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Background: Metabolic dysfunction associated steatotic liver disease (MASLD) is associated with an increased risk of coronary artery disease. Computed Tomography Coronary Angiography (CTCA) can assess both the extent and the features of coronary plaques. We aimed to gather evidence about the prevalence and features of coronary plaques among MASLD patients. Methods: PubMed, Scopus, and Google Scholar databases were searched for randomized controlled trials and adjusted observational studies assessing the prevalence and features of coronary plaques by means of CTCA in MASLD patients as compared with a control group. The prevalence of coronary stenosis (defined as >30% and >50% diameter of stenosis), of increasing coronary artery calcium (CAC) score and of high‐risk features (namely low‐attenuation plaques, napkin ring sign, spotty calcification and positive remodelling) in MASLD patients were the endpoints of interest. Results: Twenty‐four observational studies were included. MASLD was associated with an increased prevalence of critical coronary stenosis compared with controls (odds ratio [OR] 1.54, 95%CI 1.23–1.93). Increased values of CAC score were observed in MASLD patients (OR 1.35, 95%CI 1.02–1.78 and OR 2.26, 95%CI 1.57–3.23 for CAC score 0–100 and >100, respectively). An increased risk of 'high‐risk' coronary plaques was observed in MASLD patients (OR 2.13, 95%CI 1.42–3.19). As high‐risk features plaques, a higher prevalence of positive remodelling and spotty calcification characterize MASLD patients (OR 2.92, 95%CI 1.79–4.77 and OR 2.96, 95%CI 1.22–7.20). Conclusions: Patients with MASLD are at increased risk of developing critical coronary stenosis and coronary plaques characterized by high‐risk features as detected by CTCA. [ABSTRACT FROM AUTHOR]

Fibrosis is a common feature of more than 50 different diseases and the cause of more than 35% of deaths worldwide, of which liver, kidney, skin, heart and, recently, lungs are receiving the most attention. Tissue changes, resulting in loss of organ function, are both a cause and consequence of disease and outcome. Fibrosis is caused by an excess deposition of extracellular matrix proteins, which over time results in impaired organ function and organ failure, and the pathways leading to increased fibroblast activation are many. This narrative review investigated the common denominator of fibrosis, fibroblasts, and the activation of fibroblasts, in response to excess energy consumption in liver, kidney, heart, skin and lung fibrosis. Fibroblasts are the main drivers of organ function loss in lung, liver, skin, heart and kidney disease. Fibroblast activation in response to excess energy consumption results in the overproduction of a range of collagens, of which types I, III and VI seem to be the essential drivers of disease progression. Fibroblast activation may be quantified in serum, enabling profiling and selection of patients. Activation of fibroblasts results in the overproduction of collagens, which deteriorates organ function. Patient profiling of fibroblast activities in serum, quantified as collagen production, may identify an organ death trajectory, better enabling identification of the right treatment for use in different metabolic interventions. As metabolically activated patients have highly elevated risk of kidney, liver and heart failure, it is essential to identify which organ to treat first and monitor organ status to correct treatment regimes. In direct alignment with this, it is essential to identify the right patients with the right organ deterioration trajectory for enrolment in clinical studies. [ABSTRACT FROM AUTHOR]

Summary: Background: The current management of metabolic dysfunction‐associated steatotic liver disease (MASLD) relies on lifestyle intervention. Prior studies have shown that nutritional wheat amylase trypsin inhibitors (ATI) activate toll‐like receptor 4 on intestinal myeloid cells to enhance intestinal and extra‐intestinal inflammation, including the promotion of murine MASLD, insulin resistance and liver fibrosis. Aims: We aimed to assess the impact of ATI (gluten)‐free diet in liver as well as metabolic parameters of biopsy‐proven MASLD patients. Methods: We performed a 6‐week, proof‐of‐concept 1:1 randomised controlled trial of an ATI‐free diet. The controls followed a balanced diet recommended by the German Nutrition Society. We assessed changes in controlled attenuation parameter (CAP), body mass index (BMI) and homeostatic model assessment of insulin resistance (HOMA‐IR). Patient‐reported outcomes were assessed by the CLDQ‐NASH questionnaire. Forty‐five patients were consecutively enrolled (21 in the intervention arm and 24 in the control arm). Results: Three patients from each arm discontinued the study. In the ATI‐free diet group, a significant decrease in BMI (p = 0.018), CAP (p = 0.018) and HOMA‐IR (p = 0.042) was observed at 6 weeks. The mean difference in CAP between the two arms at week 6 was 30.5 dB/m (p = 0.039), with a delta significantly higher in the ATI‐free diet group (p = 0.043). Only an ATI‐free diet could achieve a significant improvement in CLDQ‐NASH domains (p value for total scoring: 0.013). Conclusions: A short‐term ATI‐free diet leads to significant improvements in liver and metabolic parameters, as well as patient‐reported outcomes with good tolerability. A larger follow‐up study is justified to corroborate these findings. Clinical trial number: NCT04066400. [ABSTRACT FROM AUTHOR]

Summary: Background: The long‐term results of web‐based behavioural intervention in non‐alcoholic fatty liver disease (NAFLD) have not been described in patients followed in specialised centres. Aims: To analyse the long‐term effectiveness of web education compared with the results achieved by a group‐based behavioural intervention in the same years 2012–2014. Methods: We followed 679 patients with NAFLD (web‐based, n = 290; group‐based, n = 389) for 5 years. Weight loss ≥10% was the primary outcome; secondary outcomes were attrition, changes in liver enzymes and in biomarkers of steatosis (Fatty liver Index) and fibrosis (Fibrosis‐4 index). Results: The cohorts differed in age, education, working status and presence of diabetes. Attrition was higher in the web‐based cohort (hazard ratio: 1.53; 95% CI: 1.24–1.88), but not different after adjustment for confounders. Among patients in active follow‐up, 50% lost ≥5% of initial body weight and 19% lost ≥10%, without difference between cohorts. Alanine aminotransferase levels fell to within the normal range in 51% and 45% of web‐ and group‐based cohorts, respectively. Fatty Liver Index declined progressively and, by year 5, it ruled out steatosis in 4.8%, whereas 24.9% were in the indeterminate range. Fibrosis‐4 index increased in both cohorts, driven by age, but the prevalence of cases ruling‐in advanced fibrosis remained very low (around 1%). Improvements in the class of both surrogate biomarkers were associated with ≥5% weight loss. Conclusions: Although burdened by attrition, web‐based behavioural intervention is feasible and effective in NAFLD, expanding the cohort involved in behavioural programs and reducing the risk of progressive disease. [ABSTRACT FROM AUTHOR]

Background & Aims: Non‐alcoholic fatty liver disease (NAFLD) is a heterogeneous disorder, but the factors that determine this heterogeneity remain poorly understood. Adipose tissue dysfunction is causally linked to NAFLD since it causes intrahepatic triglyceride (IHTG) accumulation through increased hepatic lipid flow, due to insulin resistance and pro‐inflammatory adipokines release. While many studies in NAFLD have looked at total adiposity (i.e. mainly subcutaneous fat, SC‐AT), it is still unclear the possible impact of visceral fat (VF). Thus, we investigated how VF versus SC‐AT was related to NAFLD severity in lean, overweight and obese individuals versus lean controls. Methods: Thirty‐two non‐diabetic NAFLD with liver biopsy (BMI 21.4–34.7 kg/m2) and eight lean individuals (BMI 19.6–22.8 kg/m2) were characterized for fat distribution (VF, SC‐AT and IHTG by magnetic resonance imaging), lipolysis and insulin resistance by tracer infusion, free fatty acids (FFAs) and triglyceride (TAG) concentration and composition (by mass spectrometry). Results: Intrahepatic triglyceride was positively associated with lipolysis, adipose tissue insulin resistance (Adipo‐IR), TAG concentrations, and increased saturated/unsaturated FFA ratio. Compared to controls VF was higher in NAFLD (including lean individuals), increased with fibrosis stage and associated with insulin resistance in liver, muscle and adipose tissue, increased lipolysis and decreased adiponectin levels. Collectively, our results suggest that VF accumulation, given its location close to the liver, is one of the major risk factors for NAFLD. Conclusions: These findings propose VF as an early indicator of NAFLD progression independently of BMI, which may allow for evidence‐based prevention and intervention strategies. [ABSTRACT FROM AUTHOR]

Oncostatin M (OSM) is a pleiotropic cytokine of the interleukin (IL)‐6 family that contributes to the progression of chronic liver disease. Here we investigated the role of OSM in the development and progression of hepatocellular carcinoma (HCC) in non‐alcoholic fatty liver disease (NAFLD)/non‐alcoholic steatohepatitis (NASH). The role of OSM was investigated in (1) selected cohorts of NAFLD/NASH HCC patients, (2) liver cancer cells exposed to human recombinant OSM or stably transfected to overexpress human OSM, (3) murine HCC xenografts, and (4) a murine NASH‐related model of hepatic carcinogenesis. OSM was found to be selectively overexpressed in HCC cells of NAFLD/NASH patients, depending on tumor grade. OSM serum levels, barely detectable in patients with simple steatosis or NASH, were increased in patients with cirrhosis and more evident in those carrying HCC. In this latter group, OSM serum levels were significantly higher in the subjects with intermediate/advanced HCCs and correlated with poor survival. Cell culture experiments indicated that OSM upregulation in hepatic cancer cells contributes to HCC progression by inducing epithelial‐to‐mesenchymal transition and increased invasiveness of cancer cells as well as by inducing angiogenesis, which is of critical relevance. In murine xenografts, OSM overexpression was associated with slower tumor growth but an increased rate of lung metastases. Overexpression of OSM and its positive correlation with the angiogenic switch were also confirmed in a murine model of NAFLD/NASH‐related hepatocarcinogenesis. Consistent with this, analysis of liver specimens from human NASH‐related HCCs with vascular invasion showed that OSM was expressed by liver cancer cells invading hepatic vessels. In conclusion, OSM upregulation appears to be a specific feature of HCC arising on a NAFLD/NASH background, and it correlates with clinical parameters and disease outcome. Our data highlight a novel pro‐carcinogenic contribution for OSM in NAFLD/NASH, suggesting a role of this factor as a prognostic marker and a putative potential target for therapy. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Background & Aims: NAFLD patients usually have an increase in AST/ALT levels, but cholestasis can also be observed. We aimed to assess in subjects with NAFLD the impact of the (cholestatic) C pattern on the likelihood of developing major liver‐related outcomes (MALO). Methods: Five hundred and eighty‐two consecutive patients with biopsy‐proven NAFLD or a clinical diagnosis of NAFLD‐related compensated cirrhosis were classified as hepatocellular (H), C and mixed (M) patterns, by using the formula (ALT/ALT Upper Limit of Normal‐ULN)/(ALP/ALP ULN). MALO were recorded during follow‐up. An external cohort of 1281 biopsy‐proven NAFLD patients was enrolled as validation set. Results: H, M and C patterns were found in 153 (26.3%), 272 (46.7%) and 157 (27%) patients respectively. During a median follow‐up of 78 months, only 1 (0.6%) patient with H pattern experienced MALO, whilst 15 (5.5%) and 38 (24.2%) patients in M and C groups had MALO. At multivariate Cox regression analysis, age >55 years (HR 2.55, 95% CI 1.17–5.54; p =.01), platelets <150 000/mmc (HR 0.14, 95% CI 0.06–0.32; p <.001), albumin <4 g/L(HR 0.62, 95% CI 0.35–1.08; p =.09), C versus M pattern (HR 7.86, 95% CI 1.03–60.1; p =.04), C versus H pattern(HR 12.1, 95% CI 1.61–90.9; p =.01) and fibrosis F3–F4(HR 35.8, 95% CI 4.65–275.2; p <.001) were independent risk factors for MALO occurrence. C versus M pattern(HR 14.3, 95% CI 1.90–105.6; p =.008) and C versus H pattern (HR 15.6, 95% CI 2.10–115.1; p =.0068) were confirmed independently associated with MALO occurrence in the validation set. The immunohistochemical analysis found a significantly higher prevalence of moderate‐high‐grade ductular metaplasia combined with low‐grade ductular proliferation in C pattern when compared with the biochemical H pattern. Gene expression analysis showed a lower expression of NR1H3, RXRα and VCAM1 in patients with the C pattern. Conclusions: The presence of a cholestatic pattern in patients with NAFLD predicts a higher risk of MALO independently from other features of liver disease. [ABSTRACT FROM AUTHOR]

Summary: Background & Aim: Non‐alcoholic fatty liver disease (NAFLD), and especially fibrotic non‐alcoholic steatohepatitis, is associated with high risks of liver‐related events (LRE) and extrahepatic events (EHE). We evaluated the competitive risk occurrence of LRE and EHE in a large cohort of biopsy‐proven NAFLD stratified according to baseline severity of fibrosis. Methods: Two thousand one hundred thirty‐five patients with biopsy‐proven NAFLD were enrolled. Observed cumulative incidence functions (CIFs) were used to evaluate the risk of LRE and EHE; cause‐specific Cox model and predicted CIFs were fitted to identify predictors of LRE and EHE. A replication cohort of NAFLD patients with liver fibrosis severity estimated by liver stiffness measurement by transient elastography was also enrolled. Results: Observed CIFs indicated that the 60‐month probabilities of LRE and EHE were 0.2% and 3% in F0‐F1, 2% and 3.8% in F2 and 9.7% and 6.4% in F3‐F4 patients, respectively. The cause‐specific Cox model indicated that in F0‐F1 and F2 patients, age > 50 years (HR 2.7) was the only predictor of LRE, while age > 50 years (HR 2.96), previous cardiovascular events (CVE, HR 2.07), and previous extra‐hepatic cancer (HR 2.36) were independent risk factors for EHE. In F3‐F4 patients, age > 55 years (HR 1.73), obesity (HR 1.52), PLT < 150 000/mmc (HR 3.66) and log(GGT) (HR 1.77) were associated with LRE, while age > 55 years (HR 1.74) and previous CVE (HR 2.51) were independent predictors of EHE. Predicted CIFs for HE and EHE in F0‐F1, F2 and F3‐F4 patients stratified the risk of events. The results were externally replicated. Conclusion: The likelihood of EHE in NAFLD patients is relevant and increases according to the severity of liver fibrosis, while the risk of LRE is negligible in F0‐F1, low but clinically relevant in F2 and high in F3‐F4 patients. [ABSTRACT FROM AUTHOR]

Non‐alcoholic steatohepatitis has emerged as a major public health problem, and the burden of non‐alcoholic steatohepatitis cirrhosis is projected to increase by 64%‐156% by 2030. The threat is aggravated by the fact that are currently no approved drugs for the treatment of non‐alcoholic steatohepatitis. In this paper, we review the main challenges to drug development in patients with non‐alcoholic steatohepatitis cirrhosis, and describe the opportunities brought by the advances in the understanding of the clinical and pathophysiological nuances of cirrhosis. The design of therapeutic regimens for non‐alcoholic steatohepatitis cirrhosis will vary according to the specific cirrhosis substage (compensated vs decompensated), and the specific mechanistic basis of therapy, targeted either at improving aetiology‐specific pathways and/or at more general aetiology‐agnostic processes. The understanding of the probabilistic expectations for the whole range of potential outcomes, rooted at different mechanistic drivers at each specific substage, will be essential in order to choose adequate estimands and therapeutic strategies for clinical trials and individual patients with non‐alcoholic steatohepatitis cirrhosis. Finally, we provide a summary of the main pitfalls and uncertainties in the design of clinical trials for non‐alcoholic steatohepatitis cirrhosis and discuss potential biomarkers for use in trials and practice for these patients. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are common conditions with a rising burden. Yet there are significant management gaps between clinical guidelines and practice in patients with NAFLD and NASH. Further, there is no single global guiding strategy for the management of NAFLD and NASH. The American Gastroenterological Association, in collaboration with 7 professional associations, convened an international conference comprising 32 experts in gastroenterology, hepatology, endocrinology, and primary care providers from the United States, Europe, Asia, and Australia. Conference content was informed by the results of a national NASH Needs Assessment Survey. The participants reviewed and discussed published literature on global burden, screening, risk stratification, diagnosis, and management of individuals with NAFLD, including those with NASH. Participants identified promising approaches for clinical practice and prepared a comprehensive, unified strategy for primary care providers and relevant specialists encompassing the full spectrum of NAFLD/NASH care. They also identified specific high-yield targets for clinical research and called for a unified, international public health response to NAFLD and NASH. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods and Results Metabolic dysfunction‐associated steatotic liver disease (MASLD) is a heterogenous clinical and histopathological entity, where multiple metabolic co‐factors are intertwined with high interindividual variability. The impact and severity of each factor (including obesity and type 2 diabetes) define a systemic dysmetabolism that can lead to either advanced liver disease and its complication (including hepatocellular carcinoma and clinical events related to portal hypertension) or extrahepatic events: incident cardiovascular disease, chronic kidney disease and extrahepatic cancers. The balance between environmental factors and genetic susceptibility has unique implications in MASLD: the intermittent injury of metabolic co‐factors, their fluctuation over time and their specific management, are counterbalanced by the presence of gene variants that can significantly impact the disease at multiple levels. The I148M variant in the PNPLA3 gene is the most investigated genetic susceptibility that induces a more severe steatohepatitis, enhanced fibrogenesis and can shape the incidence of long‐term clinical events regardless of, or worsened by, other metabolic risk factors.In this review, we will summarise the updated evidence on the natural history of MASLD accounting for classical metabolic risk factors, the role of PNPLA3 in clinical sub‐phenotyping (e.g., ‘lean MASLD’), impact on disease severity and fibrosis progression, as well as its role for prognostication, alone or in combination with non‐invasive tools into polygenic risk scores. [ABSTRACT FROM AUTHOR]

Non‐alcoholic fatty liver disease (NAFLD) is the fastest growing cause of chronic liver disease worldwide. Although only a small proportion of NAFLD patients will progress to end‐stage liver disease and death, the clinical burden of NAFLD is substantial due the sheer number of individuals affected worldwide. In fact, recent estimates suggest that 25% of the world have NAFLD, which is now one of the leading causes of cirrhosis and indications for liver transplantation. Although liver‐related mortality is common, the most common cause of death in patients with NAFLD is related to cardiovascular diseases, followed by extra‐hepatic cancers. There is a significant interindividual variability in the susceptibility to liver disease. The severity of metabolic alterations is the main risk factor for progressive NAFLD, but the qualitative components of diet, physical activity and genetic factors also play an important role. In particular, common variants in patatin‐like phospholipase domain‐containing 3 (PNPLA3), transmembrane 6 superfamily member 2 (TM6SF2), membrane bound O‐acyl transferase 7 (MBOAT7) and glucokinase regulator (GCKR) have been shown to contribute to the full spectrum of NAFLD. In those at risk of a potentially progressive form of NAFLD or non‐alcoholic steatohepatitis or in those with hepatic fibrosis, additional assessment must be made. [ABSTRACT FROM AUTHOR]

Background and aims: Non‐alcoholic steatohepatitis (NASH) is a chronic disease that can progress to end‐stage liver disease (ESLD). A large proportion of early‐stage NASH patients remain undiagnosed compared to those with advanced fibrosis, who are more likely to receive disease management interventions. This study estimated the disease burden and economic impact of diagnosed NASH in the adult population of France, Germany, Italy, Spain and the United Kingdom in 2018. Methods: The socioeconomic burden of diagnosed NASH was estimated using cost‐of‐illness methodology applying a prevalence approach to estimate the number of adults with NASH and the attributable economic and wellbeing costs. Given undiagnosed patients do not incur costs in the study, the probability of diagnosis is central to cost estimation. The analysis was based on a literature review, databases and consultation with clinical experts, economists and patient groups. Results: The proportion of adult NASH patients with a diagnosis ranged from 11.9% to 12.7% across countries, which increased to 38.8%‐39.1% for advanced fibrosis (F3‐F4 compensated cirrhosis). Total economic costs were €8548‐19 546M. Of these, health system costs were €619‐1292M. Total wellbeing costs were €41 536‐90 379M. The majority of the undiagnosed population (87.3%‐88.2% of total prevalence) was found to have early‐stage NASH, which, left untreated, may progress to more resource consuming ESLD over time. Conclusions: This study found that the majority of economic and wellbeing costs of NASH are experienced in late disease stages. Earlier diagnosis and care of NASH patients could reduce future healthcare costs. [ABSTRACT FROM AUTHOR]

Objective: Patients with chronic liver disease (CLD), both non‐alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC), are at high risk of diabetes (T2D), but mechanisms are still unknown. Muscle/liver insulin resistance (IR) and pancreatic dysfunction are the major metabolic defects leading to T2D. However, if the risk of T2D in CLD patients is because of reduced insulin response and/or to IR, and the impact of liver histology has not been investigated. Design: We studied 220 non‐T2D patients with chronic liver disease (129 NAFLD, BMI = 27.3 kg/m2; 91 CHC, BMI = 25.0 kg/m2) that received a 75‐gram oral glucose tolerance test (OGTT) with the measurement of glucose and insulin concentrations for 2 hours, glucose tolerance (NGT vs IGT) and liver biopsy. The results were compared to 26 controls (CT‐NGT, BMI = 25.6 kg/m2). We evaluated peripheral insulin sensitivity (OGIS), OGTT‐insulin response (ΔAUC‐I/ΔAUC‐G) and disposition‐index (DI = OGIS∙ΔAUC‐I/ΔAUC‐G) for the risk to develop T2D. Results: NAFLD had increased muscle IR (associated to NASH, steatosis and fibrosis), higher than in CHC or CT‐NGT (OGIS = 8.9 vs 11.3 and 10.5 mL/min kg, P <.0001). In NAFLD, OGTT‐insulin response (ΔAUC‐I/ΔAUC‐G) was the highest while it was significantly decreased in CHC (2.2 vs 1.1 and 1.6, NAFLD vs. CHC and CT‐NGT, P <.005). The highest T2D risk (low DI) was observed in CHC‐IGT (7.5), CHC‐NGT (13.5) and NAFLD‐IGT (10.8) vs CT‐NGT (14.9, all P <.0001), but not in NAFL‐NGT or NASH‐NGT. Conclusion: We observed an increased T2D risk in NAFLD‐IGT, CHC‐IGT and CHC‐NGT mainly because of reduced OGTT‐insulin response, while insulin response in NAFLD‐NGT compensates the IR thus maintaining normal glycaemia. [ABSTRACT FROM AUTHOR]

Abstract: Background & Aims: The non‐invasive identification of steatohepatitis (NASH) in patients with Non‐Alcoholic Fatty Liver Disease is an unmet need in clinical practice. Index of NASH (ION) is a new tool for the prediction of NASH. We aimed to externally validate ION and to compare it with CK‐18. Since necroinflammation precedes fibrosis, we also tested ION in combination with non‐invasive tools for fibrosis. Methods: We analysed data from 292 Italian patients (169 Southern cohort, and 123 Northern cohort) with an histological diagnosis of NAFLD. The ION, FIB‐4 and NFS scores were calculated according to published algorithms. Serum cytokeratin18‐Aspartate396 levels and liver stiffness (LS) by Fibroscan were assessed within three months from liver biopsy. Results: The diagnostic accuracy of ION for the identification of NASH was not as satisfactory as reported (area under the ROC curve, AUROC = 0.687 [95% CI = 0.62‐0.75]). The proposed cut‐off value ≥50 showed a poor sensitivity (Se) (28%) and a good specificity (Sp) (92%), with a positive predictive value (PPV) of 91% and a negative predictive value (NPV) of 30%. A new cut‐off value >26 improved Se (73%) but decreased Sp (60%) (PPV of 84% and a NPV of 43%). ION performed slightly better in obese NAFLD (AUROC = 0.700). The combination of ION and markers of fibrosis did not improve the identification of advanced liver disease. Conclusions: ION is not feasible for the non‐invasive diagnosis of NASH across different populations of NAFLD patients, mainly because its limited reproducibility in non‐obese subjects. [ABSTRACT FROM AUTHOR]

Many studies showed insulin resistance amelioration in HCV-patients achieving Sustained Virologic Response (SVR) but results on glycemic control in diabetic patients are unclear. This study aimed to assess fasting glucose (FG) and glycated hemoglobin (HbA1c) values before and after therapy with direct-acting antivirals (DAAs) in HCV-patients with type 2 diabetes mellitus (T2DM). Of the 122 consecutively recruited patients with chronic hepatitis C and T2DM, 110 patients were treated with DAAs and 12 remained untreated. Clinical, biochemical, virological, and metabolic features were collected both at baseline and at 12 weeks after the end of therapy (EOT) or after a comparable period of time in untreated patients. A total of 101 patients obtained a SVR (Group 1), while nine were relapsers. Group 2 (21 patients) was composed by the nine relapsers and the 12 untreated patients. A significant reduction of mean FG (134.3 ± 41.32 mg/dL vs 152.4 ± 56.40 mg/dL, P = 0.002) and HbA1c values (46.51 ± 16.15 mmoL/moL vs 52.15 ± 15.43 mmoL/moL, P < 0.001) was found in Group 1 but not in Group 2 (140.6 ± 47.87 mg/dL vs. 145.31 ± 30.18 mg/dL, P = 0.707, and 55.31 ± 20.58 mmoL/moL vs. 53.38 ± 9.49 mmoL/moL, P = 0.780). In Group 1, 20.7% of patients could reduce or suspend their antidiabetic therapy compared to none in Group 2 ( P = 0.03), despite the significant weight increase observed in Group 1. SVR induced a significant amelioration of glycemic control in diabetic HCV-patients, despite a significant weight increase; larger prospective studies are needed to verify whether these results are maintained over the long-term. [ABSTRACT FROM AUTHOR]

Background & Aims Metabolic syndrome ( MS) and its individual components are associated with the severity and progression of nonalcoholic fatty liver disease ( NAFLD). We sought to evaluate the relationship between MS components and the risk of severe hepatic fibrosis in NAFLD patients discriminated by age. Methods We considered 863 consecutive patients with biopsy-proven NAFLD, who had been fully evaluated for components of MS. Results Multivariate logistic regression analysis showed that F3-F4 was associated with visceral obesity, IFG/diabetes, and low high-density lipoprotein ( HDL) cholesterol, but not triglycerides >150 or arterial hypertension. A significant interaction was found between age and visceral obesity ( P=.04). By stratifying patients for age, we confirmed the interaction between inclusion in the third age tertile (>54 years) and visceral obesity ( P=.04). In the lower (<41 years) and middle (41-54 years) age tertiles, the risk for F3-F4 fibrosis was mostly driven by visceral obesity and IFG/diabetes. This risk was higher in those with all three metabolic risk factors. Finally, among patients in the higher age tertile (>54 years), obesity did not affect the severity of fibrosis, and the risk of severe fibrosis was higher in those with low HDL and IFG/diabetes with/without visceral obesity (52%-54%). Conclusions Among patients with NAFLD, the metabolic profiles associated with risk for severe fibrosis varied among age groups. Low HDL, obesity and IFG/diabetes were prevalent among patients in the lower and middle age tertiles. HDL and IFG/diabetes but not visceral obesity were prevalent among those in the highest age tertile. [ABSTRACT FROM AUTHOR]

Growing epidemiological evidence suggests that nonalcoholic fatty liver disease (NAFLD) is an early predictor of and determinant for the development of type 2 diabetes and other features of the metabolic syndrome. This finding may have important clinical implications for the diagnosis, prevention and treatment of type 2 diabetes and its chronic complications. However, given the complex and bi-directional relationships between NAFLD, insulin resistance and chronic hyperglycaemia, it is extremely difficult to distinguish whether NAFLD is a cause or a consequence of insulin resistance and type 2 diabetes. Indeed, at the molecular level, hepatic lipogenesis and hepatic glucose production depend on differentially regulated branches of the insulin signalling pathway. Furthermore, genetic studies suggest that excess hepatic fat is associated with progressive liver disease, but does not always increase the risk of incident type 2 diabetes. Here, we will briefly review the epidemiological, pathophysiological and molecular evidence linking NAFLD to the development of type 2 diabetes. We will also discuss some recent genetic and therapeutic advances that seem to challenge a causal role of NAFLD in the pathogenesis type 2 diabetes, and propose a working hypothesis to explain this apparent conundrum. In conclusion, progressive liver disease and type 2 diabetes are divergent though inter-related consequences of insulin resistance and the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Background & Aims Macrophage activation plays a key pathogenic role in experimental non-alcoholic fatty liver disease ( NAFLD) and contributes to the progression of steatohepatitis ( NASH) and fibrosis. We studied macrophage activation in human NAFLD by measuring soluble (s) CD163, a specific macrophage activation marker, hypothesizing that sCD163 would be associated with the patients' morphological disease grade. Furthermore, we investigated an association between sCD163 and the apoptosis marker cytokeratin-18 ( CK-18) to explore a link between macrophage activation and apoptosis. Methods sCD163 associations with biochemical and histological measures of NAFLD were investigated in two independent cohorts of 157 Australian and 174 Italian NAFLD patients, with liver biopsies graded for NAFLD severity, steatosis and fibrosis. sCD163 and CK-18 were measured by enzyme-linked immunosorbent assay. Results In both cohorts sCD163 increased in parallel with the patients' morphological disease grading, being independently associated with the Kleiner fibrosis score ( P < 0.001). A high sCD163 predicted advanced fibrosis {F ≥ 3; Australian cohort: area under receiver-operating characteristics curve 0.77 [95% confidence interval ( CI): 0.76-0.87], Italian cohort: 0.80 (95% CI: 0.72-0.88)}. In both groups, sCD163 was independently associated with CK-18 ( P < 0.001). Conclusion Soluble CD163 reflecting macrophage activation is associated with morphological features of NAFLD suggesting their involvement in the pathogenesis of NAFLD, NASH and particularly fibrosis. An independent association between sCD163 and cytokeratin-18 suggests that apoptosis may contribute to macrophage activation in NAFLD/ NASH. [ABSTRACT FROM AUTHOR]

Background & Aims We elaborate a non-invasive score system for liver fibrosis ( NISF), exploring its diagnostic performance and comparing its accuracy to FibroScan in patients with chronic viral hepatitis ( CH) and non-alcoholic fatty liver disease ( NAFLD). Methods Clinical, biochemical, elastographic and ultrasound parameters derived from patients with CH ( n = 83) or NAFLD ( n = 58), undergoing liver biopsy for fibrosis assessment, were prospectively collected as potential predictors of fibrosis. Each parameter was evaluated for its correlation with the liver biopsy (Gold Standard). Candidate predictors with good interobserver agreement and correlation with histological stages were combined into two algorithms ( NISF) to predict fibrosis in chronic viral hepatitis and NAFLD. Results The CH- NISF included six parameters: bluntness of liver edges, irregularity of left lobe surface, diameter of segment 4, liver stiffness measurement, platelet count and ALT values. The ability of the model to discriminate F3-F4 vs F0-F1 stages and F2 vs F0-F1 was high ( AUROC of 0.95 and 0.83 respectively) and better than FibroScan alone, especially in intermediate stages (F2 vs F0-F1), AUROC 0.83 vs 0.57 ( P = 0.003). The resulting algorithm is available as mathematical formula, nomogram or free online link. [] The NAFLD- NISF included liver stiffness, platelet count and AST levels, had good ability to discriminate F0-F1 vs F2-F3-F4 stages ( AUROC 0.86), however, not significantly higher than FibroScan. Conclusions CH- NISF can be proposed as preliminary and easily available staging tool, superior to FibroScan alone in predicting histological fibrosis, especially in intermediate stages. Further validations are needed to improve NISF accuracy in NAFLD. [ABSTRACT FROM AUTHOR]

Background & Aims The accuracy of noninvasive tools for the diagnosis of severe fibrosis in patients with nonalcoholic fatty liver disease( NAFLD) in clinical practice is still limited. We aimed at assessing the diagnostic performance of combined noninvasive tools in two independent cohorts of Italian NAFLD patients. Methods We analysed data from 321 Italian patients(179 Sicilian-training cohort, and 142 northern Italy-validation cohort) with an histological diagnosis of NAFLD. Severe fibrosis was defined as fibrosis ≥ F3 according to Kleiner classification. The APRI, AST/ ALT, BARD, FIB-4, and NFS scores were calculated according to published algorithms. Liver stiffness measurement( LSM) was performed by FibroScan. Cut-off points of LSM, NFS and FIB-4 for rule-in or rule-out F3-F4 fibrosis were calculated by the reported formulas. Results In the Sicilian cohort AUCs of LSM, NFS, FIB-4, LSM plus NFS, LSM plus FIB-4, and NFS plus FIB-4 were 0.857, 0.803, 0.790, 0.878, 0.888 and 0.807, respectively, while in the northern Italy cohort the corresponding AUCs were 0.848, 0.730, 0.703, 0.844, 0.850, and 0.733 respectively. In the training cohort, the combination of LSM plus NFS was the best performing strategy, providing false positive, false negative and uncertainty area rates of 0%,1.1% and 48% respectively. Similar results were obtained in the validation cohort with false positive, false negative and uncertainty area rates of 0%,7.3% and 40.8%. Conclusions The combination of LSM with NFS, two complementary, easy-to-perform, and widely available tools, is able to accurately diagnose or exclude the presence of severe liver fibrosis, also reducing of about 50-60% the number of needed diagnostic liver biopsies. [ABSTRACT FROM AUTHOR]

Background and Aim Oxidative stress is considered a key element in the progression of non-alcoholic fatty liver to non-alcoholic steatohepatitis ( NASH). Unconjugated bilirubin is the main endogenous lipid antioxidant and is cytoprotective in different tissues and organs. In this study, it was evaluated if unconjugated bilirubin levels are associated with the degree of liver injury in patients with non-alcoholic fatty liver disease. Methods Two hundred and eighty-five patients were retrospectively evaluated with biopsy-confirmed non-alcoholic fatty liver disease. Multiple logistic regression models were used to assess the relationship of steatosis, inflammation, and fibrosis levels to the features of patients. Results Unconjugated bilirubin levels differed significantly according to inflammation and fibrosis scores. Unconjugated bilirubin was lower in patients with moderate-severe inflammation compared with those with absent-mild ( P = 0.001) and in patients with moderate-severe fibrosis compared with those with absent-mild ( P < 0.001), whereas no difference was observed for steatosis grades. At logistic regression analysis, low unconjugated bilirubin levels were associated with moderate-severe inflammation (odds ratio, 0.11; 95% confidence interval 0.02-0.76; P = 0.025) and moderate-severe fibrosis (odds ratio, 0.013; 95% confidence interval 0.001-0.253; P = 0.004). Conclusions Low unconjugated bilirubin levels are independent predictors of advanced inflammation and fibrosis in patients with steatohepatitis, indicating the lack of antioxidant protection as a possible molecular determinant for the progression of liver injury. [ABSTRACT FROM AUTHOR]

Background and Aim: Significant hepatic fibrosis is prognostic of liver morbidity and mortality in non-alcoholic fatty liver disease (NAFLD); however, it remains unclear whether non-invasive fibrosis models can determine this end-point. We therefore compared the accuracy of simple bedside versus complex fibrosis models across a range of fibrosis in a multi-centre NAFLD cohort. Methods: Simple (APRI, BARD) and complex (Hepascore, Fibrotest, FIB4) fibrosis models were calculated in 242 NAFLD subjects undergoing liver biopsy. Significant (F2-4) and advanced fibrosis (F3,4) were defined using Kleiner criteria. Models were compared using area under the receiver operator characteristic curves (AUC). Cut-offs were determined by Youden Index or 90% predictive values. Results: For significant fibrosis, non-invasive fibrosis models had modest accuracy (AUC 0.707-0.743) with BARD being least accurate (AUC 0.609, P < 0.05 vs others). Using single cut-offs, sensitivities and predictive values were < 80%; using two cut-offs, > 75% of subjects fell within indeterminate ranges. Simple models had significantly more subjects within indeterminate ranges than complex models (99.1-100% vs 82.1-84.4% respectively, P < 0.05 for all). For advanced fibrosis, complex models were more accurate than BARD (AUC 0.802-0.858 vs 0.701, P < 0.05). Using two cut-offs, complex models had fewer individuals within indeterminate ranges than BARD (11.1-32.3% vs 70.7%, P < 0.01 for all). For cirrhosis, complex models had higher AUC values than simple models. Conclusions: In NAFLD subjects, non-invasive models have modest accuracy for determining significant fibrosis and have predictive values less than 90% in the majority of subjects. Complex models are more accurate than simple bedside models across a range of fibrosis. [ABSTRACT FROM AUTHOR]

The effectiveness of cognitive-behavior treatment (CBT) in nonalcoholic fatty liver disease (NAFLD), largely related to overweight/obesity and considered the hepatic expression of the metabolic syndrome (MS), has so far been tested in very limited samples. In a tertiary referral center, consecutively observed NAFLD subjects were offered a CBT program aimed at weight loss and increased physical activity, based on 13 group sessions; 68 cases entered the treatment protocol, those who refused (n = 82) were given recommendations for diet and physical activity. Treatment goals (weight loss ≥7% initial body weight, normalization of liver enzymes, and improved parameters of MS) were tested by logistic regression at 6 months (all cases) and at 2 years, both on intention-to-treat and in completers (Diet, 78; CBT, 65). The results were adjusted for the propensity score of attending the CBT program, based on civil, anthropometric and clinical variables. At baseline the CBT group had a larger prevalence of obesity and more severe insulin resistance (homeostasis model assessment (HOMA)). At follow-up, CBT was associated with a higher probability of weight loss and normal liver enzymes (6-month: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.15-5.69; 2-year intention-to-treat: OR, 3.57, 95% CI, 1.59-8.00), after adjustment for propensity and changes in body weight. A similar trend was observed in the outcome goals of insulin resistance and the score of MS, which were both reduced. In conclusion, subjects with NAFLD participating in a CBT program significantly improve their general and liver parameters. The beneficial effects are largely maintained at 2-year follow-up, in keeping with the lifestyle-related pathogenesis of disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusion Trial Registration Semaglutide, a glucagon‐like peptide‐1 receptor agonist, has demonstrated potential beneficial effects in metabolic dysfunction‐associated steatohepatitis (MASH).To describe the trial design and baseline characteristics of the ‘Effect of Semaglutide in Subjects with Non‐cirrhotic Non‐alcoholic Steatohepatitis’ (ESSENCE) trial (NCT04822181).ESSENCE is a two‐part, phase 3, randomised, multicentre trial evaluating the effect of subcutaneous semaglutide 2.4 mg in participants with biopsy‐proven MASH and fibrosis stage 2 or 3. The primary objective of Part 1 is to demonstrate that semaglutide improves liver histology compared with placebo. The two primary endpoints are: resolution of steatohepatitis and no worsening of liver fibrosis, and improvement in liver fibrosis and no worsening of steatohepatitis. The Part 2 objective is based on clinical outcomes. The current work reports baseline characteristics of the first 800 randomised participants which includes demographics, laboratory parameters, liver histology, non‐invasive tests and presence of metabolic dysfunction‐associated steatotic liver disease (MASLD) cardiometabolic criteria.Of 800 participants, 250 (31.3%) had fibrosis stage 2 and 550 (68.8%) had fibrosis stage 3. In the overall population, mean (standard deviation [SD]) age was 56 (11.6) years, 57.1% were female, mean (SD) body mass index was 34.6 (7.2) kg/m2, 55.5% had type 2 diabetes and > 99% had at least one MASLD cardiometabolic criterion according to the published definition.The ESSENCE baseline population includes participants with clinically significant fibrosis stages 2 and 3. Although MASLD cardiometabolic criteria were not a requirement for study enrolment, almost all participants (> 99%) had at least one MASLD cardiometabolic criterion.NCT04822181 [ABSTRACT FROM AUTHOR]

ABSTRACT: Previous studies have shown that hepatic function, quantitatively measured by dynamic liver function tests, progressively declines with ageing. Urea synthesis is a specific process taking place in the liver; a reduced urea synthesis in response to a protein-rich metal has previously been demonstrated in the elderly, but the process has never been standardized in relation to amino acid supply. We measured the hepatic conversion of α-amino nitrogen into urea nitrogen in response to alanine infusion in 32 subjects, with normal routine liver and renal function tests and without evidence of previous hepatic disorders, belonging to three different age-groups (≤55 years, 56-70, ≥71). The functional hepatic nitrogen clearance was reduced on average by 20% in subjects aged 56-70 years, and by 30% in subjects over 70 years old in comparison to the age-group under 55 years (ANOVA: P=0.0001), and significantly correlated with age (r=-0.684). No sex differences were observed on the effects of age on hepatic clearance. Also, liver volume, measured by ultrasonography, was reduced with advancing age, but the age-related decrease in hepatic nitrogen conversion was not primarily dependent on decreased liver volume. The measurement of functional hepatic nitrogen clearance has already been validated as a quantitative liver function test in clinical hepatology. In keeping with previous studies, the age-related deceline in hepatic nitrogen conversion points to a decreased functional capacity of the ageing hepatic parenchyma. [ABSTRACT FROM AUTHOR]

ABSTRACT- The prognosis of cirrhotic patients may depend on their liver function, but very few data are available to predict life expectancy in individual subjects on the basis of their liver function tests. The yearly changes in liver function, based on galactose elimination capacity (GEC), were retrospectively analyzed in 76 cirrhotic patients. The first GEC measurement had always been performed at the time of diagnosis. From that time on, mean GEC changes (in mmol/min per year) were +0.13 [SD 0.60] in the 1st year (range: +1.42/ -1.35), and -0.03 [0.30] in the 2nd year (P = ns). Only after 36 months could a significant deterioration in liver function be demonstrated, but GEC changes still ranged from +0.14 to -0.35. The trend in liver function was similar in patients with alcoholic and non-alcoholic cirrhosis, but in alcoholics a favourable effect of abstinence was proved. In individual subjects, 2 consecutive GEC measurements, at least 6 months apart, failed to predict the following GEC values. The coefficients of determination between expected and measured GEC or ΔGEC were 0.13 and 0.36, respectively (n = 58). When forecasting was limited to 2 years (n = 38), still only 31% and 55% of GEC values and ΔGEC variance was predictable on the basis of preceding GEC values. The study shows that no definite trends in liver function deterioration rates can be observed in cirrhosis. This limits the usefulness of liver function tests in predicting prognosis in cirrhotic patients. [ABSTRACT FROM AUTHOR]