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Objectives: The aim of this study was to investigate the role of reduced lecithin: cholesterol acyltransferase (LCAT) function on atherogenesis using 3.0-T carotid magnetic resonance imaging (MRI) and B-mode ultrasound. Background: The role of low high-density lipoprotein cholesterol as a causal factor in atherogenesis has recently been questioned. LCAT plays a key role in high-density lipoprotein cholesterol metabolism. Methods: Carotid 3.0-T MRI and B-mode ultrasound measurements were performed in 40 carriers of LCAT gene mutations and 40 controls, matched for age. Patients with cardiovascular disease were excluded. Results: Carriers had 31% lower LCAT activity levels and 38% decreased high-density lipoprotein cholesterol levels (both p < 0.001 vs. controls). Carriers presented with a 10% higher normalized wall index (0.34 ± 0.07 vs. 0.31 ± 0.04, p = 0.002), a 22% higher mean wall area (17.3 ± 8.5 mm(2) vs. 14.2 ± 4.1 mm(2), p = 0.01), and a 22% higher total wall volume (1,039 ± 508 mm(3) vs. 851 ± 247 mm(3), p = 0.01 vs. controls) as measured by MRI. The prevalence (20 vs. 5, p = 0.002) and the total volume (102 mm(3) vs. 3 mm(3)) of atherosclerotic plaque components on MRI relating to lipid-rich tissue or calcification were also higher in carriers than in controls. All differences retained significance after adjustment for age, sex, blood pressure, low-density lipoprotein cholesterol, body mass index, smoking, and family history of cardiovascular disease. Common carotid intima-media thickness measured with ultrasound was increased in carriers by 12.5% (0.72 ± 0.33 mm vs. 0.64 ± 0.15 mm, p = 0.14). Conclusions: Carriers of LCAT gene mutations exhibit increased carotid atherosclerosis, indicating an increased risk of cardiovascular disease. The present findings imply that increasing LCAT activity may be an attractive target in cardiovascular prevention strategies. [ABSTRACT FROM AUTHOR]

Background & Aims: There is a need to reduce the screen failure rate (SFR) in metabolic dysfunction-associated steatohepatitis (MASH) clinical trials (MASH+F2-3; MASH+F4) and identify people with high-risk MASH (MASH+F2-4) in clinical practice. We aimed to evaluate non-invasive tests (NITs) screening approaches for these target conditions., Methods: This was an individual participant data meta-analysis for the performance of NITs against liver biopsy for MASH+F2-4, MASH+F2-3 and MASH+F4. Index tests were the FibroScan-AST (FAST) score, liver stiffness measured using vibration-controlled transient elastography (LSM-VCTE), the fibrosis-4 score (FIB-4) and the NAFLD fibrosis score (NFS). Area under the receiver operating characteristics curve (AUROC) and thresholds including those that achieved 34% SFR were reported., Results: We included 2281 unique cases. The prevalence of MASH+F2-4, MASH+F2-3 and MASH+F4 was 31%, 24% and 7%, respectively. Area under the receiver operating characteristics curves for MASH+F2-4 were .78, .75, .68 and .57 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F2-3 were .73, .67, .60, .58 for FAST, LSM-VCTE, FIB-4 and NFS. Area under the receiver operating characteristics curves for MASH+F4 were .79, .84, .81, .76 for FAST, LSM-VCTE, FIB-4 and NFS. The sequential combination of FIB-4 and LSM-VCTE for the detection of MASH+F2-3 with threshold of .7 and 3.48, and 5.9 and 20 kPa achieved SFR of 67% and sensitivity of 60%, detecting 15 true positive cases from a theoretical group of 100 participants at the prevalence of 24%., Conclusions: Sequential combinations of NITs do not compromise diagnostic performance and may reduce resource utilisation through the need of fewer LSM-VCTE examinations., (© 2024 The Authors. Liver International published by John Wiley & Sons Ltd.)

Accurate non-invasive biomarkers to diagnose metabolic dysfunction-associated steatotic liver disease (MASLD)-related fibrosis are urgently needed. This study applies a translational approach to develop a blood-based biomarker panel for fibrosis detection in MASLD. A molecular gene expression signature identified from a diet-induced MASLD mouse model (LDLr-/-.Leiden) is translated into human blood-based biomarkers based on liver biopsy transcriptomic profiles and protein levels in MASLD patient serum samples. The resulting biomarker panel consists of IGFBP7, SSc5D and Sema4D. LightGBM modeling using this panel demonstrates high accuracy in predicting MASLD fibrosis stage (F0/F1: AUC = 0.82; F2: AUC = 0.89; F3/F4: AUC = 0.87), which is replicated in an independent validation cohort. The overall accuracy of the model outperforms predictions by the existing markers Fib-4, APRI and FibroScan. In conclusion, here we show a disease mechanism-related blood-based biomarker panel with three biomarkers which is able to identify MASLD patients with mild or advanced hepatic fibrosis with high accuracy., (© 2024. The Author(s).)

Aims/hypothesis: The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in type 1 diabetes remain unclear. Therefore, we investigated the prevalence and severity of MASLD in type 1 diabetes and assessed which clinical features are most important in predicting MASLD severity., Methods: A total of 453 individuals with type 1 diabetes (41.6 ± 15.0 years, 64% female, body mass index [BMI] 25.4 ± 4.2 kg/m2, and HbA1c 55.6 ± 12 mmol/mol) underwent vibration-controlled transient elastography (VCTE), with a controlled attenuation parameter (CAP) score for steatosis (≥280.0 dB/m) and a liver stiffness measurement (LMS) for fibrosis (≥8.0 kPa). A machine learning Extra-Trees classification model was performed to assess the predictive power of the clinical features associated with type 1 diabetes with respect to steatosis and fibrosis., Results: The prevalence of hepatic steatosis and fibrosis was 9.5% (95% CI, 6.8-12.2) and 3.5% (95% CI, 1.8-5.2). Higher LMS was associated with a longer duration of type 1 diabetes (median 30.5 [IQR 18.0-39.3] years vs 15.0 [IQR 6.0-27.0] years), and individuals were older, had a higher BMI (mean 27.8 ± 5.2 vs 25.3 ± 4.1 kg/m2), and a higher CAP score (mean 211.4 ± 51.7 dB/m vs 241.4 ± 75.6 dB/m). The most important predictive features of fibrosis were duration of type 1 diabetes, age, and systolic blood pressure, with a mean ± SD area under the curve of 0.73 ± 0.03., Conclusion: Individuals with type 1 diabetes and high blood pressure, older age, higher BMI, and longer duration of disease could be considered at high-risk for developing MASLD., Competing Interests: Conflict of interest: C.M.F.S., A.S.M, P.d.G., and E.R. have no conflicts of interest to disclose. M.N. is in the Scientific Advisory Board of Caelus Pharmaceuticals, in The Netherlands. D.H.v.R. has acted as a consultant for and received honoraria from Boehringer Ingelheim-Eli Lilly Alliance, Merck, Sanofi, and AstraZeneca and has received research operating funds from Boehringer Ingelheim-Lilly Diabetes Alliance, AstraZeneca, and Merck. All honoraria are paid to his employer. N.M.J.H. has received honoraria from Boehringer Ingelheim and Novo Nordisk. A.G.H. reports support from Novo Nordisk, Inventiva, and Julius Clinical. F.K.K. has served on scientific advisory panels and/or been part of speaker’s bureaus for, served as a consultant to, and/or received research support from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly, Gubra, MedImmune, MSD/Merck, Mundipharma, Norgine, Novo Nordisk, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara and is a cofounder and minority shareholder of Antag Therapeutics. Moreover, F.K.K. is on the editorial board of EJE. He was not involved in the review or editorial process for this paper, on which he is listed as author. Overall, none of these are relevant for the current manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a growing health problem for which no therapy exists to date. The modulation of the gut microbiome may have treatment potential for MASLD. Here, we investigated Anaerobutyricum soehngenii , a butyrate-producing anaerobic bacterium with beneficial effects in metabolic syndrome, in a diet-induced MASLD mouse model. Male C57BL/6J mice received a Western-type high-fat diet and water with 15% fructose (WDF) to induce MASLD and were gavaged with A. soehngenii (10 8 or 10 9 colony-forming units (CFU) 3 times per week) or a placebo for 6 weeks. The A. soehngenii gavage increased the cecal butyrate concentrations. Although there was no effect on histological MASLD scores, A. soehngenii improved the glycemic response to insulin. In the liver, the WDF-associated altered expression of three genes relevant to the MASLD pathophysiology was reversed upon treatment with A. soehngenii : Lipin-1 ( Lpin1 ), insulin-like growth factor binding protein 1 ( Igfbp1 ) and Interleukin 1 Receptor Type 1 ( Il1r1 ). A. soehngenii administration also increased the intestinal expression of gluconeogenesis and fructolysis genes. Although these effects did not translate into significant histological improvements in MASLD, these results provide a basis for combined gut microbial approaches to induce histological improvements in MASLD.

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., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Quentin M. Anstee has received research grant funding from AstraZeneca, Boehringer Ingelheim, and Intercept Pharmaceuticals, Inc.; has served as a consultant on behalf of Newcastle University for Alimentiv, Akero, AstraZeneca, Axcella, 89bio, Boehringer Ingelheim, Bristol Myers Squibb, Galmed, Genfit, Genentech, Gilead, GSK, Hanmi, HistoIndex, Intercept Pharmaceuticals, Inc., Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGM Bio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI, Shionogi, and Terns; has served as a speaker for Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; and receives royalties from Elsevier Ltd. Jörn M. Schattenberg has served as consultant for Alentis Therapeutics, Astra Zeneca, Apollo Endosurgery, Bayer, Boehringer Ingelheim, Gilead Sciences, GSK, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers. Research Funding: Gilead Sciences, Boehringer Ingelheim, Siemens Healthcare GmbH. Stock Options: AGED diagnostics, Hepta Bio. Speaker Honorarium: Advanz, Echosens, MedPublico GmbH. Andreas Geier served as a speaker and consultant for AbbVie, Advanz, Alexion, AstraZeneca, Bayer, BMS, Burgerstein, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis; received research funding from Intercept, Falk, Novartis. Dina Tiniakos served as consultant on behalf of the University or for ICON, Merck Greece, Madrigal, Inventiva, Histoindex, Cymabay and Clinnovate. This does not alter our adherence to PLOS ONE policies on sharing data and materials. We are not opposed to any reviewers., (Copyright: © 2024 McTeer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further testing. However, liver enzymes within the normal range do not exclude the presence of MASLD. We examined the prevalence of MASLD in a middle-aged population with overweight and normal liver enzymes. In addition, we examined the accuracy of 4 sets of noninvasive proxies for MASLD. We included 1017 participants from the Netherlands epidemiology of obesity cohort study with body mass index ≥25 kg/m2 and liver enzymes (asparate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase) within normal range. The diagnostic accuracy of biomarker scores (fatty liver index, liver fat score [LFS], STEATO-ELSA, and hepatic steatosis index) was determined against elevated hepatic triglyceride content measured by 1proton magnetic resonance spectroscopy. Participants (mean age 56 years, 49% women), had a median body mass index of 29.6 kg/m2 and a median hepatic triglyceride content of 4.4%. MASLD was present in 42% of participants and was more common in men than women, with respectively 47% and 36% being affected. The LFS showed the highest accuracy with an area under the curve of 0.72. We identified metabolic syndrome as the prime predictor for MASLD with an odds ratio of 2.95 (95% confidence interval 2.20-3.98). The prevalence of MASLD in middle-aged men and women with overweight and liver enzymes within the normal range is over 40%. LFS showed the highest accuracy to detect MASLD, but, overall, biomarker scores performed relatively poor. The presence of metabolic syndrome was the prime predictor of MASLD., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

As morbidity and mortality related to potentially preventable liver diseases are on the rise globally, early detection of liver fibrosis offers a window of opportunity to prevent disease progression. Early detection of non-alcoholic fatty liver disease allows for initiation and reinforcement of guidance on bodyweight management, risk stratification for advanced liver fibrosis, and treatment optimisation of diabetes and other metabolic complications. Identification of alcohol-related liver disease provides the opportunity to support patients with detoxification and abstinence programmes. In all patient groups, identification of cirrhosis ensures that patients are enrolled in surveillance programmes for hepatocellular carcinoma and portal hypertension. When considering early detection strategies, success can be achieved from applying ad-hoc screening for liver fibrosis in established frameworks of care. Patients with type 2 diabetes are an important group to consider case findings of advanced liver fibrosis and cirrhosis, as up to 19% have advanced fibrosis (which is ten times higher than the general population) and almost 70% have non-alcoholic fatty liver disease. Additionally, patients with type 2 diabetes with alcohol use disorders have the highest proportion of liver-related morbidity of people with type 2 diabetes generally. Patients with type 2 diabetes receive an annual diabetes review as part of their routine clinical care, in which the health of many organs are considered. Yet, liver health is seldom included in this review. This Viewpoint argues that augmenting the existing risk stratification strategy with an additional liver health check provides the opportunity to detect advanced liver fibrosis, thereby opening a window for early interventions to prevent end-stage liver disease and its complications, including hepatocellular carcinoma., Competing Interests: Conflict of interests LV reports consulting fees from Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Intercept Pharmaceuticals, Diatech Pharmacogenetics, IONIS, and Boehringer Ingelheim; grant support from Gilead; and speaker fees from MSD, Gilead, AlfaSigma, AbbVie, and Viatris. JFD reports consulting fees from Intelligent Ultrasound and speaker fees for Gilead and GE systems. AMA reports consulting fees from NovoNordisk and grant support from Target, Novo Nordisk, and Pfizer. MN reports consulting fees from Altimmune, Cytodyn, 89bio, GlaxoSmithKline, Madrigal, Merck, Novo Nordisk, Northsea Therapeutics, Perspectum, Terns, and Takeda; grant support from Allergan, Akero, Bristol Myers Squibb, Gilead, Galectin, Genfit, GlaxoSmithKline, Conatus, Corcept, Enanta, Madrigal, Novartis, Novo Nordisk, Shire, Takeda, Terns, Viking, and Zydus; and stock options with Rivus Pharma, CIMA, Cytodyn, and ChronWell. MER reports consulting fees from Intercept Pharmaceuticals, Gilead Sciences, Genfit, NGM Biopharmaceuticals, Enanta, Immuron, Fractyl, Prociento, Gelesis, Merck, Bristol Myers Squibb, Metacrine, Viking Therapeutics, Allergan, Cymabay, Boehringer Ingelheim, Genentech, 89bio, Galecto, Terns, Sagimet, Thetis, Fractyl, Lipicine, GSK, Coherus, and Novartis. FT reports consulting fees for Allergan, AstraZeneca, Bayer, Gilead, Bristol Myers Squibb, Boehringer, Intercept, Ionis, Inventiva, Merz, Pfizer, Alnylam, NGM Biopharma, CSL Behring, Madrigal, Novo Nordisk, and Novartis; grant support from Allergan, Bristol Myers Squibb, Inventiva, and Gilead (funding to institution); speaker fees from Gilead, AbbVie, Falk, Merz, Intercept, Sanofi, and AstraZeneca; expert testimony for Alnylam; participation on a data safety monitoring board for Pfizer; and travel support from Gilead. SF reports consulting fees from AbbVie, Actelion, Aelin Therapeutics, Aligos Therapeutics, Allergan, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Meyers Squibb, CSL Behring, Coherus, Echosens, Eisai, Enyo, Galapagos, Galmed, Genentech, Genfit, Gilead Sciences, Intercept, Inventiva, Janssens Pharmaceutica, Julius Clinical, Madrigal, Medimmune, Merck Sharp & Dohme, NGM Bio, Novartis, Novo Nordisk, Promethera, and Roche; research grants from Astellas, Falk Pharma, Genfit, Gilead Sciences, GlympsBio, Janssens Pharmaceutica, Inventiva, Merck Sharp & Dohme, Pfizer, and Roche; and speaker fees from AbbVie, Allergan, Bayer, Eisai, Genfit, Gilead Sciences, Janssens Cilag, Intercept, Inventiva, Merck Sharp & Dohme, Novo Nordisk, and Promethera. MT reports speaker fees from Echosens and Siemens Healthcare. PNN reports consulting fees from Boehringer Ingelheim, Intercept, Madrigal, Bristol Myers Squibb, AstraZeneca, Gilead, Pfizer, GlaxoSmithKline, Novo Nordisk, Poxel Pharamceuticals, and Sun Pharma and grant support from Novo Nordisk. ING reports grant support from Gilead. JMS reports consulting fees from Apollo Endosurgery, Albireo Pharma, Bayer, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, Madrigal, MSD, Northsea Therapeutics, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, and Siemens Healthineers; grant support from Gilead Sciences, Boehringer Ingelheim, and Siemens Healthcare; and speaker fees from Boehringer Ingelheim, Echosens, MedPublico, Novo Nordisk, and Madrigal Pharmaceuticals. AB reports consulting fees from Inventiva and grant support from Boehringer Ingelheim. AGH reports consulting fees from Inventiva, Echosens, Novo Nordisk, Gilead, and Julius Clinical. CC reports consulting fees from Novo Nordisk, Gilead, AstraZeneca, Bayer, E-Scopics, Intercept, and Lilly; research support from Echosens, E-scopics, and Gilead; and speaker fees from Madrigal, AstraZeneca, Gilead, Novo Nordisk, Lilly, and LVL. KC reports consulting fees from Altimmune, Arrowhead, AstraZeneca, Boehringer Ingelheim, Covance, 89bio, Bristol Myers Squibb, Lilly, Madrigal, Merck, Myovant, Novo Nordisk, Prosciento, Quest, Sagimet, Sonic Incytes, and Terns and grant support from Echosens, Inventiva, Novo Nordisk, Nordic Bioscience, Poxel, Labcorp, and Zydus. MR reports consulting fees from Boehringer, Pfizer, Novo Nordisk, and Eli Lilly and grant support from Boehringer, Novo Nordisk, Nutricia Danone, and Sanofi. HH reports consulting fees from AstraZeneca and grant support from AstraZeneca, EchoSens, Gilead, Intercept, MSD, and Pfizer. VW-SW reports consulting fees from AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna; speaker fees from AbbVie, Gilead Sciences, Novo Nordisk, and Unilab; travel support from AbbVie and Gilead Sciences; grant support from Gilead Sciences; and stock options for Illuminatio Medical Technology. LC reports consulting fees from Echosens, Madrigal, MSD, Novo Nordisk, Pfizer, Sagimet, and Siemens Healthineers and speaker fees from Echosens, Inventiva, and Novo Nordisk. JVL reports grants and speaker fees from AbbVie, Gilead Sciences, MSD, and Roche Diagnostics and speaker fees from Intercept, Jannsen, Novo Nordisk, and ViiV, outside of the submitted work. EAT reports consulting fees from Alexion, Novo Nordisk, Pfizer, Boehringer, Orphalan, and Univar and speaker fees from Novo Nordisk, Orphalan, and Dr Falk. All other authors report no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Individuals with nonalcoholic fatty liver disease (NAFLD) have an altered gut microbiota composition. Moreover, hepatic DNA methylation may be altered in the state of NAFLD. Using a fecal microbiota transplantation (FMT) intervention, we aimed to investigate whether a change in gut microbiota composition relates to altered liver DNA methylation in NAFLD. Moreover, we assessed whether plasma metabolite profiles altered by FMT relate to changes in liver DNA methylation. Twenty-one individuals with NAFLD underwent three 8-weekly vegan allogenic donor ( n  = 10) or autologous ( n  = 11) FMTs. We obtained hepatic DNA methylation profiles from paired liver biopsies of study participants before and after FMTs. We applied a multi-omics machine learning approach to identify changes in the gut microbiome, peripheral blood metabolome and liver DNA methylome, and analyzed cross-omics correlations. Vegan allogenic donor FMT compared to autologous FMT induced distinct differential changes in I) gut microbiota profiles, including increased abundance of Eubacterium siraeum and potential probiotic Blautia wexlerae ; II) plasma metabolites, including altered levels of phenylacetylcarnitine (PAC) and phenylacetylglutamine (PAG) both from gut-derived phenylacetic acid, and of several choline-derived long-chain acylcholines; and III) hepatic DNA methylation profiles, most importantly in Threonyl-TRNA Synthetase 1 ( TARS) and Zinc finger protein 57 ( ZFP57) . Multi-omics analysis showed that Gemmiger formicillis and Firmicutes bacterium &#95; CAG &#95;170 positively correlated with both PAC and PAG. E siraeum negatively correlated with DNA methylation of cg16885113 in ZFP57 . Alterations in gut microbiota composition by FMT caused widespread changes in plasma metabolites (e.g. PAC, PAG, and choline-derived metabolites) and liver DNA methylation profiles in individuals with NAFLD. These results indicate that FMTs might induce metaorganismal pathway changes, from the gut bacteria to the liver.

The prevalence and severity of metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing. Physicians who treat patients with MASLD may acknowledge the strong coincidence with cardiometabolic disease, including atherosclerotic cardiovascular disease (asCVD). This raises questions on co-occurrence, causality, and the need for screening and multidisciplinary care for MASLD in patients with asCVD, and vice versa. Here, we review the interrelations of MASLD and heart disease and formulate answers to these matters. Epidemiological studies scoring proxies for atherosclerosis and actual cardiovascular events indicate increased atherosclerosis in patients with MASLD, yet no increased risk of asCVD mortality. MASLD and asCVD share common drivers: obesity, insulin resistance and type 2 diabetes mellitus (T2DM), smoking, hypertension, and sleep apnea syndrome. In addition, Mendelian randomization studies support that MASLD may cause atherosclerosis through mixed hyperlipidemia, while such evidence is lacking for liver-derived procoagulant factors. In the more advanced fibrotic stages, MASLD may contribute to heart failure with preserved ejection fraction by reduced filling of the right ventricle, which may induce fatigue upon exertion, often mentioned by patients with MASLD. Some evidence points to an association between MASLD and cardiac arrhythmias. Regarding treatment and given the strong co-occurrence of MASLD and asCVD, pharmacotherapy in development for advanced stages of MASLD would ideally also reduce cardiovascular events, as has been demonstrated for T2DM treatments. Given the common drivers, potential causal factors and especially given the increased rate of cardiovascular events, comprehensive cardiometabolic risk management is warranted in patients with MASLD, preferably in a multidisciplinary approach., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The estimated global prevalence and burden of non-alcoholic fatty liver disease (NAFLD) and its advanced stage, non-alcoholic steatohepatitis (NASH), is increasing. Yet, NAFLD remains largely underdiagnosed. In addition to hepatic morbidity and mortality, NAFLD is associated with increased cardiovascular complications, warranting a multidisciplinary approach. Despite its rapidly increasing prevalence, knowledge of NAFLD among healthcare workers is limited, especially with specialists outside the field of hepatology and gastroenterology., Objectives: To investigate knowledge, practice and opinions/attitudes of healthcare workers towards diagnosis and management of NAFLD/NASH., Methods: The survey was designed in collaboration with a multidisciplinary scientific committee established especially for this study. The survey was disseminated to healthcare workers from seven different disciplines through four collaborating societies, social media and at a cardiology-themed conference from February to June 2022. Median and interquartile range were mentioned for numeric responses and proportions for categorical responses or responses on a Likert scale. Likert scale responses were treated as ordinal data and analysed with the appropriate tests., Results: The full dataset included 613 respondents from 88 different countries (including 488 physicians). 64% of the surveyed physicians underestimated the prevalence of NAFLD. General practitioners and cardiologists underestimated the prevalence most often (74% and 77%, respectively). Compared to the other disciplines, cardiologists were least familiar with the symptoms and diagnostic criteria and felt least confident in diagnosing and managing NAFLD. Overall, 65% of physicians reported regularly using evidence-based guidelines for managing NAFLD, yet 72% reported challenges in providing lifestyle recommendations. A lack of awareness was the most common reported reason for the lack of screening for NAFLD (68% respectively)., Conclusions: Despite the growing burden of NAFLD, there is a significant gap in awareness, knowledge, and management among physicians treating patients with cardiometabolic comorbidities, particularly cardiologists. Hepatologists and gastroenterologists could play a role in educating their fellow physicians., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Background: The reference standard for detecting non-alcoholic steatohepatitis (NASH) and staging fibrosis-liver biopsy-is invasive and resource intensive. Non-invasive biomarkers are urgently needed, but few studies have compared these biomarkers in a single cohort. As part of the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) project, we aimed to evaluate the diagnostic accuracy of 17 biomarkers and multimarker scores in detecting NASH and clinically significant fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) and identify their optimal cutoffs as screening tests in clinical trial recruitment., Methods: This was a comparative diagnostic accuracy study in people with biopsy-confirmed NAFLD from 13 countries across Europe, recruited between Jan 6, 2010, and Dec 29, 2017, from the LITMUS metacohort of the prospective European NAFLD Registry. Adults (aged ≥18 years) with paired liver biopsy and serum samples were eligible; those with excessive alcohol consumption or evidence of other chronic liver diseases were excluded. The diagnostic accuracy of the biomarkers was expressed as the area under the receiver operating characteristic curve (AUC) with liver histology as the reference standard and compared with the Fibrosis-4 index for liver fibrosis (FIB-4) in the same subgroup. Target conditions were the presence of NASH with clinically significant fibrosis (ie, at-risk NASH; NAFLD Activity Score ≥4 and F≥2) or the presence of advanced fibrosis (F≥3), analysed in all participants with complete data. We identified thres holds for each biomarker for reducing the number of biopsy-based screen failures when recruiting people with both NASH and clinically significant fibrosis for future trials., Findings: Of 1430 participants with NAFLD in the LITMUS metacohort with serum samples, 966 (403 women and 563 men) were included after all exclusion criteria had been applied. 335 (35%) of 966 participants had biopsy-confirmed NASH and clinically significant fibrosis and 271 (28%) had advanced fibrosis. For people with NASH and clinically significant fibrosis, no single biomarker or multimarker score significantly reached the predefined AUC 0·80 acceptability threshold (AUCs ranging from 0·61 [95% CI 0·54-0·67] for FibroScan controlled attenuation parameter to 0·81 [0·75-0·86] for SomaSignal), with accuracy mostly similar to FIB-4. Regarding detection of advanced fibrosis, SomaSignal (AUC 0·90 [95% CI 0·86-0·94]), ADAPT (0·85 [0·81-0·89]), and FibroScan liver stiffness measurement (0·83 [0·80-0·86]) reached acceptable accuracy. With 11 of 17 markers, histological screen failure rates could be reduced to 33% in trials if only people who were marker positive had a biopsy for evaluating eligibility. The best screening performance for NASH and clinically significant fibrosis was observed for SomaSignal (number needed to test [NNT] to find one true positive was four [95% CI 4-5]), then ADAPT (six [5-7]), MACK-3 (seven [6-8]), and PRO-C3 (nine [7-11])., Interpretation: None of the single markers or multimarker scores achieved the predefined acceptable AUC for replacing biopsy in detecting people with both NASH and clinically significant fibrosis. However, several biomarkers could be applied in a prescreening strategy in clinical trial recruitment. The performance of promising markers will be further evaluated in the ongoing prospective LITMUS study cohort., Funding: The Innovative Medicines Initiative 2 Joint Undertaking., Competing Interests: Declaration of interests QMA is the coordinator of the Innovative Medicines Initiative 2 (IMI2) LITMUS consortium funded by the IMI2 Program of the EU (777377) and is a Newcastle National Institute for Health and Care Research Biomedical Research Centre investigator. The multistakeholder LITMUS consortium includes industry partners and received funding from the European Federation of Pharmaceutical Industries and Associations. QMA also declares research grant funding from AbbVie, AstraZeneca, Boehringer Ingelheim, Glympse Bio, Intercept, Novartis, and Pfizer; is a consultant on behalf of Newcastle University to Alimentiv, Akero, AstraZeneca, Axcella, 89Bio, Boehringer Ingelheim, Bristol-Myers Squibb, Galmed, Genfit, Genentech, Gilead, GlaxoSmithKline, Hanmi, HistoIndex, Intercept, Inventiva, Ionis, IQVIA, Janssen, Madrigal, Medpace, Merck, NGMBio, Novartis, Novo Nordisk, PathAI, Pfizer, Poxel, Resolution Therapeutics, Roche, Ridgeline Therapeutics, RTI International, Shionogi, and Terns; has received speaker fees from Fishawack, Integritas Communications, Kenes, Novo Nordisk, Madrigal, Medscape, and Springer Healthcare; is on the North Sea Therapeutics Data Safety and Monitoring Committee at Medpace on behalf of Newcastle University; and has received royalties from Elsevier. JB declares research grant funding from Echosens, Intercept, Inventiva, and Siemens; consulting fees from Echosens, Intercept, and Siemens; speaker fees from Gilead, Intercept, Lilly, and Siemens; and is a member of advisory boards of Bristol-Myers Squibb, Echosens, Intercept, Novo Nordisk, and Merck Sharp & Dohme. DT declares grants from and contracts with Histoindex; consulting fees from Alimentiv, Clinnovate Health UK, Allergan, Cirius Therapeutics, Intercept Pharmaceuticals, ICON Clinical Research, and Ionis Pharmaceuticals; and was the past President of the European Society of Pathology (unpaid). PB is the owner and Director of Liverpat. AG declares support from the IMI2 LITMUS project and research grants from Falk and Intercept; consulting fees from AbbVie, Alexion, Bayer, Bristol-Meyers Squibb, Eisai, Gilead, Intercept, Ipsen, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Sanofi-Aventis, and Sequana; research fees from AbbVie, Alexion, Bristol-Meyers Squibb, Burger Stein, CSL Behring, Falk, Gilead, Intercept, Mert, Merck Sharp & Dohme, Novartis, Roche, and Sequana; travel and meeting support from Intercept, Gilead, AbbVie, and Falk; and is a member of an advisory board of Falk. SF has a Senior Clinical Investigator fellowship from the Research Foundation Flanders (1802154N); declares grants to his institution (University of Antwerp, Belgium) from Genfit, Gilead Sciences, Roche, and Bristol-Meyers Squibb; has been a consultant to Roche, Intercept, Gilead Sciences, Echosens, Allergan, Genentech, AbbVie, Novo Nordisk, Bayer, Novartis, Bristol-Meyers Squibb, AstraZeneca, Boehringer Ingelheim, Galmed, Merck Sharp & Dohme, Promethera, Janssen Pharmaceutica, Coherus, Actelion Madrigal, Astellas, Julius Clinical, Genfit, NGM Bio, and Inventiva; and has been lecturer for AbbVie, Allergan, Bayer, Genfit, and Gilead Sciences. MA declares research grants from GlaxoSmithKline, Takeda, and AstraZeneca and consulting fees from Intercept and AstraZeneca. GP declares support from AbbVie, Gilead Sciences, Janssen, and Takeda; consulting fees from AbbVie, Amgen, Astellas, Astra Zeneca, Gilead Sciences, GlaxoSmithKline, Janssen, Ipsen, Merck Sharp & Dohme, Novartis, Novo Nordisk, and Roche; speaker fees from AbbVie, Gilead Sciences, GlaxoSmithKline, Ipsen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, and Takeda; and travel support from AbbVie, Gilead Sciences, Ipsen, Janssen, and Novo Nordisk. HC-P declares support from the IMI2 LITMUS project; consulting fees from Intercept, Novo Nordisk, and Orphalan; and speaker fees from Eisai and Roche Portugal. J-FD is a member of the advisory committees of Alentis, AstraZeneca, Bayer, Bristol-Myers Squibb, Enyo, Esai, Falk, Genfit, Gilead Sciences, Intercept, Inventiva, Ipsen, Lilly, Madrigal, Merck, Novartis, Novo Nordisk, and Roche; declares travel and meeting support from Gilead and speaking and teaching fees from Bayer, Bristol-Myers Squibb, Intercept, Gilead Sciences, Novartis, and Roche; has received fees from the journal GUT as an Associate Editor and Uptodate; and is President of the Swiss NASH Foundation and the Swiss Foundation against Liver Cancer. DJL declares support from the IMI2 LITMUS project and Nordic Bioscience and has stock in Nordic Bioscience. SAH declares grants from Akero Therapeutics, Axcella Health, Cirius Therapeutics, CiVi Biopharma, Cymabay, Enyo Pharma, Galectin, Galmed Research and Development, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Metacrine, NGM Bio, Northsea Therapeutics, Novartis Pharmaceuticals, Novo Nordisk, Poxel, Sagimet Biosciences, and Viking Therapeutics; consulting and speaker fees from AgomAB, Akero Therapeutics, Alentis Therapeutics, Alimentiv, Altimmune, Axcella Health, Boston Pharmaceuticals, Riley FBR, BVF Partners, Cohbar, Canfite, Corcept Therapeutics, Cymabay, Echosens North America, Enyo Pharma, Fibronostics, Foresite Labs, Fortress Biotech, Galectin Therapeutics, Genfit, Genius Group, Hepion Pharmaceuticals, Hightide Therapeutics, HistoIndex, Inipharm, Intercept Pharmaceuticals, Ionis, Kowa Research Institute, Madrigal Pharmaceuticals, Medpace, Metacrine, Microba, NGM Biopharmaceuticals, Northsea Therapeutics, Novo Nordisk, Nutrasource, Perspectum Diagnostics, Piper, Sandler, Poxel, Prometic Pharma, Ridgeline, Sagimet Biosciences, Sonic Incytes, Medical, Terns, and Viking Therapeutics; is a member of advisory boards of 89 Bio, Akero Therapeutics, Altimmune, Arrowhead, Axcella Health, Chronwell, CiVi, Cymabay, Echosens North America, Foresite Labs, Galectin Therapeutics, Galmed Research and Development, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, HistoIndex, Indalo, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Medpace, Metacrine, NGM Bio, Northsea Therapeutics, Novartis Pharmaceuticals, Novo Nordisk, PathAI, Poxel, Prometic Pharma, Ridgeline, Sagimet Biosciences, Sonic Incytes Medical, Terns, and Theratechnologies; has stock in Akero Therapeutics, Chronwell, Cirius Therapeutics, Galectin Therapeutics, Genfit, Hepion Pharmaceuticals, HistoIndex, Metacrine, NGM Bio, Northsea Therapeutics, Sonic Incytes, and Medical Corp; and declares consultancy services to Akero Therapeutics, Axcella Health, Cirius Therapeutics, CiVi Biopharma, Cymabay, Enyo Pharma, Galectin Therapeutics, Galmed Research and Development, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept Pharmaceuticals, Madrigal Pharmaceuticals, Metacrine, NGM Bio, Northsea Therapeutics, Novartis Pharmaceuticals, Novo Nordisk, Poxel, Sagimet Biosciences, and Viking Therapeutics. YC is an employee of Eli Lilly and the company and hold stocks and shares in Eli Lilly. JFC declares support from Oxford National Institute for Health and Care Research Biomedical Research Centre; consulting fees from Intercept and Alnylam; speaker fees from AstraZeneca; and is a member of an advisory board of Intercept. MP declares support from the IMI2 LITMUS project and grants from Cancer Research UK (C30358/A29725); has a patent for medical imaging (WO2015155521A1); and is a shareholder in Perspectum. HY-J declares support from the IMI2 LITMUS project; grants from Academy of Finland, Sigrid Juselius Foundation, and EVO foundation; consulting fees from Boehringer Ingelheim; speaker fees from Novo Nordisk and GlaxoSmithKline; and is a member of advisory boards of Merck Sharp & Dohme, Eli Lilly, and Hamni. JC declares grants and research support from Gilead Sciences, AbbVie, and Intercept Pharmaceuticals; consultant fees from Gilead Sciences, AbbVie, Merck Sharp & Dohme, Shionogi, Intercept Pharmaceuticals, Janssen Pharmaceuticals, Celgene, and Alexion; speaker support from Gilead Sciences, AbbVie, Shionogi, Janssen Pharmaceuticals, and Celgene; meeting and travel support from Gilead Sciences, AbbVie, and Janssen Pharmaceuticals; and is President of the Spanish Society of Digestive Pathology. MK declares support from the IMI2 LITMUS project and Nordic Bioscience. He is a Nordic Bioscience stock share holder. RO is an employee of SomaLogic; declares support from the IMI2 LITMUS project (SomaLogic funded the SomaScan proteomic assay results as a contribution to LITMUS); is on the patent application of SomaLogic for NASH biomarkers; and has stock in SomaLogic. RT is an employee of and holds stock in AstraZeneca, Sweden. KD is an employee of Eli Lilly and the company and hold stocks and shares in Eli Lilly. CY is an employee and stock and share holder of Pfizer. CB is a former employee of Novartis Pharma and declares financial support from Novartis Pharma; has pending patents for treatment of NASH (Novartis); and has stock in Novartis Pharma and Merck. ME is a member of the advisory board of AMRA Medical. GPA declares support from the IMI2 LITMUS project and consulting fees from Clinicpace, Servier Pharmaceuticals, GlaxoSmithKline, NuCana, AstraZeneca, and Benevolent AI. JMS declares grants from Gilead Sciences, Boehringer Ingelheim, Nordic Bioscience, and Siemens Healthcare; consulting fees from Apollo Endosurgery, Albireo Pharma, Bayer, Bristol-Meyers Squibb, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, GlaxoSmithKline, Heel, Intercept Pharmaceuticals, Ipsen, Inventiva Pharma, Julius Clinical, Madrigal, Merck Sharp & Dohme, Nordic Bioscience, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Shinogi, Siemens Healthcare, and Summit Clinical Research; speaker fees from Apollo Endosurgery, MedPublico, and Boehringer Ingelheim; and is a member of advisory boards of Novo Nordisk and Boehringer Ingelheim. EB declares consulting fees from Gilead, Novo Nordisk, Boehringer Ingelheim, and Intercept; speaker fees from Novo Nordisk, Intercept, and Merck Sharp & Dohme; and is a member of advisory boards of Novo Nordisk and Intercept. MR-G declares grants from Siemens, Gilead, and Intercept; consulting fees from AbbVie, Alpha-sigma, Allergen, AstraZeneca, Inventia, Kaleido, Novo Nordisk, Pfizer, Axcella, Bristol-Meyers Squibb, Boehringer Ingelheim, and Gilead; speaker fees from Inventia, Sobi, Novo Nordisk, Rubio, and Shionogi; meeting and travel support from Abbvie and Gilead; and is a member of an advisory board of Galmed. VR declares grants from Gilead Sciences and Intercept Pharmaceuticals and consulting fees from GlaxoSmithKline, Galmed, Novo Nordisk, Prosciento, Terns, NorthSea Therapeutics, Enyo, Sagimet, NGM Pharmaceuticals, and Madrigal. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD., Methods: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: <10 vs 10 to <20 vs ≥20 kPa; FIB-4: <1·3 vs 1·3 to ≤2·67 vs >2·67; NFS: <-1·455 vs -1·455 to ≤0·676 vs >0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226., Findings: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression., Interpretation: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases., Funding: Innovative Medicines Initiative 2., Competing Interests: Declaration of interests KS is an employee of Versantis AG. MT received speaker fees from BMS, Falk Foundation, Gilead, Intercept, Janssen, MSD, and Roche; advised for AbbVie, Albireo, BiomX, Boehringer Ingelheim, Falk Pharma, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens, and Shire; received travel grants from AbbVie, Falk, Gilead, Intercept, and Janssen; and received research grants from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. MT is also co-inventor of patents on the medical use of norUDCA filed by the Medical Universities of Graz and Vienna. AGH reports consultancy for Julius Clinical, Novo Nordisk, Echosens, Inventiva, and has received research grants from Novo Nordisk and Gilead. EB has served as a consultant or advisory board member for Boehringer Ingelheim, Gilead Sciences, Intercept, Merck, Novo Nordisk, Pfizer, ProSciento, and as a speaker for Gilead Sciences, Intercept, Merck, Novo Nordisk, and Pfizer. EB has also received a research grant from Gilead Sciences for fatty liver research. VW-SW has served as a consultant or advisory board member for 3V-BIO, AbbVie, Allergan, Boehringer Ingelheim, Center for Outcomes Research in Liver Diseases, Echosens, Gilead Sciences, Hanmi Pharmaceutical, Intercept, Merck, Novartis, Novo Nordisk, Perspectum, Pfizer, ProSciento, Sagimet Biosciences, TARGET PharmaSolutions, and Terns; and as a speaker for AbbVie, Bristol-Myers Squibb, Echosens, and Gilead Sciences. VW-SW has also received a research grant from Gilead Sciences for fatty liver research. TK and JW received unrestricted research grants from Echosens. TK has served as a speaker for Echosens. GPA has served as a consultant and an advisory board member for Pfizer, Inventiva Pharma, GlaxoSmithKline, and KaNDy Therapeutics; has been a consultant to BerGenBio, Median Technologies, FRACTYL, Amryt Pharmaceuticals, and AstraZeneca; and has given presentations on behalf of Roche Diagnostics and Medscape all through the University of Nottingham contract. GS has acted as speaker for Merck, Gilead, AbbVie, Novo Nordisk, and Pfizer; served as an advisory board member for Pfizer, Merck, Novo Nordisk, Gilead, and Intercept; and has received unrestricted research funding from Theratechnologies. ETs has served on the advisory boards for Boehringer, Pfizer, NovoNordisk, Orphalan, Univar, and Alexion; and has been a speaker for NovoNordisk and Dr Falk. MY received research support from Kowa Co. HH's institutions have received research grants from Astra Zeneca, EchoSens, Gilead, Intercept, MSD, and Pfizer. W-KC has served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, and Novo Nordisk; and as a speaker for Hisky Medical and Viatris. SM received honorarium fees from Echosens. MV has served as a consultant or a speaker for Gilead Sciences and Intercept Pharmaceuticals. VdL reports consultancy fees for AbbVie, BMS, Echosens, Gilead Sciences, Intercept Pharmaceuticals, MSD, Myr-Pharma, Pfizer, Supersonic Imagine, and Tillotts. MN has been on the advisory board or has been a consultant for 89BIO, Altimmune, BI, Gilead, cohBar, Cytodyn, Pfizer, GSK, Novo Nordisk, EchoSens, Madrigal, NorthSea, Perspectum, Terns, Takeda, Sami-Sabina group, Siemens, and Roche diagnostic; has received research support from Allergan, Akero, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Corcept, Enanta, Madrigal, Novartis, Pfizer, Shire, TERNS, Viking, and Zydus; and is a shareholder or has stocks in Anaetos, Chrownwell, Cytodyn, Ciema, Rivus Pharma, and Viking. CF-P is employed by Echosens. AG has served as a speaker and consultant for AbbVie, Alexion, AstraZeneca, Bayer, BMS, CSL Behring, Eisai, Falk, Gilead, Heel, Intercept, Ipsen, Merz, MSD, Novartis, Pfizer, Roche, Sanofi-Aventis, Sequana; and received research funding from Intercept, Falk, and Novartis. MM is employed by Novartis. TT is employed by Pfizer. QMA is coordinator of the IMI2 LITMUS consortium; has received research grant funding from AbbVie, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer, Vertex; has received consultancy fees on behalf of Newcastle University for Abbott Laboratories, Acuitas Medical, Allergan/Tobira, Blade, BNN Cardio, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly, Galmed, Genfit, Gilead, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept Pharma Europe, Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk, Pfizer, Poxel, ProSciento, Raptor Pharma, Servier, Viking Therapeutics; and has received speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit, Gilead, Integritas Communications, MedScape. SAH has received research grants from Akero, Altimmune, Axcella-Cirius, CiVi Biopharma, Cymabay, Galectin, Genfit, Gilead Sciences, Hepion Pharmaceuticals, Hightide Therapeutics, Intercept, Madrigal, Metacrine, NGM Bio, Northsea Therapeutics, Novartis, Novo Nordisk, Poxel, Sagimet, and Viking; and has received consulting fees from Akero, Altimmune, Alentis, Arrowhead, Axcella, Echosens, Enyo, Foresite Labs, Galectin, Genfit, Gilead Sciences, Hepion, Hightide, HistoIndex, Intercept, Kowa, Madrigal, Metacrine, NeuroBo, NGM, Northsea, Novartis, Novo Nordisk, Poxel, Perspectum, Sagimet, Terns, and Viking. MP is a shareholder of Perspectum. All other authors declared no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD., Approach and Results: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82)., Conclusions: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: With the rising global prevalence of fatty liver disease related to metabolic dysfunction, the association of this common liver condition with chronic kidney disease (CKD) has become increasingly evident. In 2020, the more inclusive term metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed to replace the term non-alcoholic fatty liver disease (NAFLD). The observed association between MAFLD and CKD and our understanding that CKD can be a consequence of underlying metabolic dysfunction support the notion that individuals with MAFLD are at higher risk of having and developing CKD compared with those without MAFLD. However, to date, there is no appropriate guidance on CKD in individuals with MAFLD. Furthermore, there has been little attention paid to the link between MAFLD and CKD in the Nephrology community., Methods and Results: Using a Delphi-based approach, a multidisciplinary panel of 50 international experts from 26 countries reached a consensus on some of the open research questions regarding the link between MAFLD and CKD., Conclusions: This Delphi-based consensus statement provided guidance on the epidemiology, mechanisms, management and treatment of MAFLD and CKD, as well as the relationship between the severity of MAFLD and risk of CKD, which establish a framework for the early prevention and management of these two common and interconnected diseases., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-22-421/coif). DCW reports honoraria from Amgen, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Gilead, Janssen, Mundipharma, Merck Sharp and Dohme, Tricida, Vifor and Zydus. VWSW reports grants from Gilead Sciences; consulting fees from AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, TARGET PharmaSolutions; honoraria for lectures from Abbott, AbbVie, Gilead Sciences, Novo Nordisk and he is Chairman of Subspecialty Board of Gastroenterology and Hepatology, Hong Kong College of Physicians and Co-founder of Illuminatio Medical Technology Limited. CW reports consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, GSK, MSD, Sanofi; honoraria for lectures from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly. MTL reports research grants from Gilead Sciences and Echosens and he is on Advisory Board of Novo Nordisk. MHN reports research support from Pfizer, Enanta, Gilead, Exact Sciences, Vir Biotech, Helio Health, National Cancer Institute, Glycotest, B.K. Kee Foundation, CurveBio and he is on consulting/advisory Board of Intercept, Exact Science, Gilead, GSK, Eli Lilly, Laboratory of Advanced Medicine. SDN reports consulting fees from ACI clinical, Bayer, Lily, Vifor, Vertex and DSMB: AstraZeneca. JB reports grants from Echosens, Intercept, Inventiva, Siemens; consulting fees from Diafir, Echosens, Intercept, Siemens, BMS, Gilead, Intercept, Pfizer, MSD, Novo Nordisk; honoraria from Echosens, Gilead, Intercept, Siemens. LV reports consulting fees from Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Intercept pharmaceuticals, Diatech Pharmacogenetics, IONIS, Viatris; honoraria from MSD, Gilead, AlfaSigma, AbbVie. YJW reports honoraria from AbbVie and Gilead Science. MEK reports honoraria from AstraZeneca, Roche, MSD, AbbVie, Eva, Mash Premier, Takeda, Organon, AUG, Inspire, HSO, Gilead, Janssen, Intercept, Rameda, Ipsen, Onxeo, MinaPharm, Pharco, Zeta, Alfa Cure, Bayer, Oncoustics, PDC, and Spimaco. SS serves as the unpaid editorial board member of Hepatobiliary Surgery and Nutrition. MP reports he is a shareholder in Perspectum Ltd. AGH reports grants from Novo Nordisk, Gilead, Co-lead PI LEGEND trial Inventiva; consulting fees from Novo Nordisk, Gilead, Echosens and Norgine and Julius Clinical. WKC reports consulting fees from Abbvie, Boehringer Ingelheim and Novo Nordisk; honoraria form Viatris and Hisky Medical. HCP reports honoraria from Intercept, Orphalan, Novo Nordisk, Roche Portugal and EISAI. MHZ reports honoraria from Hisky Medical and serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. The other authors have no conflicts of interest to declare., (2023 Hepatobiliary Surgery and Nutrition. All rights reserved.)

Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.

Background: Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis., Methods: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS)., Results: LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study., Conclusion: This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Grobbee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Nonalcoholic fatty liver disease (NAFLD) is increasing in prevalence and severity globally, prompting noninvasive testing, yet limited data exist on noninvasive liver tests (NITs) including transient elastography (TE) in ethnically diverse populations. Therefore, we studied prevalence and ethnic differences in NAFLD with NITs in the multi-ethnic HEalthy Life In an Urban Setting (HELIUS) cohort. NITs of liver steatosis (Fatty Liver Index [FLI]) and fibrosis (Fibrosis-4 index [FIB-4], and aspartate aminotransferase-to-platelet ratio [APRI]) were assessed in 10,007 participants. A subpopulation of 399 participants, selected on high-risk criteria for NAFLD (obesity, type 2 diabetes mellitus [T2DM], and/or elevated NITs), was examined with TE. FLI was ≥60 in 27.3% of 10,007 participants, indicating steatosis. Most participants (71.8%) had FIB-4 < 1.30, excluding advanced liver fibrosis, and 1.1% (n = 113) had high FIB-4 (FIB-4 ≥ 2.67), indicating likely advanced liver fibrosis. In the TE subpopulation, 37.8% and 17.3% had steatosis and fibrosis (continuation attenuation parameter [CAP] ≥ 280 dB/m, liver stiffness measurement [LSM] ≥ 7.0 kPa, respectively). Turkish participants had highest adjusted odds ratio (OR) for elevated LSM (1.72, 95% confidence interval [CI] 0.59-5.01) and Ghanaians the lowest (0.24, 95% CI 0.09-0.65). Ghanaians had lowest adjusted OR for elevated CAP: 0.18 (95% CI 0.09-0.37). In diabetics, CAP and LSM were 17.6% and 14.6% higher than in nondiabetics, respectively. Correlations of FIB-4 and APRI with LSM were absent and weak. Conclusion : Liver steatosis proxy FLI was elevated in 27.3% of this multi-ethnic population. In Turkish background and in those with T2DM, proxies for steatosis and fibrosis were high, whereas in Ghanaian background, NITs were generally low. Together, this warrants awareness for NAFLD among high-risk populations, taking ethnic background into account. The absence of clear correlation between FIB-4 and APRI with LSM questions the accuracy of these fibrosis NITs to detect advanced fibrosis in the general population., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc on behalf of the American Association for the Study of Liver Diseases.)

To test the hypothesis that the gut microbiota of individuals with nonalcoholic fatty liver disease (NAFLD) produce enough ethanol to be a driving force in the development and progression of this complex disease, we performed one prospective clinical study and one intervention study. Ethanol was measured while fasting and 120 min after a mixed meal test (MMT) in 146 individuals. In a subset of 37 individuals and in an external validation cohort, ethanol was measured in portal vein blood. In an intervention study, ten individuals with NAFLD and ten overweight but otherwise healthy controls were infused with a selective alcohol dehydrogenase (ADH) inhibitor before an MMT. When compared to fasted peripheral blood, median portal vein ethanol concentrations were 187 (interquartile range (IQR), 17-516) times higher and increased with disease progression from 2.1 mM in individuals without steatosis to 8.0 mM in NAFL 21.0 mM in nonalcoholic steatohepatitis. Inhibition of ADH induced a 15-fold (IQR,1.6- to 20-fold) increase in peripheral blood ethanol concentrations in individuals with NAFLD, although this effect was abolished after antibiotic treatment. Specifically, Lactobacillaceae correlated with postprandial peripheral ethanol concentrations (Spearman's rho, 0.42; P < 10 -5 ) in the prospective study. Our data show that the first-pass effect obscures the levels of endogenous ethanol production, suggesting that microbial ethanol could be considered in the pathogenesis of this highly prevalent liver disease., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Recent literature suggests that tri-exponential models may provide additional information and fit liver intravoxel incoherent motion (IVIM) data more accurately than conventional bi-exponential models. However, voxel-wise fitting of IVIM results in noisy and unreliable parameter maps. For bi-exponential IVIM, neural networks (NN) were able to produce superior parameter maps than conventional least-squares (LSQ) generated images. Hence, to improve parameter map quality of tri-exponential IVIM, we developed an unsupervised physics-informed deep neural network (IVIM 3 -NET). We assessed its performance in simulations and in patients with non-alcoholic fatty liver disease (NAFLD) and compared outcomes with bi-exponential LSQ and NN fits and tri-exponential LSQ fits. Scanning was performed using a 3.0T free-breathing multi-slice diffusion-weighted single-shot echo-planar imaging sequence with 18 b-values. Images were analysed for visual quality, comparing the bi- and tri-exponential IVIM models for LSQ fits and NN fits using parameter-map signal-to-noise ratios (SNR) and adjusted R 2 . IVIM parameters were compared to histological fibrosis, disease activity and steatosis grades. Parameter map quality improved with bi- and tri-exponential NN approaches, with a significant increase in average parameter-map SNR from 3.38 to 5.59 and 2.45 to 4.01 for bi- and tri-exponential LSQ and NN models respectively. In 33 out of 36 patients, the tri-exponential model exhibited higher adjusted R 2 values than the bi-exponential model. Correlating IVIM data to liver histology showed that the bi- and tri-exponential NN outperformed both LSQ models for the majority of IVIM parameters (10 out of 15 significant correlations). Overall, our results support the use of a tri-exponential IVIM model in NAFLD. We show that the IVIM 3 -NET can be used to improve image quality compared to a tri-exponential LSQ fit and provides promising correlations with histopathology similar to the bi-exponential neural network fit, while generating potentially complementary additional parameters., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Troelstra, Van Dijk, Witjes, Mak, Zwirs, Runge, Verheij, Beuers, Nieuwdorp, Holleboom, Nederveen and Gurney-Champion.)

The prevalence of nonalcoholic fatty liver disease (NAFLD) and the more severe and inflammatory type, nonalcoholic steatohepatitis (NASH), is increasing rapidly. Especially in high-risk patients, that is those with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of NAFLD can be as high as 80% while NASH may be present in 20% of these subjects. With the worldwide increase of obesity, it is most likely that these numbers will rise. Since advanced stages of NAFLD and NASH are strongly associated with morbidity and mortality-in particular, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma-it is of great importance to identify subjects at risk. A great variety of noninvasive tests has been published to diagnose NAFLD and NASH, especially using blood- and imaging-based tests. Liver biopsy remains the gold standard for NAFLD/NASH. This review aims to summarize the different mechanisms leading to NASH and liver fibrosis, the different noninvasive liver tests to diagnose and evaluate patients with severe obesity., (© 2022 World Obesity Federation.)

(1) Background: Given the high prevalence of non-alcoholic fatty liver disease (NAFLD) and the limitations of liver biopsies, multiple non-invasive tests (NITs) have been developed to identify non-alcoholic fatty liver disease (NAFLD) patients at-risk of progression. The availability of these new NITs varies from country to country, and little is known about their implementation and adoption in routine clinical practice. This study aims to explore barriers and facilitators that influence the adoption of NAFLD NITs, from healthcare professionals' perspectives. (2) Methods: A cross-sectional study was performed using an exploratory mixed-methods approach. Twenty-seven clinicians from eight different countries with different specialties filled in our questionnaire. Of those, 16 participated in semi-structured interviews. Qualitative and quantitative data were collected and summarized using the recently published Non-adoption, Abandonment, Scale-up, Spread, and Sustainability (NASSS) framework for new medical technologies in healthcare organizations. (3) Results: Several factors were reported as influencing the uptake of NITs for NAFLD in clinical practice. Among those: insufficient awareness of tests; lack of practical guidelines and evidence for the performance of tests in appropriate patient populations and care settings; and absence of sufficient reimbursement systems were reported as the most important barriers. Other factors, most notably 'local champions', proper functional payment systems, and sufficient resources in academic hospitals, were indicated as important facilitating factors. (4) Conclusions: Clinicians see the adoption of NITs for NAFLD as a complex process that is modulated by several factors, such as robust evidence, practical guidelines, a proper payment system, and local champions. Future research could explore perspectives from other stakeholders on the adoption of NITs.

Background & Aims: Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model., Methods and Results: Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity., Conclusions: Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The prevalence and severity of non-alcoholic fatty liver disease (NAFLD) is increasing, yet adequately validated tests for care paths are limited and non-invasive markers of disease progression are urgently needed. The aim of this work was to summarize the performance of Pro-C3, a biomarker of active fibrogenesis, in detecting significant fibrosis (F ≥ 2), advanced fibrosis (F ≥ 3), cirrhosis (F4) and non-alcoholic steatohepatitis (NASH) in patients with NAFLD. A sensitive search of five databases was performed in July 2021. Studies reporting Pro-C3 measurements and liver histology in adults with NAFLD without co-existing liver diseases were eligible. Meta-analysis was conducted by applying a bivariate random effects model to produce summary estimates of Pro-C3 accuracy. From 35 evaluated reports, eight studies met our inclusion criteria; 1568 patients were included in our meta-analysis of significant fibrosis and 2058 in that of advanced fibrosis. The area under the summary curve was 0.81 (95% CI 0.77-0.84) in detecting significant fibrosis and 0.79 (95% CI 0.73-0.82) for advanced fibrosis. Our results support Pro-C3 as an important candidate biomarker for non-invasive assessment of liver fibrosis in NAFLD. Further direct comparisons with currently recommended non-invasive tests will demonstrate whether Pro-C3 panels can outperform these tests, and improve care paths for patients with NAFLD.

Physical activity (PA) at recommended levels contributes to the prevention of non-communicable diseases, such as atherosclerotic cardiovascular disease (asCVD) and type 2 diabetes mellitus (T2DM). Since the composition of the gut microbiota is strongly intertwined with dietary intake, the specific effect of exercise on the gut microbiota is not known. Moreover, multiple other factors, such as ethnicity, influence the composition of the gut microbiota, and this may be derived by distinct diet as well as PA patterns. Here we aim to untangle the associations between PA and the gut microbiota in a sample ( n = 1334) from the Healthy Life In an Urban Setting (HELIUS) multi-ethnic cohort. The associations of different food groups and gut microbiota were also analyzed. PA was monitored using subjective ( n = 1309) and objective ( n = 162) methods, and dietary intake was assessed with ethnic-specific food frequency questionnaire (FFQ). The gut microbiota was profiled using 16S rRNA gene amplicon sequencing, and the functional composition was generated with the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2). Associations were assessed using multivariable and machine learning models. In this cohort, a distinct gut microbiota composition was associated with meeting the Dutch PA norm as well as with dietary intake, e.g., grains. PA related parameters such as muscle strength and calf circumference correlated with gut microbiota diversity. Furthermore, gut microbial functionality differed between active and sedentary groups. Differential representation of ethnicities in active and sedentary groups in both monitor methods hampered the detection of ethnic-specific effects. In conclusion, both PA and dietary intake were associated with gut microbiota composition in our multi-ethnic cohort. Future studies should further elucidate the role of ethnicity and diet in this association.

Background: Noninvasive diagnostic methods are urgently required in disease stratification and monitoring in nonalcoholic fatty liver disease (NAFLD). Multiparametric magnetic resonance imaging (MRI) is a promising technique to assess hepatic steatosis, inflammation, and fibrosis, potentially enabling noninvasive identification of individuals with active and advanced stages of NAFLD., Purpose: To examine the diagnostic performance of multiparametric MRI for the assessment of disease severity along the NAFLD disease spectrum with comparison to histological scores., Study Type: Prospective, cohort., Population: Thirty-seven patients with NAFLD., Field Strength/sequence: Multiparametric MRI at 3.0 T consisted of magnetic resonance (MR) spectroscopy (MRS) with multi-echo stimulated-echo acquisition mode, magnitude-based and three-point Dixon using a two-dimensional multi-echo gradient echo, MR elastography (MRE) using a generalized multishot gradient-recalled echo sequence and intravoxel incoherent motion (IVIM) using a multislice diffusion weighted single-shot echo-planar sequence., Assessment: Histological steatosis grades were compared to proton density fat fraction measured by MRS (PDFF MRS ), magnitude-based MRI (PDFF MRI-M ), and three-point Dixon (PDFF Dixon ), as well as FibroScan® controlled attenuation parameter (CAP). Fibrosis and disease activity were compared to IVIM and MRE. FibroScan® liver stiffness measurements were compared to fibrosis levels. Diagnostic performance of all imaging parameters was determined for distinction between simple steatosis and nonalcoholic steatohepatitis (NASH)., Statistical Tests: Spearman's rank test, Kruskal-Wallis test, Dunn's post-hoc test with Holm-Bonferroni P-value adjustment, receiver operating characteristic curve analysis. A P-value <0.05 was considered statistically significant., Results: Histological steatosis grade correlated significantly with PDFF MRS (r s  = 0.66, P < 0.001), PDFF MRI-M (r s  = 0.68, P < 0.001), and PDFF Dixon (r s  = 0.67, P < 0.001), whereas no correlation was found with CAP. MRE and IVIM diffusion and perfusion significantly correlated with disease activity (r s  = 0.55, P < 0.001, r s  = -0.40, P = 0.016, r s  = -0.37, P = 0.027, respectively) and fibrosis (r s  = 0.55, P < 0.001, r s  = -0.46, P = 0.0051; r s  = -0.53, P < 0.001, respectively). MRE and IVIM diffusion had the highest area-under-the-curve for distinction between simple steatosis and NASH (0.79 and 0.73, respectively)., Data Conclusion: Multiparametric MRI is a promising method for noninvasive, accurate, and sensitive distinction between simple hepatic steatosis and NASH, as well as for the assessment of steatosis and fibrosis severity., Level of Evidence: 2 TECHNICAL EFFICACY: 2., (© 2021 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC. on behalf of International Society for Magnetic Resonance in Medicine.)

The Fatty Liver Index (FLI) is a proxy for the steatotic component of non-alcoholic fatty liver disease (NAFLD). For sub-Saharan African populations, the contribution of dietary factors to the development of NAFLD in the etiology of type 2 diabetes mellitus (T2DM) remains to be clarified. We identified sex-specific dietary patterns (DPs) related to the FLI using reduced ranked regression (RRR) and evaluated the associations of these DPs with T2DM. This analysis used data from the RODAM, a multi-center cross-sectional study of Ghanaian populations living in Ghana and Europe. The daily intake frequencies of 30 food groups served as the predictor variables, while the FLI was the response variable. The odds ratios and 95% confidence intervals for T2DM were calculated per one standard deviation increase in the DP score using logistic regression. In males, the DP score explained 9.9% of the variation in their food intake and 16.0% of the variation in the FLI. This DP was characterized by high intakes of poultry, whole-grain cereals, coffee and tea, condiments, and potatoes, and the chance of T2DM was 45% higher per 1 DP score-SD (Model 2). Our results indicate that the intake of modernized foods was associated with proxies of NAFLD, possibly underlying the metabolic pathways to developing T2DM.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent and potentially severe liver disease, emphasizing the need for implementation of widely supported care paths for patients at risk for advanced stages of NAFLD. In particular, the distinction of patients with a progressive and/or advanced, fibrotic NAFLD from those with simple steatosis requires improvement, as well as the awareness for NAFLD among health care professionals. Broad acceptance and implementation of interdisciplinary care paths in the near future will bring enhanced identification of those patients that benefit from surveillance, intensive lifestyle management, and empirical or investigational pharmacotherapy and enhance our epidemiological grasp of NAFLD in relation to lifestyle, genetic background, and cardiometabolic comorbidities related to NAFLD., (© 2021 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC. on behalf of United European Gastroenterology.)

Background and Aims: Metabolic-associated fatty liver disease (MAFLD) is driven by high caloric intake and sedentary lifestyle. Migration towards high income countries may induce these driving factors; yet, the influence of such on the prevalence of MAFLD is clearly understudied. Here, we investigated the Fatty Liver Index (FLI), a proxy of steatosis in MAFLD, after migration of Ghanaian subjects., Methods: Cross-sectional data of 5282 rural, urban and migrant participants from the Research on Obesity and Diabetes among African Migrants (also known as RODAM) study were analyzed with logistic regression for geographical differences in FLI and associations with type 2 diabetes mellitus (T2DM), waist-to-hip ratio, and 10-year predicted risk of atherosclerotic cardiovascular disease (ASCVD)., Results: Both FLI and the proportion with an FLI indicative of MAFLD steatosis (FLI ≥60) were higher in migrants compared with non-migrants. Prevalence of elevated FLI (FLI ≥60) in non-migrant males was 4.2% compared to 28.9% in migrants. For females, a similar gradient was observed, from 13.6% to 36.6% respectively. Compared to rural residents, the odds for a FLI ≥60 were higher in migrants living in urban Europe (odds ratio [OR] 9.02, 95% confidence interval [CI]: 5.02-16.20 for men, and 4.00, 95% CI: 3.00-5.34 for women). Compared to controls, the ORs for FLI ≥60 were 2.43 (95% CI: 1.73-3.41) for male T2DM cases and 2.02 (95% CI: 1.52-2.69) for female T2DM cases. One-unit higher FLI was associated with an elevated (≥7.5%) 10-year ASCVD risk (OR: 1.051, 95% CI: 1.041-1.062 for men, and 1.020, 95% CI: 1.015-1.026 for women)., Conclusions: FLI as a proxy for MAFLD increased stepwise in Ghanaians from rural areas, through urban areas, to Europe. Our results clearly warrant awareness for MAFLD in migrant population as well as confirmation with imaging modalities., Competing Interests: The authors have no conflict of interests related to this publication., (© 2021 Authors.)

Early detection of liver fibrosis is crucial to select the correct care path for patients with non-alcoholic fatty liver disease (NAFLD). Here, we systematically review the evidence on the performance of FibroMeter versions in detecting different levels of fibrosis in patients with NAFLD. We searched four databases (Medline, Embase, the Cochrane library, and Web of Science) to find studies that included adults with NAFLD and biopsy-confirmed fibrosis (F1 to F4), compared with any version of FibroMeter. Two independent researchers screened the references, collected the data, and assessed the methodological quality of the included studies. We used a bivariate logit-normal random effects model to produce meta-analyses. From 273 references, 12 studies were eligible for inclusion, encompassing data from 3425 patients. Meta-analyses of the accuracy in detecting advanced fibrosis (F ≥ 3) were conducted for FibroMeter Virus second generation (V2G), NAFLD, and vibration controlled transient elaFS3stography (VCTE). FibroMeter VCTE showed the best diagnostic accuracy in detecting advanced fibrosis (sensitivity: 83.5% (95%CI 0.58-0.94); specificity: 91.1% (95%CI 0.89-0.93)), followed by FibroMeter V2G (sensitivity: 83.1% (95%CI 0.73-0.90); specificity: 84.4% (95%CI 0.62-0.95)) and FibroMeter NAFLD (sensitivity: 71.7% (95%CI 0.63-0.79); specificity: 82.8% (95%CI 0.71-0.91)). No statistically significant differences were found between the different FibroMeter versions. FibroMeter tests showed acceptable sensitivity and specificity in detecting advanced fibrosis in patients with NAFLD, but an urge to conduct head-to-head comparison studies in patients with NAFLD of the different FibroMeter tests remains.

Protein glycosylation is a post-translational modification consisting in the enzymatic attachment of carbohydrate chains to specific residues of the protein sequence. Several types of glycosylation have been described, with N-glycosylation and O-glycosylation being the most common types impacting on crucial biological processes, such as protein synthesis, trafficking, localization, and function. Genetic defects in genes involved in protein glycosylation may result in altered production and activity of several proteins, with a broad range of clinical manifestations, including dyslipidaemia and atherosclerosis. A large number of apolipoproteins, lipoprotein receptors, and other proteins involved in lipoprotein metabolism are glycosylated, and alterations in their glycosylation profile are associated with changes in their expression and/or function. Rare genetic diseases and population genetics have provided additional information linking protein glycosylation to the regulation of lipoprotein metabolism., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction) associated liver disease (MAFLD), is, with a global prevalence of 25%, the most common liver disorder worldwide. NAFLD comprises a spectrum of liver disorders ranging from simple steatosis to steatohepatitis, fibrosis, cirrhosis and eventually end-stage liver disease. The cause of NAFLD is multifactorial with genetic susceptibility and an unhealthy lifestyle playing a crucial role in its development. Disrupted hepatic lipid homeostasis resulting in hepatic triglyceride accumulation is an hallmark of NAFLD. This disruption is commonly described based on four pathways concerning 1) increased fatty acid influx, 2) increased de novo lipogenesis, 3) reduced triglyceride secretion, and 4) reduced fatty acid oxidation. More recently, lipophagy has also emerged as pathway affecting NAFLD development and progression. Lipophagy is a form of autophagy (i.e. controlled autolysosomal degradation and recycling of cellular components), that controls the breakdown of lipid droplets in the liver. Here we address the role of hepatic lipid homeostasis in NAFLD and specifically review the current literature on lipophagy, describing its underlying mechanism, its role in pathophysiology and its potential as a therapeutic target., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Grefhorst, van de Peppel, Larsen, Jonker and Holleboom.)

Background and Aims: Vacuolar H+-ATP complex (V-ATPase) is a multisubunit protein complex required for acidification of intracellular compartments. At least five different factors are known to be essential for its assembly in the endoplasmic reticulum (ER). Genetic defects in four of these V-ATPase assembly factors show overlapping clinical features, including steatotic liver disease and mild hypercholesterolemia. An exception is the assembly factor vacuolar ATPase assembly integral membrane protein (VMA21), whose X-linked mutations lead to autophagic myopathy., Approach and Results: Here, we report pathogenic variants in VMA21 in male patients with abnormal protein glycosylation that result in mild cholestasis, chronic elevation of aminotransferases, elevation of (low-density lipoprotein) cholesterol and steatosis in hepatocytes. We also show that the VMA21 variants lead to V-ATPase misassembly and dysfunction. As a consequence, lysosomal acidification and degradation of phagocytosed materials are impaired, causing lipid droplet (LD) accumulation in autolysosomes. Moreover, VMA21 deficiency triggers ER stress and sequestration of unesterified cholesterol in lysosomes, thereby activating the sterol response element-binding protein-mediated cholesterol synthesis pathways., Conclusions: Together, our data suggest that impaired lipophagy, ER stress, and increased cholesterol synthesis lead to LD accumulation and hepatic steatosis. V-ATPase assembly defects are thus a form of hereditary liver disease with implications for the pathogenesis of nonalcoholic fatty liver disease., (© 2020 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Non-Alcoholic Fatty Liver Disease (NAFLD), a progressive liver disease that is closely associated with obesity, type 2 diabetes, hypertension and dyslipidaemia, represents an increasing global public health challenge. There is significant variability in the disease course: the majority exhibit only fat accumulation in the liver but a significant minority develop a necroinflammatory form of the disease (non-alcoholic steatohepatitis, NASH) that may progress to cirrhosis and hepatocellular carcinoma. At present our understanding of pathogenesis, disease natural history and long-term outcomes remain incomplete. There is a need for large, well characterised patient cohorts that may be used to address these knowledge gaps and to support the development of better biomarkers and novel therapies. The European NAFLD Registry is an international, prospectively recruited observational cohort study that aims to establish a large, highly-phenotyped patient cohort and linked bioresource. Here we describe the infrastructure, data management and monitoring plans, and the standard operating procedures implemented to ensure the timely and systematic collection of high-quality data and samples. Already recruiting subjects at secondary/tertiary care centres across Europe, the Registry is supporting the European Union IMI2-funded LITMUS 'Liver Investigation: Testing Marker Utility in Steatohepatitis' consortium, which is a major international effort to robustly validate biomarkers that diagnose, risk stratify and/or monitor NAFLD progression and liver fibrosis stage. The European NAFLD Registry has the demonstrable capacity to support research and biomarker development at scale and pace., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The intestinal microbiota has been linked to the development and prevalence of steatohepatitis in humans. Interestingly, steatohepatitis is significantly lower in individuals taking a plant-based, low-animal-protein diet, which is thought to be mediated by gut microbiota. However, data on causality between these observations in humans is scarce. In this regard, fecal microbiota transplantation (FMT) using healthy donors is safe and is capable of changing microbial composition in human disease. We therefore performed a double-blind randomized controlled proof-of-principle study in which individuals with hepatic steatosis on ultrasound were randomized to two study arms: lean vegan donor (allogenic n = 10) or own (autologous n = 11) FMT. Both were performed three times at 8-week intervals. A liver biopsy was performed at baseline and after 24 weeks in every subject to determine histopathology (Nonalcoholic Steatohepatitis Clinical Research Network) classification and changes in hepatic gene expression based on RNA sequencing. Secondary outcome parameters were changes in intestinal microbiota composition and fasting plasma metabolomics. We observed a trend toward improved necro-inflammatory histology, and found significant changes in expression of hepatic genes involved in inflammation and lipid metabolism following allogenic FMT. Intestinal microbial community structure changed following allogenic FMT, which was associated with changes in plasma metabolites as well as markers of . Conclusion: Allogenic FMT using lean vegan donors in individuals with hepatic steatosis shows an effect on intestinal microbiota composition, which is associated with beneficial changes in plasma metabolites and markers of steatohepatitis., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Objectives: Disturbances in lipid metabolism play an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Using lipidomics, an analytical technique that is used to broadly survey lipid metabolism, we searched for biomarkers in plasma that are correlated with the presence of hepatic steatosis in children with obesity., Methods: Lipidomics was performed in plasma samples of 21 children with obesity in whom steatosis was detected using proton magnetic resonance spectroscopy (H-MRS) and were compared with the lipidome of 21 samples of nonsteatotic subjects with obesity., Results: Forty-two samples were analyzed (57% boys; median age 15 years). A total of 18 lipid classes constituting 839 different lipid species were identified. A statistically significant increase in alkyldiacylglycerol (TG[O]) and phosphatidylethanolamine (PE) species and a significant decrease in alkyl/alkenyl-phosphatidylethanolamine (PE[O]), alkyl/alkenyl-lysophosphatidylethanolamine (LPE[O]) and alkyl/alkenyl-phosphatidylcholine (PC[O]) was observed in children with hepatic steatosis compared with controls. Twelve individual lipid species of 3 lipid classes were significantly increased in steatotic subjects compared with controls., Conclusions: In this pilot study, we found statistically significant alterations in 5 major lipid classes and 12 individual lipid species in children with steatosis. These might be potential biomarkers for pediatric NAFLD. Lipidomic studies in larger cohorts of children are needed to determine the diagnostic value of these lipids and determine whether results can be generalized for different age groups and ethnic backgrounds.

In recent years, the human gut microbiome has been found to influence a multitude of non-communicable diseases such as cardiovascular disease and metabolic syndrome, with its components type 2 diabetes mellitus and obesity. It is recognized to be mainly influenced by environmental factors, such as lifestyle, but also genetics may play a role. The interaction of gut microbiota and obesity has been widely studied, but in regard to non-alcoholic fatty liver disease (NAFLD) as a manifestation of obesity and insulin resistance, the causal role of the gut microbiome has not been fully established. The mechanisms by which the gut microbiome influences lipid accumulation, inflammatory responses, and occurrence of fibrosis in the liver are a topic of active research. In addition, the influence of exercise on gut microbiome composition is also being investigated. In clinical trials, exercise reduced hepatic steatosis independently of weight reduction. Other studies indicate that exercise may modulate the gut microbiome. This puts forward the question whether exercise could mediate its beneficial effects on NAFLD via changes in gut microbiome. Yet, the specific mechanisms underlying this potential connection are largely unknown. Thus, associative evidence from clinical trials, as well as mechanistic studies in vivo are called for to elucidate the relationship between exercise and the gut microbiome in NAFLD. Here, we review the current literature on exercise and the gut microbiome in NAFLD., Competing Interests: Conflict of interest statement: MN is on the Scientific Advisory Board of Caelus Health, The Netherlands, and Kaleido Biosciences, USA. However, none of these possible conflicts of interest bear direct relation to the manuscript., (© The Author(s), 2020.)

The acyltransferase LCAT mediates FA esterification of plasma cholesterol. In vitro studies have shown that LCAT also FA-esterifies several oxysterols, but in vivo evidence is lacking. Here, we measured both free and FA-esterified forms of sterols in 206 healthy volunteers and 8 individuals with genetic LCAT deficiency, including familial LCAT deficiency (FLD) and fish-eye disease (FED). In the healthy volunteers, the mean values of the ester-to-total molar ratios of the following sterols varied: 4β-hydroxycholesterol (4βHC), 0.38; 5,6α-epoxycholesterol (5,6αEC), 0.46; 5,6β-epoxycholesterol (5,6βEC), 0.51; cholesterol, 0.70; cholestane-3β,5α,6β-triol (CT), 0.70; 7-ketocholesterol (7KC), 0.75; 24S-hydroxycholesterol (24SHC), 0.80; 25-hydroxycholesterol (25HC), 0.81; 27-hydroxycholesterol (27HC), 0.86; and 7α-hydroxycholesterol (7αHC), 0.89. In the individuals with LCAT deficiency, the plasma levels of the FA-esterified forms of cholesterol, 5,6αEC, 5,6βEC, CT, 7αHC, 7KC, 24SHC, 25HC, and 27HC, were significantly lower than those in the healthy volunteers. The individuals with FLD had significantly lower FA-esterified forms of 7αHC, 24SHC, and 27HC than those with FED. It is of note that, even in the three FLD individuals with negligible plasma cholesteryl ester, substantial amounts of the FA-esterified forms of 4βHC, 5,6αEC, 7αHC, 7KC, and 27HC were present. We conclude that LCAT has a major role in the FA esterification of many plasma oxysterols but contributes little to the FA esterification of 4βHC. Substantial FA esterification of 4βHC, 5,6αEC, 7αHC, 7KC, and 27HC is independent of LCAT., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2020 Yamamuro et al.)

Non-alcoholic fatty liver disease (NAFLD) is a growing health problem with a global prevalence of over 25% and prevalence rates of over 60% in high-risk populations. It is considered the hepatic component of the metabolic syndrome and is associated with an increased risk of the development of various liver-associated and cardiometabolic complications. Given the complexity of NAFLD and associated comorbidities and complications, treatment requires interventions from a variety of different healthcare specialties. However, many clinicians are currently insufficiently aware of the potential harm and severity of NAFLD and associated comorbidities, complications and the steps that should be taken when NAFLD is suspected. Recognizing which patients suffer from non-progressive simple steatosis, metabolically active NASH with high risk of developing cardiovascular disease and which patients have a high risk of developing cirrhosis and hepatocellular carcinoma is important. Unfortunately, this can be difficult and guidelines towards the optimal diagnostic and therapeutic approach are ambivalent. Here we review the pathogenesis, diagnostics and treatment of NAFLD and discuss how multidisciplinary care path development could move forward.

Background and Aims: The rare ASGR1 del12 variant is associated with a beneficial effect on coronary artery disease (CAD) that is disproportionate to the small reductions in plasma LDL cholesterol (LDLc). This unexplained benefit has sparked the debate on potential additional pleiotropic effects of ASGR1 variants. Since ASGR1 has also been implicated in platelet homeostasis, we evaluated platelet function in heterozygous ASGR1 del12 carriers and controls. In addition, we compared the magnitude of various LDLc lowering genetic scores in the UK-biobank using Mendelian randomization., Methods: Desialylation of platelet surface glycoproteins and platelet aggregation capacity were measured in 12 carriers and 10 controls. We selected 3 common genetic variants in the ASGR1 locus that were significantly associated with plasma LDLc and assessed the association with coronary artery disease (CAD) and compared it with the effects of HMCGR, LDLR, NCI1L1 and PCSK9 gene scores., Results: Platelet surface GlcNAC residues were significantly lower in carriers but platelet aggregation did not differ. The relative risk reduction of ASGR1 GRS on CAD and myocardial infarction per 10 mg/dl LDLc reduction was 23% (OR 0.77, 95% CI 0.62-0.96). This risk reduction was proportionally similar to the gene risk scores in HMCGR, NPC1L1, PCSK9, and LDLR., Conclusions: Unlike previous reports, we did not find any evidence for a pleiotropic effect of the rare del12 variant in the ASGR1 locus on CAD, as platelet function did not differ between carriers and controls. Moreover, the observed effect of ASGR1 variants on CAD risk was proportional to the reduction in plasma LDLc levels., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Dyslipidemias are strongly linked to the development of atherosclerotic cardiovascular disease. Most dyslipidemias find their origin in the liver. In recent years, the differentiation of induced pluripotent stem cells (iPSCs) into hepatocyte-like cells has provided a versatile platform for the functional study of various dyslipidemias, both rare genetic dyslipidemia as well as common lipid disorders associated with insulin resistance or non-alcoholic fatty liver disease. In addition, iPSC-derived hepatocytes can serve as a cell model for developing novel lipid lowering therapies and have the potential of regenerative medicine. This review provides an overview of these developments., Competing Interests: Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript., (Copyright © 2020. Published by Elsevier B.V.)

Gut microbiota dysbiosis has been repeatedly observed in obesity and type 2 diabetes mellitus, two metabolic diseases strongly intertwined with non-alcoholic fatty liver disease (NAFLD). Animal studies have demonstrated a potential causal role of gut microbiota in NAFLD. Human studies have started to describe microbiota alterations in NAFLD and have found a few consistent microbiome signatures discriminating healthy individuals from those with NAFLD, non-alcoholic steatohepatitis or cirrhosis. However, patients with NAFLD often present with obesity and/or insulin resistance and type 2 diabetes mellitus, and these metabolic confounding factors for dysbiosis have not always been considered. Patients with different NAFLD severity stages often present with heterogeneous lesions and variable demographic characteristics (including age, sex and ethnicity), which are known to affect the gut microbiome and have been overlooked in most studies. Finally, multiple gut microbiome sequencing tools and NAFLD diagnostic methods have been used across studies that could account for discrepant microbiome signatures. This Review provides a broad insight into microbiome signatures for human NAFLD and explores issues with disentangling these signatures from underlying metabolic disorders. More advanced metagenomics and multi-omics studies using system biology approaches are needed to improve microbiome biomarkers.

The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying the effects of defective glycosylation on plasma lipids in patients with B4GALT1-CDG, caused by a mutation in B4GALT1 with defective N-linked glycosylation. We studied plasma lipids, cholesteryl ester transfer protein (CETP) glyco-isoforms with isoelectric focusing followed by a western blot and CETP activity in three known B4GALT1-CDG patients and compared them with 11 age- and gender-matched, healthy controls. B4GALT1-CDG patients have significantly lowered non-high density lipoprotein cholesterol (HDL-c) and total cholesterol to HDL-c ratio compared with controls and larger HDL particles. Plasma CETP was hypoglycosylated and less active in B4GALT1-CDG patients compared to matched controls. Our study provides insight into the role of protein glycosylation in human lipoprotein homeostasis. The hypogalactosylated, hypo-active CETP found in patients with B4GALT1-CDG indicates a role of protein galactosylation in regulating plasma HDL and LDL. Patients with B4GALT1-CDG have large HDL particles probably due to hypogalactosylated, hypo-active CETP., (© 2019 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of fatty liver disease. NAFLD is defined as the presence of fatty liver disease observed in imaging or histopathological examinations when there is no secondary cause such as excessive alcohol use or use of certain medications. NAFLD encompasses a whole spectrum, from simple steatosis to steatohepatitis ('non-alcoholic steatohepatitis', NASH), fibrosis and - ultimately - cirrhosis and hepatocellular carcinoma. Several factors play a role in the complex pathogenesis of NAFLD such as genetic predisposition, overweight, insulin resistance, inflammation, bile salts, gut microbiome and nutrition. Patients with NAFLD have an increased risk of developing type 2 diabetes mellitus, cardiovascular disease and malignancies such as hepatocellular carcinoma. To date, no medicines have been authorised for the treatment of NAFLD. The cornerstone of NAFLD treatment is lifestyle adjustment aimed at weight reduction.