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Non-alcoholic fatty liver diseases: current challenges and future directions.

ABSTRACT: Non-alcoholic fatty liver diseases (NAFLD) is rapidly becoming the most common cause of chronic liver disease in Western Countries, and a similar trend is expected in Eastern Countries within the next years. This review focusses on the definition of NAFLD and NASH, possible screening mechanisms and the question who should be screened. Still there is a need for non-invasive diagnostic tools and biomarkers for NASH that can quickly and easily diagnose the severity of NAFLD, monitor liver changes, and identify high risk patients. In addition, treatment strategies are discussed as well as the clientele, who should be treated. There are currently no drugs approved for NAFLD. Successful clinical studies with e.g., obeticholic acid and new substances (e.g., cenicriviroc with anti-inflammatory activity) have already been published. If weight-reducing diets and a change in lifestyle fail in the case of severe obesity, bariatric surgery (e.g., gastric bypass or stomach reduction) should be considered. In the case of manifest type 2 diabetes, metformin can be used as an oral antidiabetic of first choice, and GLP-1 agonists have shown beneficial effects on NAFLD. However, up to now the prevention of overweight and lack of exercise targets the most important risk factors. This review aims to identify therapy relevant risk factors, management strategies, and open questions concerning NAFLD patients.

SUBMITTER: Roeb E

PROVIDER: S-EPMC8106107 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:One of the most common complications of childhood obesity is the non-alcoholic fatty liver disease (NAFLD), which is the most common form of liver disease in children. NAFLD is defined by hepatic fat infiltration > 5% hepatocytes, as assessed by liver biopsy, in the absence of excessive alcohol intake, viral, autoimmune and drug-induced liver disease. It encompasses a wide spectrum of liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis, which, in turn, can evolve into cirrhosis and end stage liver disease. Obesity and insulin resistance are the main risk factors for pediatric NAFLD. In fact, NAFLD is strongly associated with the clinical features of insulin resistance especially the metabolic syndrome, prediabetes and type 2 diabetes mellitus (T2D). In particular, it has been clearly shown in obese youth that the prevalence of metabolic syndrome, pre-diabetes and type 2 diabetes increases with NAFLD severity progression. Evidence that not all of the obese patients develop NAFLD suggests that the disease progression is likely to depend on complex interplay between environmental factors and genetic predisposition. Recently, a non-synonymous SNP (rs738409), characterized by a C to G substitution encoding an isoleucine to methionine substitution at the amino acid position 148 in the patatin like phospholipase containing domain 3 gene (PNPLA3), has been associated with hepatic steatosis in a multiethnic cohort of adults as well as in children. Another important polymorphisms that acts with PNPLA3 to convey susceptibility to fatty liver in obese youths is the rs1260326 polymorphism in the glucokinase regulatory protein. The pharmacological approach in NAFLD children poorly adherent to or being unresponsive/partially responsive to lifestyle changes, is aimed at acting upon specific targets involved in the pathogenesis. There are some therapeutic approaches that are being studied in children. This article reviews the current knowledge regarding the pediatric fatty liver disease, the new insights and the future directions.

Project description:Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions in patients with type 2 diabetes. Patients with NAFLD are at increased risk of more aggressive liver disease (non-alcoholic steatohepatitis [NASH]) and at a higher risk of death from cirrhosis, hepatocellular carcinoma and cardiovascular disease. Dysfunctional adipose tissue and insulin resistance play an important role in the pathogenesis of NASH, creating the conditions for hepatocyte lipotoxicity. Mitochondrial defects are at the core of the paradigm linking chronic excess substrate supply, insulin resistance and NASH. Recent work indicates that patients with NASH have more severe insulin resistance and lipotoxicity compared with matched obese controls with only isolated steatosis. This review focuses on available agents and future drugs under development for the treatment of NAFLD/NASH in type 2 diabetes. Reversal of lipotoxicity with pioglitazone is associated with significant histological improvement, which occurs within 6 months and persists with continued treatment (or for at least 3 years) in patients with prediabetes or type 2 diabetes, holding potential to modify the natural history of the disease. These results also suggest that pioglitazone may become the standard of care for this population. Benefit has also been reported in non-diabetic patients. Recent promising results with glucagon-like peptide 1 receptor agonists have opened another new treatment avenue for NASH. Many agents in Phase 2-3 of development are being tested, aiming to restore glucose/lipid metabolism, ameliorate adipose tissue and liver inflammation, or to inhibit liver fibrosis. By targeting a diversity of relevant pathways, combination therapy in NASH will likely provide greater success in the future. In summary, increased clinical awareness and improved screening strategies (as currently done for diabetic retinopathy and nephropathy) are needed, to translate recent treatment progress into early treatment and improved quality of life for patients with type 2 diabetes and NASH. This review summarises a presentation given at the symposium 'The liver in focus' at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by John Jones, DOI: 10.1007/s00125-016-3940-5 , and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1 ) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x ).

Project description:Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A "multiple-hit" pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the "imperfect" gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended lifestyle changes. When morbid obesity prevails, bariatric surgery should be considered.

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Non-alcoholic fatty liver diseases: current challenges and future directions.

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