Search Results (91)

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is rapidly becoming the most prevalent form of chronic liver disease in both pediatric and adult populations. It encompasses a wide spectrum of liver abnormalities, ranging from simple fat accumulation to severe conditions such as inflammation, fibrosis, cirrhosis, and liver cancer. Major risk factors for MASLD include obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia. Methods: This narrative review employed a comprehensive search of recent literature to identify the latest studies on the relationship between MAFLD and obesity, the health consequences and the latest treatment options to prevent long-term damage to the liver and other organs. Additionally, the article presents perspectives on diagnostic biomarkers. Results: Childhood obesity is linked to a multitude of comorbid conditions and remains a primary risk factor for adult obesity. This abnormal fat accumulation is known to have long-term detrimental effects into adulthood. Scientific evidence unequivocally demonstrates the role of obesity-related conditions, such as insulin resistance, dyslipidemia, and hyperglycemia, in the development and progression of MASLD. Oxidative stress, stemming from mitochondrial dysfunction, is a leading factor in MASLD. This review discusses the interconnections between oxidative stress, obesity, dyslipidemia, and MASLD. Conclusions: Atherogenic dyslipidemia, oxidative stress, inflammation, insulin resistance, endothelial dysfunction, and cytokines collectively contribute to the development of MASLD. Potential treatment targets for MASLD are focused on prevention and the use of drugs to address obesity and elevated blood lipid levels. Full article

Background: The most common cause of chronic liver disease is now known to be non-alcoholic fatty liver disease (NAFLD), recently redefined as metabolic-associated fatty liver disease (MAFLD). This review aims to synthesize current evidence on the pathophysiology and clinical implications of nephrological, pulmonary, and dermatological manifestations among NAFLD/MAFLD patients. In order to find safe and efficient treatments, NAFLD/MAFLD has emerged as a primary concern for hepatologists worldwide. Methods: We conducted a comprehensive review of the literature from major databases, focusing on studies that evaluated the extrahepatic manifestations of NAFLD/MAFLD. Emphasis was placed on identifying pathophysiological mechanisms and assessing their clinical impact on renal, pulmonary, and dermatological systems. Results: Recent developments in the management of chronic viral hepatitis have lowered the mortality rate associated with chronic liver disease. However, the prevalence of NAFLD/MAFLD continues to rise, making chronic liver disease a significant health concern for the future. An increasing percentage of patients on liver transplant waiting lists now have cirrhosis and hepatocellular carcinoma due to non-alcoholic liver disease. Furthermore, the incidence and prevalence of chronic kidney disease have surged, linking NAFLD/MAFLD to higher morbidity, mortality, and healthcare costs. Conclusions: NAFLD/MAFLD is underdiagnosed and underappreciated, yet its incidence is rapidly increasing, raising concerns about a potential global epidemic. Given its multisystemic impact—extending to renal, pulmonary, and dermatological complications—it is crucial to develop interdisciplinary strategies for early detection and effective management of the disease. Full article

Background and Objectives: Fatty Liver Disease is a major health problem worldwide. We can distinguish liver steatosis as non-associated or associated with chronic/acute alcohol consumption. These two entities share similar stages ranging from hepatic fat storage (namely, steatosis) to inflammation, necrosis, and fibrosis until hepatocellular carcinoma (HCC). Over time, “Metabolic Associated Fatty Liver Disease” (MAFLD) has replaced nonalcoholic fatty liver disease (NAFLD) nomenclature and has included cardiometabolic criteria in these patients definition. Thus, obesity, type 2 diabetes mellitus (T2DM), hypertension, and dyslipidemia are MAFLD features and are of the metabolic syndrome. Importantly, there is not a specific treatment for MAFLD, but there are therapeutic strategies that act on metabolic dysfunction related to MAFLD. They can reduce the progression of liver fibrosis and its complications. Materials and Methods: For all these reasons, we conducted a narrative review of the literature, and we focused on metabolic dysfunction related to MAFLD, with a special regard for cholesterol metabolism. Results: MAFLD is a recently redefined condition that better describes the metabolism derangement responsible for fatty liver disease. This distinguishes MAFLD from NAFLD. In fact, the diagnostic criteria for MAFLD require the presence of liver steatosis together with at least one of the following: obesity, T2DM, or evidence of metabolic disorder such as hypertriglyceridemia, low high-density lipoprotein cholesterol, or hypertension. As a result, MAFLD is closely linked to an increased cardiometabolic risk. Current therapeutic approaches can be used to reduce this risk, focusing on lifestyle interventions and pharmacological strategies. Several treatments in patients diagnosed with MAFLD are mainly cholesterol-lowering remedies. Among these, Pro-protein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9i) show the most promising efficacy profile but data on liver fibrosis are lacking. Agonists of GLP-1 receptor, Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and Dipeptidyl Peptidase-4 inhibitors (DPP-4i) have a “ multi-hit “ action allowing their use also in diabetic patients with MAFLD. Conclusions: Lifestyle modifications, some nutraceuticals, statins, incretins, and PCSK9i have changed the natural course and significantly improved the cardiometabolic outcomes of MAFLD. Emerging cholesterol-lowering drugs, such as Bempedoic acid, can overcome low compliance to statins’ use and their controversial effect on liver fibrosis. Finally, medications targeting insulin resistance allow for strategic interventions of the convoluted pathophysiology of MAFLD in multiple steps, with the potential to reduce liver steatosis, inflammation, and necrosis and, sometimes even to reverse liver fibrosis. Full article

Background: Non-alcoholic fatty liver disease (NAFLD), more recently redefined as metabolic-associated fatty liver disease (MAFLD), is now recognized as the most prevalent cause of chronic liver disease. Its strong association with cardiovascular disease (CVD) underscores its emerging role in global morbidity and mortality. Objective: This review critically examines the pathophysiological mechanisms that link NAFLD/MAFLD with CVD. It focuses on shared metabolic disturbances, inflammatory pathways, and alterations in the gut microbiota that contribute to hepatic and cardiovascular pathology. Review and Gaps: Current evidence highlights insulin resistance, dyslipidemia, systemic inflammation, and gut dysbiosis as pivotal factors connecting NAFLD/MAFLD to CVD. Despite these insights, inconsistencies in diagnostic criteria and a lack of validated non-invasive biomarkers hinder a clear understanding of the causal relationship between liver and cardiovascular diseases. Conclusions: Addressing these knowledge gaps through standardized diagnostic protocols and large-scale longitudinal studies is essential. Improved biomarker validation and clearer delineation of the underlying mechanisms will improve cardiovascular risk stratification and enable more personalized therapeutic strategies for patients with NAFLD/MAFLD. Full article

Non-alcoholic fatty liver disease (NAFLD), now referred to as metabolic dysfunction-associated steatotic liver disease (MASLD), is the most prevalent liver disorder globally, linked to obesity, type 2 diabetes, and cardiovascular risk. Understanding its potential progression from simple steatosis to cirrhosis and hepatocellular carcinoma (HCC) is crucial for patient management and treatment strategies. The disease’s complexity requires innovative approaches for early detection and personalized care. Omics technologies—such as genomics, transcriptomics, proteomics, metabolomics, and exposomics—are revolutionizing the study of MASLD. These high-throughput techniques allow for a deeper exploration of the molecular mechanisms driving disease progression. Genomics can identify genetic predispositions, whilst transcriptomics and proteomics reveal changes in gene expression and protein profiles during disease evolution. Metabolomics offers insights into the metabolic alterations associated with MASLD, while exposomics links environmental exposures to MASLD progression and pathology. By integrating data from various omics platforms, researchers can map out the intricate biochemical pathways involved in liver disease progression. This review discusses the roles of omics technologies in enhancing the understanding of disease progression and highlights potential diagnostic and therapeutic targets within the MASLD spectrum, emphasizing the need for non-invasive tools in disease staging and treatment development. Full article

Nonalcoholic fatty liver disease (NAFLD), recently renamed metabolic-associated fatty liver disease (MAFLD), is the most prevalent liver disease worldwide. It is associated with an increased risk of developing hepatocellular carcinoma (HCC) in the background of cirrhosis or without cirrhosis. The prevalence of NAFLD-related HCC is increasing all over the globe, and HCC surveillance in NAFLD cases is not that common. In the present review, we attempt to summarize promising treatments and clinical trials focused on NAFLD, nonalcoholic steatohepatitis (NASH), and HCC in the past five to seven years. We categorized the trials based on the type of intervention. Most of the trials are still running, with only a few completed and with conclusive results. In clinical trial NCT03942822, 25 mg/day of milled chia seeds improved NAFLD condition. Completed trial NCT03524365 concluded that Rouxen-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) results in histological resolution of NASH without worsening of fibrosis, while NCT04677101 validated sensitivity/accuracy of blood biomarkers in predicting NASH and fibrosis stage. Moreover, trials with empagliflozin (NCT05694923), curcuvail (NCT06256926), and obeticholic acid (NCT03439254) were completed but did not provide conclusive results. However, trial NCT03900429 reported effective improvement in fibrosis by at least one stage, without worsening of NAFLD activity score (NAS), as well as improvement in lipid profile of the NASH patients by 80 or 100 mg MGL-3196 (resmetirom). Funded by Madrigal Pharmaceuticals, Rezdiffra (resmetirom), used in the clinical trial NCT03900429, is the first FDA-approved drug for the treatment of NAFLD/NASH. Full article

Metabolic-associated fatty liver disease (MAFLD), also known as non-alcoholic fatty liver disease (NAFLD), is a worldwide liver disease without definitive or widely used therapeutic drugs in clinical practice. In this study, we confirm that 6-gingerol (6-G), an active ingredient of ginger (Zingiber officinale Roscoe) in traditional Chinese medicine (TCM), can alleviate fructose-induced hepatic steatosis. It was found that 6-G significantly decreased hyperlipidemia caused by high-fructose diets (HFD) in rats, and reversed the increase in hepatic de novo lipogenesis (DNL) and triglyceride (TG) levels induced by HFD, both in vivo and in vitro. Mechanistically, chemical proteomics and cellular thermal shift assay (CETSA)–proteomics approaches revealed that stearoyl-CoA desaturase (SCD) is a direct binding target of 6-G, which was confirmed by further CETSA assay and molecular docking. Meanwhile, it was found that 6-G could not alter SCD expression (in either mRNA or protein levels), but inhibited SCD activity (decreasing the desaturation levels of fatty acids) in HFD-fed rats. Furthermore, SCD deficiency mimicked the ability of 6-G to reduce lipid accumulation in HF-induced HepG2 cells, and impaired the improvement in hepatic steatosis brought about by 6-G treatment in HFD supplemented with oleic acid diet-induced SCD1 knockout mice. Taken together, our present study demonstrated that 6-G inhibits DNL by targeting SCD to alleviate fructose diet-induced hepatic steatosis. Full article

Cell-death-inducing DNA fragmentation factor-alpha (DFFA)-like effector b (CIDEB) was first identified as an apoptosis-inducing protein. Further research revealed a pivotal role in lipid metabolism, regulating very-low-density lipoprotein (VLDL), lipid droplets (LD), sterol response element-binding protein (SREBP), and chylomicrons. Recent studies have uncovered that rare germline variants in CIDEB protect against liver diseases, including MAFLD, cirrhosis, and viral hepatitis. Furthermore, CIDEB influences steps of the hepatitis C virus (HCV) replication cycle. This review summarizes the current knowledge about CIDEB’s roles in apoptosis, lipid metabolism, and viral hepatitis, and highlights its critical role in liver diseases. Full article

The prevalence of nonalcoholic fatty liver disease (NAFLD) is likely to be approaching 38% of the world’s population. It is predicted to become worse and is the main cause of morbidity and mortality due to hepatic pathologies. It is particularly worrying that NAFLD is increasingly diagnosed in children and is closely related, among other conditions, to insulin resistance and metabolic syndrome. Against this background is the concern that the awareness of patients with NAFLD is low; in one study, almost 96% of adult patients with NAFLD in the USA were not aware of their disease. Thus, studies on the therapeutic tools used to treat NAFLD are extremely important. One promising treatment is a well-formulated ketogenic diet (KD). The aim of this paper is to present a review of the available publications and the current state of knowledge of the effect of the KD on NAFLD. This paper includes characteristics of the key factors (from the point of view of NAFLD regression), on which ketogenic diet exerts its effects, i.e., reduction in insulin resistance and body weight, elimination of fructose and monosaccharides, limitation of the total carbohydrate intake, anti-inflammatory ketosis state, or modulation of gut microbiome and metabolome. In the context of the evidence for the effectiveness of the KD in the regression of NAFLD, this paper also suggests the important role of taking responsibility for one’s own health through increasing self-monitoring and self-education. Full article

Non-alcoholic fatty liver disease (NAFLD) is a common long-lasting liver disease that affects millions of people around the world. It is best identified with a hepatic fat build-up that ultimately leads to inflammation and damage. The classification and nomenclature of NAFLD have long been a controversial topic, until 2020 when a group of international experts recommended substituting NAFLD with MAFLD (metabolic dysfunction-associated FLD). MAFLD was then terminologically complemented in 2023 by altering it to MASLD, i.e., metabolic dysfunction-associated steatotic liver disease (MASLD). Both the MAFLD and the MASLD terminologies comprise the metabolic element of the disorder, as they offer diagnostic benchmarks that are embedded in the metabolic risk factors that underlie the disease. MASLD (as a multisystemic disease) provides a comprehensive definition that includes a larger population of patients who are at risk of liver morbidity and mortality, as well as adverse cardiovascular and diabetes outcomes. MASLD highlights metabolic risks in lean or normal weight individuals, a factor that has not been accentuated or discussed in previous guidelines. Novel antihyperglycemic agents, anti-hyperlipidemic drugs, lifestyle modifications, nutritional interventions, and exercise therapies have not been extensively studied in MAFLD and MASLD. Nutrition plays a vital role in managing both conditions, where centralizing on a diet rich in whole vegetables, fruits, foods, healthy fats, lean proteins, and specific nutrients (e.g., omega-3 fatty acids and fibers) can improve insulin resistance and reduce inflammation. Thus, it is essential to understand the role of nutrition in managing these conditions and to work with patients to develop an individualized plan for optimal health. This review discusses prevention strategies for NAFLD/MAFLD/MASLD management, with particular attention to nutrition and lifestyle correction. Full article

The incidence of nonalcoholic fatty liver disease (NAFLD), or metabolic dysfunction-associated fatty liver disease (MAFLD), is increasing in adults and children. Unfortunately, effective pharmacological treatments remain unavailable. Single nucleotide polymorphisms (SNPs) in the patatin-like phospholipase domain-containing protein (PNPLA3 I148M) have the most significant genetic association with the disease at all stages of its progression. A roadblock to identifying potential treatments for PNPLA3-induced NAFLD is the lack of a human cell platform that recapitulates the PNPLA3 I148M-mediated onset of lipid accumulation. Hepatocyte-like cells were generated from PNPLA3^−/− and PNPLA3^I148M/M-induced pluripotent stem cells (iPSCs). Lipid levels were measured by staining with BODIPY 493/503 and were found to increase in PNPLA3 variant iPSC-derived hepatocytes. A small-molecule screen identified multiple compounds that target Src/PI3K/Akt signaling and could eradicate lipid accumulation in these cells. We found that drugs currently in clinical trials for cancer treatment that target the same pathways also reduced lipid accumulation in PNPLA3 variant cells. Full article

Non-alcoholic fatty liver disease (NAFLD) is a global public health problem that causes liver-related morbidity and mortality. It is also an independent risk factor for non-communicable diseases. In 2020, a proposal was made to refer to it as “metabolic dysfunction-associated fatty liver disease (MAFLD)”, with concise diagnostic criteria. Given its widespread occurrence, its treatment is crucial. Increased levels of oxidative stress cause this disease. This review aims to evaluate various studies on antioxidant therapies for patients with MAFLD. A comprehensive search for relevant research was conducted on the PubMed, SCOPUS, and ScienceDirect databases, resulting in the identification of 87 studies that met the inclusion criteria. In total, 31.1% of human studies used natural antioxidants, 53.3% used synthetic antioxidants, and 15.5% used both natural and synthetic antioxidants. In human-based studies, natural antioxidants showed 100% efficacy in the treatment of MAFLD, while synthetic antioxidants showed effective results in only 91% of the investigations. In animal-based research, natural antioxidants were fully effective in the treatment of MAFLD, while synthetic antioxidants demonstrated effectiveness in only 87.8% of the evaluations. In conclusion, antioxidants in their natural form are more helpful for patients with MAFLD, and preserving the correct balance of pro-oxidants and antioxidants is a useful way to monitor antioxidant treatment. Full article

Oxidative stress plays a central role in most chronic liver diseases and, in particular, in metabolic dysfunction-associated fatty liver disease (MAFLD), the new definition of an old condition known as non-alcoholic fatty liver disease (NAFLD). The mechanisms leading to hepatocellular fat accumulation in genetically predisposed individuals who adopt a sedentary lifestyle and consume an obesogenic diet progress through mitochondrial and endoplasmic reticulum dysfunction, which amplifies reactive oxygen species (ROS) production, lipid peroxidation, malondialdehyde (MDA) formation, and influence the release of chronic inflammation and liver damage biomarkers, such as pro-inflammatory cytokines. This close pathogenetic link has been a key stimulus in the search for therapeutic approaches targeting oxidative stress to treat steatosis, and a number of clinical trials have been conducted to date on subjects with NAFLD using drugs as well as supplements or nutraceutical products. Vitamin E, Vitamin D, and Silybin are the most studied substances, but several non-pharmacological approaches have also been explored, especially lifestyle and diet modifications. Among the dietary approaches, the Mediterranean Diet (MD) seems to be the most reliable for affecting liver steatosis, probably with the added value of the presence of extra virgin olive oil (EVOO), a healthy food with a high content of monounsaturated fatty acids, especially oleic acid, and variable concentrations of phenols (oleocanthal) and phenolic alcohols, such as hydroxytyrosol (HT) and tyrosol (Tyr). In this review, we focus on non-pharmacological interventions in MAFLD treatment that target oxidative stress and, in particular, on the role of EVOO as one of the main antioxidant components of the MD. Full article

The epidemiological burden of liver steatosis associated with metabolic diseases is continuously growing worldwide and in all age classes. This condition generates possible progression of liver damage (i.e., inflammation, fibrosis, cirrhosis, hepatocellular carcinoma) but also independently increases the risk of cardio-metabolic diseases and cancer. In recent years, the terminological evolution from “nonalcoholic fatty liver disease” (NAFLD) to “metabolic dysfunction-associated fatty liver disease” (MAFLD) and, finally, “metabolic dysfunction-associated steatotic liver disease” (MASLD) has been paralleled by increased knowledge of mechanisms linking local (i.e., hepatic) and systemic pathogenic pathways. As a consequence, the need for an appropriate classification of individual phenotypes has been oriented to the investigation of innovative therapeutic tools. Besides the well-known role for lifestyle change, a number of pharmacological approaches have been explored, ranging from antidiabetic drugs to agonists acting on the gut–liver axis and at a systemic level (mainly farnesoid X receptor (FXR) agonists, PPAR agonists, thyroid hormone receptor agonists), anti-fibrotic and anti-inflammatory agents. The intrinsically complex pathophysiological history of MASLD makes the selection of a single effective treatment a major challenge, so far. In this evolving scenario, the cooperation between different stakeholders (including subjects at risk, health professionals, and pharmaceutical industries) could significantly improve the management of disease and the implementation of primary and secondary prevention measures. The high healthcare burden associated with MASLD makes the search for new, effective, and safe drugs a major pressing need, together with an accurate characterization of individual phenotypes. Recent and promising advances indicate that we may soon enter the era of precise and personalized therapy for MASLD/MASH. Full article

Worldwide, metabolic dysfunction-associated fatty liver disease (MAFLD) is a significant public health concern, especially since more than fifty percent of people with type 2 diabetes are affected by it. This pathological condition includes all states of fatty liver disease, from non-alcoholic fatty liver disease (NAFLD) to steatohepatitis (NASH). Prolonged evolutions can lead to cirrhosis and cancer, so treatment must be started early. Hepatic steatosis may be improved by sodium glucose co-transporter 2 inhibitors (SGLT2 inhibitors), which prevent glucose reabsorption in the proximal renal tubule and increase urinary excretion, thus lowering plasma glucose levels. Experimental studies in animal models have suggested that SGLT2 inhibitors may have beneficial modulatory effects on NAFLD and NASH, while numerous clinical trials have demonstrated their favorable effects on the liver enzymes, body mass index, blood lipids, blood glucose, and insulin resistance in NAFLD patients. This review highlights the state of knowledge regarding the epidemiology, diagnosis and pathogenetic pathways of MAFLD, focusing primarily on the effectiveness of SGLT2 inhibitors as a promising drug class in the treatment of NAFLD. Full article