The booming prevalence of nonalcoholic fatty liver disease (NAFLD) in adults and children will threaten the health system in the upcoming years. The “multiple hit” hypothesis is the currently accepted explanation of the complex etiology and pathophysiology of the disease. Some of the critical pathological events associated with the development of NAFLD are insulin resistance, steatosis, oxidative stress, inflammation, and fibrosis. Hence, attenuating these events may help prevent or delay the progression of NAFLD. Despite an increasing understanding of the mechanisms involved in NAFLD, no approved standard pharmacological treatment is available. The only currently recommended alternative relies on lifestyle modifications, including diet and physical activity. However, the lack of compliance is still hampering this approach. Thus, there is an evident need to characterize new therapeutic alternatives. Studies of food bioactive compounds became an attractive approach to overcome the reticence toward lifestyle changes. The present study aimed to review some of the reported compounds with beneficial properties in NAFLD; namely, coffee (and its components), tormentic acid, verbascoside, and silymarin. We provide details about their protective effects, their mechanism of action in ameliorating the critical pathological events involved in NAFLD, and their clinical applications.

The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in adolescents is challenging the global care system. No therapeutic strategies have been defined so far, and changes in the lifestyle remain the only alternative. In this study, we assessed the protective effects of silymarin in a juvenile non-alcoholic steatohepatitis (NASH) model and the in vitro effects on fat-laden human hepatocytes. C57Bl/6 mice were exposed to HFHC diet immediately after weaning. After eight weeks, animals showed histological signs of NASH. Silymarin was added to the HFHC diet, the treatment continued for additional 12 weeks and the effects on BMI, hepatomegaly, visceral fat, lipid profile, transaminases, HOMA-IR, steatosis, inflammation, fibrosis, oxidative stress, and apoptosis were determined. The switch from HFHC to control diet was used to mimic life style changes. In vitro experiments were performed in parallel in human hepatocytes. HFHC diet supplemented with silymarin showed a significant improvement in glycemia, visceral fat, lipid profile, and liver fibrosis. Moreover, it reduced (both in vitro and in vivo) ALT, hepatic inflammation, oxidative stress, and apoptosis. Lifestyle changes restored the control group parameters. The data presented show the beneficial effects of the oral administration of silymarin in the absence of changes in the dietary habits in a juvenile model of NASH.

Background: Obesity is a primary limiting factor in liver stiffness measurement (LSM). The impact of obesity has always been evaluated in terms of body mass index (BMI), without studying the effects of skin-to-liver distance (SLD) on LSM. We studied the impact of SLD on LSM in a cohort of obese patients undergoing bariatric surgery and intra-operatory liver biopsy. Materials and Methods: 299 patients underwent LSM by point-shear wave elastography (ElastPQ protocol), with two different ultrasound machines. SLD was measured as the distance between the skin and the liver capsule, perpendicular to where the region of interest (ROI) was positioned. We used the following arbitrary cut-offs: <5.7 kPa, F0–1; 5.7–7.99 kPa, F2; ≥8 kPa, F3–4. Results: We developed two logistic regression models using elastography–histology agreement (EHA) as the dependent variable and SLD as the independent variable. The model based on the second machine showed strongly more performant discriminative and calibration metrics (AIC 38.5, BIC 44.2, Nagelkerke Pseudo-R2 0.894, AUROC 0.90). The SLD cut-off value of 34.5 mm allowed a correct EHA with a sensitivity of 100%, a specificity of 93%, negative predictive value of 100%, positive predictive value of 87%, an accuracy of 96%, and positive likelihood ratio of 3.56. Conclusion: The impact of SLD is machine-dependent and should be taken into consideration when interpreting LSM. We believe that our findings may serve as a reference point for appropriate fibrosis stratification by liver elastography in obese patients.

Background & Aims: Obesity is associated with non‐alcoholic fatty liver (NAFL), which may progress towards non‐alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). Occult hepatitis B virus infection (OBI) may contribute to hepatic damage in patients with chronic liver disease of different aetiologies (eg HCV, alcohol). However, information on the prevalence and clinical impact of OBI in obese individuals is lacking. The aims of this study were to investigate NASH prevalence and risk factors in obese people who underwent bariatric surgery.Methods: Two‐hundred and twenty‐six subjects (160 females; mean age 42.9 years ±10.8 SD) without evidence of any further cause of liver disease consecutively underwent bariatric surgery in two Italian liver centers. During surgery, all patients underwent liver biopsy for histological evaluation and molecular studies. Liver DNA extracts were tested for PNPLA3, TM6SF2, MBOAT7, IRGM polymorphisms and for OBI. Univariate and multivariate analyses were used to identify predictors of NASH.Results: Histology showed NASH in 115 (50.9%) and NAFL in 111 cases (49.1%). Twenty‐nine/226 (12.8%) cases had OBI, 24 (82.8%) of whom had NASH and 5 (17.2%) NAFL, whereas among the 197 OBI‐negative cases, 91 (46.2%) had NASH and 106 (53.8%) NAFL (P = .0002). Multivariate analysis showed that older age (P = .03, OR 1.034), alanine aminotransferase values (P = .005, OR 1.023), insulin resistance/diabetes (P = .02, OR 2.257), TM6SF2 polymorphism (P = .04, OR 3.168) and OBI (P = .004, OR 5.503) were independent predictors of NASH.Conclusion: NASH is highly prevalent in obese individuals undergoing bariatric surgery. OBI is one of the strongest risk factors of NASH in these patients.

Silybin has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). In this study, we assessed the effect of Silybin in a well-established in vitro coculture model of early-stage NASH. LX2 and Huh7 cells were exposed to free fatty acid (FFA) and Silybin as mono- or coculture (SCC). Cell viability, LX2 activation, collagen deposition, metalloproteinase 2 and 9 (MMP2-9) activity, and ROS generation were determined at 24, 96, and 144 h. Exposure to FFA induced the activation of LX2 as shown by the increase in cell viability and upregulation of collagen biosynthesis. Interestingly, while cotreatment with Silybin did not affect collagen production in LX2, a significant reduction was observed in SCC. MMP2-9 activity was reduced in FFA-treated Huh7 and SCC and cotreatment with Silybin induced a dose-dependent increase, while no effect was observed in LX2. Silybin also showed antioxidant properties by reducing the FFA-induced production of ROS in all the cell systems. Based on these data, Silybin exerts its beneficial effects by reducing LX2 proliferation and ROS generation. Moreover, MMP2-9 modulation in hepatocytes represents the driving mechanism for the net reduction of collagen in this NASH in vitro model, highlighting the importance of hepatic cells interplay in NASH development and resolution.

Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (ρ = −0.49, p < 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0/F1 (median 4753 ng/mL) to F2–F3–F4 (2760 ng/mL) and in cirrhotic subjects (1418 ng/mL). The diagnostic performance of FCN-2 in detecting F ≥ 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate/advanced) significantly improving the fibrosis diagnostic algorithms.