Search Results (41)

Background and Aims: Until now, according to the EASL Clinical Practice Guidelines on the management of chronic hepatitis B (CHB), the relationship between steatotic liver disease (SLD) and the risk of hepatocellular carcinoma (HCC) in CHB patients still yields conflicting results, with some data suggesting an increased risk of HCC, while several cohort studies have indicated a reduced risk in CHB patients with SLD. Sex is a predominant factor in the development and severity of chronic liver diseases. We aimed to understand the effect modification by sex in this association using a large population-based cohort study with long-term follow-up of patients with CHB. Approach and Results: This population-based study from Taiwan’s National Health Insurance Research Database (2009–2022) comprised two cohorts of patients with CHB aged 40–75 years: (1) 53,888 patients treated with entecavir or tenofovir, and (2) 525,109 antiviral-naive patients. HCC was identified in 4245 and 9491 patients in the treated and untreated cohorts, respectively. After adjusting for competing risk of death and relevant covariates, SLD was associated with a lower risk of HCC in males but a higher risk in females, and this sex difference (p < 0.0001 for sex–SLD interaction) was identified in both treated (subdistribution hazard ratio [SHR] [95% CI]: 0.85 [0.74–0.96] in males and 1.42 [1.17–1.73] in females) and untreated (0.75 [0.67–0.84] in males and 1.34 [1.14–1.56] in females) patients. Using propensity score matching with stratification by sex, further accounting for differences in medication use between SLD and non-SLD groups, yielded consistent results. The excess risk of HCC with SLD among females was mainly in those aged≥55 years, and even existed in the presence of diabetes, whereas among males, SLD exhibited an inverse association with HCC, regardless of age or diabetes. Conclusions: There was a sex disparity in the association between SLD and CHB-related HCC. Future studies and management of SLD for CHB should consider the sex disparity. Full article

Background/Objectives: Steatotic liver disease (SLD) is a global health priority, increasing the demand for accessible circulating biomarkers. Carboxylesterase 1 (CES1) plays a key role in hepatic lipid metabolism, but its clinical utility as a plasma biomarker remains unclear. This study aimed to validate an automated immunoassay for plasma CES1 and perform a preliminary evaluation of its diagnostic performance for hepatic steatosis quantified using advanced ultrasound. Methods: An automated ELISA for plasma CES1 was analytically validated. A preliminary clinical evaluation was performed in 95 consecutive outpatients structured to approximate a health-screening population, using ultrasound-derived attenuation coefficients (AC) to quantify steatosis. Results: The assay demonstrated robust analytical performance with intra- and inter-assay coefficients of variation < 10% and excellent sample stability. Plasma CES1 significantly correlated with AC (r = 0.585, p < 0.001), yielding an area under the receiver operating characteristic curve of 0.82 for diagnosing ultrasound-defined steatotic livers. In multivariable analysis, CES1 was independently associated with hepatic steatosis (adjusted odds ratio: 1.03 per 10 pg/mL increase, p < 0.001). Conclusions: Plasma CES1 shows strong diagnostic potential for ultrasound-defined hepatic steatosis. However, this preliminary evaluation is subject to a restricted cohort spectrum; further prospective validation in broader, unselected real-world populations is required before clinical implementation. Full article

Background: Steatotic liver disease (SLD) and sarcopenia are lifestyle-related conditions for which prevention is critical. The phase angle, which is derived from impedance, reactance, and resistance values obtained via bioelectrical impedance analysis, has emerged as a potential marker of sarcopenia. Additionally, amino acids have been implicated in the pathogenesis of both SLD and sarcopenia. This epidemiological study investigated the association between SLD and sarcopenia in a general population cohort. Methods: This cross-sectional study included 281 participants with metabolic dysfunction-associated steatotic liver disease (MASLD), 72 with metabolic alcohol-associated liver disease (MetALD), and 54 with alcohol-associated liver disease (ALD). Associations between phase angle, Mac-2-binding protein glycosylation isomer (M2BPGi) as a marker of liver fibrosis, and serum amino acid levels were analyzed. Results: The phase angle was significantly higher in the MetALD group than in the MASLD and ALD groups. Multivariate analysis identified MASLD as an independent risk factor for a low phase angle compared with MetALD. M2BPGi levels were lower in MetALD than in MASLD, and M2BPGi showed a negative correlation with the phase angle. Furthermore, MetALD was characterized by lower serine and glutamine levels than MASLD, with serine demonstrating a negative correlation with the phase angle. Conclusions: Although the possibility of residual confounding factors cannot be excluded, the present study suggests that phase angle may serve as a sensitive marker for the early decline in muscle mass in patients with SLD, comparable to grip strength and skeletal muscle mass index. Full article

Steatotic liver disease (SLD) is characterised by profound metabolic reprogramming, yet no single biomarker reliably distinguishes disease entities, stages or sex-specific risk profiles. By integrating serum metabolomic signatures as a liquid biopsy with tumour-associated CSC marker profiles in a sex-stratified analytical framework, we aimed to identify biologically meaningful differences and improve strategies for early, presymptomatic detection of SLD progression and HCC. The present study focuses on a targeted panel of 12 strongly dysregulated serum metabolites as candidate biomarkers of disease progression, quantified by NMR-based metabolomics and ELISA and complemented by CSC marker staining. We combined these NMR-based metabolomic ‘liquid biopsy’ data with circulating tumour-associated biomarkers, MELD-based risk assessment and tissue-level CSC marker expression across MetALD, MASLD, immune-mediated and cancerogenic liver disease, HCC and healthy controls. Female MetALD patients showed the second highest mortality after HCC, with lower survival than male cancer patients, despite MELD 3.0 assigning ~50% higher scores in women. MetALD mortality clustered with GP73, CD44, metabolomics and AA/3HB ratio, indicating a distinct, high-risk female phenotype. Integrating liquid-based metabolomic profiling, AA/3HB redox assessment, CSC markers and MELD 3.0 into sex-sensitive diagnostic pathways may improve early detection and risk stratification of alcohol-associated SLD, especially in women. Full article

Background/Objectives: Metabolic dysfunction–associated steatotic liver disease (MASLD) has emerged as a major global etiology of chronic liver disease. However, the prognostic impact of MASLD in patients with non-B, non-C HCC (NBNC-HCC) following curative resection remains poorly defined. This study aimed to evaluate the prognostic significance of histologic SLD and MASLD-related components in this growing patient population. Methods: We retrospectively reviewed consecutive patients with NBNC-HCC receiving curative-intent hepatectomy between 2014 and 2023, excluding those with viral hepatitis or significant alcohol use. MASLD was defined as hepatic steatosis (≥5%) combined with at least one cardiometabolic risk factor (obesity, type 2 diabetes, dyslipidemia, or hypertension). Primary endpoints were overall survival (OS) and recurrence-free survival (RFS). Cox proportional hazards models were used to identify independent prognostic factors. Results: 169 (61.7%) patients fulfilled MASLD criteria. The MASLD group showed significantly better RFS (p = 0.039) and OS (p = 0.016). Notably, after multivariate adjustment, histologic SLD remained independently associated with reduced mortality (HR 0.55, 95% CI 0.32–0.93; p = 0.027), while MASLD status was attenuated. Subgroup analysis revealed that this survival benefit was most pronounced in non-cirrhotic patients (p = 0.027 for OS). Patients with MASLD also exhibited lower liver-related mortality (p = 0.028). Conclusions: Steatotic liver disease was independently associated with improved survival in NBNC-HCC patients undergoing curative hepatectomy, particularly in non-cirrhotic individuals. Given the increasing prevalence of MASLD, incorporating hepatic steatosis, metabolic components, and fibrosis status into risk stratification may help improve postoperative management in this distinct subgroup. Full article

Background: The real-world risk profiles of newly defined steatotic liver disease (SLD) subtypes—MASLD, MetALD, and ALD—remain incompletely described in community settings. Methods: A cross-sectional analysis of 950 health-checkup participants was conducted. SLD (CAP ≥ 248 dB/m) and significant fibrosis (LSM ≥ 7.0 kPa) were evaluated by transient elastography. Associations between alcohol intake, cardiometabolic factors, fibrosis, and gut microbiota (16S rRNA sequencing) were assessed. Results: Among 950 participants, 310 (33%) had SLD (MASLD, n = 222; MetALD, n = 41; ALD, n = 23). Treated as a continuous exposure, higher alcohol intake was significantly correlated with elevated systolic/diastolic blood pressure, triglycerides, AST, and γ-GTP, but inversely correlated with HOMA-IR (all p < 0.05). In multivariable logistic regression adjusting for cardiometabolic factors, BMI was the only independent predictor of fibrosis (adjusted OR 1.22, 95% CI 1.11–1.35, p < 0.01), whereas alcohol intake showed no independent association. Furthermore, microbiota analysis revealed that ALD-related SLD was characterized by significant depletion of Blautia and enrichment of Gemella (FDR q < 0.05) compared to non-SLD controls, indicating an alcohol-associated dysbiosis signature. Conclusions: In early-stage SLD, alcohol intake continuously exacerbates cardiometabolic risk factors, whereas fibrosis is predominantly driven by BMI. These findings support quantitative alcohol/BMI integration for risk stratification, alongside microbiota profiling to detect ALD-related dysbiosis. Full article

Background: Interleukin-38 (IL-38) is an anti-inflammatory IL-1—family cytokine implicated in limiting tissue injury by its anti-inflammatory character. We evaluated the diagnostic discrimination and prognostic relevance in steatotic liver disease (SLD). Methods: We conducted a prospective, monocentric cohort analysis of 184 patients with SLD (n = 176) and healthy controls (n = 8). We tested group differences using Mann–Whitney U or Kruskal–Wallis; determined diagnostic quality using ROC curves. Logistic regression was used to assess the relationship with decompensation. Associations with MELD and routine laboratory parameters were modeled using Spearman correlation and linear regression. We analyzed survival using Kaplan–Meier and Cox regression. Findings: IL-38 concentrations were found to be higher in decompensated (n = 94) than in compensated patients (n = 82) (p < 0.001). MELD was positively associated with IL-38 (p < 0.001; 95% CI 0.057–0.120). This corresponds to a 9.2% increase in IL-38 per 1-point increase in MELD (95% CI 5.9–12.7%). IL-38 correlated positively with the MELD score (p < 0.001) and with bilirubin/AST/LDH. In the combination model (MELD + IL-38 ± CRP), a very good AUC ≈ 0.92 was achieved. Conclusion: IL-38 reflects the severity of steatotic liver disease and is therefore a potentially predictive biomarker for early risk stratification and therapy monitoring. Full article

Background/Objectives: Sarcopenia (Sp) and obesity (Ob) have significant negative effects on steatotic liver disease (SLD). Here, we examined the effects of sarcopenic Ob (SO) on liver fibrosis in patients with SLD. Methods: We included 811 patients who visited our outpatient clinic and underwent FibroScan (Echosens, France). Liver stiffness (LS) was assessed using body mass index (BMI) and grip strength (GS). We conducted a similar analysis by converting the difference in estimated glomerular filtration rate (dGFR) based on creatinine and cystatin C levels into GS. Results: The cutoff values for distinguishing metabolic dysfunction-associated steatotic liver disease (MASLD; 298 patients) with LS > 10 kPa (advanced fibrosis) were set separately for men and women using receiver operating characteristic analysis. BMI was set at >26 kg/m² in women and >27 kg/m² in men (modified Ob (mOb)), and GS was set at <16 kg in women and <31 kg in men (modified Sp (mSp)). The ratio of advanced fibrosis was higher in the group with both mSp and mOb (mSpOb) than in the group with mSp alone or mOb alone in MASLD or alcoholic liver disease (ALD, 97 patients). However, this association has not yet been observed in other diseases. The dGFR was used to set the cutoff value corresponding to advanced fibrosis. Sp-dGFR (SpdG) was >1.14 in women and >−0.76 in men in the MASLD group. mSpOb, SpdG and Ob are associated with advanced fibrosis in MASLD logistic regression analysis. Conclusions: SO, assessed using BMI and GS or dGFR, was associated with elevated LS in patients with SLD. Full article

Background: The transition from the term non-alcoholic fatty liver disease (NAFLD) to steatotic liver disease (SLD), an umbrella term for several related conditions, offers benefits, particularly in identifying cardiometabolic risk factors more effectively. However, the impact of alcohol consumption on liver disease progression remains significant, leading to the recognition of a new entity: MetALD (metabolic dysfunction-associated steatotic liver disease with moderate alcohol intake). Aim: This study aimed to compare characteristics associated with liver disease progression in diabetic patients diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD) versus those with MetALD. Materials and Methods: In this prospective study, 286 diabetic patients were followed for 12 months. All patients underwent transient elastography (TE) and ultrasound to assess hepatic steatosis. Participants were classified into MASLD and MetALD groups. The performance of fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) were also evaluated. Results: MASLD was diagnosed in 58.2% (167 patients), of whom 4.9% (7 patients) had TE values suggestive for liver cirrhosis. Among those with MetALD, 17.6% (21 patients) had TE values compatible with advanced fibrosis. MASLD subjects presented a slight decrease in liver fibrosis values from 6.58 ± 2.27 kPa to 6.03 ± 1.57 kPa in the 12 months. On the contrary, MetALD subjects had an increase of liver stiffness measurements (LSM) values from 11.83 ± 6.27 kPa to 12.24 ± 8.66 kPa. Conclusions: in diabetic patients, the coexistence of moderate alcohol intake and cardiometabolic risk factors (MetALD) is associated with more advanced liver fibrosis and impaired long-term glycemic control, compared to MASLD alone. Full article

Steatotic liver disease (SLD) represents a major global health burden, with environmental toxicants emerging as critical contributors alongside metabolic dysfunction. Bisphenol F (BPF), an increasingly prevalent replacement for bisphenol A, is widely detected in human biological samples and environment, yet its hepatotoxic mechanisms remain incompletely characterized. This review synthesizes current evidence on BPF-induced SLD, with a particular focus on resolving the “pregnane X receptor (PXR) paradox”, the mismatch between BPF’s weak direct activation of PXR and the PXR-like metabolic effects observed in vivo. Comprehensive analysis of mechanistic pathways reveals that BPF-induced SLD develops predominantly through PXR-independent mechanisms involving oxidative stress, endoplasmic reticulum dysfunction, Drp1-mediated mitochondrial fission, NLRP3/NF-κB-driven inflammation, dysregulated post-translational modifications, and epigenetic remodelling. These converging pathways collectively disrupt hepatic lipid metabolism, promote triglyceride accumulation, and establish a self-perpetuating cycle of metabolic dysfunction. Notably, weak indirect PXR modulation via oxidative stress represents a secondary, non-causal mechanism unsupported by functional validation. This framework distinguishes toxicant-induced steatosis from metabolic dysfunction-associated steatotic liver disease while highlighting critical evidence gaps—particularly the absence of causal PXR validation studies and human epidemiological data. Therapeutic opportunities exist at validated convergence points including mitochondrial dynamics (Drp1), inflammatory signalling (NLRP3/NF-κB), and energy metabolism (AMPK-mTOR), though combination strategies targeting multiple pathways will likely be required for durable disease reversal. These findings necessitate the expansion of regulatory screening paradigms to incorporate cellular stress pathway biomarkers alongside traditional nuclear receptor endpoints, ensuring comprehensive hepatotoxic risk assessment of emerging BPA substitutes. Full article

Background/Objectives: In the present study, the Metabolic dysfunction-associated fatty liver disease (MAFLD) and Metabolic dysfunction-associated steatotic liver disease (MASLD) diagnostic criteria were applied to evaluate the relative performance in predicting short-term advanced fibrosis (AF) progression (AFpr) and hepatocellular carcinoma (HCC), as well as an ancillary outcome, i.e., the occurrence of acute cardiovascular events (ACEs) in steatotic liver disease (SLD) patients. Methods: We retrospectively analyzed the data stored in the University Hospital (UH)’s Official Health Documents Digitization Archive of 931 SLD patients, with a follow-up of 3 years. Based on the Body Mass Index (BMI), patients were subdivided into lean “L” (BMI < 25 kg/m²) (n = 134) and not-lean “NL” (n = 797), and, subsequently, into NL-MASLD (n = 206), NL-MASLD/MAFLD (n = 481), NL-MAFLD (n = 110), L-MASLD (n = 39), L-MASLD/MAFLD (n = 68), and L-MAFLD (n = 27). All study outcomes (AFpr, HCC, and ACE) were primarily evaluated in NL-SLD and by conducting a sub-analysis of L-SLD individuals. Results: MASLD and MAFLD criteria similarly estimated [p = 0.076] the overall 3-year risk of AF progression in NL-SLD. In the L-SLD sub-analysis, MAFLD criteria better estimated the overall 3-year risk of AF progression [p = 0.006]. Multivariate competing risk analysis (adjusted for sex, age, diabetes, steatosis, and fibrosis severity) revealed diabetes [adjusted Hazard Ratio (aHR) = 2.113, p = 0.001], high-sensitivity C-reactive protein (aHR = 1.441; p = 0.02), and Homeostatic Model Assessment for Insulin Resistance (aHR = 1.228; p = 0.03) as being associated with AF progression in L-MAFLD. Compared to MAFLD, MASLD diagnostic criteria similarly estimated the 3-year risk of HCC occurrence both in NL [HR = 1.104, C.I. 95%: 0.824–1.593, p = 0.741] and L [HR = 1.260, C.I. 95%: 0.768–2.104, p = 0.701] patients. Finally, no significant differences were reported between the MAFLD or MASLD criteria for ACE risk occurrence in all study groups. Conclusions: The MAFLD criteria better estimate the AF progression risk, limited to L-SLD patients. Full article

Background: Dotinurad (DOT) has demonstrated beneficial metabolic effects in preclinical models as a selective uric acid reabsorption inhibitor. However, its clinical impact on steatotic liver disease (SLD) with hyperuricemia (HU-SLD) remains unclear. Methods: This observational pilot study evaluated 33 patients with HU-SLD (Metabolic dysfunction-associated steatotic liver disease: n = 20; Metabolic dysfunction-associated alcohol-related liver disease: n = 1; Alcohol-related liver disease: n = 12) treated with DOT for at least 6 months. Laboratory parameters were assessed at baseline and at 6 months. The primary outcomes were changes in serum uric acid levels, hepatobiliary function markers, and renal function markers. Results: DOT significantly reduced serum uric acid levels from 8.4 (7.7–9.0) to 6.0 (5.9–6.8) mg/dL at 6 months (p < 0.001). Regarding hepatobiliary markers, gamma-glutamyl transferase decreased from 47 (30–78) to 43 (27–54) U/L (p = 0.042) and total bilirubin decreased from 0.6 (0.5–1.0) to 0.6 (0.4–0.7) mg/dL (p = 0.023). Significant but modest improvements in renal function were also observed, with serum creatinine decreasing from 1.1 (0.9–1.3) to 1.0 (0.9–1.1) mg/dL (p = 0.010) and estimated glomerular filtration rate increasing from 55.6 (44–67.3) to 56.6 (48.8–71.5) mL/min/1.73 m² (p = 0.007). No significant changes were observed for aspartate aminotransferase, alanine aminotransferase, fibrosis-related markers, lipid profiles, or glycemic markers. Moreover, no treatment discontinuations or adverse events were recorded during the study period. Conclusions: DOT effectively reduced serum uric acid and modestly improved renal and hepatobiliary parameters in HU-SLD without any patient-reported complications. These real-world findings support the potential of DOT as a well-tolerated therapeutic option beyond urate lowering and warrant further investigation in larger, controlled studies. Full article

Aim: The recently updated steatotic liver disease (SLD) nomenclature provides a refined classification accounting for both metabolic dysfunction and alcohol exposure. However, the relationship between SLD subtypes and upper gastrointestinal (UGI) cancer risk remains unclear. Methods: We analyzed 456,367 UK Biobank participants, categorizing them into non-SLD, metabolic dysfunction-associated steatotic liver disease with no alcohol (MASLD1), MASLD with minimal alcohol use (MASLD2), metabolic dysfunction-associated alcohol-related liver disease (MetALD), and alcohol-associated liver disease (ALD) groups. Cox proportional hazards models estimated cancer risks over a median 13-year follow-up, with histologic subtype-specific analyses. Results: Compared to non-SLD, esophageal cancer risk was significantly elevated in all SLD groups with any alcohol consumption (MASLD2, MetALD, and ALD), but not in purely metabolic SLD without alcohol (MASLD1). This association was driven by adenocarcinoma subtype, with hazard ratios ranging from 1.67 to 1.80 in alcohol-exposed SLD groups. For gastric cancer, elevated risk was observed primarily in ALD and MetALD groups, affecting intestinal-type cancers. Squamous cell esophageal cancer and non-intestinal gastric cancer showed no significant associations. Conclusions: Upper GI cancer risk in SLD patients is significantly modified by alcohol consumption, with combined metabolic dysfunction and alcohol exposure conferring the highest risks for esophageal adenocarcinoma and intestinal-type gastric cancer. Clinically, these findings suggest that SLD patients with any level of alcohol consumption require heightened cancer surveillance. Even minimal alcohol intake substantially increases cancer risk in metabolically compromised individuals, supporting alcohol reduction as a key preventive strategy. Full article

Steatotic liver disease (SLD) has become one of the most prevalent chronic liver diseases, representing a significant health burden worldwide. The complex pathogenesis of SLD results in a lack of specific therapeutic targets and effective drug treatment modalities. Copper (Cu) is a trace element that plays a critical role in various physiological processes, particularly hepatic metabolism. Meanwhile, Cu overload can induce cellular toxicity, which is generally explained by its capacity to induce oxidative damage. In 2022, a novel form of programmed cell death, designated as cuproptosis, was identified. In essence, excess Cu ions bind to the lipoylated components of the tricarboxylic acid cycle, resulting in proteotoxic stress and subsequent cell death. The role of cuproptosis in the pathologies of Cu overload-induced diseases has gained considerable attention. However, the association between SLD and Cu overload, particularly cuproptosis, remains to be elucidated. This review provides a concise overview of cuproptosis. The significance of Cu overload in SLD, as well as the potential association between cuproptosis and SLD, is explored. This review aims to offer insights into the potential of cuproptosis as a therapeutic target for SLD. Full article