This study explored the clinical prognosis and lipidomics of hepatitis B virus steatohepatitic hepatocellular carcinoma (HBV-SHHCC) and aimed to identify a noninvasive and convenient method to diagnose this phenotype and guide treatment using MRI.

A total of 433 HBV-infected HCC patients were enrolled in this retrospective study. Survival data were analyzed using Cox regression analyses, and lipidomics was used to study HCC tissue composition. Logistic regression identified an independent predictor for HBV-SHHCC, and receiver-operating characteristic (ROC) analysis verified its discrimination.

HBV-SHHCC patients had longer disease-free survival (DFS, p < 0.0001) and overall survival (OS) time (p = 0.00097). Compared with common HCC (cHCC), SHHCC was associated with significantly higher mean triacylglyceride (p = 0.010) and diacylglyceride contents (p = 0.002) in tumor tissues. Fat fraction (FF) was linearly correlated with lipid composition and fatty acid degradation (FAD) subtype, which could help in treatment options for HCC. The univariate and multivariate logistic regression indicated FF (p < 0.001) as an independent predictor for diagnosing this phenotype. ROC analysis confirmed excellent discrimination (area under the curve (AUC), 0.914; sensitivity, 92.3%; specificity, 78.7.0%). After using the optimal cutoff point, the DFS time of patients with SHHCC stratified by FF was significantly higher than that of patients with cHCC.

The biological behavior and prognosis of HBV-SHHCC were better than those of other types. FF is a valuable tool for the clinical diagnosis of SHHCC, prognosis prediction, and treatment guidance in patients with HCC.

Question Can the diagnosis of steatohepatitic hepatocellular carcinoma (SHHCC) be made noninvasively? Findings Fat fraction (FF) correlated with lipid composition and could be used to diagnose SHHCC with an AUC of 0.914, sensitivity of 92.3%, and specificity of 78.7%. Clinical relevance MRI-based FF could be used to diagnose HBV-related SHHCC, indicate prognosis, and guide the clinical treatment of patients with HCC.

This study aims to explore the characteristics and influencing factors of ultrasound-derived fat fraction (UDFF) in obese patients with polycystic ovary syndrome (PCOS). Evaluate the diagnostic value of UDFF for MAFLD. This study included 124 obese PCOS patients and 106 age- and body mass index (BMI)-matched obese women, collecting clinical data from both groups. Compare the characteristics and related factors of hepatic steatosis between two groups. A total of 124 obese PCOS patients were divided into MAFLD group (n = 64) and no MAFLD group (n = 60). Binary logistic regression was used to analyze the independent risk factors for MAFLD in obese PCOS patients, and Spearman correlation analysis was used to examine the correlation between UDFF and various variables. The MAFLD group was further divided into mild group (S1, n = 16), moderate group (S2, n = 24), and severe group (S3, n = 24). Based on the ultrasound results, draw a receiver operating characteristic curve (ROC) for diagnosing the degree of hepatic steatosis in obese PCOS patients using UDFF. MAFLD was more common in the obese PCOS group than in the simple obese group (51.61% vs. 40.57%, P < 0.05). UDFF is positively correlated with the severity of MAFLD (r = 0.603, P < 0.01). The AUC for diagnosing liver steatosis with S ≥ 1, S ≥ 2, and S = 3 using UDFF is 0.935, 0.951, and 0.916. UDFF has certain diagnostic value for metabolic-related fatty liver disease in obese PCOS patients, and UDFF levels gradually increase with the severity of MAFLD.

This article discusses a recent study by Wang et al that sheds light on the metabolic and immunological mechanisms driving the progression of metabolic dysfunction-associated fatty liver disease (MAFLD) to hepatocellular carcinoma (HCC). The study highlights the role of mitochondrial carnitine palmitoyltransferase II (CPT II) inactivity, which activates liver cancer stem cells marked by cluster of differentiation 44 (CD44) and CD24 expression, promoting HCC development. Using dynamic mouse models and clinical samples, Wang et al identified CPT II downregulation, mitochondrial membrane potential alterations, and reduced intrahepatic CD4+ T cell as key drivers of disease progression. The findings link these changes to steroid biosynthesis and p53 signaling, contributing to T-cell dysfunction and immunosuppression. This article emphasizes the relevance of these results in understanding MAFLD pathogenesis and discusses potential therapeutic strategies targeting CPT II activity, mitochondrial function, and immune surveillance to prevent or mitigate HCC development in advanced MAFLD.

Previous studies have reported a correlation between telomere length (TL) and Alzheimer's disease (AD); however, the specific biological mechanisms supporting this association remain unclear. We used two-sample Mendelian randomization (MR) to systematically explore the putative causal relationships between TL, brain imaging-derived phenotypes (IDPs), and AD, while further evaluating the mediating role of IDPs using both two-step MR and multivariable MR. In addition, we utilized several independent validation cohorts to repeat the analysis, further strengthening our inferences. The MR analysis showed that a longer TL was causally associated with a lower risk for AD (OR, 0.84; 95% CI, 0.75 to 0.93; P = 0.001). In addition, the subsequent two-step MR results indicate that nine brain IDPs partially mediate the effect of TL on AD. The inverse association of genetically predicted TL with AD was attenuated after adjusting for these IDPs in multivariable MR. Our study provides further evidence for the causal relationship between TL and AD, with IDPs potentially partially mediating this association. Therefore, telomere biology may be a potential pathway involved in AD development, and identifying the important role of telomeres can draw more attention to the development of telomere-related diagnostics, treatments, and AD therapies.

This study aimed to explore the causal association between imaging measurement indicators of major internal organs and liver lesions using a two-sample Mendelian randomization (MR) method.

Data from the UK Biobank and GWAS Catalog platform were used to select single nucleotide polymorphisms (SNPs) associated with MRI or derived measurement results of various organ indicators as genetic instrumental variables. Data from the FinnGen project's R9 version were used to select liver lesion outcomes, such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic cirrhosis, and primary hepatocellular carcinoma (HCC). UVMR analysis were utilized variable-by-variable, and MVMR was used to adjust for confounding on significant variables. Steiger directional test, heterogeneity, pleiotropy, and sensitivity tests were conducted to enhance reliability.

Univariate Mendelian randomization analysis (UVMR) indicated that liver volume (LV), liver fat (LF), and subcutaneous adipose tissue measurement (SATM) are risk factors for NAFLD. The multivariable MR (MVMR) results for NAFLD showed that LV and LF remained significant, while SATM did not. For cirrhosis (NAC), UVMR suggested that LV, LF, and SATM are risk factors, but MVMR results showed that only LV and LF remained significant. Additionally, pancreatic volume (PV) was found to be a protective factor, while splenic volume (SV) was a pathogenic factor for NAC. For HCC, both UVMR and MVMR analyses suggested that LF and liver iron (LI) are risk factors, while SATM did not remain significant in the MVMR analysis.

LV, LF, and SATM are associated with NAFLD. In the NAC stage, additional pathogenic effects of PV and SV were observed. The related results for LF and LI support the pathogenic effect of liver iron factors in the HCC stage.

To explore the application of ultrasound derived fat fraction (UDFF) in evaluating metabolic associated fatty liver disease in obese polycystic ovary syndrome.

This study included 124 obese PCOS patients and 106 age and body mass index (BMI) matched non PCOS control group women. The two groups of data were compared to determine the prevalence of metabolic associated fatty liver disease (MAFLD) in PCOS obese patients. The 124 obese PCOS patients were divided into MAFLD group (n = 64) and non MAFLD group (n = 60). Using ROC curve analysis to evaluate the diagnostic performance of UDFF and SWV values for MAFLD. The MAFLD group was divided into mild group (n = 16), moderate group (n = 24), and severe group (n = 24). Use Spearman correlation method to analyze the relationship between UDFF value, SWV value and the severity of MAFLD.

MAFLD was more common in the obese PCOS group than in the control group (51.61 vs 27.36%) (χ2 = 13.9583, P = 0.00019). The UDFF of obese PCOS patients was higher than those of the control group, while SWV was lower than those of the control group. ROC analysis showed that the AUC of UDFF for diagnosing MAFLD was 0.935, with sensitivity, specificity, and cut-off values of 92.2, 85.0, and 4.5%, respectively. UDFF was positively correlated with the severity of MAFLD (r = 0.603, P < 0.01). The AUC of SWE for diagnosing MAFLD was 0.728, with sensitivity, specificity, and cut-off values of 51.6, 93.3%, and 1.015 m/s, respectively. SWV was negatively correlated with the severity of MAFLD (r = - 0.551, P < 0.01).

The prevalence of MAFLD is significantly higher in obese PCOS patients, and UDFF technology can detect and quantitatively analyze liver fat infiltration in obese PCOS patients early. At the same time, auto-pSWE also has diagnostic significance for the progression of liver disease.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of end-stage liver disease and liver transplantation in the Western world, with an approximate prevalence of 30% worldwide which is continuously rising. It is characterized by intrahepatic fat deposition along with at least one cardiometabolic risk factor, such as diabetes mellitus, obesity, hypertriglyceridemia, and hypertension. MASLD consists of a spectrum of liver diseases ranging from simple liver steatosis to steatohepatitis, liver fibrosis, and cirrhosis. Recently, the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD), and the European Association for the Study of Obesity (EASO) released the latest guidelines regarding the management of patients with MASLD. This article highlights the critical points of these guidelines and emphasizes problematic issues that need further evaluation.

Non-invasive diagnostics for metabolic dysfunction-associated fatty liver disease (MAFLD) remain challenging. We aimed to identify novel key genes as non-invasive biomarkers for MAFLD, elucidate causal relationships between biomarkers and MAFLD and determine the role of immune cells as potential mediators.

Utilizing published transcriptome data of patients with biopsy-proven MAFLD, we applied linear models for microarray data, least absolute shrinkage and selector operation (LASSO) regressions and receiver operating characteristic (ROC) curve analyses to identify and validate biomarkers for MAFLD. Using the expression quantitative trait loci database and a cohort of 778 614 Europeans, we used Mendelian randomization to analyse the causal relationships between key biomarkers and MAFLD. Additionally, mediation analysis was performed to examine the involvement of 731 immunophenotypes in these relationships.

We identified 31 differentially expressed genes, and LASSO regression showed three hub genes, IGFBP2, PEG10, and P4HA1, with area under the receiver operating characteristic (AUROC) curve of 0.807, 0.772 and 0.791, respectively, for identifying MAFLD. The model of these three genes had an AUROC of 0.959 and 0.800 in the development and validation data sets, respectively. This model was also validated using serum-based enzyme-linked immunosorbent assay data from MAFLD patients and control subjects (AUROC: 0.819, 95% confidence interval: 0.736-0.902). PEG10 was associated with an increased MAFLD risk (odds ratio = 1.106, p = 0.032) via inverse variance-weighted analysis, and about 30% of this risk was mediated by the percentage of CD11c + CD62L- monocytes.

The MAFLD panels have good diagnostic accuracy, and the causal link between PEG10 and MAFLD was mediated by the percentage of CD11c + CD62L- monocytes.

Non-invasive methods to diagnose non-alcoholic steatohepatitis (NASH), an inflammatory subtype of non-alcoholic fatty liver disease (NAFLD), are currently unavailable.

To develop an integrin αvβ3-targeted molecular imaging modality to differentiate NASH.

Integrin αvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids (FFA). Hepatic integrin αvβ3 expression was analyzed in rabbits fed a high-fat diet (HFD) and in rats fed a high-fat, high-carbohydrate diet (HFCD). After synthesis, cyclic arginine-glycine-aspartic acid peptide (cRGD) was labeled with gadolinium (Gd) and used as a contrast agent in magnetic resonance imaging (MRI) performed on mice fed with HFCD.

Integrin αvβ3 was markedly expressed on FFA-cultured hepatocytes, unlike the control hepatocytes. Hepatic integrin αvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver (FL) progressed to steatohepatitis. The distribution of integrin αvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas. In comparison to mice with simple FL, the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis (P < 0.05), showing a positive correlation with the NAFLD activity score (r = 0.945; P < 0.01). Hepatic integrin αvβ3 expression was significantly upregulated during NASH development, with hepatocytes being the primary cells expressing integrin αvβ3.

After using Gd-labeled cRGD as a tracer, NASH was successfully distinguished by visualizing hepatic integrin αvβ3 expression with MRI.

We examined the association of objective measures of cardiometabolic risk with progression to a high-risk for advanced fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) at initially low- and indeterminate-risk for advanced fibrosis.

We performed a retrospective cohort study of primary care patients with MASLD between 2012 and 2021. We evaluated patients with MASLD and low- or indeterminate-risk Fibrosis-4 Index (FIB-4) scores and followed them until the outcome of a high-risk FIB-4 (≥2.67), or the end of the study period. Exposures of interest were body mass index, systolic blood pressure, hemoglobin A1c, cholesterol, estimated glomerular filtration rate, and smoking status. Variables were categorized by the threshold for primary care therapy intensification. Unadjusted and adjusted Cox regression models were developed for the outcome of time to a high-risk FIB-4 value.

The cohort included 1347 patients with a mean follow-up of 3.6 years (SD 2.7). Of the cohort, 258 (19%) had a subsequent FIB-4 > 2.67. In the fully adjusted Cox regression models, mean systolic blood pressure ≥ 150 mm Hg (1.57; 95% confidence interval (CI) 1.02-2.41) and glomerular filtration rate ≤ 59 ml/min (hazard ratio 2.78; 95%CI 2.17-3.58) were associated with an increased hazard of a high-risk FIB-4, while receiving a statin prescription (hazard ratio 0.51; 95%CI 0.39-0.66) was associated with a lower risk.

Nearly 1 in 5 primary care patients with MASLD transitioned to a high-risk FIB-4 score during 3.6 years of follow-up, and uncontrolled blood pressure and reduced kidney function were associated with an increased hazard of a FIB-4 at high-risk for advanced fibrosis.

Low birthweight is an issue during pregnancy associated with an increased risk of developing liver disease later in life. Previous Mendelian randomisation (MR) studies which explored this issue have not isolated the direct impact of the foetus on birthweight. In the present study, MR was used to assess whether direct foetal effects on birthweight were causally associated with liver structure, function and disease risk independent of intrauterine effects.

We extracted single nucleotide polymorphisms (SNPs) from genome-wide association studies (GWAS) about direct foetal-affected birthweight (321 223 cases) to conduct univariable and multivariable MR analyses to explore the relationships between birthweight and 4 liver structure measures, 9 liver function measures and 18 liver diseases. A two-step MR analysis was used to further assess and quantify the mediating effects of the mediators.

When isolating direct foetal effects, genetically predicted lower birthweight was associated with a higher risk of non-alcoholic fatty liver disease (NAFLD) (odds ratios [OR], 95% confidence interval [CI]: 1.61, 1.29-2.02, p < 0.001), higher magnetic resonance imaging [MRI] proton density fat fraction (PDFF) and higher serum gamma glutamyltransferase (GGT). Two-step MR identified two candidate mediators that partially mediate the direct foetal effect of lower birthweight on NAFLD, including fasting insulin (proportion mediated: 22.29%) and triglycerides (6.50%).

Our MR analysis reveals a direct causal association between lower birthweight and liver MRI PDFF, as well as the development of NAFLD, which persisted even after accounting for the potential influence of maternal factors. In addition, we identified fasting insulin and triglycerides as mediators linking birthweight and hepatic outcomes, providing insights for early clinical interventions.

Epilepsy, a complex neurological disorder, is closely linked with structural and functional irregularities in the brain. However, the causal relationship between brain imaging-derived phenotypes (IDPs) and epilepsy remains unclear. This study aimed to investigate this relationship by employing a two-sample bidirectional Mendelian randomization (MR) approach.

The analysis involved 3935 cerebral IDPs from the UK Biobank and all documented cases of epilepsy (all epilepsies) cohorts from the International League Against Epilepsy, with further validation through replication and meta-analyses using epilepsy Genome-Wide Association Studies datasets from the FinnGen database. Additionally, a multivariate MR analysis framework was utilized to assess the direct impact of IDPs on all epilepsies. Furthermore, we performed a bidirectional MR analysis to investigate the relationship between the IDPs identified in all epilepsies and the 15 specific subtypes of epilepsy.

The study identified significant causal links between four IDPs and epilepsy risk. Decreased fractional anisotropy in the left inferior longitudinal fasciculus was associated with a higher risk of epilepsy (odds ratio [OR]: 0.89, p = 3.31×10-5). Conversely, increased mean L1 in the left posterior thalamic radiation (PTR) was independently associated with a heightened epilepsy risk (OR: 1.14, p = 4.72×10-5). Elevated L3 in the left cingulate gyrus was also linked to an increased risk (OR: 1.09, p = .03), while decreased intracellular volume fraction in the corpus callosum was correlated with higher epilepsy risk (OR: 0.94, p = 1.15×10-4). Subtype analysis revealed that three of these IDPs are primarily associated with focal epilepsy (FE). Notably, increased L1 in the left PTR was linked to an elevated risk of hippocampal sclerosis (HS) and lesion-negative FE, whereas elevated L3 in the left cingulate gyrus was associated with HS-related FE.

Our research offers genetic evidence for a causal link between brain IDPs and epilepsy. These results enhance our understanding of the structural brain changes associated with the onset and progression of epilepsy.

The UK Biobank (UKB) imaging project is a crucial resource for biomedical research, but is limited to 100,000 participants due to cost and accessibility barriers. Here we used genetic data to predict heritable imaging-derived phenotypes (IDPs) for a larger cohort. We developed and evaluated 4,375 IDP genetic scores (IGS) derived from UKB brain and body images. When applied to UKB participants who were not imaged, IGS revealed links to numerous phenotypes and stratified participants at increased risk for both brain and somatic diseases. For example, IGS identified individuals at higher risk for Alzheimer's disease and multiple sclerosis, offering additional insights beyond traditional polygenic risk scores of these diseases. When applied to independent external cohorts, IGS also stratified those at high disease risk in the All of Us Research Program and the Alzheimer's Disease Neuroimaging Initiative study. Our results demonstrate that, while the UKB imaging cohort is largely healthy and may not be the most enriched for disease risk management, it holds immense potential for stratifying the risk of various brain and body diseases in broader external genetic cohorts.

The prevalence of at-risk metabolic dysfunction-associated steatohepatitis (at-risk MASH) has not been systematically assessed.

To delineate the prevalence of at-risk MASH in a large population-based cohort.

We conducted a cross-sectional analysis of 40,189 patients in the UK Biobank who underwent liver MRI. Hepatic steatosis was determined by proton density fat fraction (PDFF) ≥5%. Based on AASLD criteria, participants were classified as alcohol-associated steatotic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), combined metabolic alcoholic liver disease (MetALD) and at-risk MASH.

Among 40,189 patients, 10,886 (27.0%) had a PDFF ≥5%, indicating SLD. Among patients with SLD, 1% had ALD, 89.0% had MASLD, 7.9% had MetALD and 2.2% had at-risk MASH. The at-risk MASH group, which included 0.6% of the general population, had the highest mean liver fat on MRI and the highest BMI. Serum biomarkers highlighted increased inflammation and metabolic changes in at-risk MASH. The prevalence of MASLD was significantly higher among men with a BMI ≥30 kg/m2. Non-obese women showed only a 12% risk of MASLD. Conversely, MetALD had similar prevalence in obese men and women and was absent in non-obese women.

MASLD is prevalent among patients with elevated PDFF on MRI. There are different sex- and BMI-specific prevalence of different steatotic liver disorders. At-risk MASH demonstrates the most severe metabolic and inflammatory profiles. This study provides novel estimates for the at-risk MASH population that will be eligible for treatment with pharmacologic therapy when approved by regulatory authorities.