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Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD) recurrence after liver transplantation (LT) seems unavoidable and gradual. We aimed to evaluate the diagnostic accuracy in the post‐LT setting of patients transplanted for metabolic dysfunction‐associated steatohepatitis (MASH) of recurrent hepatic steatosis and fibrosis identified with FibroScan, compared to biopsy findings. Methods: This prospective cohort study included adults transplanted for MASH between 2010 and 2022 in three LT centres in Spain who underwent FibroScan and biopsy at least 1‐year after LT. Results: In total, 44 patients transplanted for MASH after LT were included. The median time from LT to biopsy and FibroScan was 24.5 (interquartile range [IQR]:16–46) and 26.0 (IQR: 16.8–41.5) months, respectively. The median time between biopsy and FibroScan was 2.0 (IQR: 0–5) months. On FibroScan, significant steatosis was diagnosed in about half of the patients (n = 21, 47.7%), yet advanced fibrosis in only two cases (4.6%). On biopsy, a quarter of biopsied patients (n = 11, 25%) had a MASH diagnosis, two (4.6%) with significant fibrosis and one (2.3%) with cirrhosis. All patients with liver stiffness measurement (LSM) values <8 kPa (n = 35, 79.5%) had a fibrosis stage ≤F1 (negative predictive value = 100%). The combination of post‐LT hypertension (odds ratio [OR]: 12.0, 95% confidence interval [CI]: 1.8–80.4, p =.010) and post‐LT dyslipidaemia (OR: 7.9, 95% CI: 1.3–47.1, p =.024) with LSM (OR: 1.7, 95% CI: 1.1–2.8, p =.030) was independently associated with MASLD. Conclusions: Although biopsy remains the gold standard for detecting fibrosis, our results suggest that LSM values <8 kPa after LT for MASH are strongly correlated with absence of significant/advanced fibrosis. [ABSTRACT FROM AUTHOR]

Background: Monotherapy to treat obesity‐associated liver insult is limited. Objectives: In diet‐induced obese mice showing metabolic dysfunction‐associated steatotic liver disease (MASLD), we aimed to compare the combinations of sodium‐glucose cotransporter‐2 inhibitor (SGLT2i, empagliflozin, E), dipeptidyl peptidase‐4 inhibitor (DPP4i, linagliptin, L), and glucagon‐like peptide type 1 receptor agonist (GLP1RA, dulaglutide, D). Methods: Male 3‐month‐old C57BL/6J mice were fed for 12 weeks in a control (C, n = 10) or high‐fat (HF, n = 30) diet. Then, mice were followed for three additional weeks: C, HF, HF E + L, and HF E + D (n = 10/group). Results: HF versus C showed higher hepatic triacylglycerol (TAG, +82%), steatosis (+850%), glucose intolerance (+71%), insulin (+98%), and insulin resistance (+68%). Compared to the HF group, HF E + L showed lower glucose intolerance (−60%), insulin (−61%), insulin resistance (−46%), TAG (−61%), and steatosis (−58%), and HF E + D showed lower glucose intolerance (−71%), insulin (−58%), insulin resistance (−62%), TAG (−61%), and steatosis (−82%). The principal component analysis (PCA) placed the HF group and the HF E + D group on opposite sides, while the HF E + L group was placed between C and HF E + D. Conclusion: PCA separated the groups considering the metabolism‐related genes (glucose and lipid), mitochondrial biogenesis, and steatosis. The two pharmacological combinations showed beneficial effects in treating obesity and MASLD. However, the combination of SGLT2i and GLP1RA showed more potent beneficial effects on MASLD than SGLT2i and DPP4i and, therefore, should be the recommended combination. [ABSTRACT FROM AUTHOR]

There are few descriptions of the epidemiology of chronic liver disease (CLD) after allogeneic hematopoietic stem cell transplantation (allo-HCT). Among those transplanted before 2000, viral hepatitis was the dominant cause of CLD. Recently, the prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD, previously known as nonalcoholic fatty liver disease) is increasing in the general population. In addition, survivors of allo-HCT are known to be at increased risk of metabolic syndrome. We set out to describe the epidemiology of CLD in a modern cohort of allo-HCT recipients. We hypothesized that MASLD would be the most common cause of CLD in the cohort. We undertook a retrospective cohort and nested case-control study of 2-year survivors of allo-HCT in Alberta transplanted between 2008 and 2018. Among 392 2-year survivors of allo-HCT between 2008 and 2018, the prevalence of CLD was 41.8% and MASLD was identified in 56% of those with CLD, followed by iron overload in 47% of those with CLD. The prevalence of MASLD among the entire cohort was 46%. Although most patients developed CLD before 2 years post-transplant, there was a 13% cumulative incidence of new CLD after 2 years posttransplant. Grade 2-4 acute graft-versus-host disease and/or moderate-to-severe chronic graft-versus-host disease and pretransplant CLD were strongly associated with CLD. In the case-control study examining the association between cardiovascular risk factors and CLD, type 2 diabetes was associated with CLD. Cirrhosis developed in 1.5% of survivors, and MASLD was an underlying etiology in one half of these cases. There was no difference in overall survival and non-relapse mortality between those who did and did not develop CLD. MASLD is the main cause of CLD in recent long-term survivors of allo-HCT and may be associated with post-transplant corticosteroid exposure and type 2 diabetes. We note a shift in the underlying etiology of CLD post-HCT: previous studies describe viral hepatitis as the most common cause of CLD. The high prevalence of MASLD in allo-HCT recipients has important implications for survivorship care. [Display omitted] [ABSTRACT FROM AUTHOR]

Both metabolic dysfunction and alcohol consumption cause steatotic liver disease (SLD). The distinction between metabolic dysfunction-associated SLD (MASLD) and MetALD categories is based on arbitrary thresholds of alcohol intake. Thus, we assessed the impact of different levels of alcohol consumption on SLD severity and their interaction with metabolic comorbidities. We performed a population-based study with transient elastography (FibroScan®) data from participants in Spain (derivation cohort) and the US (validation cohort). A controlled attenuation parameter ≥275 dB/m was used to define SLD. At least one cardiometabolic risk factor was required to define MASLD. Among patients with MASLD, low alcohol consumption was defined as an average of 5-9 drinks/week, moderate consumption as 10-13 drinks/week for females and 10-20 drinks/week for males, and increased alcohol intake (MetALD) as 14-35 drinks/week for females and 21-42 drinks/week for males. Significant fibrosis was defined as a liver stiffness measurement ≥8 kPa and at-risk metabolic dysfunction-associated steatohepatitis (MASH) as a FAST score ≥0.35. The derivation cohort included 2,227 individuals with MASLD (9% reported low, 14% moderate alcohol consumption) and 76 cases with MetALD. Overall prevalences of significant fibrosis and at-risk MASH were 7.6% and 14.8%, respectively. In the multivariable analysis, alcohol consumption was independently associated with significant fibrosis and at-risk MASH. A dose-dependent increase in the prevalence of significant fibrosis and at-risk MASH was observed between the number of drinks/week and the number of cardiometabolic factors. The validation cohort included 1,732 participants with MASLD, of whom 17% had significant fibrosis and 13% at-risk MASH. This cohort validated the association between moderate intake and MASLD at risk of progression (odds ratio 1.69, 95% CI 1.06-2.71). Moderate alcohol intake is commonly seen in MASLD and increases the risk of advanced disease to a level similar to that observed in MetALD. Metabolic risk factors such as overweight, diabetes or dyslipidemia, and alcohol consumption can cause liver disease. These factors frequently coexist, but their joint effects on liver fibrosis remain uncertain. In this study, we have analyzed individuals from the general population with MASLD (metabolic dysfunction-associated steatotic liver disease) enrolled in Spain and the US. We show that moderate alcohol consumption has a supra-additive effect with metabolic risk factors, exponentially increasing the risk of liver fibrosis. These results suggest that there are no safe limits of daily alcohol intake in patients with unhealthy metabolic status and MASLD. [Display omitted] • The distinction of MASLD and MetALD categories is based on arbitrary thresholds of alcohol intake. • Low-to-moderate alcohol consumption is prevalent among patients with MASLD. • Alcohol increases the risk of significant fibrosis in a dose-dependent supra-additive interaction with cardiometabolic risk factors. • In those without SLD, moderate alcohol intake can also increase the risk of fibrosis when combined with cardiometabolic risk factors. [ABSTRACT FROM AUTHOR]

Background & aim: SGLT2 inhibitors (SGLT2i) improve hepatic steatosis in patients with type 2 diabetes mellitus (T2DM) and MASLD. We aimed to investigate the impact of SGLT2i on the incidence of liver-related events and extrahepatic cancer compared to DPP4 inhibitors (DPP4i) in patients with T2DM and suspected MASLD using a medical claims database in Japan. Methods: We conducted a retrospective study using a Japanese medical claims database. Among patients with T2DM who were prescribed SGLT2i or DPP4i (n = 1,628,656), patients with suspected MASLD were classified into SGLT2i (n = 4204) and DPP4i (n = 4204) groups. Effects of SGLT2i on the following outcomes were compared to DPP4i: (1) changes in HbA1c and ALT levels after 6 months, (2) changes in hepatic fibrosis index, and (3) the incidence of liver-related events/extrahepatic cancer over 12 months. Results: After 6 months, DPP4i significantly decreased HbA1c levels compared to SGLT2i. In contrast, SGLT2i significantly decreased ALT levels compared to DPP4i. SGLT2i significantly decreased FIB-4 index compared to DPP4i over 12 months. Although no significant difference was observed in the incidence of overall liver-related events between the two groups, SGLT2i significantly reduced the incidence of esophageal varices (HR 0.12, 95%CI 0.01–0.95, P = 0.044). Moreover, SGLT2i significantly suppressed the incidence of extrahepatic cancer (HR 0.50, 95%CI 0.30–0.84, P = 0.009) compared to DPP4i. Conclusion: SGLT2i was more beneficial than DPP4i in improving the hepatic inflammation and fibrosis indices. Moreover, SGLT2i suppressed the incidence of esophageal varices and extrahepatic cancer compared to DPP4i. SGLT2i may suppress life-threatening events in patients with T2DM and suspected MASLD. [ABSTRACT FROM AUTHOR]

Aim: The aim was to examine the prevalence of metabolic dysfunction–associated steatotic liver disease (MASLD), a risk factor for atherosclerotic cardiovascular disease, and its association with glycaemic control metrics in children and adolescents with type 1 diabetes (T1D). Materials and Methods: We enrolled 244 children and adolescents with T1D (115 girls, mean age: 16.2 ± 3.2 years). The diagnosis of MASLD was defined by the presence of hepatic steatosis on ultrasonography in combination with at least one of five common cardiometabolic risk factors. Metrics of short‐term and long‐term glycaemic control, blood pressure, lipids, anthropometric characteristics and three genetic variants strongly related to MASLD susceptibility (rs738409 [patatin‐like phospholipase domain‐containing 3], rs58542926 [transmembrane 6 superfamily member 2] and rs1260326 [glucokinase regulator]) were assessed. Characteristics of these subjects with and without MASLD were compared using the unpaired Student t test, Mann–Whitney test or χ2 test as appropriate. Logistic regression analyses were performed to determine the main independent predictors of MASLD. Results: The prevalence of MASLD was 27.5% in children and adolescents with T1D. Blood pressure, total cholesterol, low‐density lipoprotein (LDL) cholesterol, non‐high‐density lipoprotein cholesterol, HbA1c and time above range (TAR) were significantly higher in subjects with MASLD than in those without MASLD. Mean HbA1c values from diabetes onset (adjusted odds ratio [OR]: 1.703, 95% confidence interval [CI]: 1.040–2.787, p = 0.034), TAR (adjusted OR: 1.028, 95% CI: 1.009–1.047, p = 0.006) and plasma LDL cholesterol (adjusted OR: 1.045, 95% CI: 1.013–1.078, p = 0.004) were independently associated with the presence of MASLD. Conclusions: MASLD is a common condition in children and adolescents with T1D. The mean HbA1c values from diabetes onset, TAR and LDL cholesterol levels were the independent predictors of MASLD. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the performances of quantitative ultrasound (QUS) for the detection and assessment of hepatic steatosis when implemented using an ultraportable ultrasound scanner. Seven established QUS parameters were investigated. Ultrasound signals were acquired using a new ultraportable ultrasound device, the Hepatoscope. The feasibility of QUS using the Hepatoscope was first assessed in vitro. Clinical reliability, accuracy and staging capabilities were evaluated in 60 patients referred to a hepatology consultation for known chronic liver disease and enrolled in a prospective clinical investigation using the controlled attenuation parameter (CAP) as ground truth. QUS parameters showed moderate (intra-class correlation coefficient [ICC] >0.50) to excellent (ICC >0.90) reliability. Two parameters, namely Lizzi-Feleppa mid-band fit and attenuation, were both reliable (ICC = 0.89 and 0.86, respectively) and correlated with the CAP (squared Pearson correlation coefficient of R2 = 0.65 and R2 = 0.6, respectively). For steatosis detection (S0 vs. ≥S1), the two parameters yielded an area under the receiving operating characteristic curve of 0.90 and 0.86, respectively (95% confidence interval: [0.81–0.99] and [0.76–0.96], respectively). QUS can be reliably and accurately implemented on ultraportable ultrasound scanners. The combination of ultraportability and quantitative assessment of liver fat is promising for large-scale screening and monitoring of hepatic steatosis. [ABSTRACT FROM AUTHOR]

Background: Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) help manage type 2 diabetes (T2DM) and may have efficacy in steatotic liver disease. Objective: To determine the prevalence and clinical impact of GLP-1 RA use in patients with T2DM and liver disease. Methods: This was a retrospective study of adult patients with T2DM and nonalcoholic fatty liver disease (NAFLD), nonalcoholic fatty liver (NAFL), or nonalcoholic steatohepatitis (NASH) between 1/1/21-12/31/21. Patients with hepatitis B or C, or on pioglitazone were excluded. Eligible patients treated with a GLP-1 RA were compared to controls. The primary outcome was change in Fibrosis-4 (FIB-4) score, with NAFLD Fibrosis Score (NFS) as a secondary outcome. Follow-up scores were calculated from labs within 3 to 15 months after baseline. Results: Of 242 eligible patients, 79 patients (32.6%) were treated with a GLP-1 RA. At baseline, FIB-4 score was lower and NFS was higher in the GLP-1 RA group vs controls (1.80 vs 2.33; P =.101,.36 vs −.47, P <.001; respectively). At follow up, FIB-4 score decreased to 1.77 in the GLP-1 RA group and increased to 2.71 in controls (P =.045). Follow up NFS was stable in the GLP-1 RA group and increased in the control group (.36 vs −.43; P =.308). Conclusion: Patients treated with GLP-1 RAs had less evidence of liver fibrosis progression compared to no treatment, although the differences were small. These results suggest that treatment with GLP-1 RAs may have clinical impact on slowing liver fibrosis, however results should be confirmed in a larger, more diverse sample. [ABSTRACT FROM AUTHOR]

In patients with NAFLD, liver fibrosis increases liver-related complications, but there is controversy about the increase in CVD. Based on a prospective cohort study, this study investigated the risk of cardiovascular disease due to liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study analyzed KCPS-II prospective cohort that tracked 104,399 people who participated in health check-ups at 18 institutions nationwide from 2004 to 2013. If the fatty liver index was 30 or higher, it was defined as SLD, and participants were classified into No-SLD, MASLD, MetALD, ALD, and Cryptogenic SLD. Liver fibrosis was defined by the FIB-4 index, and the occurrence of cardiovascular disease according to SLD classification was analyzed using Cox proportional model regression analysis. Out study included a total of 6,942 participants (6.6%) had MASLD, 6,694 (6.4%) had MetALD, 4,751 (4.6%) had ALD, and 382 (0.3%) had Cryptogenic SLD. For the cases of FIB-4 index ≥1.3, the multivariable-adjusted HR (95% CI) of cardiovascular disease was 2.27 (1.87-2–76) in MASLD, 1.67 (1.30–2.10) in MetALD, and 2.56 (1.99–3.30) in ALD, but it was 0.78 (0.19–3.10) in Cryptogenic_SLD, which was not significant. The risk of cardiovascular disease according to the fibrosis stage classified by BARD also presented similar results. This prospective cohort study of Korean patients with newly defined MASLD, MetALD, and ALD with FIB-4 ≥ 1.3 at high risk of developing cardiovascular disease. • Using the new definition of SLD subgroups, the aim was to assess the prognosis of each group by analyzing the association between FIB-4 and CVD. • Non-invasive approaches to patients with SLD may help identify the risk group for advanced fibrosis. • In the KCPS-II prospective cohort, MASLD, MetALD, and ALD patients have a high risk of CVD when FIB-4 ≥ 1.30. • This is the first study to report the association between newly defined MASLD and the risk of CVD by FIB-4. [ABSTRACT FROM AUTHOR]

Purpose of Review: To explain the relevance of Fecal Microbiota Transplantation (FMT) for the treatment of MASLD, the scientific evidence supporting its usefulness, and the difficulties of its translation into effective treatments for use in routine clinical practice. Recent Findings: FMT has been proven effective and safe in other indications and several procedures have been tested for delivery of fecal microbiota to the intestine. The field awaits results from ongoing clinical trials to better understand the role of FMT in the management of MASLD. Summary: The pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is multifaceted, involving an intricate interaction among genetic predisposition, diet, environmental factors, lifestyle choices, and the gut microbiota (GM). The complexity of these interactions may explain the difficulties to obtain an effective pharmacological treatment for MASLD. [ABSTRACT FROM AUTHOR]

Background: Steatotic liver disease (SLD) prevalence is rising worldwide, linked to insulin resistance and obesity. SLD prevalence can surpass 10% even among those with normal weight. In Lao People's Democratic Republic (Lao PDR), where Opisthorchis viverrini (OV) trematode infection and type 2 diabetes mellitus (T2DM) are common, infection related liver morbidity such as cholangiocarcinoma (CCA) is high, but data on SLD prevalence is lacking. The objective of this study was to estimate the prevalence and explore determinants of SLD in rural southern Lao PDR for lean and non-lean populations. Method: A cross-sectional community-based study assessed SLD prevalence using abdominal ultrasonography (US). Factors investigated for association with SLD were identified by interview, serological tests (Hepatitis B surface antigen (HBsAg); lipids and HbA1c), anthropometrical measurements, and parasitological assessments (OV infection). Uni- and multivariable logistic regression analyses with SLD as endpoint were conducted separately for lean (body mass index (BMI) <23.0kg/m²) and non-lean (BMI ≥ 23.0kg/m²) participants. Result: 2,826 participants were included. SLD prevalence was 27.1% (95% confidence interval (95% CI) 24.0%-30.4%), higher among non-lean (39.8%) than lean individuals (17.4%). Lean individuals with OV infection had a statistically significant association with lower odds of SLD (adjusted odds ratio (aOR) 0.49, 95% CI 0.33-0.73). T2DM showed a significant positive association with SLD in both lean (aOR 3.58, 95% CI 2.28-5.63) and non-lean individuals (aOR 3.31, 95% CI 2.31-4.74) while dyslipidemia was significantly associated only in the non-lean group (aOR 1.83, 95% CI 1.09-3.07). Females participants exhibited elevated odds of SLD in both lean (aOR 1.43, 95% CI 1.02-2.01) and non-lean SLD (aOR 1.50, 95% CI 1.12-2.01). Conclusion: SLD prevalence is notably high among Laotian adults in rural areas, particularly in females and in non-lean individuals. Lean individuals with OV infection exhibited lower SLD prevalence. SLD was more prevalent in individuals with T2DM, independent of BMI. SLD adds to the burden of infection-related liver morbidity in Lao PDR. [ABSTRACT FROM AUTHOR]

Background: We explored the changes in metabolic dysfunction-associated steatotic liver disease (MASLD) severity over time by analyzing data from the placebo arms of randomized controlled trials (RCTs), focusing on the presence of diabetes. Methods: RCTs on MASLD that included a placebo arm were identified using a systematic search of the literature. Primary outcomes were changes in hepatic steatosis and fibrosis. Results: The meta-analysis included 8 RCTs involving 386 patients without diabetes and 24 RCTs involving 637 patients with diabetes. The pooled estimate of mean change in steatosis grade was − 0.1 in patients without diabetes, and − 0.37 in patients with diabetes (P = 0.066). The mean change in fibrosis stage was 0.05 in patients without diabetes, and − 0.03 in patients with diabetes (P = 0.359). The mean change in nonalcoholic fatty liver disease activity score was − 0.55 in patients without diabetes, and − 1.50 in patients with diabetes (P = 0.100). The mean change in ALT and AST were significantly larger in patients without diabetes compared to those with diabetes (P < 0.05). Conclusion: Placebo treatment had a greater effect in improving liver steatosis in patients with diabetes compared to those without. These findings highlight the importance of tailored treatment strategies in MASLD, particularly considering diabetes status. [ABSTRACT FROM AUTHOR]

ABSTRACT Background Aims Methods Results Conclusions Serum ferritin has been suggested as a potential biomarker associated with disease progression in metabolic dysfunction–associated steatotic liver disease (MASLD).We investigated the association between serum ferritin levels and liver‐related events (LREs) in individuals with steatotic liver disease (SLD).This cohort study included 17,560 adults with SLD (MASLD [n = 15,744], MASLD with increased alcohol intake (MetALD) [n = 1103] and cryptogenic SLD [n = 713]) without LRE at baseline. A steatotic liver was diagnosed using ultrasound, and LRE was defined as the development of decompensation (ascites, variceal bleeding and hepatic encephalopathy) or hepatocellular carcinoma. Participants were categorised into high (≥ 300 μg/L for males, ≥ 200 μg/L for females) or normal to low (< 300 μg/L for males, < 200 μg/L for females) ferritin levels.During 211,425 person‐years of follow‐up (median: 12.3 years), 74 incident LRE cases were identified, with 63 cases in MASLD, 10 in MetALD and 1 in cryptogenic SLD. The multivariable‐adjusted hazard ratio (aHR) for LRE comparing individuals with high and normal‐to‐low ferritin level was 3.13 (95% confidence interval [CI] 1.89–5.18). Increased risk of LRE in individuals with high serum ferritin level compared to those with normal to low serum ferritin level was consistent across SLD subtypes (aHR 2.69, 95% CI 1.55–4.67 for MASLD; aHR 5.73, 95% CI 1.31–25.0 for MetALD), and SLD severity assessed by Fibrosis‐4 (FIB‐4) index (aHR 2.38, 95% CI 1.34–4.21 for FIB‐4 ≥ 1.3; aHR 3.13, 95% CI 1.18–8.29 for FIB‐4 < 1.3).Serum ferritin levels correlated with the risk of LRE in patients with SLD. [ABSTRACT FROM AUTHOR]

Simple Summary: The impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on post-hepatectomy portal vein thrombosis (PH-PVT) was investigated. One hundred six patients who underwent hepatectomy were categorized based on the presence of liver steatosis as MASLD (n = 20), MetALD (MASLD with moderate alcohol consumption) (n = 5), Other SLD (hepatic steatosis of other etiology) (n = 13), and No SLD (no hepatic steatosis) (n = 68). PH-PVT was observed in twelve patients. The incidences were 35.0% in MASLD, 20.0% in MetALD, 7.7% in Other SLD, and 4.4% in No SLD. The MASLD group (including MASLD and MetALD) was an independent significant risk factor for PH-PVT. Moreover, the incidence of MASLD was significantly higher than that of No SLD, along with metabolic factors, excluding alcohol consumption. In conclusion, MASLD and MetALD are risk factors for PH-PVT, and hepatic steatosis and metabolic dysfunction may play a synergistic role in the development of PH-PVT. Background: Due to the increasing global prevalence of non-alcoholic fatty liver disease (NAFLD), which is closely linked to metabolic disorders, there has been a rise in the number of patients with NAFLD undergoing hepatectomy. The metabolic disorders, as well as NAFLD, increase venous thrombotic risk. NAFLD was recently updated to a new concept of hepatic steatosis: metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the impact of MASLD on post-hepatectomy portal vein thrombosis (PH-PVT). Methods: A total of 106 patients who underwent hepatectomy for liver cancer were included. Steatotic liver disease (SLD) was diagnosed using a CT L/S ratio of <1.1. SLD was classified as follows: MASLD, SLD associated with metabolic factors without alcohol consumption; MetALD, SLD with metabolic factors and moderate alcohol consumption; Other SLD, alcohol or other specific etiology of SLD; and No SLD, no hepatic steatosis. Results: PH-PVT was detected in 12/106 patients (11.3%); MASLD, 7/20 (35%); MetALD, 1/5 (20%); Other SLD, 1/13 (8%); and No SLD, 3/68 (4.4%). Multivariate analysis showed that the MASLD group (including MASLD and MetALD) (odds ratio [OR], 9.27) and left lateral sectionectomy (OR, 6.22) were significant independent risk factors for PH-PVT. Additionally, the incidence of PH-PVT was significantly higher in patients with MASLD than in those without SLD, along with metabolic factors, excluding alcohol consumption. Conclusions: MASLD and MetALD were identified as independent and significant risk factors for PH-PVT. Consideration was given to the idea that hepatic steatosis and metabolic dysfunction play synergistic roles in PH-PVT development. [ABSTRACT FROM AUTHOR]

Simple Summary: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease, affects over one billion adults worldwide. It can progress to more severe conditions, like metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma (HCC). Recent studies have highlighted the role of microRNAs (miRNAs) in this progression due to their ability to regulate genes involved in lipid metabolism, inflammation, fibrosis, and cell proliferation. Modulating miRNAs through synthetic molecules represents a promising therapeutic strategy. Preclinical models demonstrate that miRNA-based therapies can reduce liver inflammation and fibrosis and inhibit tumorigenesis, potentially delaying or preventing HCC onset. However, challenges such as delivery mechanisms, side effects, and long-term safety remain to be addressed. This review, focusing on recent preclinical and clinical studies, explores the pharmacological potential of miRNA-based interventions to counteract MASLD/MASH and their progression to HCC. It provides insights into an emerging field with significant implications for liver disease treatment. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is a growing health concern worldwide, affecting more than 1 billion adults. It may progress to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and ultimately hepatocellular carcinoma (HCC). Emerging evidence has demonstrated the role in this transition of microRNAs (miRNAs), which regulate the expression of genes associated with lipid metabolism, inflammation, fibrosis, and cell proliferation. Specific miRNAs have been identified to exacerbate or mitigate fibrotic and carcinogenic processes in hepatic cells. The modulation of these miRNAs through synthetic mimics or inhibitors represents a promising therapeutic strategy. Preclinical models have demonstrated that miRNA-based therapies can attenuate liver inflammation, reduce fibrosis, and inhibit tumorigenesis, thus delaying or preventing the onset of HCC. However, challenges such as delivery mechanisms, off-target effects, and long-term safety remain to be addressed. This review, focusing on recently published preclinical and clinical studies, explores the pharmacological potential of miRNA-based interventions to prevent MASLD/MASH and progression toward HCC. [ABSTRACT FROM AUTHOR]

Background and Aims: Multiple non-invasive tests (NITs) for identifying advanced fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) are available, but, due to the limitations of single NITs, the American Association for the Study of Liver Disease (AASLD) guidelines suggest a two-step strategy, combining the Fibrosis-4 Index (FIB-4) score with the Enhanced Liver Fibrosis (ELF) test to improve diagnostic accuracy and minimize unnecessary liver biopsies. However, few real-world studies have used such a sequential approach. We here evaluated the diagnostic accuracy of the ELF test in patients with recently established metabolic dysfunction-associated steatotic liver disease (MASLD) and assessed the clinical utility of applying a two-step strategy, including the ELF test following the FIB-4 score assessment, in patients with MASLD. Methods: We enrolled 153 patients diagnosed with MASLD who underwent liver biopsy at the Dong-A University Hospital between June 2018 and August 2023. The degree of fibrosis was determined based on liver biopsy results. Various NITs were used, including the Aminotransferase-to-Platelet Ratio Index (APRI), FIB-4 score, NAFLD Fibrosis score (NFS) and ELF test. The diagnostic efficacy of these NITs was evaluated based on the area under the receiver operating characteristic curve (AUROC). Additionally, the performance of each test was further examined both when applied individually and in a two-step approach, where FIB-4 was used followed by ELF testing. Key metrics such as sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were used for this analysis. Results: Overall, 153 patients with MASLD (mean age: 46.62 years; 52.3% men; 28.1% with type 2 diabetes) were included. The performance of the NITs in identifying advanced fibrosis was as follows: the AUROC of the APRI, FIB-4, NFS, and ELF tests were 0.803 (95% confidence interval (CI), 0.713–0.863), 0.769 (95% CI, 0.694–0.833), 0.699 (95% CI, 0.528–0.796), and 0.829 (95% CI, 0.760–0.885), respectively. The combination of the FIB-4 score ≥ 1.30 and the ELF score ≥ 9.8 showed 67.86% sensitivity, 90.40% specificity, a PPV of 75.18%, an NPV of 86.78%, an accuracy of 83.64%, and an AUROC of 0.791 for predicting the diagnosis of advanced fibrosis. This approach excluded 28 patients (71.8%) from unnecessary liver biopsies. Conclusions: Our study demonstrated that ELF testing maintained diagnostic accuracy in assessing liver fibrosis in patients with MASLD in real-world practice. This test was used as a second step in the evaluation, reducing clinically unnecessary invasive liver biopsies and referrals to tertiary institutions. This approach allows assessment of MASLD severity in primary care settings without requiring additional equipment. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated liver disease (MASLD) and alcohol-associated liver disease (ALD) are among the leading causes of liver disease worldwide. The exact roles of epigenetic factors in both diseases remains largely unknown. In this context, liver DNA methylation remains a field that requires further exploration and understanding. Methods: We performed a systematic review of liver DNA methylation in humans with MASLD or ALD using Ovid MEDLINE, Ovid Embase, and Cochrane Library. We included human studies where liver DNA methylation was assessed in patients with MASLD and/or ALD. The Rayyan platform was used to select studies. Risk of bias was assessed with the "risk of bias in non-randomized studies of interventions" tool, ROBINS-I. We performed pathway analysis using the most important differentially methylated genes selected in each article. Results: Fifteen articles were included in this systematic review. The risk of bias was moderate to serious in all articles and bias due to confounding and patient selection was high. Sixteen common pathways, containing differentially methylated genes, including cancer pathways, were identified in both diseases. Conclusions: There are common pathways, containing differentially methylated genes, in ALD and MASLD, such as pathways in cancer and peroxisome proliferator-activated receptor (PPAR) signaling pathways. In MASLD, the insulin signaling pathway is one of the most important, and in ALD, the MAPK signaling pathway is the most important. Our study adds one more piece to the puzzle of the mechanisms involved in steatotic liver disease. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing public health concern worldwide. Liver biopsy is the gold standard for diagnosing and staging MASLD, but it is invasive and carries associated risks. In recent years, there has been significant progress in developing noninvasive techniques for evaluation. This review article discusses briefly current available noninvasive assessments and the various liver biopsy techniques available for MASLD, including invasive techniques such as transjugular and transcutaneous needle biopsy, intraoperative/laparoscopic biopsy, and the evolving role of endoscopic ultrasound-guided biopsy. In addition to discussing the various biopsy techniques, we review the current state of knowledge on the histopathologic evaluation of MASLD, including the various scoring systems used to grade and stage the disease. We also explore current and alternative modalities for histopathologic evaluation, such as whole slide imaging and the utility of immunohistochemistry. Overall, this review article provides a comprehensive overview of the progress in liver biopsy techniques for MASLD and compares invasive and noninvasive modalities. However, beyond clinical trials, the practical application of liver biopsy may be limited, as ongoing advancements in noninvasive fibrosis assessments are expected to more effectively identify candidates for MASLD treatment in real-world settings. Plain language summary: Modernizing metabolic dysfunction-associated steatotic liver disease diagnostics: the progressive shift from liver biopsy to non-invasive techniques Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a condition where fat builds up in the liver, causing inflammation and scarring. This problem is becoming more common worldwide and can lead to serious health issues like chronic liver disease, liver failure, and liver cancer. Doctors can use a method called a liver biopsy to check if a patient has a liver problem like MASLD. However, this method can be a bit risky because it involves inserting a needle into the liver to get a sample. Although doctors can also rely on blood work and different medical imaging approaches to assess the severity of liver disease, specifically MASLD, these options aren't completely accurate. Therefore, there is still a need for a liver biopsy. This article explores various methods and techniques that doctors can use to perform a liver biopsy. It explains how the sample taken with the needle can be analyzed under a microscope to help guide the management of patients with MASLD. We hope this review will be useful for doctors and researchers in the field of gastroenterology and hepatology. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods Results Conclusions The impact of metabolic syndrome (MetS) traits on chronic kidney disease (CKD) risk in metabolic dysfunction‐associated steatotic liver disease (MASLD) is unknown. We investigated the impact of type and number of MetS traits and liver fibrosis on prevalent CKD and incident end‐stage renal disease (ESRD) risk in SLD.234 488 UK Biobank participants' were analysed. Hepatic steatosis index (> 36 for SLD, < 30 for no SLD) and MRI‐proton density fat fraction (≥ 5.56%) were used to identify SLD. MetS traits were identified using MASLD criteria. Advanced fibrosis (FIB‐4 score > 2.67) was determined using FIB‐4 scores. eGFR < 60 mL/min/1.73 m2 or albuminuria > 3 mg/mmol identified prevalent CKD. A validated algorithm identified incident ESRD. Binary logistic and Cox regressions were used to test associations with prevalent CKD ([adjusted odds ratios (ORs)]) and incident ESRD (adjusted hazard ratios [HRs]) respectively.102 410 participants (41.2%) had SLD. 64.4% had MetS. 1.3% had FIB‐4 score > 2.67. With SLD and only one MetS trait, hypertension (OR 1.35, 95% CI 1.35–1.72) or type 2 diabetes (T2D) (OR 1.89, 95% CI 1.06–3.38) increased risk of prevalent CKD. MetS (≥ 3 traits) increased prevalent CKD risk (OR 1.94, 95% CI 1.75–2.15), which was further increased by advanced liver fibrosis (OR 4.29, 95% CI 3.36–5.47). CKD prevalence increased with increasing MetS traits. Over 13.6 years (median follow‐up), MetS was associated with increased risk of developing ESRD (HR 1.70, 95% CI 1.19–2.43).In MASLD, hypertension, and T2D, number of MetS traits and liver fibrosis increased risk of prevalent CKD and presence of MetS increased the risk of incident ESRD. [ABSTRACT FROM AUTHOR]

ABSTRACT Polyphenols, known for their potent antioxidant and anti‐inflammatory properties, have emerged as promising, natural, and safe complementary treatment options for metabolic‐associated steatotic liver disease (MASLD). Among these, curcumin, resveratrol, and silymarin are the most extensively studied; however, their differential effects on MASLD outcomes remain inconclusive. This systematic review and meta‐analysis of RCTs aimed to evaluate the efficacy of curcumin, resveratrol, and silymarin in patients with MASLD. A comprehensive search of seven databases was conducted up to September 2024. Odds ratios (OR), mean differences (MD), and standardized MD (SMD) with 95% confidence intervals (CI) were used to assess treatment effects. Primary outcomes included improvement in hepatic steatosis and ALT activity, while secondary outcomes included changes in AST activity, blood lipids, glucose, BMI, blood pressure, and TNF‐α. Twenty‐seven studies involving 1691 participants were included. Curcumin significantly improved hepatic steatosis compared to placebo (OR: 4.39, 95% CI: 1.45 to 13.27, p = 0.009), followed by resveratrol (OR: 3.18, 95% CI: 1.20 to 8.42, p = 0.02). Silymarin exhibited the strongest effect in reducing ALT levels (MD: −6.44 U/L, 95% CI: −10.03 to −2.85, p = 0.0004), with curcumin (MD: −5.88 U/L, 95% CI: −9.05 to −2.72, p = 0.0003) also showing significant reductions. A marked reduction in AST was observed with silymarin (MD: −6.99 U/L, 95% CI: −8.56 to −5.42, p < 0.00001), followed by curcumin (MD: −3.36 U/L, 95% CI: −5.35 to −1.36, p = 0.001). Furthermore, curcumin intake significantly improved metabolic indicators (TG, FBG, HOMA‐IR, and BMI). Resveratrol reduced FBG and DBP. Curcumin had the strongest effect on hepatic steatosis and improved both transaminase levels and metabolic markers. Silymarin demonstrated the greatest reduction in transaminase levels, while resveratrol showed modest benefits in steatosis and metabolic improvements. The three polyphenols appear as promising therapeutics for the treatment of MASLD. [ABSTRACT FROM AUTHOR]

Background and Aims Methods Results Conclusions This study sought to assess the capabilities of large language models (LLMs) in identifying clinically significant metabolic dysfunction‐associated steatotic liver disease (MASLD).We included individuals from NHANES 2017–2018. The validity and reliability of MASLD diagnosis by GPT‐3.5 and GPT‐4 were quantitatively examined and compared with those of the Fatty Liver Index (FLI) and United States FLI (USFLI). A receiver operating characteristic curve was conducted to assess the accuracy of MASLD diagnosis via different scoring systems. Additionally, GPT‐4V's potential in clinical diagnosis using ultrasound images from MASLD patients was evaluated to provide assessments of LLM capabilities in both textual and visual data interpretation.GPT‐4 demonstrated comparable performance in MASLD diagnosis to FLI and USFLI with the AUROC values of .831 (95% CI .796–.867), .817 (95% CI .797–.837) and .827 (95% CI .807–.848), respectively. GPT‐4 exhibited a trend of enhanced accuracy, clinical relevance and efficiency compared to GPT‐3.5 based on clinician evaluation. Additionally, Pearson's r values between GPT‐4 and FLI, as well as USFLI, were .718 and .695, respectively, indicating robust and moderate correlations. Moreover, GPT‐4V showed potential in understanding characteristics from hepatic ultrasound imaging but exhibited limited interpretive accuracy in diagnosing MASLD compared to skilled radiologists.GPT‐4 achieved performance comparable to traditional risk scores in diagnosing MASLD and exhibited improved convenience, versatility and the capacity to offer user‐friendly outputs. The integration of GPT‐4V highlights the capacities of LLMs in handling both textual and visual medical data, reinforcing their expansive utility in healthcare practice. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods Results Conclusions Alcohol use is prevalent among hepatology clinic patients with chronic liver disease (CLD). We explored factors associated with the importance and confidence dimensions of motivation to reduce drinking.Participants (N = 121) with unhealthy alcohol use (i.e., over NIH guidelines) receiving care in hepatology clinics from a safety‐net hospital (SN, N = 54) and two Veterans Affairs Healthcare Systems (VA, N = 67) were enrolled in an alcohol intervention trial from March 2022 through October 2023. Baseline assessments included Generalised Anxiety Disorder (GAD‐7), Patient Health Questionnaire (PHQ‐8), Alcohol Use Disorders Identification Test (AUDIT), COVID‐19 stress; and measures of importance and confidence to decrease alcohol use (readiness rulers, scales of 1–10). Liver disease aetiology and severity were extracted from electronic health records. We performed multivariable linear regression models with forward selection to assess pre‐specified variables' associations with importance and confidence.The sample was 84% male, 40% Latino, 31% White, 18% Black and 11% other races; median age was 61 years. Median (Q1–Q3) AUDIT score was 16 (12–24), importance was 9 (6–10) and confidence was 8 (5–9). On multivariable analysis, VA site (vs. SN) participants had a 0.97‐point lower importance score (p = 0.02); higher symptoms of depression (PHQ‐8 score ≥ 10 vs. < 10) and AUDIT scores (for each point increase) were associated with higher importance score (estimates 1.2 and 0.08, p < 0.05, respectively). Liver disease aetiology and severity were not significantly associated with outcomes.Depression, alcohol problem severity and treatment site may influence motivation to reduce alcohol use and could inform future hepatology‐based interventions. [ABSTRACT FROM AUTHOR]

Background: Non-Alcoholic Fatty Liver Disease, recently better recognised as Metabolic Dysfunction–Associated Steatotic Liver Disease, is the most prevalent form of chronic liver disease at present time. It is estimated to impact 32% of the world's population, hence representing a significant health burden. Aim of the work: To assess the significance of plasma Lipocalin-2 (LCN2) levels in the diagnosis and prognosis of NAFLD patients. Patients and methods: In this retrospective case–control study we recruited 102 subjects aged between 18 and 70 years. The included participants were split into two study groups. Group I: 51 NAFLD patients (61% men, 39% females) and Group II: 51 healthy controls (51% men and 49% females), for whom plasma LCN2 levels were assessed and correlated with NAFLD fibrosis score, FIB4 and fatty liver index. Results: In this study, LCN2 levels in NAFLD patients were significantly greater compared to individuals in the control group (p < 0.001), with a mean of 1893.214 ± 1002.852 ng/dL in the cases and a mean of 466.020 ± 397.699 ng/dL in the controls. This suggests the use of LCN2 as a possible diagnostic marker of NAFLD. The mean LCN2 levels in this study also significantly increased as the grade of fatty liver increased from I to III (p < 0.001). This in turn proposes the use of LCN2 as a prognostic marker for NAFLD progression. LCN2 also significantly correlated with the fatty liver index and NAFLD Fibrosis scoring systems, but not with Fib-4. With an area under the ROC of 0.906, it demonstrated excellent diagnostic performance with 84% sensitivity, 90% specificity, 89.6% PPV and 85.2% NPV for the prediction of NAFLD patients. Conclusion: Lipocalin-2 performs as a diagnostic and a possible prognostic marker for metabolic dysfunction-associated steatotic liver disease. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is often asymptomatic and underdiagnosed; consequently, there is a demand for simple, non-invasive diagnostic tools. In this study, we developed a method to quantify liver steatosis based on miRNAs, present in liver and serum, that correlate with liver fat. The miRNAs were analyzed by miRNAseq in liver samples from two cohorts of patients with a precise quantification of liver steatosis. Common miRNAs showing correlation with liver steatosis were validated by RT-qPCR in paired liver and serum samples. Multivariate models were built using partial least squares (PLS) regression to predict the percentage of liver steatosis from serum miRNA levels. Leave-one-out cross validation and external validation were used for model selection and to estimate predictive performance. The miRNAseq results disclosed (a) 144 miRNAs correlating with triglycerides in a set of liver biobank samples (n = 20); and (b) 124 and 102 miRNAs correlating with steatosis by biopsy digital image and MRI analyses, respectively, in liver samples from morbidly obese patients (n = 24). However, only 35 miRNAs were common in both sets of samples. RT-qPCR allowed to validate the correlation of 10 miRNAs in paired liver and serum samples. The development of PLS models to quantitatively predict steatosis demonstrated that the combination of serum miR-145-3p, 122-5p, 143-3p, 500a-5p, and 182-5p provided the lowest root mean square error of cross validation (RMSECV = 1.1, p-value = 0.005). External validation of this model with a cohort of mixed MASLD patients (n = 25) showed a root mean squared error of prediction (RMSEP) of 5.3. In conclusion, it is possible to predict the percentage of hepatic steatosis with a low error rate by quantifying the serum level of five miRNAs using a cost-effective and easy-to-implement RT-qPCR method. [ABSTRACT FROM AUTHOR]

Background/Aims: Combi-elastography is a B-mode ultrasound-based method in which two elastography modalities are utilized simultaneously to assess metabolic dysfunction-associated steatotic liver disease (MASLD). However, the performance of combi-elastography for diagnosing metabolic dysfunction-associated steatohepatitis (MASH) and determining fibrosis severity is unclear. This study compared the diagnostic performances of combi-elastography and vibrationcontrolled transient elastography (VCTE) for identifying hepatic steatosis, fibrosis, and high-risk MASH. Methods: Participants who underwent combi-elastography, VCTE, and liver biopsy were selected from a prospective cohort of patients with clinically suspected MASLD. Combi-elastographyrelated parameters were acquired, and their performances were evaluated using area under the receiver-operating characteristic curve (AUROC) analysis. Results: A total of 212 participants were included. The diagnostic performance for hepatic steatosis of the attenuation coefficient adjusted by covariates from combi-elastography was comparable to that of the controlled attenuation parameter measured by VCTE (AUROC, 0.85 vs 0.85; p=0.925). The performance of the combi-elastography-derived fibrosis index adjusted by covariates for diagnosing significant fibrosis was comparable to that of liver stiffness measured by VCTE (AUROC, 0.77 vs 0.80; p=0.573). The activity index from combi-elastography adjusted by covariates was equivalent to the FibroScan-aspartate aminotransferase score in diagnosing high-risk MASH among participants with MASLD (AUROC, 0.72 vs 0.74; p=0.792). Conclusions: The performance of combi-elastography is similar to that of VCTE when evaluating histology of MASLD. [ABSTRACT FROM AUTHOR]

• Iron overload links to metabolic dysfunction-associated steatotic liver disease. • Iron overload links to hepatic fibrosis. • Nonlinear associations seen in serum ferritin with controlled attenuation parameter. 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. The study analyzed data from 5,927 NHANES participants to reveal an association between iron overload, MASLD, and liver fibrosis. It showed significant correlations between serum ferritin and CAP, LSM, after adjusting for covariates. Additionally, molecular analyses identified the hub genes linked to iron overload, which may exacerbate MAFLD and hepatic fibrosis. CAP, controlled attenuation parameter; LSM, liver stiffness measurement; NHANES, nutrition examination survey; MASLD, metabolic dysfunction-associated steatotic liver disease. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Inflammatory bowel disease (IBD) is associated with an increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). The Fibrosis-4 (FIB-4) index is a non-invasive tool for assessing liver fibrosis that has been validated in various liver diseases. The main objective of this study was to study whether the FIB-4 index is a reliable predictor of liver fibrosis, as assessed through elastography, in patients with IBD. We additionally aimed to analyze if FIB-4 associates with IBD characteristics such as lipid profile, subclinical carotid atherosclerosis, and insulin resistance indices. Methods: A cross-sectional study was conducted, enrolling 197 patients with IBD. Subjects underwent comprehensive clinical and laboratory evaluations. Hepatic fibrosis was assessed non-invasively using the FIB-4 index and transient elastography, while abdominal ultrasonography was performed to grade hepatic steatosis based on the degree of fat infiltration. To investigate the associations between disease characteristics and FIB-4 score and the correlation of this index to elastography, a multivariable linear regression analysis was conducted. Results: The presence of diabetes, hypertension, and metabolic syndrome was associated with significantly higher FIB-4 levels. However, FIB-4 did not show a relationship with disease characteristics such as phenotype or activity indices. Furthermore, FIB-4 did not demonstrate a correlation with liver stiffness values measured by elastography. Conclusions: Our findings suggest that the FIB-4 index may not be a reliable tool for assessing hepatic fibrosis in patients with IBD. This observation is particularly significant given the high prevalence of MASLD in the IBD population. [ABSTRACT FROM AUTHOR]

Aims: We aimed to explore the extent to which individuals previously diagnosed with nonalcoholic fatty liver disease (NAFLD) meet the criteria fulfilled with the new nomenclature, metabolic dysfunction‐associated steatotic liver disease (MASLD), within an Asian primary clinic cohort. Additionally, we assessed the reliability of the diagnostic performance of FIB‐4 and NAFLD fibrosis score (NFS) for MASLD within the primary clinic cohort. Methods: This retrospective cross‐sectional study included participants who underwent magnetic resonance elastography and abdominal ultrasonography during their health checkups at nationwide health promotion centers (n = 6740). Results: The prevalence rates of NAFLD and MASLD diagnosed based on ultrasonography results were 36.7% and 38.0%, respectively. Notably, 96.8% of patients in the NAFLD cohort fulfilled the new criteria for MASLD. A small proportion of patients with NAFLD (n = 80, 3.2%) did not meet the MASLD criteria. Additionally, 168 patients (6.6%) were newly added to the MASLD group. The areas under the receiver operating characteristic curves for diagnosing advanced hepatic fibrosis for FIB‐4 (0.824 in NAFLD vs. 0.818 in MASLD, p = 0.891) and NFS (0.803 in NAFLD vs. 0.781 in MASLD, p = 0.618) were comparable between the MASLD and NAFLD groups. Furthermore, the sensitivity, specificity, positive predictive value, and negative predictive value of FIB‐4 and NFS for advanced fibrosis in MASLD were also comparable to those in NAFLD. Conclusions: Most patients (96.8%) previously diagnosed with NAFLD fulfilled the new criteria for MASLD in an Asian primary clinic cohort. Diagnostic performance of FIB‐4 in the MASLD cohort demonstrated satisfactory results. [ABSTRACT FROM AUTHOR]

Aim: Advanced fibrosis has a strong influence on the occurrence of liver‐related events in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD), while diabetes mellitus (DM), which is often complicated by MASLD, is associated with the progression of MASLD. We stratified patients with MASLD according to the severity of liver pathological findings and the presence of DM, aiming to examine whether these indices could be used to accurately assess the risk of developing liver‐related events. Methods: A total of 282 patients with liver biopsy‐proven MASLD were included. Liver‐related events were defined as the occurrence of hepatocellular carcinoma (HCC) and complications of liver cirrhosis, such as ascites, hepatic encephalopathy, Child–Pugh class B and C, as well as treatment‐eligible esophageal and gastric varices. Results: Multivariate analysis adjusted for age, sex, body mass index, alanine aminotransferase, creatinine, hemoglobin A1c, smoking habits, dyslipidemia, hypertension, nonalcoholic fatty liver disease activity score (NAS), or fibrosis stage showed that advanced fibrosis with or without DM was a risk factor for liver‐related events. The combined effect of DM and advanced fibrosis increased the risk of HCC onset. However, DM alone or in combination with NAS did not affect the development of liver‐related events, including the occurrence of HCC and complications of liver cirrhosis. Conclusions: While the assessment of fibrosis in patients with MASLD is important for evaluating the risk of developing liver‐related events, combining the assessment of DM may be possible to stratify groups at higher risk of developing HCC. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods Results Conclusions Glucagon‐like peptide‐1 receptor (GLP1R) agonists and glucose‐dependent insulinotropic polypeptide receptor (GIPR) agonists may help treat metabolic dysfunction‐associated steatotic liver disease (MASLD) and metabolic dysfunction‐associated steatohepatitis (MASH). However, their definitive effects are still unclear. Our study aims to clarify this uncertainty.We utilised conventional Mendelian randomisation (MR) analysis to explore potential causal links between plasma GLP‐1/GIP concentrations and MASLD and its related traits. Next, we conducted drug‐target MR analysis using highly expressed tissue data to assess the effects of corresponding drug perturbation on these traits. Finally, mediation analysis was performed to ascertain whether the potential causal effect is direct or mediated by other MASLD‐related traits.Circulating 2‐h GLP‐1 and GIP concentrations measured during an oral glucose tolerance test showed hepatoprotective effects on MASLD risk (ORGLP‐1 = 0.168 [95% CI 0.033–0.839], p = 0.030; ORGIP = 0.331 [95% CI 0.222–0.494], p = 6.31 × 10−8). GLP1R expression in the blood had a minimal causal effect on MASLD risk, whereas GIPR expression significantly affected MASLD risk (OR = 0.671 [95% CI 0.531–0.849], p = 9.07 × 10−4). Expression levels of GLP1R or GIPR in the blood significantly influenced MASLD‐related clinical traits. Mediation analysis revealed that GIPR expression protected against MASLD, even after adjusting for type 2 diabetes or body mass index.GLP‐1/GIP receptor agonists offer promise in lowering MASLD/MASH risk. GIP receptor agonists can exert direct and indirect effects on MASLD mediated by weight reduction or glycemic control improvement. [ABSTRACT FROM AUTHOR]

• Steatotic liver disease heightened risk for major adverse cardiac events (MACE). • Metabolic dysfunction-associated steatotic liver disease (MASLD) has recently emerged. • A machine-learning model using age and risk factors of MASLD predicts MACE risk. • Age ≥ 60 and ≥ 4 MASLD risk factors significantly predict MACE in derivation cohort. • Validation cohort confirms high MACE risk with both age and risk factor criteria. Steatotic liver disease (SLD) is associated with adverse cardiac events. Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a condition characterized by the abnormal accumulation of hepatic lipids that is closely linked to five metabolic disorders: overweight or obesity, impaired glucose regulation, hypertension, hypertriglyceridemia, and low high-density lipoprotein-cholesterol. This retrospective study aimed to stratify the risk of cardiac events in patients with MASLD. Patients diagnosed with MASLD through ultrasonography were evaluated. We implemented a machine learning-based approach using a survival classification and regression tree (CART) model to stratify patients based on age, and the number of risk scores was investigated as a predictor of adverse outcomes in the derivation cohort. The primary outcomes were major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, and revascularization due to coronary artery disease. Among 2,962 patients (median age, 62 years; men, 53.5 %), the distribution of risk factors was as follows: one (10.8 %), two (28.5 %), three (33.0 %), four (19.9 %), and five (7.8 %). Over a median follow-up period of 6.8 years, 170 (5.7 %) patients experienced MACE. In the derivation cohort of 2,073 patients, the CART model identified age ≥60 years old and risk factors ≥4 as significant predictors of MACE. These findings were corroborated in a validation cohort of 889 patients. Patients meeting both criteria exhibited the highest risk of MACE (log-rank test, p < 0.001). Patients aged ≥60 years old with risk factors ≥4 indicates at high risk of MACE in patients with MASLD. This risk stratification system provides a practical tool for identifying high-risk individuals in the MASLD population. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims: Metabolic dysfunction‐associated steatotic liver disease (MASLD), in the context of autoimmune hepatitis (AIH) among liver transplantation (LT) candidates or recipients remains poorly understood. This study compares waitlist and post‐LT outcomes in patients with MASLD/AIH to MASLD and AIH alone. Methods: Using the united network organ sharing database (2002–2022), we compared waitlist outcomes and post‐LT survival among patients with MASLD/AIH (n = 282), AIH (n = 5812), and MASLD (n = 33 331). Competing risk, Kaplan Meier estimates and Cox proportional hazard analyses were performed. Results: MASLD/AIH group had the highest rates of encephalopathy and ascites, and highest MELD scores. MASLD/AIH patients had higher transplantation incidence (adjusted subdistribution hazard ratio [aSHR] 1.64, 95% CI 1.44–1.85; p <.001) and lower waitlist removal risk (aSHR.30, 95% CI.20–.44; p <.001) compared to MASLD alone. One‐year post‐LT survival favoured MASLD compared to AIH (patient: 92% vs. 91%, p <.001; graft: 89% vs. 88%, p <.001) and MASLD/AIH (patient: 92% vs. 90%, p =.008; graft: 89% vs. 88%, p =.023). Recipients with MASLD/AIH showed no significant difference in survival at 10‐year post‐LT compared to MASLD (patient: 63% vs. 61%, p =.68; graft 60% vs. 59%, p =.83) and AIH (patient: 63% vs. 70%, p =.07; graft: 60% vs. 64%, p =.42). Conclusions: Our study showed that MASLD/AIH patients demonstrate higher LT incidence and lower dropout rates. Long‐term post‐LT outcomes did not significantly differ between groups. Further prospective multicenter studies are needed to validate these findings. [ABSTRACT FROM AUTHOR]

The liver has many functions including the regulation of nutrient and metabolite levels in the systemic circulation through efficient transport into and out of hepatocytes. To sustain these functions, hepatocytes display large functional heterogeneity. This heterogeneity is reflected by zonation of metabolic processes that take place in different zones of the liver lobule, where nutrient‐rich blood enters the liver in the periportal zone and flows through the mid‐zone prior to drainage by a central vein in the pericentral zone. Metabolite transport plays a pivotal role in the division of labor across liver zones, being either transport into the hepatocyte or transport between hepatocytes through the blood. Signaling pathways that regulate zonation, such as Wnt/β‐catenin, have been shown to play a causal role in the development of metabolic dysfunction‐associated steatohepatitis (MASH) progression, but the (patho)physiological regulation of metabolite transport remains enigmatic. Despite the practical challenges to separately study individual liver zones, technological advancements in the recent years have greatly improved insight in spatially divided metabolite transport. This review summarizes the theories behind the regulation of zonation, diurnal rhythms and their effect on metabolic zonation, contemporary techniques used to study zonation and current technological challenges, and discusses the current view on spatial and temporal metabolite transport. [ABSTRACT FROM AUTHOR]

Background and Aims: The rise in obesity highlights the need for improved therapeutic strategies, particularly in addressing metabolic dysfunction‐associated steatotic liver disease (MASLD). We aim to assess the role of tryptophan metabolic pathways in the pathogenesis of obesity and in the different histological stages of MASLD. Materials and Methods: We used ultra‐high performance liquid chromatography to quantify circulating levels of 15 tryptophan‐related metabolites from the kynurenine, indole and serotonin pathways. A cohort of 76 subjects was analysed, comprising 18 subjects with normal weight and 58 with morbid obesity, these last being subclassified into normal liver (NL), simple steatosis (SS) and metabolic dysfunction‐associated steatohepatitis (MASH). Then, we conducted gene expression analysis of hepatic IDO‐1 and kynyrenine‐3‐monooxygenase (KMO). Results: Key findings in obesity revealed a distinct metabolic signature characterized by a higher concentration of different kynurenine‐related metabolites, a decrease in indole‐3‐acetic acid and indole‐3‐propionic acid, and an alteration in the serotonin pathway. Elevated tryptophan levels were associated with MASLD presence (37.659 (32.577–39.823) μM of tryptophan in NL subjects; 41.522 (38.803–45.276) μM in patients with MASLD). Overall, pathway fluxes demonstrated an induction of tryptophan catabolism via the serotonin pathway in SS subjects and into the kynurenine pathway in MASH. We found decreased IDO‐1 and KMO hepatic expression in NL compared to SS. Conclusions: We identified a distinctive metabolic signature in obesity marked by changes in tryptophan catabolic pathways, discernible through altered metabolite profiles. We observed stage‐specific alterations in tryptophan catabolism fluxes in MASLD, highlighting the potential utility of targeting these pathways in therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Numerous recent studies have explored the association between metabolic dysfunction‐associated steatotic liver disease (MASLD) and the risk of various extrahepatic cancers. However, the conclusions were inconclusive. The aim of this study was to clarify this relationship by conducting a robust meta‐analysis. Methods: Systematic searches were conducted on PubMed, Embase and Web of Science databases to identify relevant cohort studies published prior to February 2024. Hazard ratios (HRs) and their corresponding 95% confidence intervals (95% CIs) were combined using a random‐effects model in this meta‐analysis. Results: Eighteen cohort studies (approximately 16.7 million participants) were finally included in this meta‐analysis. MASLD was linked to a higher risk of extrahepatic cancers, such as gastric (n = 10, HR = 1.47, 95% CI: 1.07–2.01), colorectal (n = 13, HR = 1.33, 95% CI: 1.16–1.53), pancreatic (n = 8, HR = 1.41, 95% CI: 1.11–1.79), biliary tract (n = 5, HR = 1.27, 95% CI: 1.18–1.37), thyroid (n = 6, HR = 1.46, 95% CI: 1.02–2.09), urinary system (n = 10, HR = 1.45, 95% CI: 1.25–1.69), breast (n = 11, HR = 1.17, 95% CI: 1.08–1.26) and female genital organ cancers (n = 10, HR = 1.36, 95% CI: 1.11–1.66). However, there was no statistically significant association between MASLD and the risk of head and neck (n = 6, HR = 1.03, 95% CI: 99–1.07), oesophageal (n = 9, HR = 1.26, 95% CI: 0.86–1.86), lung (n = 9, HR = 1.01, 95% CI: 0.92–1.10), prostate (n = 9, HR = 1.06, 95% CI: 0.94–1.19) or small intestine cancer (n = 2, HR = 1.75, 95% CI: 1.00–3.06). Conclusions: This latest large‐scale meta‐analysis indicated that MASLD was associated with an increased risk of various extrahepatic cancers, such as gastric, colorectal, pancreatic, biliary duct, thyroid, urinary system, breast, skin and female genital cancers. Further research is needed to investigate the mechanisms underlying these associations. [ABSTRACT FROM AUTHOR]

Chronic liver disease leads to hepatocellular injury that triggers a pro-inflammatory state in several parenchymal and non-parenchymal hepatic cell types, ultimately resulting in liver fibrosis, cirrhosis, portal hypertension and liver failure. Thus, an improved understanding of inflammasomes – as key molecular drivers of liver injury – may result in the development of novel diagnostic or prognostic biomarkers and effective therapeutics. In liver disease, innate immune cells respond to hepatic insults by activating cell-intrinsic inflammasomes via toll-like receptors and NF-κB, and by releasing pro-inflammatory cytokines (such as IL-1β, IL-18, TNF-α and IL-6). Subsequently, cells of the adaptive immune system are recruited to fuel hepatic inflammation and hepatic parenchymal cells may undergo gasdermin D-mediated programmed cell death, termed pyroptosis. With liver disease progression, there is a shift towards a type 2 inflammatory response, which promotes tissue repair but also fibrogenesis. Inflammasome activation may also occur at extrahepatic sites, such as the white adipose tissue in MASH (metabolic dysfunction-associated steatohepatitis). In end-stage liver disease, flares of inflammation (e.g., in severe alcohol-related hepatitis) that spark on a dysfunctional immune system, contribute to inflammasome-mediated liver injury and potentially result in organ dysfunction/failure, as seen in ACLF (acute-on-chronic liver failure). This review provides an overview of current concepts regarding inflammasome activation in liver disease progression, with a focus on related biomarkers and therapeutic approaches that are being developed for patients with liver disease. [ABSTRACT FROM AUTHOR]

Non-invasive tests (NITs) for liver fibrosis have been recognized for their clinical utility in metabolic dysfunction-associated steatotic liver disease (MASLD). However, their diagnostic efficacy in detecting liver fibrosis is notably reduced in patients with alcohol-related liver disease. Therefore, ascertaining the reliability of NITs in patients with MASLD with moderate alcohol intake (MetALD) is essential. In this cross-sectional study, we reviewed data from 7,918 health check-up participants who underwent both magnetic resonance elastography (MRE) and ultrasound for the diagnosis of hepatic steatosis. The participants were categorized into MASLD and MetALD groups, and the performance of fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) were assessed. Advanced hepatic fibrosis (F3) was defined as MRE ≥3.6 kPa. The prevalence of MetALD was 5.8% in this health check-up cohort, and 1.5% of these patients exhibited advanced hepatic fibrosis. Both MetALD and MASLD displayed similar metabolic profiles and hepatic fibrosis burdens. The diagnostic performance of FIB-4 and NFS for MRE ≥3.6 kPa showed no noticeable differences in the area under the receiver-operating characteristic values between the two groups (0.85 vs. 0.80 in FIB-4). Moreover, the sensitivity (71.4%), specificity (77.3%), and both positive (4.6%) and negative (99.4%) predictive values of NITs for MetALD closely mirrored those observed for MASLD. FIB-4 performed well for the initial screening of advanced hepatic fibrosis in MetALD, demonstrating reasonable sensitivity and negative predictive values. In this cross-sectional study, data from 7,918 participants who underwent MRE were analyzed to assess the performance of fibrosis-4 (FIB-4) and non-alcoholic fatty liver disease fibrosis scores in metabolic dysfunction-associated steatotic liver disease (MASLD) and MASLD with moderate alcohol intake (MetALD). We found that FIB-4 had high diagnostic accuracy in the newly identified MetALD group, similar to that in the MASLD population. These results highlight the potential of FIB-4 as a reliable screening tool for MetALD, even when specific subgroups are considered. Therefore, FIB-4 is a valuable screening tool for identifying advanced fibrosis in the MetALD population. [Display omitted] • The effectiveness of NITs for detecting liver fibrosis in patients with MetALD is not well established. • In a study of 7,918 participants undergoing MRE, FIB-4 achieved an AUROC of 0.85 for detecting advanced fibrosis (MRE ≥3.6 kPa). • Sensitivity (71.4%), specificity (77.3%), and both positive (4.6%) and negative (99.4%) predictive values of FIB-4 were similar for MetALD as for MASLD. • FIB-4 is established as a valuable screening tool for identifying advanced fibrosis in the MetALD population. [ABSTRACT FROM AUTHOR]

Introduction: Patients with type 2 diabetes (T2D), particularly those from historically marginalized racial and ethnic groups, are at high risk of poor outcomes from metabolic dysfunction-associated steatotic liver disease (MASLD). Evidence-based management (EBM) of MASLD can prevent its progression to cirrhosis and poor outcomes, yet rates of EBM of MASLD are low in T2D. Methods: In this pilot study of ten participants, we examined the feasibility and acceptability of a telehealth intervention that delivered EBM of MASLD in Latino/a and Black patients with T2D in the Duke Healthcare System. The intervention included: (a) MASLD education; (b) diet/lifestyle counseling; (c) T2D medication adjustment (i.e., to promote liver health) and (d) ordering of clinically indicated tests and referrals. This 3-month intervention was delivered by an endocrinologist over three virtual study visits. Phone interviews were conducted at study conclusion. We examined rates of recruitment, retention, T2D medication adjustment, and ordering of clinically indicated tests/referrals. Results: The median age of our cohort was 54.0 (44.0, 59.0); six and four participants self-identified as Latino/a ethnicity and Black race, respectively. Retention rate in this study was 100% (n = 10/10), and all scheduled visits were completed (n = 30/30). Recruitment occurred over one month, and the rate was 25.8% (n = 8/31) by telephone call and 10% (n = 2/20) by electronic health record message. The intervention was highly acceptable based on a median Treatment Acceptability and Preferences score of 4.0 (4.0, 4.0). In exit interviews, all participants reported improved understanding of MASLD and its link to diabetes. All participants received T2D medication adjustment (n = 5/10) and/or clinically indicated testing/referral (n = 10/10) for the purpose of improving MASLD. Conclusions: We demonstrated that a telehealth intervention designed to proactively deliver EBM of MASLD was feasible and acceptable in a cohort of Latino/a and Black patients with T2D. Opportunities existed to better align each participants' care with guideline-based care of MASLD. [ABSTRACT FROM AUTHOR]

Aim: To compare the effectiveness of sodium‐glucose co‐transporter‐2 inhibitors (SGLT2is) with dipeptidyl peptidase‐4 inhibitors (DPP4is) on major liver outcomes (MLO) in patients with type 2 diabetes (T2D) and metabolic dysfunction‐associated steatotic liver disease (MASLD). Materials and Methods: We included adult patients with T2D and MASLD, using metformin without specific liver conditions or surgeries, from the Merative MarketScan database. Patients initiating SGLT2is or DPP4is from 1 January 2014 to 31 December 2022 were identified. The primary outcome was time to MLO diagnosis. Overlap weighting balanced covariates, integrated with a Cox proportional hazards model for survival analysis. Results: Among 44 651 patients, 22 100 initiated SGLT2is, and 22 551 began DPP4is. After weighting, the incidence rate of MLO in the SGLT2i group was 3.8 per 1000 person‐years, and it was 3.9 per 1000 person‐years in the DPP4i group, resulting in an adjusted hazard ratio (aHR) of 0.82 (95% CI, 0.60‐1.10). SGLT2i initiation was not associated with cirrhosis (aHR: 0.77; 95% CI, 0.55‐1.06) or hepatocellular carcinoma (aHR: 0.99; 95% CI, 0.47‐1.83) separately. Subgroup and sensitivity analyses did not yield significant results. Conclusions: In patients with T2D and MASLD, SGLT2is did not show a lower risk of MLO compared with DPP4is. Clinicians should consider the overall patient conditions and the additional benefits of SGLT2is to support the decision to switch from DPP4is. [ABSTRACT FROM AUTHOR]

Currently, there remains ongoing controversy about the selection of postoperative antiviral drugs for hepatocellular carcinoma (HCC) patients with concurrent metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatitis B virus (HBV) infection (HPMH) who underwent hepatectomy. A multivariate Cox proportional hazards model and a propensity score matching (PSM) analysis were implemented to ensure equal baseline characteristics. The Kaplan‒Meier survival curves were employed for prognosis comparison between the two groups. This study included 225 HPMH who all received post-hepatectomy antiviral therapy; with 107 in the tenofovir disoproxil fumarate (TDF) group and 118 in the entecavir (ETV) group. In the entire cohort, according to the multivariate analysis, patients in the TDF group showed better recurrence-free survival (RFS) (HR = 0.78; 95% CI, 0.55–0.95; p = 0.030) and overall survival (OS) (HR = 0.52; 95% CI, 0.30–0.97; p = 0.021) than those in the ETV group. After executing a PSM analysis, Kaplan‒Meier survival curve analysis disclosed significant differences for both RFS and OS between the two groups (p = 0.03 and p = 0.01, respectively). In summary, our study suggests a more significant association of TDF in improving RFS and OS than ETV in HPMH who underwent hepatectomy through multivariate and PSM analysis. These findings indicate that the choice of antiviral drugs in HPHM holds crucial significance in guiding patient long-term prognosis. [ABSTRACT FROM AUTHOR]

Background/Objectives: Recent data indicate the involvement of skeletal muscles in the regulation of metabolism and in the pathogenesis of chronic noncommunicable diseases. The goal of our study was to describe the serum concentrations of myokines in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hypertension (HTN) and their correlation with laboratory parameters, blood pressure (BP), and MASLD severity. Methods: A total of 67 patients with MASLD and HTN underwent anthropometric measurements, laboratory tests, and point shear-wave elastography. The serum concentrations of myokines were measured using enzyme-linked immunosorbent assay (ELISA). Results: Patients with detectable serum myonectin concentrations had significantly higher maximum systolic blood pressure (p = 0.022) and higher blood levels of uric acid (p = 0.029). Serum irisin concentration ≥ 6.1 μg/mL was associated with higher FLI values (p = 0.042) and liver stiffness (p = 0.034), as well as with slightly higher waist circumference (p = 0.082) and triglyceride level (p = 0.062). Patients with serum myostatin concentration ≥ 4.98 ng/mL were significantly older (p = 0.033) and had a lower blood albumin level (p = 0.043). Conclusions: In conclusion, the myokine profile in patients with MASLD and HTN correlates both with the severity of MASLD and the parameters characteristic of metabolic health, suggesting the possible contribution of altered irisin, myonectin, and myostatin concentrations to the occurrence of cardiometabolic risks in patients with MASLD. [ABSTRACT FROM AUTHOR]

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease. Body mass index (BMI) is the most used obesity index but has important limitations. The weight-adjusted waist index (WWI) is a novel obesity metric and accurately reflects body composition. We explored the association of WWI with all-cause and cardiovascular disease (CVD) mortality in MASLD. Methods: Adult participants with MASLD were included from NHANES 1999-2018. WWI was calculated by dividing the waist circumference (WC) by the square root of body weight. MASLD was diagnosed by the presence of hepatic steatosis and at least one cardiometabolic risk factor in the absence of other causes of steatosis. A fatty liver index =60 suggested the presence of hepatic steatosis. Mortality data was obtained by prospectively linking to the National Death Index. Multivariate Cox proportional hazards regression analyses were used to explore these associations and multiple adjustment models were constructed including crude, partial, and fully adjusted models. Results: After adjusting for all covariates including BMI, WWI remained positively and linearly associated with all-cause and CVD mortality in MASLD (hazard ratios [HR] 1.247 and 1.218, respectively). Higher WWI was associated with a significantly increased risk of mortality (both p for trend <0.05). There was an "obesity paradox" between BMI and all-cause mortality in MASLD, with significantly lower all-cause mortality in those with overweight/obesity compared to normal BMI (HR 0.625 and 0.596, respectively, p for trend = 0.024), and no association between BMI and CVD mortality. Interaction analyses indicated that these associations were influenced by several demographic variables and disease status. Time-dependent receiver operating characteristic curves indicated that the predictive value of WWI for mortality in MASLD was higher than that of BMI, WC, and waist-to-height ratio across all follow-up durations. Conclusions: WWI was positively and linearly associated with all-cause and CVD mortality in MASLD, whereas BMI did not accurately reflect mortality risk. WWI provided the optimal predictive value for mortality compared to traditional obesity indicators. These findings emphasize the potential use of WWI as a novel obesity indicator for mortality risk assessment, stratification, and prevention in MASLD. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that adaptive immune cells are important contributors to metabolic dysfunction–associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease, NAFLD). In liver biopsies from MASLD patients, the accumulation of intrahepatic B cells is positively correlated with the MASLD activity score. Hepatic B-cell infiltration is observed in experimental models of metabolic dysfunction-associated steatohepatitis (MASH, formerly non-alcoholic steatohepatitis, NASH). Intrahepatic B2 cells have been shown to contribute to MASLD/MASH by activating T cells, macrophages and hepatic stellate cells, and by producing pathogenic IgG antibodies. In mice fed a MASH diet, selective depletion of B2 cells reduces steatohepatitis and fibrosis. Intestinal B cells are metabolically activated in MASH and promote T-cell activation independently of TCR signaling. In addition, B cells have been shown to contribute to liver fibrosis by activating monocyte-derived macrophages through the secretion of IgA immunoglobulins. Furthermore, our recent study indicates that certain B cell subsets, very likely regulatory B cells, may play a protective role in MASLD. This review summarizes the molecular mechanisms of B cell functions and discusses future research directions on the different roles of B cells in MASLD and MASH. [ABSTRACT FROM AUTHOR]

Introduction: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading chronic liver disease worldwide. Emerging evidence suggests a close crosstalk between iron status and metabolic syndrome. Therefore, this cohort study aimed to investigate the relationship between serum iron status and all-cause mortality in individuals with MASLD. Methods: A total of 3393 subjects with MASLD identified by ultrasound from the Third National Health and Nutrition Examination Survey (NHANES III) were included in the analysis. Iron status indicators included serum iron, ferritin, transferrin saturation, total iron binding capacity, hemoglobin concentration, mean corpuscular hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin concentration. Cox proportional hazards models and restricted cubic spline models with adjustment for multiple confounders were applied. Stratified analyses were performed by sex and age. Results: During a median of 26.08 years of follow-up, high serum iron and transferrin saturation were significantly associated with reduced all-cause mortality in a linear pattern (P overall<0.001). Compared with the lowest quartile, individuals with serum iron and transferrin saturation in the third or fourth quartile intervals had a 20-40% reduction in long-term mortality. However, there was no independent association of serum ferritin, total iron binding capacity, and red blood cell indices with all-cause mortality in MASLD. Conclusion: This study suggests that serum iron and transferrin saturation have the potential to serve as independent biomarkers of all-cause mortality in patients with MASLD and implies the therapeutic potential of modifying iron status. [ABSTRACT FROM AUTHOR]

Summary To evaluate the relationship between serum gamma‐glutamyl transferase (GGT) levels and fatty pancreas in subjects with concurrent obesity, insulin resistance and metabolic dysfunction‐associated steatotic liver disease (MASLD) without a history of pancreatitis. From March 2019 to September 2021, 31 adult subjects with concurrent obesity and MASLD were recruited as part of the study investigating the biological impact of bariatric surgery and lifestyle modification on obesity. Chemical shift encoded MRI of the abdomen, LiverMultiScan, anthropometric, clinical and blood biochemistry analyses were performed prior to any intervention at baseline. GGT (p <.001) was significantly different between those ‘with fatty pancreas’ and ‘without fatty pancreas’ groups. GGT (p <.001) was significantly different between those ‘with both metabolic syndrome and fatty pancreas’ and those ‘with metabolic syndrome but without fatty pancreas.’ GGT (p <.001) was also significantly different between those ‘with both diabetes and fatty pancreas’ and those ‘with diabetes but without fatty pancreas’. Logistic regression analysis showed that abnormal GGT levels (p = .010) and Hypertension (p = .045) were significant independent predictors of fatty pancreas. GGT was associated with fatty pancreas by an odds ratio 7.333 (95% [CI]: 1.467–36.664), while the AUROC of GGT in determining fatty pancreas was 0.849. Elevation in serum GGT might be a potential marker to identify fatty pancreas. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and Aims Methods Results Conclusions Metabolic dysfunction‐associated steatotic liver disease (MASLD) is linked to various intrahepatic and extrahepatic diseases, but its association with severe infectious disease remains to be investigated.We analysed data from the Shanghai Suburban Adult Cohort and Biobank, encompassing participants enrolled in 2016 and 2017 with available abdominal ultrasonography data, and followed them up until December 2022 (median follow‐up = 5.71 years). We categorised the participants into the MASLD group and those without steatotic liver disease (non‐SLD). Multivariable‐adjusted Cox regression was used to estimate hazard ratios (HR) for severe infections in patients with MASLD compared to the non‐SLD group. Cumulative incidences were calculated while accounting for competing risks (non‐infection‐related deaths). Mediation analyses were performed to explore the roles of cardiometabolic risk factors in the association between MASLD and severe infections.Among the 33 072 eligible participants (mean age 56.37 years; 38.20% male), 11 908 (36.01%) were diagnosed with MASLD at baseline. Severe infections occurred in 912 (7.66%) MASLD patients and 1258 (5.94%) non‐SLD. The rate of severe infections per 1000 person‐years was higher in MASLD patients (13.58) than in comparators (10.48) (fully adjusted HR 1.18, 95% CI 1.07–1.30). The most frequent infections in MASLD were respiratory (7.25/1000 person‐years) and urinary tract infections (2.61/1000 person‐years). The 5‐year cumulative incidence of severe infections was 6.79% (95% CI 6.36–7.26) in MASLD and 5.08% (95% CI 4.79–5.38) in comparators. Cardiometabolic risk factors, including waist circumference, triglycerides and HbA1C, partially mediate the association between MASLD and severe infections.Patients with MASLD were at significantly higher risk of incident severe infections compared to the non‐SLD group. Future studies are needed to elucidate the mechanisms linking MASLD to severe infections. [ABSTRACT FROM AUTHOR]