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Aims: Fibroblast growth factor 21 (FGF21) decreases hepatic lipogenesis in animal models, and FGF21 analogues decrease serum triglycerides (TG) in adults in phase-2 trials. On the other hand, serum FGF21 is associated with higher TG in observational studies of people with obesity, raising a sort of paradox. We tested the hypothesis that FGF21 is induced by TG in youth with obesity, as a compensatory mechanism., Materials and Methods: We recruited 159 children/adolescents with obesity (80 males, 12.7 ± 2.1 years). Besides serum FGF21 and lipid dosages, we genotyped the Pro446Leu variant at glucokinase regulator (GCKR) as a known marker of genetically increased hepatic de novo lipogenesis, and we used it as an instrumental variable to establish a cause-and-effect relationship between FGF21 and TG, according to a Mendelian randomization analysis., Results: The Pro446Leu variant increased circulating TG (β = +0.35, p < 0.001), which was positively associated with circulating FGF21 (β = +0.42, p < 0.001). The Pro446Leu variant increased FGF-21 (β = +0.14, p = 0.031) with the expected slope (β-coefficient) in case of association entirely mediated by TG: 0.35 (slope between Pro446Ala and TG) × 0.42 (slope between TG and FGF21) = 0.14., Conclusions: Hepatic lipogenesis, marked by GCKR-modulated triglycerides, is significantly associated with increased serum FGF-21 in children/adolescents with obesity., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: The global burden of metabolic diseases is increasing, but estimates of their impact on primary liver cancer are uncertain. We aimed to assess the global burden of primary liver cancer attributable to metabolic risk factors, including high body mass index (BMI) and high fasting plasma glucose (FPG) levels, between 1990 and 2021., Methods: The total number and age-standardized rates of deaths and disability-adjusted life years (DALYs) from primary liver cancer attributable to each metabolic risk factor were extracted from the Global Burden of Disease Study 1990-2021. The metabolic burden trends of liver cancer across regions and countries by sociodemographic index (SDI) and sex were estimated. The annual percentage changes in age-standardized DALYs rate were also calculated., Results: Globally, in 2021, primary liver cancer attributable to high BMI and/or high FPG was estimated to have caused 59,970 deaths (95% uncertainty interval [UI]: 20,567 to 104,103) and 1,540,437 DALYs (95% UI: 540,922 to 2,677,135). The age-standardized rates of death and DALYs were 0.70 (95% UI: 0.24 to 1.21) and 17.64 (95% UI: 6.19 to 30.65) per 100,000 person-years. A consistent global rise in liver cancer attributable to metabolic risks was observed from 1990 to 2021, with high BMI identified as the major contributing risk factor. The highest burden of deaths and DALYs of liver cancer consistently occurred in high SDI countries, while the fastest growth trends were observed in low-middle SDI countries. The burdens of high levels of BMI and FPG were higher in men than in women., Conclusions: Primary liver cancer attributable to high BMI and/or high FPG imposes an increasingly substantial clinical burden on global public health, particularly in high SDI countries. Rapid growth trends are also found in middle-SDI countries., (Copyright © 2025 by The American College of Gastroenterology.)

Background and Aim: Fibrosis-4 (FIB-4) index is a widely used test for non-invasively assessing liver fibrosis. We aimed to investigate the association between FIB-4 index and risk of all-cause mortality in patients at high cardiovascular (CV) risk and to determine whether coexisting renal dysfunction mediates this association., Methods and Results: Single-center prospective study of 994 patients with established or suspected coronary artery disease undergoing coronary angiography, followed for a median of 44 months. Mortality data were obtained through the Italian Health Card Database. At baseline, the median FIB-4 index was greater in deceased vs. alive patients (1.71 vs. 1.38, p < 0.001) and in those with reduced eGFR than in those with normal eGFR (1.65 vs. 1.37, p < 0.001). For each unit increase in the baseline log-FIB-4 index, the risk of all-cause mortality sharply increased during the follow-up (hazard ratio [HR] 2.31, 95%CI 1.31-4.08, p = 0.004). Similarly, assuming the lowest baseline FIB-4 risk category as the reference, the risk of all-cause mortality progressively increased across the indeterminate (HR 1.82, 95%CI 1.18-2.82, p = 0.007) and the highest baseline FIB-4 risk categories (HR 2.33, 95%CI 1.37-3.97; p = 0.002). A causal mediation analysis showed that about one-third of the effect of FIB-4 index on mortality risk was mediated by reduced eGFR (32.8 %, p = 0.01)., Conclusions: Increased FIB-4 index predicts the long-term risk of all-cause mortality in patients at high CV risk, and this risk is, at least in part, mediated by reduced eGFR. Further prospective studies are needed to confirm these findings., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (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.)

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a public health threat as it affects approximately 38% of the adult population worldwide, with its prevalence rising in step with that of obesity and type 2 diabetes. Beyond the implications of MASLD for liver health, it is also associated with cardiovascular and vascular dysfunction. Although the many shared risk factors and common metabolic milieu might indicate that cardiovascular disease and MASLD are discrete outcomes from common systemic pathogeneses, a growing body of evidence has identified a potential causal relationship between MASLD and coronary artery disease, which is the leading cause of morbidity and mortality in people with MASLD and all-cause mortality worldwide. This Review takes an interdisciplinary approach, drawing on hepatology, cardiology, endocrinology, and metabolic and internal medicine specialists to help to delineate the intricate interplay between MASLD and coronary artery disease. It sheds light on novel opportunities for targeted interventions and personalised management strategies., Competing Interests: Declaration of interests JVL has received grant funding from AbbVie, Boehringer Ingelheim, Echosens, Gilead Sciences, Madrigal, Merck, Sharp, & Dohme (MSD), Novo Nordisk, Pfizer, and Roche Diagnostics; consulting fees from Echosens, Novovax, GlaxoSmithKline, Novo Nordisk, and Pfizer; payment or honoraria for presentations from AbbVie, Echosens, Gilead Sciences, Janssen, Moderna, MSD, Novo Nordisk, and Pfizer; participated on a data safety monitoring board or advisory board; had a leadership or fiduciary role on Healthy Livers, Health Livers (formed by AASLD, ALEH, APASL, EASL, and Global NASH Council); and was HIV Outcomes co-chair, all unrelated to the current study. PNB has received grant funding for the National Institute for Health and Care Research (NIHR); consulting fees for Resolution Therapeutics; payment or honoraria for presentations from Takeda; support for attending meetings for EASL Bursary for EASL International Liver Conference 2024 and EASL Bursary for School of Hepatology, Steatotic Liver Disease, Aarhus; and leadership or fiduciary role in the Global NASH Council; all unrelated to the current study. CCL has received grant funding from the British Heart Foundation, UK Research and Innovation, NIHR, Chief Scientist Office, European Commission, Juvenile Diabetes Research Foundation, Applied Therapeutics, Anacardia, AstraZeneca, Boehringher Ingelheim, Eli Lilly, Moderna, Roche Diagnostics, Novo Nordisk, and Novartis; and has participated on a data safety monitoring board or advisory board with The International Coronary Microvascular Angina study, TIME Study, and the Dapagliflozin, Exercise Training and physicAl function: the DETA trial; all unrelated to the current study. SSV received grant funding from the Department of Veterans Affairs, National Institutes of Health, UK NIHR, Tahir and Jooma Family, and Asharia Family, all unrelated to the current study. CJL has received payment or honoraria for presentations from Amgen, Global Organization for EPA and DHA Omega-3s, and Diagnostic and Statistical Manual of Mental Disorders; and participated on a data safety monitoring board or advisory board with Novo Nordisk; all unrelated to the current study. SI has received payment for expert testimonies and had a leadership or fiduciary role on the American Association of Clinical Endocrinology, all unrelated to the current study. KC received grant funding from Boehringer Ingelheim, Echosens, Inventiva, LabCorp, Perspectum, and Target-NASH; and consulting fees from Aligos Therapeutics, Arrowhead, AstraZeneca, 89Bio, Bristol Myers Squibb, Boehringer Ingelheim, Covance, Eli Lilly & Co, Molecular Genetics & Genomic Medicine, Novo Nordisk, Prosciento, Sagimet Biosciences, Siemens USA, and Terns Pharma, all unrelated to the current study. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Studies have reported an association between metabolic dysfunction-associated steatotic liver disease (MASLD) and an increased risk of developing atrial fibrillation (AF). However, the magnitude of the risk and whether this risk varies with the severity of MASLD remains uncertain., Methods: In this systematic review and meta-analysis, we searched three large electronic databases using predefined keywords to identify cohort studies (published up to 30 September 2024) in which MASLD was diagnosed by liver biopsy, imaging methods, International Classification of Diseases (ICD) codes, or blood-based scores. The primary outcome was the occurrence of AF based on ICD codes, medical records, or electrocardiograms. Meta-analysis was performed using random-effects modelling., Results: We identified 16 retrospective cohort studies with aggregate data on ~19.5 million individuals followed for a median of 7.2 years. MASLD was significantly associated with an increased risk of developing incident AF (random-effects hazard ratio 1.20, 95% CI 1.10-1.32; I 2  = 92%). This risk did not appear to further increase with the severity of liver fibrosis (n = 3 studies; random-effects hazard ratio 1.22, 95% CI 1.18-1.26; I 2  = 10%). The risk of AF remained significant even after adjusting for age, sex, body mass index, hypertension, Type 2 diabetes or other cardiometabolic risk factors. Sensitivity analyses did not modify these findings. The funnel plot and Egger's test showed no significant publication bias., Conclusions: This updated and comprehensive meta-analysis provides evidence that MASLD is significantly associated with an increased long-term risk of developing incident AF. Further research is required to better decipher the link between MASLD and increased AF incidence., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)