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Objective: Nonalcoholic fatty liver disease (NAFLD) coexists with insulin resistance (IR), but it is uncertain whether NAFLD and IR contribute independently to atherosclerosis. We tested whether fatty liver, IR, and metabolic syndrome (MetS) features (waist, glucose, triglyceride, HDL cholesterol [HDL-C], and blood pressure) were associated with a marker of atherosclerosis (coronary artery calcium [CAC] score >0), independently of cardiovascular risk factors and cardiovascular disease (CVD).Research Design and Methods: Data were analyzed from a South Korean occupational cohort of 10,153 people who all received ultrasound measurements of fatty liver and a cardiac computed tomography CAC score. IR was defined by homeostasis model assessment of IR (HOMA-IR) ≥75th percentile. Odds ratios (ORs) (95% CIs) for the presence of a CAC score >0 were estimated using logistic regression.Results: There were 915 people with a CAC score >0. MetS features were increased (glucose, blood pressure, triglyceride, and waist) or decreased (HDL-C) among people with a CAC score >0 (all comparisons against CAC score ≤0; P < 0.0001). Of subjects with a CAC score >0, 55% had fatty liver and 33.7% were insulin resistant. Fatty liver (OR 1.21 [95% CI 1.01-1.45]; P = 0.04) and HOMA-IR (1.10 [1.02-1.18]; P = 0.02) were associated with CAC score >0, independently of all MetS features, conventional cardiovascular risk factors, and prior evidence of CVD. The presence of IR and fatty liver combined was associated with CAC score >0 (1.53 [1.20-1.95]; P = 0.001).Conclusions: Fatty liver and HOMA-IR are both associated with a CAC score >0 (independently of each other), features of MetS, conventional cardiovascular risk factors, and existing CVD. [ABSTRACT FROM AUTHOR]

Objective: There is dissociation between insulin resistance, overweight/obesity, and fatty liver as risk factors for type 2 diabetes, suggesting that different mechanisms are involved. Our aim was to 1) quantify risk of incident diabetes at follow-up with different combinations of these risk factors at baseline and 2) determine whether each is an independent risk factor for diabetes.Research Design and Methods: We examined 12,853 subjects without diabetes from a South Korean occupational cohort, and insulin resistance (IR) (homeostasis model assessment-IR ≥75th centile, ≥2.0), fatty liver (defined by standard ultrasound criteria), and overweight/obesity (BMI ≥25 kg/m(2)) identified at baseline. Odds ratios (ORs) and 95% confidence intervals (CIs) for incident diabetes at 5-year follow-up were estimated using logistic regression.Results: We identified 223 incident cases of diabetes from which 26 subjects had none of the three risk factors, 37 had one, 56 had two, and 104 had three. In the fully adjusted model, the OR and CI for diabetes were 3.92 (2.86-5.37) for IR, 1.62 (1.17-2.24) for overweight/obesity, and 2.42 (1.74-3.36) for fatty liver. The OR for the presence of all three factors in a fully adjusted model was 14.13 (8.99-22.21).Conclusions: The clustering of IR, overweight/obesity, and fatty liver is common and markedly increases the odds of developing type 2 diabetes, but these factors also have effects independently of each other and of confounding factors. The data suggest that treatment for each factor is needed to decrease risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

AIMS: To study patterns and predictors of early mortality in individuals with a new diagnosis of Type 2 diabetes, compared with a local age- and sex-matched comparison cohort. METHODS: A total of 736 individuals diagnosed with Type 2 diabetes between 1 May 1996 and 30 June 1998 and non-diabetic age- and sex-matched control subjects were studied. Follow-up was 5.25 years. Age- and gender-specific all-cause mortality odds ratios were calculated for the diabetic cohort compared with the non-diabetic comparator group. Mortality odds ratios were ascertained using conditional logistic regression. RESULTS: There were 147 deaths in the diabetic cohort [cardiovascular (42.2%), cancer (21.1%)]. Compared with the non-diabetic cohort, mortality odds more than doubled [odds ratio (OR) 2.47; 95% confidence interval (CI) 1.74, 3.49]. These increased odds were present in all age bands (including those aged > 75 years at diagnosis) for both cardiovascular and non-cardiovascular causes. In women, a new diagnosis of Type 2 diabetes was associated with a sevenfold increase in mortality odds in those aged 60-74 years (OR 7.00; 95% CI 2.09, 23.47). CONCLUSIONS: Type 2 diabetes is associated with a 2.5-fold increase in the odds of mortality in both men and women over the first 5 years from diagnosis. Our data strongly support the contention that the mortality risk associated with Type 2 diabetes essentially exists from, or may even predate, the time of diagnosis. [ABSTRACT FROM AUTHOR]

The metabolic syndrome is present in approximately 20% of general populations in developed countries and in approximately 80% of people with type 2 diabetes. High triglyceride levels, low high-density cholesterol levels and central obesity are three of the five features of the metabolic syndrome and contribute to the increased risk of cardiovascular disease (CVD) among people with the metabolic syndrome. Lifestyle interventions and treatment with statins reduce risk of CVD but absolute risk of cardiovascular events among high-risk populations remains high. This article reviews the options for treating the atherogenic dyslipidaemia associated with the metabolic syndrome. [ABSTRACT FROM AUTHOR]

AIMS: To determine the prognostic value of the Framingham equation and the United Kingdom Prospective Diabetes Study (UKPDS) risk engine in patients with newly diagnosed Type 2 diabetes. METHODS: A community-based cohort (n=428; aged 30-74 years) free of clinically evident CVD and newly diagnosed with Type 2 diabetes were studied over a median 4.2 (sd+/-0.62) years. Predicted (using baseline variables at diagnosis) and observed proportions of primary CVD and CHD events were compared using the Framingham equations and the UKPDS risk engine (only CHD events). The discrimination (c-statistic) and calibration (HLchi2) of the risk equations were calculated. The sensitivity and specificity of the Framingham equation at a 15%, 10-year CHD risk threshold (NICE guidelines) was compared with that of the ADA lipid threshold (LDLc>or=2.6 mmol/l or triglycerides>or=4.5 mmol/l). RESULTS: The Framingham equations underestimated the overall number of cardiovascular events by 33% and coronary events by 32% and showed modest discrimination and poor calibration for CVD [c=0.673; HLchi2=32.8 (P<0.001)] and CHD risk [c=0.657; HLchi2=19.8 (P=0.011)]. Although the overall underestimate was lower and non-significant with the UKPDS risk engine for CHD (13%), its performance in terms of discrimination and calibration were similar [c=0.670; HLchi2=17.1 (P=0.029)]. The 15%, 10-year CHD risk threshold with both the Framingham and UKPDS risk engines had similar sensitivity for primary CVD as the lipid level threshold [85.7 and 89.8% vs. 93.9% (P=0.21 and 0.34)] and both had greater specificity [33.0 and 30.3% vs. 12.1% (P<0.001 and P<0.001)]. CONCLUSIONS: In people with newly diagnosed Type 2 diabetes, both the Framingham equation and UKPDS risk engine are moderately effective at identifying those at high-risk (discrimination) and are poor at quantifying risk (calibration). Nonetheless, at a population level, a 15% 10-year CHD risk threshold using either risk calculator has similar sensitivity as an approach based on a single lipid risk factor level and may have benefits in terms of cost-effectiveness given the improved specificity. [ABSTRACT FROM AUTHOR]

Background and Aims: The impact of metabolic syndrome (MetS) traits on chronic kidney disease (CKD) risk in metabolic dysfunction-associated steatotic liver disease (MASLD) is unknown. We investigated the impact of type and number of MetS traits and liver fibrosis on prevalent CKD and incident end-stage renal disease (ESRD) risk in SLD., Methods: 234 488 UK Biobank participants' were analysed. Hepatic steatosis index (> 36 for SLD, < 30 for no SLD) and MRI-proton density fat fraction (≥ 5.56%) were used to identify SLD. MetS traits were identified using MASLD criteria. Advanced fibrosis (FIB-4 score > 2.67) was determined using FIB-4 scores. eGFR < 60 mL/min/1.73 m 2 or albuminuria > 3 mg/mmol identified prevalent CKD. A validated algorithm identified incident ESRD. Binary logistic and Cox regressions were used to test associations with prevalent CKD ([adjusted odds ratios (ORs)]) and incident ESRD (adjusted hazard ratios [HRs]) respectively., Results: 102 410 participants (41.2%) had SLD. 64.4% had MetS. 1.3% had FIB-4 score > 2.67. With SLD and only one MetS trait, hypertension (OR 1.35, 95% CI 1.35-1.72) or type 2 diabetes (T2D) (OR 1.89, 95% CI 1.06-3.38) increased risk of prevalent CKD. MetS (≥ 3 traits) increased prevalent CKD risk (OR 1.94, 95% CI 1.75-2.15), which was further increased by advanced liver fibrosis (OR 4.29, 95% CI 3.36-5.47). CKD prevalence increased with increasing MetS traits. Over 13.6 years (median follow-up), MetS was associated with increased risk of developing ESRD (HR 1.70, 95% CI 1.19-2.43)., Conclusions: In MASLD, hypertension, and T2D, number of MetS traits and liver fibrosis increased risk of prevalent CKD and presence of MetS increased the risk of incident ESRD., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: Metabolic risk factors are a significant cause of global burden among adolescents and young adults, but there is a lack of attention to the burden attributable to these metabolic risk factors globally., Aims: This study aims to provide comprehensive estimates of five important metabolic risk factors and the attributable disease burden in people aged 15-39 years from 1990 to 2021, based on the Global Burden of Disease Study (GBD) database., Methods: Global total deaths and disability-adjusted life years (DALYs) were used to describe the burden attributable to five common metabolic risk factors, including high fasting plasma glucose (FPG), high low-density lipoprotein cholesterol (LDL-C), high systolic blood pressure (SBP), high body mass index (BMI), and kidney dysfunction, in adolescents and young adults. The estimated annual percentage changes (EAPC) of DALYs were utilized to depict the trends from 1990 to 2021., Results: From 1990 to 2021, the DALY rates attributable to all metabolic risk factors showed a globally significant upward trend, with EAPC reaching 33.0 % (27.4-38.7). Compared to females, males had a heavier burden and a more significant increase in deaths and DALYs attributable to metabolic risk factors. High BMI and high FPG have become the top two metabolic risk factors in 2021, with summary exposure variables (SEV) rising by 84.2 % and 53.6 %, respectively. Low-middle socio-demographic index (SDI), middle SDI, and high SDI regions experienced upward regional trends in DALY rates, while low SDI regions remained stable. Among 204 countries and territories, 101 (49.5 %) showed a significant increase in DALY rates, as indicated by the EAPC., Conclusions: There is a substantial global burden attributable to metabolic risk factors in adolescents and young adults in 2021, especially high BMI and high FPG. This calls for further investigation and intervention to address this emerging trend., Competing Interests: Conflict of interest Christopher D. Byrne has received grant support from Echosens. Ming-Hua Zheng has received honoraria for lectures from AstraZeneca, Hisky Medical Technologies and Novo Nordisk, consulting fees from Boehringer Ingelheim. Anoop Misra has received honoraria from Novo Nordisk, Astra Zeneca, Janssen, Lupin, Eli Lilly, US Vitamins, and Boehringer Ingelheim. Wah-Kheong Chan is a consultant or advisory board member for Abbott, Roche, Abbvie, Boehringer Ingelheim and Novo Nordisk; and a speaker for Abbott, Novo Nordisk, Echosens, Viatris and Hisky Medical. Alice P.S. Kong has received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Eli-Lilly, Kyowa Kirin, Merck Serono, Nestle, Novo-Nordisk, Pfizer and Sanofi and Zuellig Pharma. Sander Lefere has received research grant from Inventiva. Mohit Kehar is a consultant for Mirum. Nicholas Beng Hui Ng has received honoraria from Novo Nordisk and Abbott. No other disclosures were reported., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Objective: To examine the hepatic effectiveness of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) through a head-to-head comparison with glucagon-like peptide-1 receptor agonists (GLP-1RA) or thiazolidinediones (TZD) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Design: This population-based cohort study was conducted using a nationwide healthcare claims database (2014-2022) of Korea. We included individuals with MASLD (aged ≥40 years) who initiated SGLT-2i or comparator drugs (GLP-1RA or TZD). Primary outcome was a composite of hepatic decompensation events, including ascites, oesophageal varices with bleeding, hepatic failure or liver transplant. Liver-cause death and all-cause death were also assessed as secondary outcomes. Cox proportional hazards models were used to estimated HRs with 95% CIs., Results: After 1:1 propensity score matching, we included 22 550 patients who initiated SGLT-2i and GLP-1RA (median age=57 years, 60% male), and 191 628 patients who initiated SGLT-2i and TZD (median age=57 years, 72% male). Compared with GLP-1RA, SGLT-2i showed a similar risk of hepatic decompensation events (HR 0.93, 95% CI 0.76 to 1.14). Compared with TZD, SGLT-2i demonstrated a reduced risk of hepatic decompensation events (HR 0.77, 95% CI 0.72 to 0.82). As compared with TZD, the results of secondary analyses showed significantly lower hepatic decompensation event risks with SGLT-2i when stratified by sex (male: HR 0.87 (95% CI 0.80-0.94); female: HR 0.62 (95% CI 0.55-0.69))., Conclusions: In this nationwide cohort study, SGLT-2i was associated with a lower risk of hepatic decompensation events in patients with MASLD compared with TZD, while demonstrating similar effectiveness to GLP-1RA., Competing Interests: Competing interests: J-YS received grants from the Ministry of Food and Drug Safety, the Ministry of Health and Welfare, the National Research Foundation of Korea, and pharmaceutical companies, including LG Chem, UCB, SK bioscience and Pfizer, outside the submitted work., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Nonalcoholic fatty liver disease (NAFLD) has become a common health care burden worldwide. The high heterogeneity of NAFLD remains elusive and impairs outcomes of clinical diagnosis and pharmacotherapy. Several NAFLD classifications have been proposed on the basis of clinical, genetic, alcoholic, or serum metabolic analyses. Yet, accurately predicting the progression of NAFLD to cirrhosis or hepatocellular carcinoma (HCC) in patients remains a challenge. Here, on the basis of a Chinese cohort of patients, we classified NAFLD into three distinct molecular subtypes (NAFLD-mSI, NAFLD-mSII, and NAFLD-mSIII) using integrative multiomics including whole-genome sequencing (WGS), proteomics, phosphoproteomics, lipidomics, and metabolomics across a broad range of liver, blood, and urine specimens. We found that NAFLD-mSI had higher expression of CYP1A2 and CYP3A4, which alleviate hepatic steatosis through mediating free fatty acid/bile acid-mTOR-FXR/PPARα signaling. NAFLD-mSII displayed an elevated risk of liver cirrhosis along with increased hepatic infiltration of M1 and M2 macrophages because of lipid-triggered hepatic CCL2 and CRP production. NAFLD-mSIII exhibited a potential risk for HCC development by increased transcription of CEBPB- and ERCC3-regulated oncogenes because of activation of the EGF-EGFR/CHKA/PI3K-PDK1-AKT cascade. Next, we validated the existence of these three NAFLD molecular subtypes in an external cohort comprising 92 patients with NAFLD across three different Chinese hospitals. These findings may aid in understanding the molecular features underlying NAFLD heterogeneity, thereby facilitating clinical diagnosis and treatment strategies with the aim of preventing the development of liver cirrhosis and HCC.

Background: Common metabolic diseases, such as type 2 diabetes mellitus (T2DM), hypertension, obesity, hypercholesterolemia, and metabolic dysfunction-associated steatotic liver disease (MASLD), have become a global health burden in the last three decades. The Global Burden of Disease, Injuries, and Risk Factors Study (GBD) data enables the first insights into the trends and burdens of these metabolic diseases from 1990 to 2021, highlighting regional, temporal and differences by sex., Methods: Global estimates of disability-adjusted life years (DALYs) and deaths from GBD 2021 were analyzed for common metabolic diseases (T2DM, hypertension, obesity, hypercholesterolemia, and MASLD). Age-standardized DALYs (mortality) per 100,000 population and annual percentage change (APC) between 1990 and 2021 were estimated for trend analyses. Estimates are reported with uncertainty intervals (UI)., Results: In 2021, among five common metabolic diseases, hypertension had the greatest burden (226 million [95 % UI: 190-259] DALYs), whilst T2DM (75 million [95 % UI: 63-90] DALYs) conferred much greater disability than MASLD (3.67 million [95 % UI: 2.90-4.61]). The highest absolute burden continues to be found in the most populous countries of the world, particularly India, China, and the United States, whilst the highest relative burden was mostly concentrated in Oceania Island states. The burden of these metabolic diseases has continued to increase over the past three decades but has varied in the rate of increase (1.6-fold to 3-fold increase). The burden of T2DM (0.42 % [95 % UI: 0.34-0.51]) and obesity (0.26 % [95 % UI: 0.17-0.34]) has increased at an accelerated rate, while the rate of increase for the burden of hypertension (-0.30 % [95 % UI: -0.34 to -0.25]) and hypercholesterolemia (-0.33 % [95 % UI: -0.37 to -0.30]) is slowing. There is no significant change in MASLD over time (0.05 % [95 % UI: -0.06 to 0.17])., Conclusion: In the 21st century, common metabolic diseases are presenting a significant global health challenge. There is a concerning surge in DALYs and mortality associated with these conditions, underscoring the necessity for a coordinated global health initiative to stem the tide of these debilitating diseases and improve population health outcomes worldwide., Competing Interests: Declaration of competing interest John D. Ryan received consultancy fees from Falk, Gilead, Pfizer and a speaker honorarium from Takeda. Luca Valenti reports consulting fees from Gilead, Pfizer, Astra Zeneca, Novo Nordisk, Intercept pharmaceuticals, Diatech Pharmacogenetics, IONIS, Viatris; honoraria from MSD, Gilead, AlfaSigma, AbbVie, Resalis, grants from Gilead. Alice Pik-Shan Kong has received research grants and/or speaker honoraria from Abbott, Astra Zeneca, Bayer, Boehringer Ingelheim, Dexcom, Eli-Lilly, Kyowa Kirin, Merck Serono, Nestle, Novo-Nordisk, Pfizer and Sanofi and Zuellig Pharma. Gregory Y. H. Lip serves as consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, Anthos. He is a National Institute for Health and Care Research (NIHR) Senior Investigator and co-PI of the AFFIRMO project on multimorbidity in AF (grant agreement No 899871), TARGET project on digital twins for personalised management of atrial fibrillation and stroke (grant agreement No 101136244) and ARISTOTELES project on artificial intelligence for management of chronic long term conditions (grant agreement No 101080189), which are all funded by the EU's Horizon Europe Research & Innovation programme. Anoop Misra has received honorarium from Abbott, Roche, Jannsen, Boehringer Ingelheim, Lupin, Cipla, US Vitamins, and Novo Nordisk. Christopher D. Byrne has received grant support from Echosens. Wah-Kheong Chan is a consultant or advisory board member for Abbott, Roche, Abbvie, Boehringer Ingelheim and Novo Nordisk; and a speaker for Abbott, Novo Nordisk, Echosens, Viatris and Hisky Medical. Christos S. Mantzoros reports grants through his institution from Merck, Massachusetts Life Sciences Center and Boehringer Ingelheim, has received grants through his Institution and personal consulting fees from Coherus Inc. and AltrixBio, he reports personal consulting fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal consulting fees from Olympus, Genfit, Lumos, Novo Nordisk, Amgen, Biodexa, Laekna, Corcept, Intercept, 89 Bio, Madrigal, Aligos, Esperion and Regeneron, travel support and fees from UptoDate, TMIOA, Elsevier, and the Cardio Metabolic Health Conference. Ming-Hua Zheng has received honoraria for lectures from AstraZeneca, Hisky Medical Technologies and Novo Nordisk, consulting fees from Boehringer Ingelheim. No other disclosures were reported., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metabolites produced as intermediaries or end-products of microbial metabolism provide crucial signals for health and diseases, such as metabolic dysfunction-associated steatotic liver disease (MASLD). These metabolites include products of the bacterial metabolism of dietary substrates, modification of host molecules [such as bile acids (BAs), trimethylamine-N-oxide, and short-chain fatty acids], or products directly derived from bacteria. Recent studies have provided new insights into the association between MASLD and the risk of developing chronic kidney disease (CKD). Furthermore, alterations in microbiota composition and metabolite profiles, notably altered BAs, have been described in studies investigating the association between MASLD and the risk of CKD. This narrative review discusses alterations of specific classes of metabolites, BAs, fructose, vitamin D, and microbiota composition that may be implicated in the link between MASLD and CKD.

Context: Low birth weight, as seen in Silver-Russell syndrome (SRS), is associated with later cardiometabolic disease. Data on long-term outcomes and adult body composition in SRS are limited., Objective: To evaluate body composition and metabolic health in adults with SRS., Methods: This was an observational study of 25 individuals with molecularly confirmed SRS, aged ≥ 18 years, from research facilities across the UK. Body composition and metabolic health were assessed at a single appointment. Individuals with SRS were compared with unaffected men and women (from the Southampton Women's Survey [SWS]). Fat mass, lean mass, bone mineral density (BMD), blood pressure, lipids, and blood glucose were measured., Results: Twenty-five adults with SRS were included (52% female). The median age was 32.9 years (range, 22.0 to 69.7). Fat percentage was greater in the SRS group than the SWS cohort (44.1% vs 30.3%, P < .001). Fat mass index was similar (9.6 vs 7.8, P = .3). Lean mass percentage (51.8% vs 66.2%, P < .001) and lean mass index (13.5 kg/m2 vs 17.3 kg/m2, P < .001) were lower in the SRS group than the SWS cohort. BMD was lower in the SRS group than the SWS cohort (1.08 vs 1.24, P < .001; all median values). Total cholesterol was ≥ 5 mmol/L in 52.0%. Triglyceride levels were ≥ 1.7 mmol/L in 20.8%. Fasting blood glucose levels were ≥ 6.1 mmol/L in 25.0%. Hypertension was present in 33.3%., Conclusion: Adults with SRS have an unfavorable body composition and predisposition to cardiometabolic disease. These results support the need for a health surveillance strategy to mitigate adverse outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Background: Statins have multiple benefits in patients with metabolic-associated steatotic liver disease (MASLD)., Aim: To explore the effects of statins on the long-term risk of all-cause mortality, liver-related clinical events (LREs) and liver stiffness progression in patients with MASLD., Methods: This cohort study collected data on patients with MASLD undergoing at least two vibration-controlled transient elastography examinations at 16 tertiary referral centres. Cox regression analysis was performed to examine the association between statin usage and long-term risk of all-cause mortality and LREs stratified by compensated advanced chronic liver disease (cACLD): baseline liver stiffness measurement (LSM) of ≥10 kPa. Liver stiffness progression was defined as an LSM increase of ≥20% for cACLD and from <10 kPa to ≥10 or LSM for non-cACLD. Liver stiffness regression was defined as LSM reduction from ≥10 kPa to <10 or LSM decrease of ≥20% for cACLD., Results: We followed up 7988 patients with baseline LSM 5.9 kPa (IQR 4.6-8.2) for a median of 4.6 years. At baseline, 40.5% of patients used statins, and cACLD was present in 17%. Statin usage was significantly associated with a lower risk of all-cause mortality (adjusted HR=0.233; 95% CI 0.127 to 0.426) and LREs (adjusted HR=0.380; 95% CI 0.268 to 0.539). Statin usage was also associated with lower liver stiffness progression rates in cACLD (HR=0.542; 95% CI 0.389 to 0.755) and non-cACLD (adjusted HR=0.450; 95% CI 0.342 to 0.592), but not with liver stiffness regression (adjusted HR=0.914; 95% CI 0.778 to 1.074)., Conclusions: Statin usage was associated with a relatively lower long-term risk of all-cause mortality, LREs and liver stiffness progression in patients with MASLD., Competing Interests: Competing interests: TC-FY reported serving as an advisory committee member and a speaker for Gilead Sciences outside the submitted work. EAT reported receiving personal fees as advisory board member for Boehringer, Novo Nordisk, Pfizer and Siemens; receiving speaker fees from Echosens, Novo Nordisk and AbbVie outside the submitted work. HH reported personal fees from AstraZeneca, personal fees from Bristol Myers-Squibb, personal fees from MSD, personal fees from Novo Nordisk, personal fees from Boehringer Ingelheim, personal fees from KOWA and personal fees from GW Phara outside the submitted work, and grants from AstraZeneca, grants from Echosens, grants from Gilead Sciences, grants from Intercept, grants from MSD, grants from Novo Nordisk and grants from Pfizer outside the submitted work. JB reported receiving grants and personal fees from Echosens outside the submitted work. JLC reported receiving other from Echosens Clinical Trials during the conduct of the study; grants from Roche Pharma and other from Gilead Advisory Board outside the submitted work. WKC reported serving as consultant or advisory board member for Zuellig Pharma, Abbott, Roche, AbbVie, Boehringer Ingelheim and Novo Nordisk; and a speaker for Novo Nordisk, Abbott, Echosens, Viatris and Hisky Medical. AJS reported receiving grants from Intercept, personal consulting fees from Gilead, grants from Merck, personal consulting fees from Pfizer, grants and personal consulting fees from Eli Lilly, grants and personal consulting fees from Novo Nordisk, Boehringer Ingelheim, Novartis, Histoindex, and stock options from Genfit, Tiziana, Durect, Inversago and personal consulting fees from Genentech, ALnylam, Regeneron, Zydus, LG chem, Hanmi, Madrigal, Path AI, 89 Bio and stock options from Galmed outside the submitted work. VdL reported receiving non-financial support from Echosens during the conduct of the study. PNN reported receiving grants from Novo Nordisk, advisory board and personal consulting fees, honoraria for lectures and travel expenses from Novo Nordisk, personal consulting and advisory board fees from Boehringer Ingelheim, Gilead, Intercept, Poxel Pharmaceuticals, Bristol-Myers Squibb, Pfizer, MSD, Sun Pharma, Eli Lilly, Madrigal, GSK and non-financial support for educational events from AiCME outside the submitted work. LC reported receiving personal fees for consulting and speakers bureau from Echosens during the conduct of the study; personal consultancy fees from Boston pharmaceutical and Gilead, speaker bureau and consultancy personal fees from GSK, personal speaker bureau fees from Inventiva, personal consultancy fees from Madrigal, personal Consultancy fees from MSD and Novo Nordisk, personal consultancy fees from Pfizer, Sagimet and Siemens Healthineers outside the submitted work. CF reported being in the full-time employment of Echosens during the conduct of the study. GL-HW reported receiving personal fees from Echosens during the conduct of the study; grants from Gilead Sciences Research outside the submitted work. MS-WC reported being in the full-time employment of Echosens during the conduct of the study. MR-G reported receiving personal fees from Echosens outside the submitted work. SUK reported personal fees from Gilead Sciences, personal fees from GSK, personal fees from Bayer, personal fees from Eisai, personal fees from AbbVie, personal fees from Echosens, personal fees from MSD, personal fees from Bristol-Myers Squibb and personal fees from AstraZeneca outside the submitted work, and grants from AbbVie, grants from Bristol-Myers Squibb, and grants from Gilead Sciences outside the submitted work. VW-SW reported receiving personal speaker fees from Abbott, consultant and speaker fees from AbbVie, personal consultant fees from Boehringer Ingelheim, Echosens, Gilead Sciences, grants from Gilead Sciences, personal consultant fees from Intercept, Inventiva, Novo Nordisk, personal consultant fees from Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, personal speaker fees from Unilab, personal consultant fees from Visirna, and being a cofounder of Illuminatio outside the submitted work. CDB has received grant support from Echosens. No other disclosures were reported., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Metabolic dysfunction-associated steatohepatitis (MASH) and fibrotic MASH are significant health challenges. This multi-national study aimed to validate the acMASH index (including serum creatinine and aspartate aminotransferase concentrations) for MASH diagnosis and develop a new index (acFibroMASH) for non-invasively identifying fibrotic MASH and exploring its predictive value for liver-related events (LREs)., Methods: We analyzed data from 3004 individuals with biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD) across 29 Chinese and 9 international cohorts to validate the acMASH index and develop the acFibroMASH index. Additionally, we utilized the independent external data from a multi-national cohort of 9034 patients with MAFLD to examine associations between the acFibroMASH index and the risk of LREs., Results: In the pooled global cohort, the acMASH index identified MASH with an area under the receiver operating characteristic curve (AUROC) of 0.802 (95% confidence interval [CI], 0.786-0.818). The acFibroMASH index (including the acMASH index plus liver stiffness measurement) accurately identified fibrotic MASH with an AUROC of 0.808 in the derivation cohort and 0.800 in the validation cohort. Notably, the AUROC for the acFibroMASH index was 0.835 (95% CI, 0.786-0.882), superior to that of the FAST score at 0.750 (95% CI, 0.693-0.800; P < .01) in predicting the 5-year risk of LREs. Patients with acFibroMASH >0.39 had a higher risk of LREs than those with acFibroMASH <0.15 (adjusted hazard ratio, 11.23; 95% CI, 3.98-31.66)., Conclusions: This multi-ethnic study validates the acMASH index as a reliable, noninvasive test for identifying MASH. The newly proposed acFibroMASH index is a reliable test for identifying fibrotic MASH and predicting the risk of LREs., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: We examined the comparative associations between non-alcoholic fatty liver disease (NAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) definitions with risk of developing chronic kidney disease (CKD) and abnormal albuminuria., Methods: We conducted a cohort study of 214,145 Korean adults with normal kidney function at baseline who underwent liver ultrasonography. Participants were further subdivided into no steatotic liver disease (no-SLD), NAFLD-only, MASLD-only, both NAFLD and MASLD, and SLD not categorized as NAFLD or MASLD groups. Cox proportional hazards models were used to analyze the risk of incident CKD and albuminuria., Results: Compared with either the no-NAFLD or no-MASLD groups, the NAFLD and MASLD groups were associated with a higher risk of incident CKD (NAFLD: adjusted hazard ratio (HR), 1.18 [95% CI, 1.01-1.38]; MASLD: adjusted HR, 1.21 [95% CI, 1.04-1.39]). Among the five subgroups, both NAFLD and MASLD group had the strongest association with risk of incident CKD (adjusted HR, 1.21 [95% CI, 1.04-1.42]). The MASLD-only group had the strongest association with incident abnormal albuminuria, with an adjusted HR comparable to that of the both NAFLD and MASLD group (adjusted HR 1.96 [95% CI, 1.44-2.67] for the MASLD-only, and adjusted HR 1.98 [95% CI, 1.58-2.49] for the both NAFLD and MASLD group versus the no-SLD group). The NAFLD-only group was not independently associated with risk of CKD or abnormal albuminuria., Conclusions: These findings suggest that MASLD definition identifies individuals at high risk of developing incident CKD or abnormal albuminuria better than NAFLD definition., 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-23-558/coif). M.H.Z. serves as an unpaid editorial board member of Hepatobiliary Surgery and Nutrition. G.T. is supported in part by grants from the University School of Medicine of Verona, Verona, Italy. C.D.B. was supported in part by the Southampton National Institute for Health and Care Research Biomedical Research Centre (NIHR203319), UK. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background and Aims: Lifestyle intervention is the mainstay of therapy for metabolic dysfunction-associated steatohepatitis (MASH), and liver fibrosis is a key consequence of MASH that predicts adverse clinical outcomes. The placebo response plays a pivotal role in the outcome of MASH clinical trials. Second harmonic generation/two-photon excitation fluorescence (SHG/TPEF) microscopy with artificial intelligence analyses can provide an automated quantitative assessment of fibrosis features on a continuous scale called qFibrosis. In this exploratory study, we used this approach to gain insight into the effect of lifestyle intervention-induced fibrosis changes in MASH., Methods: We examined unstained sections from paired liver biopsies (baseline and end-of-intervention) from MASH individuals who had received either routine lifestyle intervention (RLI) (n = 35) or strengthened lifestyle intervention (SLI) (n = 17). We quantified liver fibrosis with qFibrosis in the portal tract, periportal, transitional, pericentral, and central vein regions., Results: About 20% (7/35) and 65% (11/17) of patients had fibrosis regression in the RLI and SLI groups, respectively. Liver fibrosis tended towards no change or regression after each lifestyle intervention, and this phenomenon was more prominent in the SLI group. SLI-induced liver fibrosis regression was concentrated in the periportal region., Conclusion: Using digital pathology, we could detect a more pronounced fibrosis regression with SLI, mainly in the periportal region. With changes in fibrosis area in the periportal region, we could differentiate RLI and SLI patients in the placebo group in the MASH clinical trial. Digital pathology provides new insight into lifestyle-induced fibrosis regression and placebo responses, which is not captured by conventional histological staging., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. In recent years, a new terminology and definition of metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed. Compared to the NAFLD definition, MAFLD better emphasizes the pathogenic role of metabolic dysfunction in the development and progression of this highly prevalent condition. Metabolic disorders, including overweight/obesity, type 2 diabetes mellitus (T2DM), atherogenic dyslipidemia and hypertension, are often associated with systemic organ dysfunctions, thereby suggesting that multiple organ damage can occur in MAFLD. Substantial epidemiological evidence indicates that MAFLD is not only associated with an increased risk of liver-related complications, but also increases the risk of developing several extra-hepatic diseases, including new-onset T2DM, adverse cardiovascular and renal outcomes, and some common endocrine diseases. We have summarized the current literature on the adverse effect of MAFLD on the development of multiple extrahepatic (cardiometabolic and endocrine) complications and examined the role of different metabolic pathways and organ systems in the progression of MAFLD, thus providing new insights into the role of MAFLD as a multisystem metabolic disorder. Our narrative review aimed to provide insights into potential mechanisms underlying the known associations between MAFLD and extrahepatic diseases, as part of MAFLD as a multisystem disease, in order to help focus areas for future drug development targeting not only liver disease but also the risk of extrahepatic complications., (© 2024. Asian Pacific Association for the Study of the Liver.)

Background: Obesity represents a major global health challenge with important clinical implications. Despite its recognized importance, the global disease burden attributable to high body mass index (BMI) remains less well understood., Methods: We systematically analyzed global deaths and disability-adjusted life years (DALYs) attributable to high BMI using the methodology and analytical approaches of the Global Burden of Disease Study (GBD) 2021. High BMI was defined as a BMI over 25 kg/m 2 for individuals aged ≥20 years. The Socio-Demographic Index (SDI) was used as a composite measure to assess the level of socio-economic development across different regions. Subgroup analyses considered age, sex, year, geographical location, and SDI., Findings: From 1990 to 2021, the global deaths and DALYs attributable to high BMI increased more than 2.5-fold for females and males. However, the age-standardized death rates remained stable for females and increased by 15.0% for males. Similarly, the age-standardized DALY rates increased by 21.7% for females and 31.2% for males. In 2021, the six leading causes of high BMI-attributable DALYs were diabetes mellitus, ischemic heart disease, hypertensive heart disease, chronic kidney disease, low back pain and stroke. From 1990 to 2021, low-middle SDI countries exhibited the highest annual percentage changes in age-standardized DALY rates, whereas high SDI countries showed the lowest., Interpretation: The worldwide health burden attributable to high BMI has grown significantly between 1990 and 2021. The increasing global rates of high BMI and the associated disease burden highlight the urgent need for regular surveillance and monitoring of BMI., Funding: National Natural Science Foundation of China and National Key R&D Program of China., Competing Interests: Christopher D. Byrne has received grant support from Echosens. Ming-Hua Zheng has received honoraria for lectures from AstraZeneca, Hisky Medical Technologies and Novo Nordisk, consulting fees from Boehringer Ingelheim. Anoop Misra has received honoraria from Novo Nordisk, AstraZendeca, Janssen, and Boehringer Ingelheim. Wah-Kheong Chan is a consultant or advisory board member for Abbott, Roche, Abbvie, Boehringer Ingelheim and Novo Nordisk; and a speaker for Abbott, Novo Nordisk, Echosens, Viatris and Hisky Medical. No other disclosures were reported; John D. Ryan received consultancy fees from Falk, Gilead, Pfizer and a speaker honorarium from Takeda. Christos S. Mantzoros reports grants through his institution from Merck, Massachusetts Life Sciences Center and Boehringer Ingelheim, has received grants through his Institution and personal consulting fees from Coherus Inc. and AltrixBio, he reports personal consulting fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal consulting fees from Olympus, Genfit, Lumos, Novo Nordisk, Amgen, Biodexa, Laekna, Corcept, Intercept, 89 Bio, Madrigal, Aligos, Esperion and Regeneron, travel support and fees from UptoDate, TMIOA, Elsevier, and the Cardio Metabolic Health Conference. The other authors report no disclosure., (© 2024 The Author(s).)

Background: Previous studies have reported an association between metabolic dysfunction-associated steatotic liver disease (MASLD) and the risk of serious bacterial infections. However, the magnitude of the risk and whether this risk varies with the severity of MASLD remains uncertain. We performed a meta-analysis of observational studies to quantify the association between MASLD and serious bacterial infections requiring hospital admission., Methods: We systematically searched PubMed, Scopus, Web of Science and Embase from database inception to 1 April 2024, using predefined keywords to identify studies examining the risk of serious bacterial infections among individuals with and without MASLD. MASLD was diagnosed using liver biopsy, imaging or International Classification of Diseases codes. Meta-analysis was performed using random-effects modelling., Results: We identified six cross-sectional and two prospective cohort studies with aggregate data on ~26.6 million individuals. MASLD was significantly associated with higher odds of serious bacterial infections (pooled random-effects odds ratio 1.93, 95% confidence interval [CI] 1.44-2.58; I 2  = 93%). Meta-analysis of prospective cohort studies showed that MAFLD was associated with an increased risk of developing serious bacterial infections (pooled random-effects hazard ratio 1.80, 95% CI 1.62-2.0; I 2  = 89%). This risk further increased across the severity of MASLD, especially the severity of fibrosis (pooled random-effects hazard ratio 2.42, 95% CI 1.89-2.29; I 2  = 92%). These results remained significant after adjusting for age, sex, obesity, diabetes and other potential confounders. Sensitivity analyses did not modify these findings. The funnel plot did not reveal any significant publication bias., Conclusions: This meta-analysis shows a significant association between MASLD and an increased risk of serious bacterial infections requiring hospital admission., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background and Aim: We examined whether a plasma ceramide-based risk score (CERT1 score), a newly proposed tool for cardiovascular risk prediction, is associated with an increased risk of all-cause mortality and nonfatal myocardial infarction in patients with suspected or known coronary artery disease (CAD)., Methods and Results: We studied 167 ambulatory patients who consecutively underwent stress myocardial perfusion scintigraphy (MPS) for clinical reasons in 2017 (at baseline) and then followed for a median of 6 years (inter-quartile range: 4.7-6.6 years). For the calculation of the CERT1 score, both before and after stress MPS, we measured three specific plasma ceramide concentrations [Cer(d18:1/16:0), Cer(d18:1/18:0) and Cer(d18:1/24:1)] and their ratio to Cer(d18:1/24:0) using a targeted liquid chromatography-tandem mass spectrometry assay. The primary outcome of the study was a composite of all-cause mortality or nonfatal myocardial infarction. During a median of 6 years, a total of 50 events occurred (26 all-cause deaths and 24 nonfatal myocardial infarctions). There was a significant association between pre-stress CERT1 risk categories (high vs. low risk) at baseline and the risk of developing the primary composite outcome (unadjusted HR 1.78, 95% CI 1.02-3.14). This risk remained significant after adjustment for age, sex, smoking, diabetes, pre-existing CAD, left ventricular ejection fraction, and stress-induced inducible myocardial ischemia on MPS (adjusted HR 2.28, 95% CI 1.17-4.41, p = 0.015). Almost identical results were observed for post-stress CERT1 risk categories., Conclusions: Pre-stress and post-stress CERT1 high-risk categories at baseline were strongly associated with an increased long-term risk of all-cause mortality or nonfatal myocardial infarction in patients with suspected or established CAD., Competing Interests: Declaration of competing interest The authors declare they have no competing interests., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Aim: To analyse the association between serum bile acid (BA) profile and heart failure (HF) with preserved ejection fraction (HFpEF) in patients with metabolic dysfunction-associated fatty liver disease (MAFLD)., Methods: We enrolled 163 individuals with biopsy-proven MAFLD undergoing transthoracic echocardiography for any indication. HFpEF was defined as left ventricular ejection fraction >50% with at least one echocardiographic feature of HF (left ventricular diastolic dysfunction, abnormal left atrial size) and at least one HF sign or symptom. Serum levels of 38 BAs were analysed using ultra-performance liquid chromatography coupled with tandem mass spectrometry., Results: Among the 163 patients enrolled (mean age 47.0 ± 12.8 years, 39.3% female), 52 (31.9%) and 43 (26.4%) met the HFpEF and pre-HFpEF criteria, and 38 serum BAs were detected. Serum ursodeoxycholic acid (UDCA) and hyocholic acid (HCA) species were lower in patients with HFpEF and achieved statistical significance after correction for multiple comparisons. Furthermore, decreases in glycoursodeoxycholic acid and tauroursodeoxycholic acid were associated with HF status., Conclusions: In this exploratory study, specific UDCA and HCA species were associated with HFpEF status in adults with biopsy-confirmed MAFLD., (© 2024 John Wiley & Sons Ltd.)

Background: Fibrotic metabolic dysfunction-associated steatohepatitis (MASH) is a condition at risk of progressing to advanced liver disease. We examined whether an innovative exhaled nitric oxide (eNO) breath test (BT) can accurately diagnose fibrotic MASH without requiring blood tests., Methods: One hundred and forty-seven patients with MASH were recruited, and all tests were undertaken within 1 week of recruitment. With fibrotic MASH (NAS ≥ 4 and fibrosis stage ≥ 2) as the main outcome indicator, the diagnostic efficacy of eNO in identifying fibrotic MASH was compared to other validated models for advanced fibrosis requiring venesection, namely FAST, Agile 3 + , and FIB-4 scores., Results: The mean age was 40.36 ± 12.28 years, 73.5% were men. Mean body mass index was 28.83 ± 4.31 kg/m 2 . The proportion of fibrotic MASH was 29.25%. The area under the receiver operating curve for eNO in diagnosing fibrotic MASH was 0.737 [95% CI 0.650-0.823], which was comparable to FAST (0.751 [0.656-0.846]), Agile 3 + (0.764 [0.670-0.858]), and FIB-4 (0.721 [0.620-0.821]) (all DeLong test p  > 0.05). A cut-off of eNO <8.5 ppb gave a sensitivity of 86.0% and a negative predictive value of 88.5% for ruling-out fibrotic MASH. A cut-off of eNO >13.5 ppb provided a specificity of 91.3% and a positive predictive value of 65.4% for ruling-in fibrotic MASH. Sensitivity analyses demonstrated that the diagnostic efficacy of eNO was similar across characteristics such as age. Moreover, adding vibration-controlled transient elastography-LSM (liver stiffness measurement) reduced the uncertainty interval from 46.9% to 39.5%., Conclusions: The eNO-BT is a promising simple test for non-invasively identifying fibrotic MASH, and its performance is further improved by adding LSM measurement.

Aims: To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC)., Materials and Methods: We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS)., Results: GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD., Conclusions: GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis., (© 2024 John Wiley & Sons Ltd.)

Metabolic dysfunction-associated fatty liver disease (MAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD), has become the leading cause of chronic liver disease worldwide. Optimal dietary intervention strategies for MAFLD are not standardized. This study aimed to achieve consensus on prevention of MAFLD through dietary modification. A multidisciplinary panel of 55 international experts, including specialists in hepatology, gastroenterology, dietetics, endocrinology and other medical specialties from six continents collaborated in a Delphi-based consensus development process. The consensus statements covered aspects ranging from epidemiology to mechanisms, management, and dietary recommendations for MAFLD. The recommended dietary strategies emphasize adherence to a balanced diet with controlled energy intake and personalized nutritional interventions, such as calorie restriction, high-protein, or low-carbohydrate diets. Specific dietary advice encouraged increasing the consumption of whole grains, plant-based proteins, fish, seafood, low-fat or fat-free dairy products, liquid plant oils, and deeply colored fruits and vegetables. Concurrently, it advised reducing the intake of red and processed meats, saturated and trans fats, ultra-processed foods, added sugars, and alcohol. Additionally, maintaining the Mediterranean or DASH diet, minimizing sedentary behavior, and engaging in regular physical activity are recommended. These consensus statements lay the foundation for customized dietary guidelines and proposing avenues for further research on nutrition and MAFLD., Competing Interests: Declaration of competing interest Christos S. Mantzoros has recused himself as EIC from handling this manuscript, reports grants through his institution from Merck, Massachusetts Life Sciences Center and Boehringer Ingelheim, has received grants through his Institution and personal consulting fees from Coherus Inc. and AltrixBio, he reports personal consulting fees and support with research reagents from Ansh Inc., collaborative research support from LabCorp Inc., reports personal consulting fees from Olympus, Genfit, Lumos, Novo Nordisk, Amgen, Biodexa, Laekna, Corcept, Intercept, 89 Bio, Madrigal, Aligos, Esperion and Regeneron, travel support and fees from UptoDate, TMIOA, Elsevier, and the Cardio Metabolic Health Conference. Ming-Hua Zheng has received honoraria for lectures from AstraZeneca, Hisky Medical Technologies, and Novo Nordisk and consulting fees from Boehringer Ingelheim and serves as a consultant for Eieling Technology. Christopher D Byrne has received an independent research grant from Echosens. France. W. Kim received honoraria for lectures from GSK, Hanmi, KOBIOLABS, and Novo Nordisk; consulting fees from Boehringer-Ingelheim, GSK, Novo Nordisk, Ildong, YUHAN, Hanmi, HK Inoen, Standigm, PharmaKing, Olix Pharma, TSD Life Sciences, Daewoong, QUEST, Therasid Bioscience, and Korea United Pharm; grants from GSK, Gilead, Novartis, Pfizer, Roche, Springbank, Ildong, BMS, DaeWoong, Hanmi, Novo Nordisk, Galmed, Enyo, and KOBIOLABS; stock options from KOBIOLABS and Lepidyne; and founded Remedygen outside the submitted work. Anoop Misra has received honorarium for lectures from Astra Zendeca, Boehringer Ingelgheim, Janssen, Lupin, Novo Nordisk and US Vitamins. Yusuf Yilmaz has served as a consultant or advisory board member for Zydus and Novo Nordisk. Boehringer Ingelheim. Wah Kheong Chan has served as a consultant or advisory board member for Abbott, Roche, Abbvie, Boehringer Ingelheim and Novo Nordisk; and a speaker for Abbott, Novo Nordisk, Echosens, Viatris and Hisky Medical. Ming-Lung Yu has received research support (grant) from Abbvie, BMS, Gilead, Merck and Roche diagnostics, served as a consultant of Abbott, Abbvie, BMS, Gilead, Roche and Roche diagnostics, and speaker of Abbvie, BMS, Eisai, Gilead, Roche and Roche diagnostics. Vincent Wong has served as a consultant or advisory board member for AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Intercept, Inventiva, Novo Nordisk, Pfizer, Sagimet Biosciences, TARGET PharmaSolutions, and Visirna; and a speaker for Abbott, AbbVie, Echosens, Gilead Sciences, Novo Nordisk, and Unilab. He has received a research grant from Gilead Sciences, and is a co-founder of Illuminatio Medical Technology. Giada Sebastiani has acted as speaker for Merck, Gilead, Abbvie, Novo Nordisk, Pfizer, served as an advisory board member for Pfizer, Merck, Novo Nordisk, Gilead, and has received unrestricted research funding from Theratecnologies Inc. Jacob George has served on advisory Boards and receives honoraria for talks from Novo Nordisk, Astra Zeneca, Roche, BMS, Pfizer, Cincera, Pharmaxis, Boehringer Mannheim, CSL, Gilead, Eisai. Carolyn Newberry serves as a consultant for Nestle Nutrition Sciences. The other authors declare no conflict of interest related to the preparation of this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: Non-invasive diagnostics for metabolic dysfunction-associated fatty liver disease (MAFLD) remain challenging. We aimed to identify novel key genes as non-invasive biomarkers for MAFLD, elucidate causal relationships between biomarkers and MAFLD and determine the role of immune cells as potential mediators., Materials and Methods: Utilizing published transcriptome data of patients with biopsy-proven MAFLD, we applied linear models for microarray data, least absolute shrinkage and selector operation (LASSO) regressions and receiver operating characteristic (ROC) curve analyses to identify and validate biomarkers for MAFLD. Using the expression quantitative trait loci database and a cohort of 778 614 Europeans, we used Mendelian randomization to analyse the causal relationships between key biomarkers and MAFLD. Additionally, mediation analysis was performed to examine the involvement of 731 immunophenotypes in these relationships., Results: We identified 31 differentially expressed genes, and LASSO regression showed three hub genes, IGFBP2, PEG10, and P4HA1, with area under the receiver operating characteristic (AUROC) curve of 0.807, 0.772 and 0.791, respectively, for identifying MAFLD. The model of these three genes had an AUROC of 0.959 and 0.800 in the development and validation data sets, respectively. This model was also validated using serum-based enzyme-linked immunosorbent assay data from MAFLD patients and control subjects (AUROC: 0.819, 95% confidence interval: 0.736-0.902). PEG10 was associated with an increased MAFLD risk (odds ratio = 1.106, p = 0.032) via inverse variance-weighted analysis, and about 30% of this risk was mediated by the percentage of CD11c + CD62L- monocytes., Conclusions: The MAFLD panels have good diagnostic accuracy, and the causal link between PEG10 and MAFLD was mediated by the percentage of CD11c + CD62L- monocytes., (© 2024 John Wiley & Sons Ltd.)