Autophagy in Non-Alcoholic Fatty Liver Disease (NAFLD)

Autophagy is a mechanism involved in cellular homeostasis under basal and stressed conditions delivering cytoplasmic content to the lysosomes for degradation to macronutrients. The potential role of autophagy in disease is increasingly recognised and investigated. To date, a key role of autophagy in hepatic lipid metabolism is recognised and dysfunctional autophagy might be an underlying cause of non-alcoholic fatty liver disease (NAFLD). Nevertheless, the exact role of autophagy in lipid metabolism remains controversial, with both a lipolytic function of autophagy and lipogenic function reported. This chapter aims to review the current knowledge on autophagy in NAFLD, with a special focus on its role in hepatic lipid metabolism, hepatic glucose metabolism and insulin resistance, steatohepatitis, hepatocellular injury and hepatic fibrogenesis. Finally, interaction with another cellular homeostatic process, the unfolded protein response (UPR), will be briefly discussed

A multistakeholder approach to innovations in NAFLD care

Non-alcoholic fatty liver disease (NAFLD) is highly prevalent globally and requires multidisciplinary care. Here, we report key findings of a NAFLD care workshop, address knowledge gaps and highlight a path to optimise healthcare resource use, to improve outcomes in patients with steatotic liver disease

The Differential Roles of T Cells in Non-alcoholic Fatty Liver Disease and Obesity

Non-alcoholic fatty liver disease (NAFLD) constitutes a spectrum of disease states characterized by hepatic steatosis and is closely associated to obesity and the metabolic syndrome. In non-alcoholic steatohepatitis (NASH), additionally, inflammatory changes and hepatocellular damage are present, representing a more severe condition, for which the treatment is an unmet medical need. Pathophysiologically, the immune system is one of the main drivers of NAFLD progression and other obesity-related comorbidities, and both the innate and adaptive immune system are involved. T cells form the cellular component of the adaptive immune system and consist of multiple differentially active subsets, i.e., T helper (Th) cells, regulatory T (Treg) cells, and cytotoxic T (Tc) cells, as well as several innate T-cell subsets. This review focuses on the role of these T-cell subsets in the pathogenesis of NAFLD, as well as the association with obesity and type 2 diabetes mellitus, reviewing the available evidence from both animal and human studies. Briefly, Th1, Th2, Th17, and Th22 cells seem to have an attenuating effect on adiposity. Th2, Th22, and Treg cells seem to decrease insulin resistance, whereas Th1, Th17, and Tc cells have an aggravating effect. Concerning NAFLD, both Th22 and Treg cells appear to have an overall tempering effect, whereas Th17 and Tc cells seem to induce more liver damage and fibrosis progression. The evidence regarding the role of the innate T-cell subsets is more controversial and warrants further exploration

Sorted B cell transcriptomes point towards actively regulated B cell responses during ongoing chronic hepatitis B infections

The natural course of chronic hepatitis B virus (HBV) infections follows distinct clinical disease phases, char-acterized by fluctuating levels of serum HBV DNA and ALT. The immune cells and their features that govern these clinical disease transitions remain unknown. In the current study, we performed RNA sequencing on pu-rified B cells from blood (n = 42) and liver (n = 10) of healthy controls and chronic HBV patients. We found distinct gene expression profiles between healthy controls and chronic HBV patients, as evidenced by 190 differentially expressed genes (DEG), but also between the clinical phenotypes of a chronic HBV infection (17?110 DEG between each phase). Numerous immune pathways, including the B cell receptor pathway were upregulated in liver B cells when compared to peripheral B cells. Further investigation of the detected DEG suggested an activation of B cells during HBeAg seroconversion and an active regulation of B cell signalling in the liver

Real-world evidence on non-invasive tests and associated cut-offs used to assess fibrosis in routine clinical practice

Background & Aims: Non-invasive tests (NITs) offer a practical solution for advanced fibrosis identification in non-alcoholic fatty liver disease (NAFLD). Despite increasing implementation, their use is not standardised, which can lead to inconsistent interpretation and risk stratification. We aimed to assess the types of NITs and the corresponding cut-offs used in a range of healthcare settings. Methods: A survey was distributed to a convenience sample of liver health experts who participated in a global NAFLD consensus statement. Respondents provided information on the NITs used in their clinic with the corresponding cut-offs and those used in established care pathways in their areas. Results: There were 35 respondents from 24 countries, 89% of whom practised in tertiary level settings. A total of 14 different NITs were used, and each respondent reported using at least one (median = 3). Of the respondents, 80% reported using FIB-4 and liver stiffness by vibration-controlled transient elastography (Fibroscan®), followed by the NAFLD fibrosis score (49%). For FIB-4, 71% of respondents used a low cut-off of <1.3 (range <1.0 to <1.45) and 21% reported using age-specific cut-offs. For Fibroscan®, 21% of respondents used a single liver stiffness cut-off: 8 kPa in 50%, while the rest used 7.2 kPa, 7.8 kPa and 8.7 kPa. Among the 63% of respondents who used lower and upper liver stiffness cut-offs, there were variations in both values (7.5 to >20 kPa, respectively). Conclusions: The cut-offs used for the same NITs for NAFLD risk stratification vary between clinicians. As cut-offs impact test performance, these findings underscore the heterogeneity in risk-assessment and support the importance of establishing consistent guidelines on the standardised use of NITs in NAFLD management. Lay summary: Owing to the high prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population it is important to identify those who have more advanced stages of liver fibrosis, so that they can be properly treated. Noninvasive tests (NITs) provide a practical way to assess fibrosis risk in patients. However, we found that the cut-offs used for the same NITs vary between clinicians. As cut-offs impact test performance, these findings highlight the importance of establishing consistent guidelines on the standardised use of NITs to optimise clinical management of NAFLD

Machine learning approaches to enhance diagnosis and staging of patients with MASLD using routinely available clinical information

Aims: Metabolic dysfunction Associated Steatotic Liver Disease (MASLD) outcomes such as MASH (metabolic dysfunction associated steatohepatitis), fibrosis and cirrhosis are ordinarily determined by resource-intensive and invasive biopsies. We aim to show that routine clinical tests offer sufficient information to predict these endpoints. Methods: Using the LITMUS Metacohort derived from the European NAFLD Registry, the largest MASLD dataset in Europe, we create three combinations of features which vary in degree of procurement including a 19-variable feature set that are attained through a routine clinical appointment or blood test. This data was used to train predictive models using supervised machine learning (ML) algorithm XGBoost, alongside missing imputation technique MICE and class balancing algorithm SMOTE. Shapley Additive exPlanations (SHAP) were added to determine relative importance for each clinical variable. Results: Analysing nine biopsy-derived MASLD outcomes of cohort size ranging between 5385 and 6673 subjects, we were able to predict individuals at training set AUCs ranging from 0.719-0.994, including classifying individuals who are At-Risk MASH at an AUC = 0.899. Using two further feature combinations of 26-variables and 35-variables, which included composite scores known to be good indicators for MASLD endpoints and advanced specialist tests, we found predictive performance did not sufficiently improve. We are also able to present local and global explanations for each ML model, offering clinicians interpretability without the expense of worsening predictive performance. Conclusions: This study developed a series of ML models of accuracy ranging from 71.9—99.4% using only easily extractable and readily available information in predicting MASLD outcomes which are usually determined through highly invasive means

Age as a Confounding Factor for the Accurate Non-Invasive Diagnosis of Advanced NAFLD Fibrosis.

OBJECTIVES Non-invasive fibrosis scores are widely used to identify/exclude advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). However, these scores were principally developed and validated in patients aged between 35 and 65 years of age. The objective of this study was to assess the effect of age on the performance of non-invasive fibrosis tests in NAFLD. METHODS Patients were recruited from European specialist hepatology clinics. The cohort was divided into five age-based groups: ≤35 (n=74), 36-45 (n=96), 46-55 (n=197), 56-64 (n=191), and ≥65 years (n=76), and the performance of the aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio, fibrosis 4 (FIB-4), and NAFLD fibrosis score (NFS) for advanced fibrosis (stage F3-F4) for each group was assessed using liver biopsy as the standard. RESULTS Six hundred and thirty-four patients were included. The diagnostic accuracy of the AST/ALT ratio was lower than NFS and FIB-4 in all the age groups. The AST/ALT ratio, NFS, and FIB-4 score performed poorly for a diagnosis of advanced fibrosis in those aged ≤35 years (area under the receiver operating characteristic curves (AUROCs 0.52, 0.52, and 0.60, respectively). For all groups >35 years, AUROCs for advanced fibrosis were similar for the NFS and FIB-4 score (range 0.77-0.84). However, the specificity for advanced fibrosis using the FIB-4 and NFS declined with age, becoming unacceptably low in those aged ≥65 years (35% for FIB-4 and 20% for NFS). New cutoffs were derived (and validated) for those aged ≥65 years, which improved specificity to 70% without adversely affecting sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%). CONCLUSIONS The NFS and FIB-4 scores have similar accuracy for advanced fibrosis in patients aged >35 years. However, the specificity for advanced fibrosis is unacceptably low in patients aged ≥65 years, resulting in a high false positive rate. New thresholds for use in patients aged ≥65 years are proposed to address this issue.Am J Gastroenterol advance online publication, 11 October 2016; doi:10.1038/ajg.2016.453