-Shaoyao-San has anti-steatohepatitis effects in ameliorating hepatic APP protein expression, reducing hepatic lysosomal CTSB release, and suppressing hepatic NF-κB activation. The study provided a more theoretical basis for the future clinical application of DGSY.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is estimated to increase to over half of the adult population by 2040 globally. Since the final diagnosis of NAFLD is made by a liver biopsy, several non-invasive approaches have been developed and validated to define NAFLD and evaluate NAFLD-associated diseases. Presently, NAFLD has been identified as an important and independent risk factor for developing several extrahepatic diseases, including atherosclerosis, cardiovascular disease (CVD), diabetes, and dementia. This review discusses current findings of up-to-date literature regarding the effects of NAFLD on the risk of atherosclerosis and CVD in Asia along with potential underlying biological mechanisms and therapeutic approaches to lower the NAFLD-related CVD risk. We further focus on the difference between NAFLD and metabolic dysfunction-associated fatty liver disease (MAFLD) on the risk of CVD and its implication by comparing the risk of NAFLD and MAFLD.

OBJECTIVE: Pre-liver transplant (LT) functional status is an important determinant of prognosis post LT. There is insufficient data on how functional status affects outcomes of transplant recipients based on the specific etiology of liver disease. We stratified LT recipients by etiology of liver disease to evaluate the effects of functional status on post-LT prognosis in each subgroup.
METHODS: 2005-2019 United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research (STAR) was used to select patients with liver transplant. A total of 14,290 patients were included in the analysis. These patients were stratified by functional status according to Karnofsky Performance Scale (KPS) score: no assistance, some assistance, or total assistance. They were then further divided into six diagnosis categories: metabolic dysfunction-associated steatotic liver disease (MASLD), hereditary disorders, hepatitis C, hepatitis B, autoimmune disease (AID), and alcoholic liver disease (ALD). Primary endpoints included all-cause mortality and graft failure, while secondary endpoints included organ-specific causes of death. Those under the age of 18 and those with non-whole liver or prior liver transplantation were excluded.
RESULTS: Patients with MASLD requiring some assistance (aHR: 1.57, 95% CI 1.03-2.39, p = 0.04) and those requiring total assistance (aHR: 2.32, 95% CI 1.48-3.64, p < 0.001) had higher incidences of graft failure compared to those requiring no assistance. Those with MASLD requiring total assistance had a higher all-cause mortality rate than those needing no assistance (aHR: 1.62, 95% CI 1.38-1.89, p < 0.001). Patients with hereditary causes of liver disease showed a lower incidence of all-cause mortality in recipients needing some assistance compared with those needing no assistance (aHR: 0.52, 95% CI 0.34-0.80, p = 0.003). LT recipients with hepatitis C, AID, and ALD all showed higher incidences of all-cause mortality in the total assistance cohort when compared to the no assistance cohort. For the secondary endpoints of specific cause of death, transplant recipients with MASLD needing total assistance had higher rates of death due to general cardiac causes, graft rejection, general infectious causes, sepsis, general renal causes, and general respiratory causes.
CONCLUSIONS: Patients with MASLD cirrhosis demonstrated the worst overall outcomes, suggesting that this population may be particularly vulnerable. Poor functional status in patients with end-stage liver disease from hepatitis B or hereditary disease was not associated with a significantly increased rate of adverse outcomes, suggesting that the KPS score may not be broadly applicable to all patients awaiting LT.

In this editorial we comment on the article titled \"Establishment and validation of an adherence prediction system for lifestyle interventions in non-alcoholic fatty liver disease\" by Zeng et al published in a recent issue of the World Journal of Gastroenterology. Non-alcoholic fatty liver disease (NAFLD) represents one of the current challenges in hepatology and public health, due to its continuous growing prevalence and the rising incidence of NAFLD-related fibrosis, non-alcoholic steatohepatitis and cirrhosis. The only effective therapeutic strategy for this disease is represented by encouraging patients to improve their lifestyle through the modification of dietary intake and increased physical exercise, but the effective application of such modifications is often limited by various factors such as lack of information, psychological barriers or poor social support. While poor adherence to a healthy lifestyle can be decisive in determining the clinical outcome, in daily practice there is a lack of quantitative instruments aimed at identifying patients with the lowest adherence to lifestyle changes and higher risk of disease progression in the course of follow-up. In this article, Zeng et al propose a quantitative scale to assess the grade of adherence of patients with NAFLD to healthy lifestyle intervention, called the Exercise and Diet Adherence Scale (EDAS). This scale, consisting of 33 items divided into 6 dimensions which relates to six subjective aspects in the self-management of NAFLD, has shown a good correlation with the identification of the sub-cohort of patients with the highest reduction in caloric intake, increase in physical exercise, probability of a reduction in liver stiffness measurement and alanine aminotransferase levels. The correlation among clinical outcomes and specific dimensions of this scale also highlights the pivotal role of a good and confidential doctor-patient relationship and of an effective communication. There is an urgent need for practical and effective instruments to assess the grade of self-management of NAFLD patients, together with the development of multidisciplinary teams with the aim of applying structured behavioral interventions.

A 19-year-old Japanese man was referred for a further evaluation of liver dysfunction. Despite the absence of symptoms or obesity, the liver biopsy results were consistent with non-alcoholic steatohepatitis. Subsequent investigations revealed low serum ceruloplasmin, increased urinary copper excretion, and a known mutation c.3809A>G (p.Asn1270Ser) in the copper-transporting enzyme P-type ATPase (ATP7B) gene, leading to a diagnosis of Wilson\'s disease. A previously unreported variant, i.e., c.3866A>T (p.Asp1289Val) was detected on the patient\'s other allele and was considered a novel mutation, classified as \'likely pathogenic\' according to the American College of Medical Genetics guidelines.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) and liver fibrosis are progressive conditions associated with non-alcoholic fatty liver disease (NAFLD), characterized by hepatocyte pyroptosis and hepatic stellate cell (HSC) activation. Gentiopicroside (GPS) has emerged as a potential treatment for NASH, yet its underlying mechanism remains unclear.
OBJECTIVE: To confirm that GPS can improve NASH and liver fibrosis by blocking the NLRP3 signaling pathway STUDY DESIGN: Initially, different animal models were used to study the effects and mechanisms of GPS on NASH and fibrosis. Subsequent in vitro experiments utilized co-cultures and other techniques to delve deeper into its mechanism, followed by validation of the findings in mouse liver tissues.
METHODS: C57BL/6 mice were fed high-fat, high-cholesterol (HFHC), or methionine-choline-deficient (MCD) diets to induce NASH and fibrosis. RAW264.7 cells and born marrow bone marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP to induce inflammation, then co-cultured with primary hepatocytes and HSCs, treated with GPS, and its efficacy and mechanism were analyzed.
RESULTS: In vivo, GPS alleviated NASH and liver fibrosis by inhibiting the NLRP3 pathway. In vitro, GPS attenuated inflammation induced by BMDMs by inhibiting TLR4 and NLRP3 signaling pathways, and Co-culture studies suggested that GPS reduced hepatocyte pyroptosis and HSC activation, which was also confirmed in liver tissues CONCLUSION: GPS improves NASH and liver fibrosis by inhibiting the TLR4 and NLRP3 signaling pathways. The specific mechanism may be related to the suppression of macrophage-mediated inflammatory responses, thereby reducing hepatocyte pyroptosis and HSC activation.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is the liver manifestation of a metabolic syndrome and is highly prevalent in the general population. There has been significant progress in non-invasive tests for MAFLD, from the diagnosis of fatty liver and monitoring of liver fat content in response to intervention, to evaluation of liver fibrosis and its change over time, and from risk stratification of patients within the context of clinical care pathways, to prognostication. Various non-invasive tests have also been developed to assess for fibrotic metabolic dysfunction-associated steatohepatitis, which has emerged as an important diagnostic goal, particularly in the context of clinical trials. Non-invasive tests can be used to diagnose clinically significant portal hypertension so that intervention can be administered to reduce the risk of decompensation. Furthermore, the use of risk stratification algorithms can identify at-risk patients for hepatocellular carcinoma surveillance. Beyond the liver, various tests that evaluate cardiovascular disease risk, assess sarcopenia and measure patient reported outcomes, can be utilized to improve the care of patients with MAFLD. This review provides an up-to-date overview of these non-invasive tests and the limitations of liver biopsy in the management of patients with MAFLD.

Non-alcoholic fatty liver disease (NAFLD) is characterized by an accumulation of hepatic fat, diagnosed histologically or radiologically (ultrasound), in the absence of a secondary cause of steatosis, especially alcohol consumption. Its prevalence is estimated to be approximately 25%. This high prevalence is correlated with the risk factors attributed to the metabolic syndrome. Non-alcoholic steatohepatitis (NASH) is a progressive form of NAFL and it can lead to end-stage liver disease in some patients. Once diagnosed, lifestyle changes must be initiated to lower hepatic fat accumulations in the liver. Physical exercise and diet play the most important role in achieving the desired weight loss goal.