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Background: The Weight-Adjusted Waist Index (WWI) is a novel indicator of obesity that accurately reflects body composition. However, the association between WWI and depression in patients with non-alcoholic fatty liver disease (NAFLD) remains unclear. This study aims to explore this relationship through a nationally representative cross-sectional analysis., Methods: This study included adult participants diagnosed with NAFLD from NHANES 2017-2020. WWI was calculated as the waist circumference (cm) divided by the square root of body weight (kg). NAFLD diagnosis relied on vibration-controlled transient elastography (VCTE) with a controlled attenuation parameter (CAP) exceeding 248 dB/m to indicate hepatic steatosis. Depression was assessed using the Patient Health Questionnaire-9 (PHQ-9), with scores ≥ 10 indicating the presence of major depression., Results: After adjusting for all covariates, a significant positive association was found between WWI and depression in NAFLD (OR = 1.725, 95% CI: 1.442-2.063, p < 0.00001), with a dose-response relationship indicated by restricted cubic spline analysis. The association was stronger in men and lean/normal weight NAFLD patients. Adjusting further for BMI did not alter these findings (OR = 1.643, 95% CI: 1.357-1.989, p < 0.00001). BMI's association with depression was negated after adjusting for WWI., Conclusions: WWI had a positive association with depression in NAFLD, independent of BMI. This association was more pronounced in men and lean/normal weight NAFLD. These findings suggest that WWI may be a novel indicator of depression in NAFLD and potentially valuable in depression prevention., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

The relationship between depression and severe non-alcoholic fatty liver disease (NAFLD) has not been clearly defined. We conducted a longitudinal cohort study and a two-sample Mendelian randomization (MR) analysis to assess the association of depression with severe NAFLD risk. We used individual data from the UK Biobank study with 481,181 participants, and summary data from published genome-wide association studies. The association between depression and severe NAFLD was assessed using Cox proportional hazards regression analysis. Two-sample MR for depression with NAFLD was conducted, the principal analysis employed the inverse variance weighted (IVW) approach. In the observational study, after a median follow-up of 13.46 years, 4,563 participants had severe NAFLD. In multivariable-adjusted model, participants with depression had an increased risk of severe NAFLD (hazards ratio:1.21, 95% confidence interval (CI):1.09-1.34), as compared to those without depression. In subgroup analyses, the association between depression and severe NAFLD risk was generally observed across different subgroups. For the MR, result also showed that genetically predicted depression was causally associated with a higher risk of NAFLD (odds ratio:1.55, 95%CI:1.10-2.19) in IVW. Our study revealed a prospective association of depression with severe NAFLD, thus potentially necessitating clinical monitoring of individuals with depression for severe NAFLD., Competing Interests: Declarations Competing interests The authors declare no competing interests. Ethical approval The UK Biobank study has approval from the North West Multi-centre Research Ethics Committee, all methods were performed in accordance with the relevant guidelines and regulations, and all participants provided written informed consent. As our MR study was based on publicly available data, no additional ethical approval or consent was required., (© 2024. The Author(s).)

Background: There is currently limited evidence comparing the association between metabolic dysfunction-associated fatty liver disease (MAFLD), nonalcoholic fatty liver disease (NAFLD), and the risk of peripheral artery disease (PAD). This study aims to analyze the associations of MAFLD and NAFLD with incident PAD., Methods and Results: Two longitudinal studies, the UKB (UK Biobank) study (n=372 216) and the ARIC (Atherosclerosis Risk in Communities) study (n=4681), categorized participants into MAFLD/non-MAFLD groups and NAFLD/non-NAFLD groups. Subsequently, participants were classified into 4 groups: non-fatty liver disease, MAFLD-only, NAFLD-only, and both MAFLD and NAFLD groups. Cox proportional hazard model estimated associations of MAFLD/NAFLD status, subtypes, and liver fibrosis severity with PAD risk. The MAFLD group had a higher risk of incident PAD compared with the non-MAFLD group, and similarly, the NAFLD group had a higher risk compared with the non-NAFLD group. Among these 4 groups, the MAFLD-only group had the strongest association with the risk of incident PAD, while the NAFLD-only group was not independently associated. Diabetic MAFLD subtype was significantly associated with increased PAD risk, and higher level of liver fibrosis scores correlated with elevated PAD risk., Conclusions: Both MAFLD and NAFLD are significantly associated with an increased incidence of PAD, with stronger associations in MAFLD and diabetic MAFLD population. These findings emphasize that the need for screening and prevention strategies for PAD in this high-risk population is warranted. The assessment of MAFLD and its subtypes should be considered as an integral component of cardiovascular risk assessment.

In recent years, with the decline in HBV and HCV infections, there has been a corresponding reduction in both the morbidity and mortality of virus-associated HCC. Nevertheless, rising living standards, coupled with the increasing prevalence of metabolic disorders like diabetes and obesity, have led to a rapid surge in non-alcoholic fatty liver disease-associated hepatocellular carcinoma (NAFLD-HCC) incidence. The mechanisms underlying the progression from NAFLD to NAFLD-HCC are multifaceted and remain incompletely understood. Current research suggests that genetic predisposition, metabolic dysregulation, lipotoxicity, oxidative stress, and inflammation are key contributing factors. Given the complexity of these mechanisms and the frequent occurrence of metabolic comorbidities like type 2 diabetes mellitus (T2DM) and cardiovascular disease in NAFLD-HCC patients, there is a pressing need for tailored therapeutic strategies, along with novel prevention, monitoring, and treatment approaches that are personalized to the patient's pathophysiology. Due to the limited depth of research, incomplete understanding of pathogenesis, and insufficient clinical data on NAFLD-HCC treatment, current therapeutic approaches largely rely on tumor staging. In this review, we synthesize current research on the pathogenesis, surveillance, diagnosis, treatment, and prevention of NAFLD-HCC, and offer perspectives for future studies, particularly regarding its underlying mechanisms.

Purpose of Review: Provide a concise update on metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), as well as a practical approach to screening and initial evaluation., Recent Findings: Nomenclature changes have placed a greater focus on cardiometabolic risk factors in the definition of MASLD. Screening for MASLD is by stepwise noninvasive serum and imaging tests which can identify patients at risk for advanced fibrosis and liver-related complications. MASLD has been increasing in prevalence and disease burden but is underrecognized in primary care and endocrinology clinics. Multiple society guidelines, synthesized here, provide a framework for the initial approach in the diagnosis and evaluation of MASLD. Recent advances in pharmacologic treatment underline the importance of screening for patients who are at risk for advanced fibrosis as they are most likely to benefit from new drug classes, such as the liver-directed thyroid receptor agonist resmiterom., Competing Interests: Declarations Human and Animal Rights This article does not contain any studies with human or animal subjects performed by any of the authors. Competing Interests The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with liver inflammation, fibrosis, and cirrhosis and is associated with a greater risk of hepatocarcinoma. Nonalcoholic steatohepatitis (NASH) is a persistent and progressive form of NAFLD. Recent evidence suggested that ertugliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2), suppresses NAFLD development in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to determine the impact of ertugliflozin on improving NAFLD in patients with T2DM and the function of liver enzymes., Methods: This prospective, randomized, double-blind, placebo-controlled, interventional study aimed to determine the effectiveness of 15 mg of ertugliflozin versus 30 mg of the standard therapy pioglitazone versus placebo in NAFLD patients with T2DM. The study was established based on patient randomization in three groups: ertugliflozin, pioglitazone, and a placebo. This study was registered under the Australian New Zealand Clinical Trial Registry (Trial ID: ACTRN12624000032550)., Results: The impact of therapy was determined in the treatment groups by utilizing liver ultrasonography and biochemical parameters. After 24 weeks of clinical study, the results revealed significant improvement in the grades of fatty liver, especially in the ertugliflozin group. The number of patients with hepatic steatosis significantly decreased among the respective groups classified according to fatty liver grade. Among patients in the ertugliflozin and pioglitazone groups, 45% to 23.4% and 41.7% to 26.6%, respectively, decreased in the Grade 2 group. The aspartate aminotransferase and alanine aminotransferase levels were significantly lower in all the study groups, especially in the ertugliflozin group (P ≤ .001)., Conclusion: The present study revealed that the concomitant use of ertugliflozin has favorable effects on liver enzymes, as it decreases liver fat intake and reduces complications in patients with NAFLD-associated T2DM. However, more in-depth studies will be required to observe every aspect of ertugliflozin., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The prevalence of steatotic liver disease (SLD) in patients with type 2 diabetes (T2DM) exceeds 50%. This study aimed to investigate the clinical characteristics of SLD and liver fibrosis in Chinese patients with T2DM., Methods: Inpatients from 2021 to 2023 were included in the study. Fatty liver index (FLI) and fibrosis-4 (FIB-4) were calculated to assess hepatic steatosis and fibrosis respectively. Statistical analysis was completed by SPSS v25 and GraphPad Prism v8.0.1., Results: Of the 1466 participants, about one-third of the patients in T2DM-SLD group were diagnosed with liver fibrosis (LF), and the percentage of patients over 50 years old was 85.9%. Patients with SLD had higher levels of BMI, blood pressure, liver enzymes, fasting blood glucose (FBG), HbA1c, C-peptide, total cholesterol (TC) and triglyceride (TG) (P<0.05 for all). Patients with liver fibrosis had lower TC, TG, hemoglobin (Hb), erythrocyte count (RBC), leukocyte count (WBC) and platelet (PLT) levels (P<0.05 for all). Compared with simple T2DM and SLD-NLF (non-liver fibrosis) groups, for patients over 50 years old, the prevalence of coronary heart disease, stroke, tumor, and diabetic nephropathy was higher in patients with liver fibrosis. Liver fibrosis might be the risk factor of arterial stiffness, stroke, coronary heart disease and numbness based on multivariable logistic regression analysis., Conclusion: Hepatic steatosis and fibrosis were common in patients with T2DM. Liver fibrosis was relevant to many macrovascular and microvascular diabetic complications., (© 2024. The Author(s).)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with an unhealthy lifestyle. However, there is limited prospective evidence regarding the association between combined lifestyle factors and MASLD. This study aims to test the association of a combination of lifestyle components, expressed as a healthy lifestyle index (HLI), and unhealthful eating behavior habits with MASLD, insulin resistance (IR), liver fibrosis, and metabolic dysfunction-associated steatohepatitis., Methods: A prospective cohort study was conducted among participants of metabolic and hepatic screening surveys. MASLD was evaluated by ultrasonography or controlled attenuation parameter at 2 time points to assess new-onset, persistence, or remission, and IR was estimated by homeostasis model assessment. Presumed liver fibrosis and metabolic dysfunction-associated steatohepatitis were evaluated using FibroMax biomarkers. The HLI was calculated as the sum of 4 lifestyle components: nonsmoking, healthy weight, healthy diet, and physical activity., Results: The final cohort included 315 subjects with 6.7 years of follow-up, 40-70 years old. In multivariable analyses, a favorable lifestyle (≥3 components) was independently associated with lower odds of new-onset MASLD (OR = 0.42; 95% CI: 0.19-0.90). Similarly, a favorable lifestyle was associated with lower odds of new-onset/persistent (vs. never/remission) MASLD and IR, respectively (OR = 0.49; 95% CI: 0.30-0.80; OR = 0.40; 95% CI: 0.24-0.66). There was a dose-response association between HLI and new-onset/persistent MASLD and IR. A favorable lifestyle was associated with lower odds of new-onset metabolic dysfunction-associated steatohepatitis (OR = 0.50; 95% CI: 0.27-0.95). Adjusting for HLI, unhealthful eating behavior habits were associated with higher odds of MASLD prevalence (OR = 1.81; 95% CI: 1.07-3.06)., Conclusions: Adherence to a healthy lifestyle is prospectively associated with lower odds of MASLD, markers of liver damage, and IR. A holistic approach that considers overall lifestyle and eating behavior may be useful for preventing MASLD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Steatotic liver disease is the overarching term for conditions characterised by abnormal lipid accumulation in the liver (liver or hepatic steatosis). Steatotic liver disease encompasses what was previously termed non-alcoholic fatty liver disease (NAFLD), which is now called metabolic dysfunction-associated steatotic liver disease (MASLD). Additionally, steatotic liver disease includes alcohol-related liver disease (ALD) and MetALD, the new classification for the overlap between MASLD and ALD, and rare causes of liver steatosis. Cirrhosis is globally the 11th leading cause of death, and steatotic liver disease has become the leading cause of cirrhosis in the EU and USA. Steatotic liver disease affects around 30% of the global population and is mainly driven by obesity, type 2 diabetes, and alcohol intake, but only a minor proportion with steatotic liver disease progress to cirrhosis. The presence and progression of liver fibrosis led by hepatic inflammation is the main predictor of liver-related death across the entire spectrum of steatotic liver diseases. A combination of recent advancements of widely available biomarkers for early detection of liver fibrosis together with considerable advancements in therapeutic interventions offer the possibility to reduce morbidity and mortality in patients with steatotic liver disease. This Seminar covers the recent reclassification of steatotic liver disease and how it reflects clinical practice and prognosis. For early detection of liver fibrosis, we propose a collaborative diagnostic framework between primary care and liver specialists. Lastly, we discuss current best practices for managing steatotic liver disease, we explore therapeutic targets across the spectrum of steatotic liver diseases, and we review the pipeline of drugs in development for MASLD., Competing Interests: Declaration of interests MI received travel support from Novo Nordisk for the 7730 ALD investigator meeting. SF holds a senior clinical investigator fellowship from the Research Foundation Flanders (1802154N); received institutional grants from Astellas, Falk Pharma, Genfit, Gilead Sciences, GlympsBio, Janssens Pharmaceutica, Inventiva, Merck Sharp & Dohme, Pfizer, and Roche; was a consultant for AbbVie, Actelion, Aelin Therapeutics, AgomAb, Aligos Therapeutics, Allergan, Alnylam, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, Coherus, Echosens, Dr Falk Pharma, Eisai, Enyo, Galapagos, Galmed, Genentech, Genfit, Genflow Biosciences, Gilead Sciences, Intercept, Inventiva, Janssens Pharmaceutica, PRO.MED.CS Praha, Julius Clinical, Madrigal, Medimmune, Merck Sharp & Dohme, Mursla Bio, NGM Bio, Novartis, Novo Nordisk, Promethera, Roche, and Siemens Healthineers; and has lectured for AbbVie, Allergan, Bayer, Eisai, Genfit, Gilead Sciences, Janssens Cilag, Intercept, Inventiva, Merck Sharp & Dohme, Novo Nordisk, Promethera, and Siemens. EAT served as a speaker for AbbVie, Dr Falk Pharma, Echosens, Novo Nordisk, and Orphalan, and participated in advisory boards for Alexion, Boehringer Ingelheim, Siemens, Merck Sharp & Dohme, Novo Nordisk, Pfizer, Orphalan, and Univar. AK served as a speaker for Novo Nordisk, Norgine, Siemens, and Nordic Bioscience; participated in advisory boards for Siemens, Boehringer Ingelheim, and Novo Nordisk, all outside the submitted work; received research support from Norgine, Siemens, Nordic Bioscience, Astra, Echosense; and is a board member and the co-founder of Evido., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background and Aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading indication for liver transplantation (LT), but also occurs after LT. The prevalence of de novo MASLD (dnMASLD) after LT, based on both surveillance (svLbx) and indication biopsies (indLbx), is unknown. Furthermore, the impact of the distinct cardiometabolic risk factors on histological disease activity has not been assessed. We aimed to evaluate the prevalence of dnMASLD and the association between the cardiometabolic risk factors and histological disease activity., Methods: We performed a retrospective single-center study in a LT cohort with indLbx and svLbx. Patients with NAFLD before LT were excluded., Results: We analyzed 249 patients who underwent either svLbx or indLbx. Forty-eight (19.2%) had either dnMASLD (n = 26/249, 10.4%) or metabolic dysfunction associated steatohepatitis (dnMASH) (n = 22/249, 8.8%). Although dnMASLD/dnMASH was more frequent in indLbx (35.1%, p < 0.01), still 16.5% of patients with svLbx had dnMASLD/dnMASH. While overweight (p < 0.01) and diabetes (p = 0.01) were more frequent in patients with dnMASH, only overweight was associated with histological disease activity in the multivariate analysis. No impact of dnMASLD on the overall survival was observed., Conclusion: While dnMASLD is more frequent in patients with indLBX, it also occurs in 16.5% of patients without signs of graft dysfunction. Overweight has the strongest impact on histological disease activity and should be monitored carefully after LT., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Background: In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), there are limited data on how changes in FIB4 and liver stiffness measurement (LSM) correlate in non-biopsy cohorts., Aims: Our objective was to evaluate associations between changes in FIB4 and LSM in MASLD patients., Methods: We included MASLD patients with serial VCTE from 2015-2022. The primary predictors were change in FIB4 and presence of diabetes, obesity, and high alanine aminotransferase (ALT). The primary outcome, applied only to patients with LSM1 < 8 kPa, was incident significant fibrosis (SF) defined as a ≥ 20% increase in LSM2 vs. LSM1 and LSM2 ≥ 8 kPa. A secondary outcome was LSM progression with a similar definition but applied to all participants, not only those with LSM1 < 8 kPa., Results: Of 285 included patients, 216 had LSM1 < 8 kPa and were included in the primary analysis; of these, 34 (16%) had incident SF. Changes in FIB4 correlated with changes in LSM (R = 0.16, p = 0.016). Independent predictors of incident SF included comorbid diabetes mellitus (OR 2.43, 95% CI 1.04-6.56), obesity (OR 3.88, 95% CI 1.63-9.25), and baseline ALT ≥ 30 (OR 8.55, 95% CI 1.10-66.29). A model including ALT, diabetes, and obesity outperformed a model with FIB4 change alone., Conclusion: Among patients with MASLD, changes in FIB4 correlated with changes in LSM but more significant correlates of incident significant fibrosis included diabetes mellitus, obesity, and high baseline ALT., Competing Interests: Declarations Conflict of interest VLC received grants from KOWA, Ipsen, and AstraZeneca (paid to his institution). The remaining authors have no conflicts of interest to disclose., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The primary objective of this study was to examine the association between iron overload (IO), metabolic dysfunction-associated steatotic liver disease (MASLD), and hepatic fibrosis. We hypothesized that there is a significant association. Data from the NHANES (2017-2020) were analyzed to explore IO's impact on MASLD and hepatic fibrosis in U.S. adults. We assessed serum ferritin, controlled attenuation parameter (CAP), liver stiffness measurement (LSM), and various covariates. Gene expression data were sourced from the FerrDb V2 and GEO databases. Differential gene expression analysis, Protein-Protein Interaction (PPI) Network construction, and Gene Ontology (GO) and KEGG pathway enrichment analyses were performed. The study verified the link between MASLD, hepatic fibrosis, and iron overload hub genes. This study of 5927 participants, averaging 46.78 years of age, revealed significant correlations between serum ferritin and CAP, LSM, after adjusting for covariates. Threshold effect analysis indicated nonlinear associations between serum ferritin and CAP, LSM, with distinct patterns observed by age and gender. Moreover, the area under the ROC curve for serum ferritin with MASLD and hepatic fibrosis was 0.8272 and 0.8376, respectively, demonstrating its performance in assessing these conditions. Additionally, molecular analyses identified potential hub genes associated with iron overload and MASLD, and hepatic fibrosis, revealing the underlying mechanisms. Our study findings reveal an association between iron overload, MASLD, and hepatic fibrosis. Additionally, the hub genes may be implicated in iron overload and subsequently contribute to the progression of MASLD and hepatic fibrosis. These findings support precision nutrition strategies., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Non-alcoholic steatohepatitis (NASH) may progress to more advanced liver disease. This study aimed to characterize NASH progression and mortality in the Medicare population., Methods: Patients with NASH in 100% Medicare fee-for-service claims accrued from 2015-2021 who were ≥ 66 years old at index diagnosis, continuously enrolled for ≥ 12 months prior to and ≥ 6 months following index (unless death), and had no evidence of other causes of liver disease were included. Diagnosis codes defined severity states: non-cirrhotic NASH, compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC), and liver transplant (LT). Survival analyses of disease progression and mortality were conducted for each state and by year of progression (Y1-5). Cox proportional hazards models assessed risk factors of worsening disease., Results: Mean age and follow-up were 72.2 and 2.8 years in 14,806 unique patients (n = 12,990 NASH; 1899 CC; 997 DCC; 209 HCC; 140 LT). Progression rates were highest for patients with CC (11-37% for Y1-5), followed by DCC (3-18%), NASH (3-12%), and HCC (2-4%). Mortality rates were highest for patients with HCC (41-85% for Y1-5), followed by DCC (41-76%), LT (7-33%), CC (6-26%), and NASH (2-12%). Patients with any disease progression had a 5-year mortality rate more than double that of patients without progression (41% vs. 16%). Delayed progression from NASH was associated with lower mortality risk; the 5-year mortality rate was 26% lower for patients with progression in Y2 vs. Y1 (32% vs. 43%) and further decreased for progression in Y3-Y5. Risk factors included age, nursing home use, congestive heart failure, coagulopathy, fluid/electrolyte disorders, and unexplained weight loss., Conclusion: Medicare patients ≥ 66 years with NASH experience high risk of disease progression associated with increased mortality rates. Slower disease progression is associated with lower mortality rates, suggesting that therapies that can delay or prevent NASH progression may reduce morbidity and mortality., (© 2024. The Author(s).)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is common in people with HIV (PWH). The morphological spectrum of MASLD compared to matched controls and of the correlation between the NAFLD activity score (NAS) and fibrosis stage in PWH remains unknown., Methods: Overall, 107 liver biopsies from PWH with MASLD (MASLD-PWH) were matched to 107 biopsies from individuals with MASLD and without HIV (MASLD controls) on age at biopsy, race/ethnicity, sex, type 2 diabetes, body mass index (BMI) and alanine aminotransferase (ALT) level. Biopsies were scored using NAS., Results: Compared to MASLD-controls, MASLD-PWH had lower steatosis grade (OR: 0.65, 95% CI: (0.47-0.90), p = 0.01), lower lobular inflammation grade (OR: 0.55, 95% CI: (0.34-0.89), p = 0.02), less portal inflammation (OR: 0.42, 95% CI: (0.25-0.72), p = 0.002) and less ballooned hepatocytes (OR: 0.60, 95% CI: (0.41-0.88), p = 0.01). Thus, NAS was lower in MASLD-PWH (OR: 0.69, 95% CI: (0.56-0.85), p < 0.001) than in MASLD controls. There was a trend towards lower prevalence of steatohepatitis in MASLD-PWH (OR: 0.84, 95% CI: (0.68-1.03), p = 0.09). A multivariate analysis demonstrated that MASLD-PWH cases had significantly less steatosis (OR: 0.66, p = 0.03), portal inflammation (OR: 0.34, p = 0.001) and ballooned hepatocytes (OR: 0.55, p = 0.01), yet higher stage fibrosis (OR: 1.42, p = 0.03) compared to MASLD controls., Conclusion: The NAS and histological drivers of fibrosis (e.g. inflammation and hepatocyte ballooning) are less pronounced in MASLD-PWH, and yet fibrosis stage was generally higher when compared to matched controls with MASLD without HIV. This suggests HIV-specific factors beyond hepatic necroinflammation may contribute to fibrosis progression in MASLD-PWH., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Aims: To evaluate the efficacy and safety of oral semaglutide for type 2 diabetes mellitus (T2DM) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Materials and Methods: This was a single-arm, multicentre, prospective study. Among 80 consecutive patients with MASLD and T2DM who newly received oral semaglutide, 70 completed 48-week oral semaglutide treatment as scheduled and were included in an efficacy analysis. Dose adjustments of oral semaglutide were determined by each physician while monitoring efficacy and adverse events., Results: Significant improvements in body weight, liver enzymes, lipid profile, and glycaemic control were found at 48 weeks compared with baseline values (all p < 0.01). Controlled attenuation parameter values significantly decreased from baseline to 48 weeks (p < 0.01). Changes in alanine aminotransferase concentrations (r = 0.37, p < 0.01) and controlled attenuation parameter values (r = 0.44, p < 0.01) were significantly correlated with changes in body weight. Liver fibrosis markers, such as type IV collagen 7S, Wisteria floribunda agglutinin-positive Mac-2-binding protein, fibrosis-4 index, and liver stiffness measurement, significantly decreased from baseline to 48 weeks (all p < 0.01). The most common adverse events were Grades 1-2 transient gastrointestinal symptoms, such as nausea (23 patients, 28.8%), dyspepsia (12, 15.0%) and appetite loss (4, 5.0%)., Conclusions: Oral semaglutide treatment for T2DM in patients with MASLD leads to an improvement in liver steatosis and injury, surrogate markers of fibrosis, diabetic status, and lipid profile, and reduces body weight., (© 2024 John Wiley & Sons Ltd.)

Introduction and Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) formerly known as Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease. Identifying MASLD risk factors could help early intervention and reduce the burden of the disease. Previous studies investigated the association between sarcopenia and NAFLD. Several trials were published after the last meta-analysis with indecisive results. This is an updated meta-analysis which aims to assess the association between sarcopenia, MASLD, and MASLD-related fibrosis., Materials and Methods: Relevant trials published on PubMed, Web of Science, Scopus, and Cochrane Library databases until October 2022 were included. We included studies in which skeletal mass index (SMI) or sarcopenia was compared between patients with and without NAFLD now MASLD. Also, studies comparing fibrosis between MASLD patients with and without sarcopenia were included. Data were pooled as odds ratios (ORs) and 95 % confidence intervals (CIs) using Review Manager Software., Results: A total of 25 studies were included. The incidence of sarcopenia was significantly higher in MASLD than controls (OR, 1.25; 95 % CI, 1.08-1.44; P = 0.003). SMI odds showed no significant difference between MASLD patients and controls (OR, 1.02; 95 % CI, 0.91-1.15; P = 0.7). MASLD patients with sarcopenia had higher odds of fibrosis than MASLD patients without sarcopenia (OR, 1.49; 95 % CI, 1.03-2.14; P = 0.03)., Conclusions: Sarcopenia increased MASLD's probability and was associated with a higher probability of liver fibrosis in MASLD patients. However, SMI had no predictive value of MASLD occurrence., Competing Interests: Conflicts of interest None., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Recent studies have suggested an association between H. pylori and metabolic dysfunction associated steatotic liver disease (MASLD). We aim to evaluate the association of H. pylori virulence genes with non-invasive markers of liver injury and fibrosis in MASLD subjects., Patients and Methods: A total of 362 dyspeptic patients who underwent gastroscopy were selected. Biochemical, clinical parameters, ultrasound, FIB-4 score, liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE), gastric biopsies, and H. pylori virulence genes (cagA, vacA) were evaluated., Results: A cohort comprised of 61 % women and 39 % men with a median age of 52 (40-60) years. MASLD was observed in 42 %, and H. pylori-positive in 45 %. No differences were observed regarding H. pylori status at co-morbid metabolic conditions. In MASLD cohort, H. pylori-positive was associated with higher AST, ALT, FIB-4 and LSM. Indeed, carriers of cagA/vacA-s1/m1-positive allelic combination were associated with higher AST, ALT, FIB-4 and LSM but not cagA/vacA-s1/m1-negative. The OR for high-risk of significant/advanced- fibrosis by VCTE (≥8 kPa) with H. pylori-positive was 2.56 (95 % CI, 1.2-5.75) and for cagA/vacA-s1/-m1-positive allelic carriers was 4.01 (95 % CI, 1.38-11.56), but non-significant association in cagA/vacA-s1/-m1-negative. After adjusting for age, gender, diabetes, BMI and hypertension the OR for VCTE ≥8 kPa with H. pylori-positive was 2.43 (95 % CI, 1.88-12.44), and cagA/vacA-s1/m1-positive allelic carriers was 4.06 (95 % CI, 1.22-14.49)., Conclusions: In our cohort of functional dyspepsia (FD) patients with MASLD, H. pylori was associated with non-invasive markers of liver injury and fibrosis. Carriers of cagA/vacA-s1/m1-positive allelic combination showed an independent risk of significant/advanced fibrosis by VCTE., Competing Interests: Conflicts of interest The authors declare that they have no conflict of interest. All authors have approved the final version of the manuscript., (Copyright © 2024 Fundación Clínica Médica Sur, A.C. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: In nonalcoholic fatty liver disease (NAFLD), liver fibrosis is the strongest predictor of adverse outcomes. We sought to investigate the relationship between liver fibrosis and cardiac remodeling in participants from the general population using magnetic resonance imaging (MRI), as well as explore potential mechanistic pathways by analyzing circulating cardiovascular biomarkers., Methods: In this cross-sectional study, we prospectively included participants with type 2 diabetes and individually matched controls from the SCAPIS (Swedish CArdioPulmonary bioImage Study) cohort in Linköping, Sweden. Between November 2017 and July 2018, participants underwent MRI at 1.5 Tesla for quantification of liver proton density fat fraction (spectroscopy), liver fibrosis (stiffness from elastography), left ventricular (LV) structure and function, as well as myocardial native T1 mapping. We analyzed 278 circulating cardiovascular biomarkers using a Bayesian statistical approach., Results: In total, 92 participants were enrolled (mean age 59.5 ± 4.6 years, 32 women). The mean liver stiffness was 2.1 ± 0.4 kPa. 53 participants displayed hepatic steatosis. LV concentricity increased across quartiles of liver stiffness. Neither liver fat nor liver stiffness displayed any relationships to myocardial tissue characteristics (native T1). In a regression analysis, liver stiffness was related to increased LV concentricity. This association was independent of diabetes and liver fat (Beta = 0.26, p = 0.0053), but was attenuated (Beta = 0.17, p = 0.077) when also adjusting for circulating levels of interleukin-1 receptor type 2., Conclusion: MRI reveals that liver fibrosis is associated to structural LV remodeling, in terms of increased concentricity, in participants from the general population. This relationship could involve the interleukin-1 signaling., Clinical Relevance Statement: Liver fibrosis may be considered a cardiovascular risk factor in patients without cirrhosis. Further research on the mechanisms that link liver fibrosis to left ventricular concentricity may reveal potential therapeutic targets in patients with non-alcoholic fatty liver disease (NAFLD)., Key Points: Previously, studies on liver fibrosis and cardiac remodeling have focused on advanced stages of liver fibrosis. Liver fibrosis is associated with left ventricular (LV) concentricity and may relate to interleukin-1 receptor type 2. Interleukin-1 signaling is a potential mechanistic interlink between early liver fibrosis and LV remodeling., (© 2024. The Author(s).)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic steatosis and metabolic dysregulation. Growth hormone (GH) augmentation has emerged as a potential therapeutic intervention for treating MASLD. This systematic review and meta-analysis aimed to evaluate the impact of GH augmentation on different parameters of MASLD. A systematic literature search identified randomized controlled trials investigating GH augmentation in MASLD patients. Search results were screened via Covidence and the Risk of Bias 2 tool was used to assess bias in randomized controlled trials. Statistical analysis utilized RevMan v5.3. We combined dichotomous outcomes employing odds ratios and continuous outcomes utilizing mean difference (MD), each with a 95% confidence interval (CI). Statistical significance was indicated by a P -value less than 0.05. Heterogeneity was evaluated using I2 tests. Our results showed that GH augmentation resulted in a significant reduction in both relative (MD: -46.26; 95% CI: -71.52, -21.00; P  = 0.0003) and absolute (MD: -5.15; 95% CI: -7.93, -2.37; P  = 0.0003) hepatic fat fraction. GH augmentation significantly reduced alanine aminotransferase (MD: -5.97; 95% CI: -10.31, -1.62; P  = 0.007) and gamma-glutamyl transferase (MD: -16.18; 95% CI: -30.76, -1.59; P  = 0.03) levels. No significant changes were observed in hemoglobin A1c, C-reactive protein, fasting serum glucose, BMI, triglycerides, and low-density lipoprotein cholesterol levels. Our meta-analysis highlights GH augmentation as a promising therapy for reducing liver steatosis and improving liver enzyme levels in MASLD patients. Further large-scale trials are warranted to examine the long-term effects, safety profiles, and potential impact on various measures., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Metabolic-dysfunction associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), is a growing global health concern with significant implications for oncogenesis. This review synthesizes current evidence on the association between MASLD and cancer risk, highlighting its role as a risk factor for both intrahepatic and extrahepatic malignancies. MASLD is increasingly recognized as a major cause of hepatocellular carcinoma (HCC), with its incidence rising in parallel with the prevalence of metabolic dysfunction. Furthermore, MASLD is associated with an elevated risk of various gastrointestinal cancers, including colorectal, esophageal, stomach, and pancreatic cancers. Beyond the digestive tract, evidence suggests that MASLD may also contribute to an increased risk of other cancers such as breast, prostate, thyroid, gynecological, renal and lung cancers. Understanding the mechanisms underlying these associations and the impact of MASLD on cancer risk is crucial for developing targeted screening and prevention strategies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Zobair Younossi reports a relationship with Gilead Sciences, Intercept, NovoNordisk, BMS, Abbvie, Merck, Madrigal, Genfit, Siemens, BMS, Terns and Viking that includes: consulting or advisory and funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Background: Non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions globally, particularly affecting individuals with type 2 diabetes mellitus (T2DM)., Objective: Our study aims to elucidate the diagnostic value of fasting C-peptide in combination with insulin resistance for assessing hepatic fibrosis in patients with T2DM and comorbid NAFLD., Design: This was a retrospective study., Setting: The study was conducted at the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine., Participants: The research involved 76 type 2 diabetes mellitus patients with nonalcoholic fatty liver disease, diagnosed at our hospital from April 2020 to October 2022. Patients were categorized into the non-progressive hepatic fibrosis group (n = 64) and progressive hepatic fibrosis group (n = 12) based on fibrosis-4 value., Interventions: General data, systolic/diastolic blood pressure, fasting plasma glucose, fasting C-peptide, fasting insulin, glycosylated hemoglobin, uric acid, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, aspartate transaminase, alanine transaminase, and γ-glutamyl transferase were collected. Insulin resistance was calculated using a designated formula., Primary Outcomes Measures: The predictive impact of fasting C-peptide in combination with insulin resistance was evaluated through receiver operating characteristic curves., Results: The age, body mass index, fasting C-peptide, fasting insulin, aspartate transaminase, and insulin resistance showed a significant increase in the progressive hepatic fibrosis group compared to the non-progressive group (P = .006, P = .014, P < .001, P < .001, P = .004, and P = .021). The combination's sensitivity demonstrated an elevation compared to fasting C-peptide or insulin resistance alone (P = .005)., Conclusions: Fasting C-peptide in combination with insulin resistance proves to have a substantial predictive impact on hepatic fibrosis in type 2 diabetes mellitus patients with nonalcoholic fatty liver disease, holding valuable clinical diagnostic potential.

Background and Aims: The patatin-like phospholipase domain-containing protein 3 ( PNPLA3 ) rs738409 variant is associated with steatotic liver disease and its progression. We examined the association between PNPLA3 and the development of major adverse liver outcomes (MALOs) and how nonmodifiable and modifiable conditions modify this relationship., Approach and Results: A total of 2075 adults with biopsy-confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) were enrolled in the metabolic dysfunction-associated steatohepatitis Clinical Research Network (MASH CRN) studies and followed prospectively until death, transplant, or withdrawal of consent. One hundred four MALOs were recorded during an average of 4.3 years. PNPLA3 G-allele (Adj. sub-hazard ratio (sHR): 1.4, 95% CI: 1.07-1.8), advanced fibrosis (AF) (Adj. sHR: 7.8, 95% CI: 4.4-13.8), age >60 years (Adj. sHR: 2.9, 95% CI: 1.3-6.8), and type 2 diabetes mellitus (Adj. sHR: 2.8, 95% CI: 1.8-4.2) were associated with MALO. Among participants with AF, those carrying the G-allele displayed the highest cumulative incidence of MALO (85%) versus noncarriers (53%), p =0.03, and p -value for interaction <0.01. The strength of the association between PNPLA3 and MALO was statistically significantly greater among older than 60 years (sHR: 2.1, 95% CI: 1.5-2.8), women (sHR: 1.4, 95% CI: 1.1-1.9), and those with AF (sHR: 1.9, 95% CI: 1.5-2.4) or type 2 diabetes mellitus (sHR: 2.1, 95% CI: 1.5-2.8) as compared with their counterparts, p -value for interaction between PNPLA3 and each factor<0.01., Conclusions: The deleterious effects of PNPLA3 rs738409 on the risk of MALO are significantly worsened by AF, age, type 2 diabetes mellitus, and sex., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: We examined the association of objective measures of cardiometabolic risk with progression to a high-risk for advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) at initially low- and indeterminate-risk for advanced fibrosis., Methods: We performed a retrospective cohort study of primary care patients with MASLD between 2012 and 2021. We evaluated patients with MASLD and low- or indeterminate-risk Fibrosis-4 Index (FIB-4) scores and followed them until the outcome of a high-risk FIB-4 (≥2.67), or the end of the study period. Exposures of interest were body mass index, systolic blood pressure, hemoglobin A1c, cholesterol, estimated glomerular filtration rate, and smoking status. Variables were categorized by the threshold for primary care therapy intensification. Unadjusted and adjusted Cox regression models were developed for the outcome of time to a high-risk FIB-4 value., Results: The cohort included 1347 patients with a mean follow-up of 3.6 years (SD 2.7). Of the cohort, 258 (19%) had a subsequent FIB-4 > 2.67. In the fully adjusted Cox regression models, mean systolic blood pressure ≥ 150 mm Hg (1.57; 95% confidence interval (CI) 1.02-2.41) and glomerular filtration rate ≤ 59 ml/min (hazard ratio 2.78; 95%CI 2.17-3.58) were associated with an increased hazard of a high-risk FIB-4, while receiving a statin prescription (hazard ratio 0.51; 95%CI 0.39-0.66) was associated with a lower risk., Conclusions: Nearly 1 in 5 primary care patients with MASLD transitioned to a high-risk FIB-4 score during 3.6 years of follow-up, and uncontrolled blood pressure and reduced kidney function were associated with an increased hazard of a FIB-4 at high-risk for advanced fibrosis., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Objectives: This study was designed to evaluate the association of four surrogate indexes of IR with NASH in patients with obesity., Methods: A total of 270 patients who underwent bariatric surgery, were included in this cross-sectional study. NASH was diagnosed based on liver biopsies. Binary logistics regression analyses were performed to assess the associations of four surrogate indexes of IR (HOMA-IR, Matsuda index, TyG, and TG/HDL-C) with NASH in patients with obesity. The restricted cubic spline was used to assess the dose-response associations of surrogate indexes of IR with NASH after adjusting for confounding factors., Results: NASH was diagnosed in 136 patients, with a prevalence of 50.37%. Compared with tertile 1, the fully adjusted ORs (95% CIs) of NASH for tertile 3 were 2.711(1.113-6.608) and 0.297 (0.152-0.579) for TyG and Matsuda index. Consistently, per SD increment of TyG were still significantly associated with 64% increased risks of NASH, and per SD increment of Matsuda index were still significantly associated with 38% decreased risks of NASH. In contrast, no significant associations were found between HOMA-IR and TG/HDL-C and the risk of NASH in patients with obesity (all P > 0.05). After adjusting covariates in restricted cubic splines, the risk of NASH decreased with the increment of Matsuda Index levels (P-nonlinear = 0.442, P-overall = 0.007) and with the decrement of TyG levels (P-nonlinear = 0.004, P-overall = 0.001)., Conclusions: In patients with obesity, TyG and Matsuda index were independently related to the risk of NASH after adjustment for traditional risk factors. In addition, compared with HOMA-IR and TG/HDL-C, the Matsuda index and TyG may be more suitable for NASH prediction in patients with obesity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: The recent change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD) and metabolic dysfunction-associated steatotic liver disease (MASLD) highlights the link between hepatic steatosis and metabolic dysfunction, taking out the stigmata of alcohol., Objective: We compared the effects of NAFLD and MAFLD definitions on the risk of overall and cardiovascular (CV) mortality, liver-related events (LRE), nonfatal CV events (CVE), chronic kidney disease (CKD), and extra-hepatic cancers (EHC)., Data Sources and Study Selection: We systematically searched four large electronic databases for cohort studies (published through August 2023) that simultaneously used NAFLD and MAFLD definitions for examining the risk of mortality and adverse CV, renal, or oncological outcomes associated with both definitions. In total, 21 eligible cohort studies were identified. Meta-analysis was performed using random-effects modelling., Results: Compared with those with NAFLD, individuals with MAFLD had significantly higher rates of overall mortality (random-effect OR 1.12, 95% CI 1.04-1.21, p = .004) and CV mortality (random-effect OR 1.15, 95% CI 1.04-1.26, p = .004), and a marginal trend towards higher rates of developing CKD (random-effect OR 1.06, 95% CI 1.00-1.12, p = .058) and EHC events (random-effect OR 1.11, 95% CI 1.00-1.23, p = .052). We found no significant differences in the risk LREs and nonfatal CVE between MAFLD and NAFLD. Meta-regression analyses identified male sex and metabolic comorbidities as the strongest risk factors related to the risk of adverse clinical outcomes in MAFLD compared to NAFLD., Conclusions and Relevance: Individuals with MAFLD have higher rates of overall and CV mortality and higher rates of developing CKD and EHC events than those with NAFLD, possibly due to the dysmetabolic risk profile related to MAFLD., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Despite the slow, progressive nature of NAFLD, the number of patients with NAFLD-related cirrhosis has significantly increased. Although the management of patients with cirrhosis is constantly evolving, improving the prognosis of patients with NAFLD-related cirrhosis is a challenge because it is situated at the crossroads between the liver, the metabolic, and the cardiovascular diseases. Therefore, the therapeutic interventions should not only target the liver but also the associated cardiometabolic conditions and should be adapted accordingly. The objective of the current review is to critically discuss the particularities in the management of patients with NAFLD-related cirrhosis. We relied on the recommendations of scientific societies and discussed them in the specific context of NAFLD cirrhosis and the surrounding cardiometabolic milieu. Herein, we covered the following aspects: (1) the weight loss strategies through lifestyle interventions to avoid sarcopenia and improve portal hypertension; (2) the optimal control of metabolic comorbidities in particular type 2 diabetes aimed not only to improve cardiovascular morbidity/mortality but also to lower the incidence of cirrhosis-related complications (we discussed various aspects related to the safety of oral antidiabetic drugs in cirrhosis); (3) the challenges in performing bariatric surgery in patients with cirrhosis related to the portal hypertension and the risk of cirrhosis decompensation; (4) the particularities in the diagnosis and management of the portal hypertension and the difficulties in managing patients awaiting for liver transplantation; and (5) the difficulties in developing drugs and conducting clinical trials in patients with NAFLD-related cirrhosis. Moreover, we discussed the emerging options to overcome these obstacles., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Methods: Our study sought to evaluate if an association exists between Helicobacter pylori (H. pylori), metabolic dysfunction- associated steatotic liver disease (MASLD), and liver fibrosis in patients with severe obesity (BMI > 35). Our retrospective study included 584 patients over the age of 18 years with severe obesity, who underwent preoperative liver transient elastography (VCTE), upper endoscopy, blood work, and intra-operative liver biopsy concurrent with bariatric surgery at a single institution from July 2020 to September 2021. Liver fibrosis scores including FIB-4, APRI, NAFLD fibrosis score, BARD score, AST: ALT ratio, and NAFLD activity score (NAS) were calculated from the laboratory results and liver biopsy findings. The presence or absence of H. pylori was determined based on gastric biopsies obtained during upper endoscopy. Other variables collected included age, gender, mean preoperative weight, BMI, and the presence or absence of comorbidities. Student's t-test and non-parametric testing were used for the analysis of continuous variables and Chi-square analysis was used for categorical data., Results: Of the 584 patients, 14.7% were H. pylori positive and 85.3% were negative. Liver fibrosis scores including FIB-4, APRI, and NAFLD fibrosis scores were significantly higher in the positive group (p < 0.05), but there was no difference in AST: ALT ratio and BARD score. A significantly higher VCTE steatosis and fibrosis scores were noted in the H. pylori-positive group (p < 0.05). Similarly, a significantly higher NAS (NAFLD activity score) on liver biopsies was noted in the positive group, with all the individual components of NAS (steatosis, lobular inflammation, and hepatocyte ballooning) being significantly higher in the positive group (p < 0.05). A significantly higher incidence of fibrosis on liver biopsies was noted in the positive group overall and across all stages of fibrosis (p < 0.05). There were no significant differences between the groups in relation to gender, mean weight, BMI, presence of comorbidities including Diabetes Mellitus, and laboratory values., Conclusion: Our study demonstrates that H. pylori colonization or infection is associated with a higher risk of development of MASLD and progression to fibrosis. Further, population-based studies are needed to corroborate our findings., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Aims: Ensemble machine-learning methods, like the superlearner, combine multiple models into a single one to enhance predictive accuracy. Here we explore the potential of the superlearner as a benchmarking tool for clinical risk prediction, illustrating the approach to identifying significant liver fibrosis among patients with NAFLD., Approach and Results: We used 23 demographic/clinical variables to train superlearner(s) on data from the NASH-clinical research network observational study (n = 648) and validated models with data from the FLINT trial (n = 270) and National Health and Nutrition Examination Survey (NHANES) participants with NAFLD (n = 1244). Comparing the superlearner's performance to existing models (Fibrosis-4 [FIB-4], NAFLD fibrosis score, Forns, AST to Platelet Ratio Index [APRI], BARD, and Steatosis-Associated Fibrosis Estimator [SAFE]), it exhibited strong discriminative ability in the FLINT and NHANES validation sets, with AUCs of 0.79 (95% CI: 0.73-0.84) and 0.74 (95% CI: 0.68-0.79) respectively., Conclusions: Notably, the SAFE score performed similarly to the superlearner, both of which outperformed FIB-4, APRI, Forns, and BARD scores in the validation data sets. Surprisingly, the superlearner derived from 12 base models matched the performance of one with 90 base models. Overall, the superlearner, being the "best-in-class" machine-learning predictor, excelled in detecting fibrotic NASH, and this approach can be used to benchmark the performance of conventional clinical risk prediction models., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as the fibrosis-4 index [FIB-4]) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification-including weight loss, dietary changes, physical exercise and discouraging alcohol consumption-as well as optimal management of comorbidities-including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for type 2 diabetes or obesity, if indicated-is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis., (© 2024. The Author(s).)

Objectives: To assess the role of adipose tissue insulin resistance (Adipo-IR) in the pathogenesis of pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) and to determine Adipo-IR evolution during a lifestyle intervention program., Study Design: In this prospective cohort study, children and adolescents with severe obesity were recruited between July 2020 and December 2022 at an inpatient pediatric rehabilitation center. Treatment consisted of dietary intervention and physical activity. Liver steatosis and fibrosis were evaluated using ultrasound examination and transient elastography with controlled attenuation parameter and liver stiffness measurement. Every 4-6 months, anthropometric measurements, serum biochemical analysis, ultrasound examination, and elastography were repeated. Adipo-IR was estimated by the product of the fasting serum insulin times the fasting free fatty acid concentration, and hepatic IR by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), respectively., Results: Of 200 patients with obesity, 56% had evidence of steatosis on ultrasound examination and 26% were diagnosed with fibrosis (≥F2). Adipo-IR increased progressively from lean controls to patients with obesity to patients with MASLD and MASLD with fibrosis. Adipo-IR was already increased in patients with only mild steatosis (P = .0403). Patients with more insulin-sensitive adipose tissue exhibited a lower liver fat content (P < .05) and serum alanine transaminase levels (P = .001). Adipo-IR correlated positively with visceral adipose tissue weight, waist circumference, and the visceral adipose tissue/gynoid adipose tissue ratio (P < .001), but not with total body fat percentage (P = .263). After 4-6 months of lifestyle management, both MASLD and Adipo-IR improved., Conclusions: Our data suggest that Adipo-IR is associated with the presence of pediatric MASLD, particularly steatosis., Competing Interests: Declaration of Competing Interest Work in the lab of A.G. and S.L. has received funding from Inventiva. The other authors declare not conflicts of interest. Supported by a grant from the Ghent University Hospital (FIKO19-TYPE2-006). S.L. is supported by a grant from the Research Foundation – Flanders (FWO) (1227824N). H.V., A.G., and R.B. are senior clinical investigators of the FWO (1801721N, 1805718N and 1843824N). These funding agencies were not involved in study design, analysis or reporting., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rising global pediatric obesity rates, increase non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) prevalence, with MetS being a NAFLD risk factor. NAFLD can be asymptomatic, with liver function tests insensitive to mild disease, and liver biopsy, risking complications. Thus, we investigated multiparametric MRI (mpMRI) metrics of liver fat (proton density fat fraction, PDFF) and disease activity (fibro-inflammation; iron-corrected T1, cT1), in a Hispanic pre-pubertal pediatric cohort, with increased risk of NAFLD. Pre-pubertal boys (n = 81) of varying Body-Mass Index (BMI) were recruited in Mexico City. Most children (81%) had normal liver transaminase levels, 38% had high BMI, and 14% had ≥ 3 MetS risk factors. Applying mpMRI thresholds, 12%, 7% and 4% of the cohort had NAFLD, NASH and high-risk NASH respectively. Participants with ≥ 3 MetS risk factors had higher cT1 (834 ms vs. 737 ms, p = 0.004) and PDFF (8.7% vs. 2.2%, p < 0.001) compared to those without risk factors. Those with elevated cT1 tended to have high BMI and high insulin (p = 0.005), HOMA-IR (p = 0.005) and leptin (p < 0.001). The significant association of increased risk of MetS with abnormal mpMRI, particularly cT1, proposes the potential of using mpMRI for routine pediatric NAFLD screening of high-risk (high BMI, high MetS risk score) populations., (© 2024. The Author(s).)

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide, affecting >30% of the global population. Metabolic dysregulation, particularly insulin resistance and its subsequent manifestation as type 2 diabetes mellitus, serves as the fundamental pathogenesis of metabolic liver disease. Clinical evidence of the recent nomenclature evolution is accumulating. The interaction and impacts are bidirectional between MASLD and diabetes in terms of disease course, risk, and prognosis. Therefore, there is an urgent need to highlight the multifaceted links between MASLD and diabetes for both hepatologists and diabetologists. The surveillance strategy, risk stratification of management, and current therapeutic achievements of metabolic liver disease remain the major pillars in a clinical care setting. Therefore, the Taiwan Association for the Study of the Liver (TASL), Taiwanese Association of Diabetes Educators, and Diabetes Association of the Republic of China (Taiwan) collaboratively completed the first guidance in patients with diabetes and MASLD, which provides practical recommendations for patient care., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Type 2 diabetes (T2DM) patients are at high risk for non-alcoholic fatty liver disease (NAFLD). Studies show SVD3 and dietary inflammatory index (DII) are associated with NAFLD. It's unknown if they interact in T2DM patients with NAFLD. We collected data from 110 hospitalized T2DM patients, measured physiological and biochemical indicators, conducted dietary surveys, and converted data into DII and NFS, FIB-4, and BARD indices. We used logistic regression, mediation effect analysis, and moderation effect analysis to explore the relationship between DII and SVD3 with NAFLD and liver fibrosis in T2DM patients. DII was not significant in either NAFLD incidence in T2DM patients or liver fibrosis in NAFLD patients. SVD3 was positively correlated with NAFLD incidence in T2DM patients, but this correlation became insignificant as DII increased towards pro-inflammation. SVD3 is positively correlated with NAFLD incidence in T2DM patients, but this correlation becomes less significant as DII increases towards pro-inflammation., (© 2024. The Author(s).)

Objective: Hepatopulmonary syndrome (HPS) is a rare complication of metabolic associated fatty liver disease (MAFLD) occurring subsequent to hypopituitarism, often developing after resection of hypothalamic or pituitary tumors. The aim of this study is to report an illustrative case of an HPS patient who was successfully treated with growth hormone replacement therapy, without liver transplantation which is conventionally regarded as the only treatment option. Additionally, we conducted a comprehensive review of published case reports of HPS in the pediatric population., Methods: We systematically searched literature databases to identify case reports and case series of HPS associated with hypopituitarism diagnosed in childhood. The search included MEDLINE/PubMed, Scopus, Embase, and Google Scholar from 1990 to 2023. The review process adhered to the PRISMA checklist for comprehensive reporting and methodological transparency., Results: An 18-year-old female, who had been followed up for MAFLD after craniopharyngioma resection, presented with cyanosis and progressive dyspnea. She was diagnosed with severe degree of HPS. The patient began treatment with recombinant human growth hormone, leading to a significant improvement in respiratory symptoms within 3 months, and normalization of lung shunt ratio after 6 months of therapy. In our systematic review, nine patients from nine studies across six countries were identified. The median age at diagnosis of hypopituitarism was 10.5 years (range 1-16 years), and HPS was diagnosed at a median interval of 7 years later (range 0-26 years). Half of the patients had not received growth hormone therapy after being diagnosed with hypopituitarism, which subsequently led to the diagnosis of HPS. Three patients underwent liver transplantation, but non-alcoholic steatohepatitis recurred in all cases. Six patients were successfully treated with growth hormone replacement therapy without undergoing liver transplantation., Conclusions: HPS can occur in pediatric patients with MAFLD who have undergone resection of the tumor in the hypothalamus or pituitary gland. Our findings suggest that growth hormone replacement therapy can be a possible alternative to liver transplantation for HPS patients. However, further investigations need to be performed to validate the efficacy of growth hormone treatment in different causes of HPS cases., 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 © 2024 Choe, Lee, Lee, Ko and Shin.)

Backgrounds: This investigation seeks to explore the correlation between nonalcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVDs), and to to provide evidence for the prevention and treatment of CVDs., Methods: This study utilized data from the Jinchang cohort platform, including 19,399 participants without pre-existing major CVDs. Based on the general population and gender stratification, Cox models were used to analyze the risk of NAFLD for CVDs. The combined effect of NAFLD and different obesity indicators on CVDs was analyzed by additive and multiplicative interaction models and subgroups., Results: There were 3129 NAFLD patients out of 19399 subjects, and 723 (23.11%) of them had the CVD. After adjusting for multiple confounding factors, the Cox model revealed a 1.17-fold increase in the risk of CVDs among patients with NAFLD compared to those without NAFLD. Moreover, there was no notable disparity in CVDs risk among most NAFLD patients at the same level of obesity. The results indicated no additive interaction between NAFLD and obesity concerning CVDs risk, but rather a positive multiplicative interaction. Using the normal population as a reference, it was found that people with both obesity and NAFLD significantly increased the risk of developing CVDs, with HRs and 95% CIs of 1.790 (1.508, 2.126), 1.356 (1.213, 1.517), and 1.807 (1.503, 2.174), respectively, for BMI, WC, and the combination of BMI and WC., Conclusions: NAFLD and obesity are independent risk factors for CVDs. The synergy of obesity and NAFLD implies that NAFLD patients should control weight gain. Larger BMI and WC values may increase the CVDs risk for NAFLD patients, especially women., (© 2024. The Author(s).)

It is currently unclear whether there is a connection between Life's Essential 8 (LE8) and cardiovascular disease (CVD), as well as mortality in people with nonalcoholic fatty liver disease (NAFLD). Our goal was to explore these relationships by examining data collected in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2018. We identified eligible participants with NAFLD based on NHANES 2005-2018 data. CVD status was acquired through self-reported information, and using the National Death Index, mortality data were prospectively matched. The diagnosis of NAFLD relied on noninvasive biomarkers. The research involved 9094 individuals who were identified as having NAFLD, with a mean age of 52.05 years. Each incremental LE8 score exhibited a significant association, leading to a 3%, 3%, 4%, 3%, 3%, 4%, and 4% reduction in the odds of experiencing CVD, ischemic heart disease, congestive heart failure, coronary heart disease, heart attack, angina, and stroke in individuals with NAFLD. A strong correlation was found between maintaining a superior level of Cardiovascular Health (CVH), as shown by a LE8 score ranging from 80 to 100, and a reduced occurrence of CVD and its various forms in NAFLD (all p for trend < 0.0001). Likewise, LE8 demonstrated protective benefits on mortality in NAFLD, showing that following a high CVH (in contrast to low CVH) was linked to reductions of 64%, 71%, and 74% in all-cause, CVD, and cancer mortality, respectively. Restricted cubic spline analyses suggested noteworthy dose-response relationships between LE8 and CVD, specifically its types in NAFLD, and a nonlinear correlation with CVD mortality. Interaction analyses highlighted age and race as significant effect modifiers. CVH, as evaluated by LE8, demonstrated an independent association with decreased odds of CVD and mortality risk in individuals with NAFLD. Our findings substantiate that adhering to LE8 may alleviate the excessive burden of CVD and mortality in the context of NAFLD., (© 2024. The Author(s).)

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.)

Polycystic ovary syndrome (PCOS) is a disease affecting as many as about 10% of women of reproductive age, also 3-11% of teenage patients, and can lead to numerous complications and coexists with many diseases. Research is ongoing to establish an appropriate diagnostic and therapeutic path for adolescent girls with PCOS. It is also important to implement appropriate check-ups among teenagers with PCOS in order to prevent PCOS complications and initiate appropriate treatment as soon as possible and prevent the long-term consequences of these complications. The relationship between the co-occurrence of PCOS and diseases such as metabolic syndrome, hypertension, obesity, insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) is increasingly being investigated. A great attention is also being paid to the problem of mental health in this group of patients. In our study, we will review the latest reports on the treatment of PCOS and look at the complications that this syndrome can cause., 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 © 2024 Jakubowska-Kowal, Skrzyńska and Gawlik-Starzyk.)

Objectives: To examine the relation between liver fibrosis and chronic kidney disease (CKD) in metabolic-associated fatty liver disease (MAFLD) patients and its risk factors., Methods: The current study was carried out at Tanta University Hospital, Tanta, Egypt, from May 2021 to January 2023 and included 84 MAFLD patients with CKD and 80 MAFLD patients without CKD. All participants had been examined by abdominal ultrasonography and transient elastography with controlled attenuation parameter., Results: Chronic kidney disease patients exhibited a greater incidence of fibrosis compared to patients without CKD (75.6% vs. 24.4%). Logistic analysis demonstrated that the presence of multiple health conditions, such as MAFLD, diabetes mellitus, hypertension, and cardiovascular disease, were individually linked to CKD. Gender and body mass index were not independent factors related to CKD. Additionally, factors such as age, hyperuricemia, hypertriglyceridemia, hypercholesterolemia, hypoalbuminemia, hyperbilirubinemia, and viral hepatitis, apart from MAFLD comorbidities, were independently linked to CKD., Conclusion: Chronic kidney disease may represent a potential risk influence for liver fibrosis development in MAFLD patients., (Copyright: © Saudi Medical Journal.)

Introduction and Aim: Liver fibrosis is a complication of metabolic dysfunction-associated steatotic liver disease (MASLD). Given the limitations and risks of liver biopsy, examining noninvasive scoring systems that are affordable for the population is necessary. Our aim was to evaluate and compare the diagnostic yield of the APRI, FIB-4, NAFLD score, and Hepamet fibrosis score instruments for detecting liver fibrosis in Mexican subjects with MASLD., Material and Methods: A retrospective study was conducted on a sample of subjects with MASLD. Liver fibrosis was calculated through transient liver elastography. Sociodemographic, epidemiologic, and biochemical variables were evaluated. Scores were calculated utilizing the fibrosis-4 (FIB-4) index, the aspartate aminotransaminase-to-platelet ratio index (APRI), the Hepamet fibrosis score (HFS), and the NAFLD score (NFS), and then compared. ROC curves were constructed, and the optimum cutoff points were determined utilizing the Youden index. Sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratio were calculated., Results: The study included 194 subjects (63% women), of whom 150 (77.3%) were classified with MASLD and 44 (22.7%) as controls with no liver disease. There was a 15.3% prevalence of advanced fibrosis. The cutoff points of 0.57 for APRI, 1.85 for FIB-4, 0.08 for HFS, and -0.058 for NFS showed diagnostic yields with areas under the ROC curves of 0.79, 0.80, 0.70, and 0.68, respectively., Conclusion: The APRI, FIB-4, NFS, and HFS scores are useful for evaluating liver fibrosis in Mexican subjects with MASLD. Better diagnostic yield was found with the FIB-4 and APRI scores., (Copyright © 2024 Asociación Mexicana de Gastroenterología. Published by Masson Doyma México S.A. All rights reserved.)

Background: Frailty is associated with obesity-related comorbidities, but the relationship with nonalcoholic fatty liver disease (NAFLD) in people with HIV has been incompletely described. Our objective was to assess the associations between NAFLD and frailty., Methods: Cross-sectional and longitudinal analysis of men in the Multicenter AIDS Cohort Study. NAFLD was defined as a liver/spleen ratio <1.0 on abdominal computed tomography scans; frailty was defined by the frailty phenotype as having 3 of the following: weakness, slowness, weight loss, exhaustion, and low physical activity., Results: Men without (n = 200) and with HIV (n = 292) were included. NAFLD prevalence was 21% vs 16% and frailty 12% vs 17%, respectively. Among men with NAFLD, frailty was more prevalent in men without HIV (21% vs 11%). In multivariate analysis, NAFLD was significantly associated with frailty after controlling for significant variables. Men without HIV and NAFLD had 2.6 times higher probability [95% confidence interval (CI): 1.2- to 5.7] of frailty relative to men with neither HIV nor NAFLD. This association was not seen in men with HIV. The probability of frailty was higher among men without HIV with NAFLD (27% vs 10% in men without NAFLD) but lower among men with HIV with NAFLD (14% vs 19% in men without NAFLD). No significant relationships were found in longitudinal analyses., Conclusions: NAFLD was independently associated with frailty among men without HIV but not men with HIV, despite increased prevalence of frailty among men with HIV. The mechanisms of the muscle-liver-adipose tissue axis underlying NAFLD might differ by HIV serostatus., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: This cross-sectional study aimed to investigate the impact of metabolic-associated diseases (MADs) on patients with autoimmune hepatitis (AIH)., Methods: The study analyzed the clinical characteristics of 283 AIH patients who underwent liver biopsy between January 2016 and February 2022 in Ruijin Hospital, Shanghai, China., Results: Among the identified AIH patients (n = 283), 87.3%, 23.0%, or 43.1% had MADs, non-alcoholic fatty liver disease (NAFLD), or severe fibrosis, respectively. The proportion of diabetes mellitus (DM) was significantly higher in patients with severe liver fibrosis than in those with mild or moderate fibrosis in the AIH cohort (31.1% vs. 18.0%, p < 0.05). Fibrosis was also more severe in patients with NAFLD than in those without (53.8% vs. 39.9%, p < 0.05). Age, Plts, IgG and the presence with MADs were identified as independent predictors of the severity of inflammation in AIH patients. Moreover, severe liver fibrosis (stages 3 to 4) was independently associated with male (OR, 2.855; p = 0.025), γ-GT (OR, 0.997; p = 0.007), and combination with MADs (OR, 4.917; p = 0.006). Furthermore, combination with DM was also an independent predictor of severe liver fibrosis in AIH patients (OR, 2.445, p = 0.038)., Conclusions: Concurrent MADs, common in AIH patients, is an independent risk factor for severe fibrosis or inflammation; of note, combination with DM was also an independent predictor of severe liver fibrosis in AIH patients. While managing with AIH, routine assessment of co-existing MADs, especially DM, is also important., (© 2024. The Author(s).)

The natural history of metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD), is complex and long. A minority of patients develop inflammation and risk progressive fibrosis that can result in cirrhosis. Progression to cirrhosis occurs in 3-5% of patients and often takes more than 20 years. This narrative review presents an update on the natural history of MASLD, discussing studies and risk estimates for progression to severe outcomes, such as decompensated cirrhosis or hepatocellular carcinoma. We highlight the dynamic progression of liver damage, how to identify patients whose disease progresses over time, and how risk factors might be mitigated to reduce the risk for disease progression., Competing Interests: Declaration of interests HHa's institutions have received research funding from AstraZeneca, EchoSens, Gilead, Intercept, MSD, Novo Nordisk, and Pfizer; he reports having served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, MSD, and Novo Nordisk; and has been part of hepatic events adjudication committees for Arrowhead, Boehringer Ingelheim, KOWA, and GW Pharma. All other authors report no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

The presence of marked hepatic steatosis in patients with high alcohol consumption was first described in 1836 by Addison et al.1 Many years later, in 1980, Ludwig and colleagues described a histological picture very similar to that seen in patients with alcoholic hepatitis but who did not consume alcohol, coining the term non-alcoholic steatohepatitis (NASH).2 In recent years, the terminology used to describe conditions related to hepatic steatosis has undergone significant evolution. In 2020, Eslam et al.3 subsequently modified it to MAFLD (Metabolic Associated Fatty Liver Disease) to better reflect its association with metabolic dysfunction, a nomenclature that, from the beginning, generated some reluctance due to the absence of clear international consensus.

Obesity, non-alcoholic fatty liver disease (NAFLD), and atherosclerotic cardiovascular diseases are common and growing public health concerns. Previous epidemiological studies unfolded the robust correlation between obesity, NAFLD, and atherosclerotic cardiovascular diseases. Obesity is a well-known risk factor for NAFLD, and both of them can markedly increase the odds of atherosclerotic cardiovascular diseases. On the other hand, significant weight loss achieved by lifestyle modification, bariatric surgery, or medications, such as semaglutide, can concomitantly improve NAFLD and atherosclerotic cardiovascular diseases. Therefore, certain pathophysiological links are involved in the development of NAFLD in obesity, and atherosclerotic cardiovascular diseases in obesity and NAFLD. Moreover, recent studies indicated that simultaneously targeting several mechanisms by tirzepatide and retatrutide leads to greater weight loss and markedly improves the complications of metabolic syndrome. These findings remind the importance of a mechanistic viewpoint for breaking the association between obesity, NAFLD, and atherosclerotic cardiovascular diseases. In this review article, we mainly focus on shared pathophysiological mechanisms, including insulin resistance, dyslipidemia, GLP1 signaling, inflammation, oxidative stress, mitochondrial dysfunction, gut dysbiosis, renin-angiotensin-aldosterone system (RAAS) overactivity, and endothelial dysfunction. Most of these pathophysiological alterations are primarily initiated by obesity. The development of NAFLD further exacerbates these molecular and cellular alterations, leading to atherosclerotic cardiovascular disease development or progression as the final manifestation of molecular perturbation. A better insight into these mechanisms makes it feasible to develop new multi-target approaches to simultaneously unhinge the deleterious chain of events linking obesity and NAFLD to atherosclerotic cardiovascular diseases., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Aim: To evaluate the impact of non-alcoholic fatty liver disease (NAFLD) presence and fibrosis risk on adverse outcomes in patients with type 2 diabetes and chronic kidney disease., Methods: Data were sourced from two longitudinal cohorts: 1172 patients from the National Health and Nutrition Examination Survey (NHANES) and 326 patients from the kidney biopsy cohort at the West China Hospital of Sichuan University. Cox regression estimated hazard ratios (HRs) for NAFLD and liver fibrosis concerning adverse clinical outcomes. Subsequently, a two-sample Mendelian randomization study using genome-wide association study statistics explored NAFLD's potential causal link to cardio-cerebrovascular events., Results: In the NHANES cohort, NAFLD stood as an independent risk factor for various outcomes: overall mortality [HR 1.53 (95% confidence interval, CI 1.21-1.95)], mortality because of cardio-cerebrovascular diseases [HR 1.63 (95% CI 1.12-2.37)], heart disease [HR 1.58 (95% CI 1.00-2.49)], and cerebrovascular disease [HR 3.95 (95% CI 1.48-10.55)]. Notably, advanced liver fibrosis, identified by a fibrosis-4 (FIB-4) score >2.67, exhibited associations with overall mortality, cardio-cerebrovascular disease mortality and heart disease mortality. Within the kidney biopsy cohort, NAFLD correlated with future end-stage kidney disease [ESKD; HR 2.17 (95% CI 1.41-3.34)], while elevated FIB-4 or NAFLD Fibrosis Scores predicted future ESKD, following full adjustment. Liver fibrosis was positively correlated with renal interstitial fibrosis and tubular atrophy in biopsies. Further Mendelian randomization analysis supported a causal relationship between NAFLD and cardio-cerebrovascular events., Conclusions: In patients with type 2 diabetes and chronic kidney disease, the NAFLD presence and elevated FIB-4 scores link to heightened mortality risk and ESKD susceptibility. Moreover, NAFLD shows a causal relationship with cardio-cerebrovascular events., (© 2024 John Wiley & Sons Ltd.)

Acute-on-chronic liver failure (ACLF) is a syndrome of liver failure due to an acute hepatic insult leading to liver failure with or without extra-hepatic organ failure in a patient of chronic liver disease (CLD) with or without cirrhosis presenting for the first time. The definition is still with controversy; hence, homogeneity and clarity of the case is an unmet need. There is a paradigm shift noted as far as the etiology of CLD is concerned with rise in metabolic dysfunction-associated fatty liver disease (MAFLD) and ethanol as the dominant cause even in developing countries. MAFLD is the change in nomenclature from NAFLD to justify the metabolic derangement in these group of patients. The shift from an exclusion-based criteria to one that has evolved to a diagnosis that requires positive criteria has profound significance. Clearly there is a difference in terms of its prevalence, disease progression, and liver-related events, as well as management of metabolic risk factors and MAFLD itself which requires further understanding. In tandem with the global rise in MAFLD, the incidence of MAFLD-ACLF is increasing. Excessive alcohol consumption causes metabolic and toxic injury to the liver resulting in nearly similar pathway of fatty liver, hepatitis, and cirrhosis. The interaction of MAFLD as an additional underlying chronic liver injury in ACLF patients is complex due to the presence of metabolic risk factors that are unique to MAFLD. There is lack of clarity on how MAFLD affects the clinical course of ACLF due to scarcity of this specific data. This narrative review aims to understand the unique effects, consequences, and management of MAFLD as the chronic liver injury component in ACLF., (© 2024. Asian Pacific Association for the Study of the Liver.)