Sufficient attention has not been given to machine learning (ML) models using longitudinal data for investigating important predictors of new onset of hypertension. We investigated the predictive ability of several ML models for the development of hypertension.

A total of 15 965 Japanese participants (men/women: 9,466/6,499, mean age: 45 years) who received annual health examinations were randomly divided into a training group (70%, n = 11,175) and a test group (30%, n = 4,790). The predictive abilities of 58 candidates including fatty liver index (FLI), which is calculated by using body mass index, waist circumference and levels of γ-glutamyl transferase and triglycerides, were investigated by statistics analogous to the area under the curve (AUC) in receiver operating characteristic curve analyses using ML models including logistic regression, random forest, naïve Bayes, extreme gradient boosting and artificial neural network.

During a 10-year period (mean period: 6.1 years), 2,132 subjects (19.1%) in the training group and 917 subjects (19.1%) in the test group had new onset of hypertension. Among the 58 parameters, systolic blood pressure, age and FLI were identified as important candidates by random forest feature selection with 10-fold cross-validation. The AUCs of ML models were 0.765-0.825, and discriminatory capacity was significantly improved in the artificial neural network model compared to that in the logistic regression model.

The development of hypertension can be simply and accurately predicted by each ML model using systolic blood pressure, age and FLI as selected features. By building multiple ML models, more practical prediction might be possible.

Currently, the Fibrosis-4 (FIB-4) and nonalcoholic fatty liver disease fibrosis score (NFS) are used to predict fibrosis and steatosis in patients with or at risk for metabolic dysfunction-associated steatotic liver disease (MASLD). More recently, the fibrotic nonalcoholic steatohepatitis (NASH) index (FNI) and steatosis-associated fibrosis estimator (SAFE) have been created. We have compared the accuracy of these noninvasive scoring systems in MASLD patients.

This is a retrospective analysis of 244 biopsy-proven MASLD patients from a tertiary health care system. Score performances were determined by calculating the area under the receiver operating characteristic (AUROC) curve with 95% confidence intervals, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV).

About 25 (10.3%) patients had fibrotic metabolic dysfunction-associated steatohepatitis (MASH). The FNI score was best at predicting fibrotic MASH with an AUROC of 0.78, while NFS was the worst at predicting fibrotic NASH with an AUROC of 0.60. In the entire cohort, FNI of 0.33, FIB-4 of 2.67, SAFE >100, and NFS >0.675 had PPVs of 17%, 31%, 17%, and 16%, respectively, and NPVs of 97%, 92%, 96%, and 91%, respectively. Specificity was greatest for FIB4 at 92% and NFS at 86%, whereas the sensitivity was greatest for FNI and SAFE scores at 88% and 80%, respectively.

FNI and SAFE scores have superior diagnostic accuracy for fibrotic MASH compared to other scoring systems. While liver biopsy remains the gold standard diagnostic method, noninvasive scores like FNI, and SAFE scores can be used in everyday clinical practice to assess for fibrotic MASH.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has garnered increasing attention for its potential link with dementia. This study aims to investigate the association between MAFLD and dementia, including its subtypes, to address existing knowledge gaps.

A total of 415,116 participants from the UK Biobank were included, with standardized screening criteria used to determine MAFLD diagnosis. Cox regression was employed to assess the relationship between MAFLD and dementia risk. Subgroup analyzes were conducted to provide further insights into the impact of MAFLD on dementia risk, and the mediation effect of inflammation was evaluated.

Among the 150,509 MAFLD patients, there was a significantly elevated risk of dementia, with hazard ratios (HR) of 1. 526 (95 % CI = 1. 460-1. 596) for all-cause dementia, 1. 356 (95 % CI = 1. 266-1. 453) for Alzheimer's disease (AD), and 2. 206 (95 % CI = 2. 000-2. 434) for vascular dementia (VaD). MAFLD patients showed a significant reduction in gray matter volume in MAFLD patients (β = -0. 07, 95 % CI = -0. 17, -0. 01) and a marked increase in deep white matter lesion volume (P < 0. 001). Elevated inflammatory markers in MAFLD patients accounted for a mediation effect of 30. 8 %.

MAFLD substantially increases the risk of dementia, underscoring the importance of early intervention and prevention strategies targeting MAFLD to reduce dementia incidence.

Heart failure with reduced ejection fraction (HFrEF) and metabolic dysfunction-associated steatotic liver disease (MASLD) are both associated with liver fibrosis. HFrEF patients may develop liver fibrosis due to hepatic congestion, MASLD, or a combination of both. The Fibrosis-4 (FIB-4) score calculated using age, aspartate aminotransferase, alanine aminotransferase, and platelet count, serves as a screening tool for advanced liver fibrosis. This study examines the association between the FIB-4 score and all-cause mortality, cardiovascular mortality, and major adverse liver outcomes (MALO) in patients with HFrEF.

This study included 4523 HFrEF patients from the Danish Heart Failure Registry. Based on FIB-4 score, 25.5 % were low-risk, 45.7 % were indeterminate-risk, and 28.8 % were high-risk for advanced liver fibrosis. After five years, the cumulative incidence of all-cause mortality was 43 % for the high-risk group, 36 % for the indeterminate-risk group, and 23 % for the low-risk group. The indeterminate-risk and high-risk group had an increased hazard ratio (HR) for all-cause mortality (HR 1.33, 95 % confidence interval [CI] 1.16-1.52; HR 1.51, 95 % CI 1.31-1.74) compared to the low-risk group. Similarly, HRs were elevated for cardiovascular mortality (HR 1.61, 95 % CI 1.27-2.05; HR 2.14, 95 % CI 1.67-2.74) and MALO (HR 1.77, 95 % CI 1.01-3.31; HR 2.54, 95 % CI 1.43-4.52).

A high FIB-4 score in patients with HFrEF is associated with increased mortality and MALO.

The association between preoperative imaging and postoperative pathological tumor size disparity, and cancer-specific survival (CSS) among patients undergoing hepatectomy for hepatocellular carcinoma (HCC) remains unclear. We sought to evaluate this association and identify predictors of size disparity.

Patients undergoing curative-intent hepatectomy for HCC (2000-2023) were identified from an international, multi-institutional database. Size ratio was defined as the ratio of pathological to imaging tumor size. Patients with a size ratio of 0.5-1.5 were classified as "without size disparity," while patients outside this range were considered "with size disparity." Multivariable Cox regression was used to identify predictors of CSS, while logistic regression was utilized to determine factors associated with size disparity. For variables identified as significant in multivariable analyses, further evaluation including cutoff determination, were performed using receiver operating characteristic (ROC) analysis.

Among 833 patients, median size ratio was 1.02, with a strong correlation between imaging and pathological tumor sizes (r = 0.87). Size disparity was present in 106 patients (12.7 %); in general, patients had smaller median imaging sizes (2.85 vs. 4.80 cm; p < 0.001) while size on pathology was noted to be larger(both 4.50 cm; p = 0.370). Patients with size disparity had worse 5-year CSS (60.1% vs. 79.0 %; p < 0.001). Multivariable Cox regression identified higher ALBI score (HR:2.56 [1.50-4.37]; p < 0.001), larger pathological tumor size (HR:1.09 [1.03-1.15]; p = 0.001), and size disparity (HR:2.53 [1.37-4.66]; p = 0.002) as independent predictors of CSS. Logistic regression demonstrated that cirrhosis (OR: 2.68 [1.43-5.02]; p = 0.002) and log alpha-fetoprotein (AFP) (OR:1.11 [1.01-1.22]; p = 0.030) were associated with an increased likelihood of size disparity. Cirrhosis and log AFP could be used to stratify patients relative to probability of a size disparity (low-risk:9.9 %, medium-risk:12.2 %, high-risk:17.7 %). The optimal AFP cutoff value was 3928 ng/mL for non-cirrhotic (AUC:0.90) versus 28.9 ng/mL for cirrhotic (AUC:0.74) patients.

Tumor size disparity was associated with worse CSS among patients with HCC undergoing hepatectomy. Size disparity could be predicted preoperatively using cirrhosis status and AFP level, which may help identify high-risk patients who may benefit from more detailed imaging assessments.

Turner syndrome (TS) is a chromosomal disorder in females characterized by the partial or complete absence of 1 X chromosome. Women with TS face a higher risk of liver disease, elevated enzymes and fibrosis, potentially linked to inflammation, and hormonal imbalances, though the cause remains unclear.

This paper investigates the associations between liver parameters, inflammatory markers, and hormonal factors in women with TS compared with age-matched female controls.

We included 82 women with TS and 59 female controls. Participants underwent clinical examinations, anthropometric measurements, and fasting biochemical assessments of liver enzymes ( γ-glutamyl transferase [GGT], aspartate aminotransferase [AST], alanine aminotransferase [ALT], FIB-4), inflammatory markers (C-reactive protein [CRP], soluble CD163 [sCD163]), sex hormones, and 11-oxygenated C19 steroids. We also assessed myeloperoxidase (MPO) and neutrophil elastase gene expression levels and performed FibroScan and dual-energy X-ray absorptiometry.

Women with TS had higher levels of liver enzymes (GGT, AST, ALT) and FIB-4 than controls (P < .001, all). The inflammatory markers CRP and sCD163 were both correlated with elevated liver parameters in women with TS. Hormonal variables such as 11β-hydroxytestosterone levels, were also associated with elevated liver enzymes in women with TS. The neutrophil activation marker MPO was elevated in TS and correlated with liver parameters and sCD163.

Women with TS have elevated liver enzymes associated with low-grade chronic inflammation and hormonal imbalances. These findings highlight the importance of regular monitoring of liver function, inflammatory markers, and hormonal levels in women with TS to enable early intervention and potentially improve clinical outcomes.

Metabolic-associated steatohepatitis (MASH), the progressive form of metabolic-associated steatotic liver disease (MASLD), poses significant risks for liver fibrosis and cardiovascular complications. Despite extensive research, reliable biomarkers for MASH diagnosis and progression remain elusive. This study aimed to identify hepatic transcriptomic and circulating proteomic signatures specific to MASH, and to develop a machine learning-based biomarker discovery model.

A systematic review of RNA-Seq and proteomic datasets was conducted, retrieving 7 hepatic transcriptomics and 3 circulating proteomics studies, encompassing 483 liver samples and 169 serum/plasma samples, respectively. Differential gene and protein expression analyses were performed, and pathways were enriched using gene set enrichment analysis. A machine learning (ML) model was developed to identify MASH-specific biomarkers, utilizing biologically significant protein ratios.

Hepatic transcriptomic analysis identified 5017 differentially expressed genes (DEGs), with significant enrichment of extracellular matrix (ECM) pathways. Serum proteomics revealed six differentially expressed proteins (DEPs), including complement-related proteins. Integration of transcriptomic and proteomic data highlighted the complement cascade as a key pathway in MASH, with discordant regulation between the liver and circulation. The ML-based biomarker discovery model, utilizing protein ratios, achieved an F1 scores of 0.83 and 0.64 in the training sets and 0.67 in an external validation set.

Our findings indicate ECM deregulation and complement system involvement in MASH progression. The novel ML model incorporating protein ratios offers a potential tool for MASH diagnosis. However, further refinement and validation across larger and more diverse cohorts is needed to generalize these results.

Both liver fibrosis and osteoporosis share inflammatory pathways, with liver fibrosis potentially contributing to decreased bone mineral density (BMD). The rising prevalence of non-alcoholic fatty liver disease (NAFLD) and associated liver fibrosis, especially in older populations, may increase the risk of osteoporosis, but evidence remains inconclusive. This study aims to investigate the relationship between liver fibrosis and osteoporosis in individuals over 50 years old.

This cross-sectional study used data from the Bushehr Elderly Health Program (BEHP), a cohort of 2,000 participants aged 50 and older, selected through multistage stratified random sampling. BMD and trabecular bone score (TBS) measurements were assessed. The Fibrosis-4 (FIB-4) index, a surrogate marker for liver fibrosis, was also calculated to examine its association with these bone health indicators. Multiple linear regression was applied to assess the relationship between FIB-4 and lumbar, hip, femoral neck BMD, and TBS scores, while logistic regression was used to evaluate osteoporosis as the dependent variable.

A total of 1,959 participants with adequate data were included in our analysis. 538 participants had osteoporosis, 936 participants had osteopenia, and 485 participants had normal bone density. FIB-4 index was higher in osteoporotic groups (1.45 ± 0.90) than in osteopenic (1.26 ± 0.58, p < 0.001) and normal groups (1.17 ± 0.48, p < 0.001). After controlling for confounders, FIB-4 index was negatively associated with hip BMD (βmen=-0.0162; 95% CI: -0.0313, -0.0012 and βwomen=-0.0221; 95% CI: -0.0340, -0.0102), femoral neck BMD (βmen=-0.0216; 95% CI: -0.0356, -0.0076 and βwomen=-0.0233; 95% CI: -0.0342, 0.0124), and TBS (βmen=-0.0154; 95% CI: -0.0264, -0.0043 and βwomen=-0.0244; 95% CI: -0.0338, -0.0149) in both genders and with lumbar BMD in women (β=-0.0176; 95% CI: -0.0307, -0.0045). An increase in the FIB-4 index was associated with more than a twofold rise in the risk of developing osteoporosis in women (OR = 2.123; 95% CI: 1.503, 3.000; p < 0.001) and a 36% higher risk in men (OR = 1.366; 95% CI: 1.012, 1.844; p = 0.042).

Liver fibrosis is associated with decreased bone density and attenuated bone architecture. Elevated FIB-4 index has been identified as a risk factor for osteoporosis, indicating a potential link between liver fibrosis and deteriorating bone health.

Severe postoperative complications still occur following hepatectomy among patients with hepatocellular carcinoma (HCC). There is a need to identify high-risk patients for severe complications to enhance patient safety. We sought to evaluate the combined impact of pre- and postoperative albumin-bilirubin (ALBI) score and Fibrosis-4 (FIB-4) index trends to predict severe complications after HCC resection.

Patients with HCC undergoing curative-intent hepatectomy (2000-2023) were identified from an international, multi-institutional database. The cohort was divided into training (n = 439) and testing (n = 651) sets. ALBI score and FIB-4 index trends from preoperative to postoperative days 1, 3, and 5 were used for K-means clustering (K = 3). A logistic regression model was developed using the training set, and its performance was evaluated using the area under the receiver operating characteristic curve (AUC) in both cohorts.

Severe complications (Clavien-Dindo Grade ≥ IIIa) occurred in 118 patients (10.8 %); 43 (9.8 %) in training and 75 (11.5 %) in testing set (p = 0.42). K-means clustering identified three groups: Cluster1 (low), Cluster2 (intermediate), and Cluster3 (high), which was associated with a progressively increasing risk of complications (p < 0.01). On multivariable logistic regression, patients in ALBI Cluster1 had 76 % decreased odds (odds ratio[OR] 0.24, 95 % CI 0.07-0.83, p = 0.02) of postoperative complications relative to Cluster3 patients. Individuals categorized into FIB-4 Cluster1 had 85 % decreased odds (OR 0.15, 95 % CI 0.02-1.24, p = 0.07) versus patients in FIB-4 Cluster3. A new prediction model incorporating ALBI and FIB-4 index clusters achieved an AUC of 0.71, outperforming models based on preoperative data. A tool was made available at https://nm49jf-miho-akabane.shinyapps.io/HCC_ALBI/.

A dynamic ALBI score and FIB-4 index trend tool improved risk stratification of patients undergoing resection of HCC relative to severe complications.

Migrants from endemic areas are key populations for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection screening in Europe. This study assessed the feasibility and outcomes of a community action that combined education, screening, and simplified access to care for migrants in Barcelona.

Adult migrants from Pakistan, Romania, and Senegal were included from 2021 to 2023, through a community action involving education, an epidemiological questionnaire, and rapid testing for HBV surface antigen (HBsAg) and HCV antibodies. If positive, DBS samples were collected for laboratory confirmation. Viremic cases were referred to an International Health Unit (IHU).

Overall, 786 participants were included (346 from Pakistan, 304 from Senegal and 136 from Romania). Previous screening for HBV and HCV was 8.0% and 7.7%, respectively. HBsAg prevalence was 0.9% for migrants from Pakistan, 8.2% for those from Senegal and 1.4% for those from Romania (n = 30/786, 23 new diagnoses). Among these, 69.6% attended the IHU and were HBV-DNA positive, but none met treatment criteria. Anti-HCV prevalence was 3.5%, 0.7% and 1.4% for migrants from Pakistan, Senegal and Romania, respectively (n = 16/768, 12 new diagnoses), and HCV-RNA prevalence was 0.9%, 0.3% and 0.7%, respectively (N = 6, all new diagnoses); 4 (66.6%) cases were linked to treatment and two were cured.

This novel community action successfully reached migrants in a situation of vulnerability and provided them access to testing and care. The high prevalence observed and the limited self-knowledge of their HBV and HCV status justify targeted screening in these groups.

Alcohol abuse is a common comorbidity among burn patients. Elevated blood alcohol levels lead to increased inflammation, delayed wound healing, and prolonged recovery. However, knowledge about outcomes in hand burn patients is limited. Our study aims to analyze the association between alcohol consumption and its impact on outcomes of patients suffering hand burns.

A retrospective analysis of patients admitted with hand burns from 2007 to 2024 was conducted. Patients were categorized into two groups based on blood alcohol content (BAC): low (<100 mg/dL) and high (≥100 mg/dL). Data collected included demographics, comorbidities, and outcomes.

Ninety-five patients (85.3 % male; mean age 43.8 ± 15.9 years) were included. Most hand burns were bilateral (58.9 %), and 7.4 % were isolated. No significant differences in demographics, comorbidities, or ICU admission rates were observed between BAC groups. Full-thickness burns were significantly more frequent in the high BAC group (15.7 % vs. 2.3 %, P = 0.035). The high BAC group had a longer hospital stay (22.3 ± 23.1 vs. 13.6 ± 16.2 days, P = 0.038), higher rates of inpatient rehabilitation (50.0 % vs. 24.3 %, P = 0.023) and poorer functional outcomes (Quick DASH, 19.0 ± 4.0 vs. 17.1 ± 4.5, P = 0.033).

Elevated BAC in hand burn patients is associated with longer hospital stays, more severe burn depth, and worse functional outcomes. Implementing targeted interventions, such as alcohol withdrawal management and enhanced therapy protocols, could improve patient outcomes in this high-risk group.

Liver dysfunction is recognized as a risk factor for poor outcome after. stroke. The FIB-4 index, a laboratory test for predicting liver fibrosis, has been shown to be. associated with poor prognosis in cardiovascular and cerebrovascular diseases. The aim of. this study was to explore the relationship between FIB-4 score and hemorrhagic. transformation, mortality, and prognosis in patients with acute ischemic stroke who received. intravenous thrombolytic therapy (IV tPA).

The records of 255 consecutive patients who received IV tPA for acute. ischemic stroke were retrospectively reviewed. Patients were divided into two groups. according to their FIB-4 scores: group 1 (FIB-4 ≤ 2.67) and group 2 (FIB-4 > 2.67). The. demographic data, NIHSS scores at admission, THRIVE scores, intracranial bleeding rates, (using the Heidelberg Bleeding Classification, NINDS and ECASS criteria for symptomatic. intracranial hemorrhage), stroke etiology subtypes (using the automated Causative. Classification System), and mRS scores at the third month were recorded.

On logistic regression analysis, group 2 patients were older, had higher mRS. scores at the third month and had increased mortality within 3 months when compared with. group 1 (p ≤ 0.05). Although group 2 patients had a higher rate of intracranial hemorrhage, the difference was not statistically significant.

The FIB-4 index may serve as a a useful predictor of poor prognosis in patients with acute ischemic stroke who received IV tPA. Large-scale prospective studies are needed to confirm this relationship and provide valuable insights for clinical practice.

Nonalcoholic fatty liver disease (NAFLD) cirrhosis is a significant health concern with a major impact on global morbidity and mortality. This study investigates the association of hemoglobin, albumin, lymphocyte, and platelet (HALP) with all-cause mortality, cardiovascular disease mortality, and cancer-related mortality in patients with NAFLD cirrhosis.

This retrospective cohort study used data from the National Health and Nutrition Examination Survey, assessing 11 550 adults. NAFLD cirrhosis was defined by a hepatic steatosis index greater than 36 and a NAFLD fibrosis score greater than 0.676 in participants without viral hepatitis or excessive alcohol use. The HALP score was categorized into low (<32), moderate (32-48.3), and high (>48.3). Logistic and weighted Cox regression analyses were conducted, along with subgroup and restricted cubic spline analyses.

Higher HALP scores were associated with lower all-cause mortality. Subgroup analyses revealed significant interactions with gender and age, showing a decreased risk of all-cause mortality in males and individuals aged 40 and above with higher HALP scores. A U-shaped relationship between HALP scores and all-cause mortality was observed.

The study demonstrates that HALP is associated with a lower risk of all-cause mortality in the NAFLD cirrhosis population, suggesting that HALP may be a useful predictor of mortality risk.

Elevated liver biochemistries are associated with increased risk of negative outcomes in patients with primary biliary cholangitis (PBC).

To evaluate whether longitudinal monitoring of liver biochemistries and fibrosis scores provides additional prognostic value and to assess the relationship between the degree of elevation of multiple biomarkers within different alkaline phosphatase (ALP) strata.

Adults with PBC were identified from Komodo's Healthcare Map. A Cox proportional hazards model examined time to first occurrence of hospitalisation due to hepatic decompensation, liver transplantation, or death as a function of the proportion of time during follow-up that liver biochemistries and fibrosis scores exceeded thresholds. Within ALP strata (ALP ≤ upper limit of normal [ULN]; ALP>ULN to ≤ 1.67 × ULN; ALP > 1.67 × ULN), separate multivariate Cox hazard models assessed the association between time-varying covariates and the composite endpoint.

Overall, 3974 patients were included; 88.2% were female, with a mean age of 59.4 years. The median follow-up was 2.5 years. Increasing magnitude and duration beyond established thresholds of ALP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), AST/platelet ratio index (APRI) and fibrosis-4 (FIB-4) were associated with increased risk of negative outcomes. Elevated ALT, AST, TB, APRI and FIB-4 were associated with increased risk of negative outcomes across all ALP strata.

Prolonged elevation of multiple hepatic biomarkers and fibrosis scores is associated with a greater risk of negative clinical outcomes, underscoring the importance of ongoing monitoring beyond the guideline-recommended initial treatment response to guide timely treatment decisions and improve PBC management.

Liver fibrosis is a chronic fibrosing hepatic disorder following recurrent injury, characterized by the excessive accumulation of extracellular matrix. Early detection has a great clinical impact because 80-90% of hepatocellular carcinomas are known to develop in fibrotic or cirrhotic (end-stage fibrotic) livers. PET imaging with FAP ligands exhibited highly promising results in recent years to visualize fibrosis in various organs due to the crucial role of activated fibroblasts in fibrosing processes. However, still little is known about the efficacy of FAP imaging in liver fibrosis. Thus, we sought to investigate the potential of FAPI-PET in a cohort of oncological and non-oncological patients.

199 patients who underwent FAPI-PET/CT at the University Hospital of Heidelberg between July 2017 and July 2020 were retrospectively analyzed. The tracer uptake of the liver was analyzed and correlated with radiological and clinical parameters.

We observed a weak but significant negative correlation between the hepatic FAPI uptake and CT density (r = - 0.273, P < 0.001***). A positive correlation was observed between hepatic FAPI uptake and the aspartate aminotransferase (AST)-to-platelet ratio index (APRI) (r = 0.183, P = 0.009**), an established surrogate for liver fibrosis. The liver SUV (standardized uptake value) mean and SUVmax of FAPI showed significant differences between groups of patients with low (< 0.5), middle (0.5-1.0) and higher (> 1.0) levels of APRI (both P < 0.001***).

These preliminary observational results suggest that FAPI-PET may be a viable non-invasive method to asses liver fibrosis.

While ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC), the autoimmune nature of PBC underscores the need for treatments targeting immunological pathways that may achieve a cure. E6011, a novel humanized anti-fractalkine monoclonal antibody, has emerged as a potential therapeutic option for PBC. We conducted a randomized, placebo-controlled, double-blind study to evaluate the efficacy and safety of E6011 in patients with PBC with an incomplete response to UDCA.

The study was composed of 12-week Double-Blind Phase (placebo, E6011 10 mg/kg/month, 15 mg/kg/month, or 10 mg/kg/every other week [eow]) followed by a 52-week Open-Label Phase. The primary endpoint was the percent change in alkaline phosphatase (ALP) at Week 12.

A total of 29 patients were enrolled. Histological evaluation at screening revealed that 83 % of the enrolled patients were classified as Stage 4 according to the Nakanuma Classification. The mean percent changes in ALP at Week 12 were +0.45 % in the placebo, +0.65 % in the 10 mg/kg/month, +1.23 % in the 15 mg/kg/month and +1.19 % in the 10 mg/kg/eow, with no observed trends toward ALP reduction in the E6011 treatment. Based on the interim analysis, the study was discontinued due to a lack of the efficacy. E6011 was generally safe and well tolerated.

This study of E6011 failed to meet the primary endpoint in patients with PBC with an incomplete response to UDCA. The advanced histological severity present in more than 80 % of patients at baseline may have contributed to these findings.

Causes of death across steatotic liver disease (SLD) subtypes remain incompletely characterized in routine clinical practice. We aimed to quantify and compare cause-specific mortality in SLD.

We conducted a retrospective cohort study of adults with imaging-confirmed hepatic steatosis receiving outpatient care in the national Veterans Health Administration (2010-2021). The primary exposure was SLD subtype, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and their intersection (MetALD). The primary outcome was cause-specific mortality, stratified by baseline cirrhosis.

Among 366,433 adults (mean age, 60.5 years; 7.7% female; 67.6% non-Hispanic White), 77.9% had MASLD, 17.5% had MetALD, and 4.6% had ALD. Over a median follow-up of 5.4 years, the 10-year cumulative incidence of cardiovascular disease (CVD)- and extrahepatic cancer-related deaths among patients without cirrhosis was 8.1% and 7.5% in MASLD, 7.5% and 7.4% in MetALD, and 8.1% and 7.4% in ALD. Among patients with cirrhosis, liver- and CVD-related deaths were 9.2% and 17.3% in MASLD, 17.7% and 13.0% in MetALD, and 22.1% and 11.5% in ALD. Compared with non-cirrhotic MASLD (0.04 per 100 person-years), liver-related mortality was higher in MetALD (0.19 per 100 person-years; HR, 3.38; 95% CI, 3.02-3.78) and highest in ALD (0.40 per 100 person-years; HR, 6.99; 95% CI, 6.08-8.04). This progressive increase persisted in cirrhosis but was less pronounced.

CVD and extrahepatic cancer were leading causes of death across SLD subtypes without cirrhosis, while liver- and CVD-related deaths predominated in cirrhosis. MetALD and ALD were associated with progressively higher risks of liver-related mortality compared with MASLD. These findings underscore the need for integrated strategies addressing alcohol use, cardiovascular risk, and cancer screening to reduce preventable deaths.

Causes of death across the steatotic liver disease spectrum remains incompletely characterized in routine clinical settings. In this large nationwide cohort study, we evaluated cause-specific mortality in patients with MASLD, MetALD, and ALD. We showed that cardiovascular disease and extrahepatic cancer were the primary causes of death in patients without cirrhosis across SLD subtypes, while liver disease and cardiovascular disease were predominant in those with cirrhosis. Importantly, MetALD and ALD were associated with progressively increasing risks of liver-related mortality compared to MASLD. Our findings highlight the need for integrated care models that simultaneously addresses cardiovascular risk factors, implements strategies to reduce alcohol consumption, and promotes cancer screening to mitigate preventable deaths in SLD.

In metabolic dysfunction-associated steatotic liver disease (MASLD) and in MASLD with alcohol consumption (MetALD), we investigated the effect of severity of metabolic dysfunction on incident major adverse liver outcomes (MALO), major cardiovascular events (MACE), obesity-related cancers, and all-cause mortality (ACM).

SLD was identified among 502,381 UK Biobank participants using the Hepatic Steatosis Index (HSI) (>36 vs.<30). Metabolic syndrome (MetS) traits and MetS (≥3 traits) using MASLD/MetALD criteria. Cox regression was used to estimate adjusted hazard ratios and 95%CIs [aHR(95%CIs)] of MASLD or MetALD plus 1 to 5 MetS traits with incident MALO, MACE, obesity-related cancers and 5-year/10-year incidence rates versus reference (no SLD/MetS traits).

Median follow-up was 148 to 149 months. Comparing MASLD with one versus five MetS traits, respectively, to the reference; for MALO, [aHRs (95%CIs)] were 2.27 (1.03-5.00) and 9.19 (4.98-16.95); for MetALD, aHRs were 1.65 (0.53-5.11) and 8.54 (3.65-19.95) respectively. For MACE, with MASLD; aHRs were 1.51 (1.19-1.92) and 4.81 (4.06-5.69) respectively; with MetALD, aHRs were 1.46 (1.00-2.13) and 4.64 (3.51-6.14) respectively. For obesity-related cancers; with MASLD, aHRs were 1.04 (0.87-1.23) and 1.46 (1.29-1.66) respectively; with MetALD, aHRs were 1.01 (0.79-1.29) and 1.51 (1.24-1.83) respectively. 5-year and 10-year incidence rates also increased progressively with increasing MetS traits. Combining SLD, MetS and high liver fibrosis risk (defined by FIB-4 ≥ 2.67) was strongly associated with MALO in both MASLD and MetALD (aHRs 27.48, (17.72-42.61); 43.36, 20.53-91.58 respectively).

In MASLD or MetALD, the numbers of MetS traits markedly influence risk and incidence of liver-related outcomes, MACE, obesity-related cancers and ACM.

Dynamic changes in the characteristics of hepatocellular carcinoma (HCC) have been observed owing to the development of antiviral therapies and an aging society. This study aimed to evaluate the clinical features and prognosis of patients with HCC but without liver fibrosis (F0 HCC).

From 2000 to 2023, 505 patients with HCC who underwent surgical resection as an initial treatment were enrolled and categorized into the F0 (n = 59) and fibrosis (F1-4, n = 446) groups based on their liver fibrosis status. Clinical features, tumor factors, and survival outcomes were retrospectively analyzed. Inverse probability weighting with propensity scores was used to control for baseline differences between the groups.

The proportion of F0 HCC (G1/G2/G3/G4 = 1.3/7.0/13.3/20.0%, p < 0.001) and nonviral (NBNC) HCC cases increased steadily over the study period. Patients in the F0 group were older and more likely to show solitary giant tumors; however, no significant differences were observed in tumor differentiation, microvascular invasion, or intrahepatic metastasis between the groups. After adjusting for baseline characteristics, the F0 group showed significantly improved overall survival and recurrence-free survival compared to the fibrosis group (adjusted median OS: not achieved vs. 90.6 months, p < 0.001; adjusted median RFS: 67.2 vs. 35.1 months, p < 0.001).

The increasing prevalence of NBNC HCC has contributed to an increase in the number of F0 HCC cases, demonstrating favorable prognoses post-curative treatment. Screening strategies tailored to detect F0 HCC are urgently needed to optimize outcomes, particularly for older patients and those with large tumors.

The prognostic value of the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear. This study aimed to evaluate the associations between the NHHR and all-cause and cause-specific mortality in patients with MASLD.

Data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES III and the National Death Index (NDI). The NHHR was calculated according to the formula. The results of mortality associated with the NDI were recorded as of December 31, 2019. We used a multivariate Cox proportional hazard model and restricted cubic spline (RCS) regression to assess the associations between the NHHR and all-cause and cause-specific mortality. In addition, subgroup analyses were performed to explore the relationships between the NHHR and all-cause and cause-specific mortality.

This study included 3155 patients with a definite diagnosis of MASLD. A total of 1,381 (43.8%) patients with MASLD died, and 1,774 (56.2%) survived. Multivariate Cox proportional hazards model analysis showed that NHHR was not significantly associated with all-cause mortality in MASLD patients. The RCS curve showed a significant nonlinear trend between the NHHR and all-cause mortality in patients with MASLD. Subgroup analysis revealed that the NHHR was better suited to predict cardiovascular mortality in patients without advanced fibrosis.

Our study revealed the clinical value of the NHHR in the prediction of mortality in the MASLD population. The NHHR can be used as a biomarker for follow-up in people without advanced fibrosis.

As the primary anthropometric measure in metabolic dysfunction-associated steatotic liver disease (MASLD), waist circumference (WC) may more accurately reflect the visceral fat distribution than body mass index (BMI). This study aimed to compare the prognostic value of BMI, WC and WC-related indices including waist-hip ratio (WHR), body shape index (BSI) and weight-adjusted-waist index (WWI) in individuals with MASLD.

The study population was derived from four large-scale cohorts: the National Health and Nutrition Examination Survey (NHANES 2017-2020 and NHANES III), the Kailuan Cohort and the UK Biobank Cohort. We evaluated the mortality risk across these measures using multivariate Cox proportional hazards regression and restrictive cubic spline.

The Pearson correlation coefficient of WC with hepatic steatosis and fibrosis was better than that of BMI. WC [Quartile 4 vs. Quartile 1: HR (hazard ratio) = 1.48 (95% confidence interval (CI) 1.13-1.93)] and WC-related indices [Quartile 4 vs. Quartile 1: WHR HR = 3.21 (95% CI 2.36-4.37); BSI HR = 3.22 (95% CI 2.48-4.17); WWI HR = 4.72 (95% CI 3.36-6.62)], but not BMI [obesity vs. lean: HR = 0.90 (95% CI 0.72-1.12)], indicated a significant mortality risk gradient among individuals with MASLD. The finding was consistent across sex and racial/ethnic subgroups, with external validation supporting the WC-related indices. MASLD and fibrosis prevalence showed a dose-dependent pattern across WC-related index quartiles. Notably, low BMI and high WC-related indices portended the highest mortality risk.

WC and WC-related indices are better parameters in prognosticating MASLD than BMI. The BMI-related 'obesity paradox' may be a misnomer resulting from the use of an incorrect metric. WC should be measured more routinely among individuals with MASLD.

The association of each of the recently classified steatotic liver diseases (SLDs), including metabolic dysfunction-associated SLD (MASLD), MASLD and increased alcohol intake (MetALD), and alcohol-associated liver disease (ALD), with new development of ischemic heart disease (IHD) remains unclear.

We investigated the associations of various SLDs with the development of IHD during a 10-year follow-up period in 13,815 Japanese individuals without a history of IHD (men/women 8,933/4,882; mean age 48 years) who underwent annual health checkups including an abdominal ultrasound examination. Among the participants, 4,639 (33.6%) subjects were diagnosed as having SLDs, and the proportions of subjects with MASLD, MetALD and ALD were 25.4%, 4.7% and 1.9%, respectively. During the follow-up period, 1,963 (16.2%; men/women 1,374 [17.2%]/589 [14.2%]) subjects had new development of IHD. Multivariable Cox proportional hazard model analysis after adjustment of age, sex, estimated glomerular filtration rate (eGFR), current smoking habit, diabetes, hypertension and dyslipidemia showed that the adjusted risk for new onset of IHD was significantly higher in subjects with MASLD (hazard ratio 1.20 [95% confidence interval 1.01-1.55]; P=0.042) than in those without SLD. Other SLDs were not selected as independent risk factors for the development of IHD.

The presence of MASLD, but not other SLDs, is an independent risk factor for new onset of IHD during a 10-year follow-up period.

HIV alone can induce liver fibrosis whereas co-infection with HCV presents a significant challenge in hastening the development of chronic liver disorders such a liver fibrosis, cirrhosis, and hepatic malignancy. Information on the influence of HIV on liver stiffness (LS) after treatment with direct-acting antiviral (DAAs) agents is scarce. The aim of this study was to assess the changes in LS using transient elastography (TE) and fibrosis scores (Fibrosis-4 [FIB-4] and AST-to-platelet ratio index [APRI]) before the initiation of treatment and six months after the end of treatment (EOT) with DAAs in HCV/HIV co-infected patients compared with HCV mono-infected patients.

All consecutive chronic HCV patients treated with DAAs during 2016-2020 were retrospectively recruited. TE was performed at baseline and SVR24. Fibrosis scores such as FIB-4 and APRI were calculated in parallel. Improvement of liver fibrosis was defined as any changes in the fibrosis category at baseline to a lower fibrosis category at SVR24.

Of 288 HCV-infected patients, 217 (75.3 %) were HCV mono-infected and 71 (24.7 %) were HCV/HIV co-infected. A significant decrease in TE values was noted at SVR24 compared with baseline (10.3 kPa vs. 7.9 kPa, respectively; P= <0.0001 in HCV mono-infection; 5.9 kPa vs. 5.3 kPa, respectively; P= <0.0001 in HCV/HIV co-infection). Moreover, the proportion of HCV mono-infected patients who had stable, improvement, and worsening in fibrosis stage at follow-up was 50.2 %, 43.3 %, and 6.5 %, respectively while it was 54.9 %, 32.4 %, and 12.7 %, respectively in HCV/HIV co-infection. In multivariable analysis, the higher fibrosis category was the only factor that influenced the improvement of liver fibrosis at follow-up, whereas HIV co-infection wasn't confirmed.

patients with HCV mono-infection and HCV/HIV co-infection experienced a rapid and significant improvement in LS and fibrosis indices. This improvement was more pronounced in those with high fibrosis grades at baseline.

Limited data have prevented routine genetic testing from being integrated into clinical practice in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to quantify the effect of genetic variants on changes in fibrosis severity per decade in MASLD.

This cross-sectional study included prospectively recruited adults with MASLD aged 18-70 who underwent magnetic resonance elastography (MRE) and genotyping for PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13. A genetic risk score (GRS) was calculated as the sum of established risk alleles in PNPLA3 minus protective variants in HSD17B13 (0=low risk, 1=high risk). We also estimated the polygenic risk score-hepatic fat content (PRS-HFC) and the adjusted version (PRS-5). The primary endpoint was the age-related change in liver stiffness measurement (LSM) on MRE by GRS. Findings were validated using an external cohort from Latin America.

Among 570 participants, the median age was 57 [49-64] years, 56.8% were women, and 34.2% were Hispanic. Median MRE was 2.4 [2.1-3.0] kPa, and 51% had high GRS. High GRS was independently associated with increased LSM (β=0.28 kPa, 95%CI:0.12-0.44, p=0.001) per 10-year age increase, while the low GRS group showed no significant difference. Similar findings were observed using PRS-HFC and PRS-5. PNPLA3 genotype alone also predicted higher LSM (C/G: β=0.32 kPa, 95%CI:0.02-0.61, p=0.034; G/G: β=0.87 kPa, 95%CI:0.52-1.22, p<0.0001) and G/G genotype was associated with significantly higher LSM by age 44, which was consistent in the validation population.

GRS, PRS-HFC, PRS-5, and PNPLA3 genotypes alone are associated with greater fibrosis per decade, resulting in divergent disease trajectories starting in midlife. Assessing genetic risk in MASLD will identify high-risk patients who require more frequent monitoring.

This study provides granular evidence that genetic predisposition, particularly the PNPLA3 G/G genotype, significantly influences the trajectory of liver fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD), with a more pronounced impact emerging after the fourth decade of life. These findings highlight the importance of incorporating genetic risk assessment into MASLD management, as it allows for the early identification of high-risk individuals who may benefit from more frequent monitoring and targeted interventions. Given the rising global burden of MASLD, clinicians, researchers, and policymakers should consider integrating genetic stratification into existing risk assessment frameworks to refine screening and surveillance strategies. By optimizing patient selection for non-invasive fibrosis assessment and potential therapeutic interventions, this approach could enhance precision medicine efforts and may improve long-term outcomes.

The link between cardiometabolic markers and hepatic steatosis and liver fibrosis in non-hypertensive, non-diabetic populations remains unclear. A study was conducted using data from the National Health and Nutrition Examination Survey. Hepatic steatosis and liver fibrosis were assessed using vibration-controlled transient elastography. Logistic regression and restricted cubic splines (RCS) were used to evaluate the associations of cardiometabolic index (CMI), atherogenic index of plasma (AIP), triglyceride-glucose index (TyG), and estimated glucose disposal rate (eGDR) on hepatic steatosis and estimated fibrosis. Mediation analysis examined the role of insulin resistance (HOMA-IR) and liver enzymes. Among 1489 participants, 39.15% had hepatic steatosis and 2.82% had liver fibrosis. Higher CMI (OR = 3.967, 95%CI: 2.297, 6.851), AIP (OR = 3.255, 95%CI: 2.031, 5.216), TyG (OR = 3.689, 95%CI: 2.363, 5.760), and FLI (OR = 2.695, 95%CI: 1.997, 7.816) tertiles of Q3 were linked to increased hepatic steatosis odds, while eGDR reduced odds (OR = 0.217, 95%CI: 0.127, 0.373). The AUC values of these four cardiac markers were greater than FLI, among which eGDR showed the highest predictive value (AUC = 0.781). In the hepatic steatosis population, CMI (OR = 1.419, 95%CI: 1.033, 2.747), AIP (OR = 5.527, 95%CI: 1.082, 28.242), and TyG (OR = 2.345, 95%CI: 1.180, 4.661) were also showed significant association with liver fibrosis, while eGDR and FIB-4 were not associated with liver fibrosis. AIP had the highest discriminative ability for liver fibrosis (AUC = 0.798). Mediation analysis showed HOMA-IR mediated 25.50%~36.20% of cardiometabolic markers' associations with hepatic steatosis, followed by liver enzymes. Cardiometabolic markers are strongly linked to hepatic steatosis and liver fibrosis in populations without traditional risk factors, even outperforming the established hepatic steatosis and the fibrosis marker, highlighting their potential for early liver disease risk identification in seemingly healthy individuals.

Post-hepatectomy liver failure (PHLF) is a severe complication following liver surgery. We aimed to develop a novel, interpretable machine learning (ML) model to predict PHLF. We enrolled 312 hepatocellular carcinoma (HCC) patients who underwent hepatectomy, and 30% of the samples were utilized for internal validation. Variable selection was performed using the least absolute shrinkage and selection operator regression in conjunction with random forest and recursive feature elimination (RF-RFE) algorithms. Subsequently, 12 distinct ML algorithms were employed to identify the optimal prediction model. The area under the receiver operating characteristic curve, calibration curves, and decision curve analysis (DCA) were utilized to assess the model's predictive accuracy. Additionally, an independent prospective validation was conducted with 62 patients. The SHapley Additive exPlanations (SHAP) analysis further explained the extreme gradient boosting (XGBoost) model. The XGBoost model exhibited the highest accuracy with AUCs of 0.983 and 0.981 in the training and validation cohorts among 12 ML models. Calibration curves and DCA confirmed the model's accuracy and clinical applicability. Compared with traditional models, the XGBoost model had a higher AUC. The prospective cohort (AUC = 0.942) further confirmed the generalization ability of the XGBoost model. SHAP identified the top three critical variables: total bilirubin (TBIL), MELD score, and ICG-R15. Moreover, the SHAP summary plot was used to illustrate the positive or negative effects of the features as influenced by XGBoost. The XGBoost model provides a good preoperative prediction of PHLF in patients with resectable HCC.

Chronic hepatitis C (CHC), caused by the hepatitis C virus, commonly leads to liver fibrosis. CHC is also related to T-cell exhaustion, phenotypically manifesting as overexpression of inhibitory receptors (iRs), e.g., programmed death receptor-1 (PD-1), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) and lymphocyte activation gene 3 (LAG-3), which have corresponding plasma-soluble analogs. Galectin-3 (Gal-3) is a pro-fibrotic and pro-inflammatory molecule, but its role in CHC is controversial. The study aimed to assess the relationship between plasma levels of soluble PD-1 (sPD-1), sTIM-3, sLAG-3 and Gal-3 and the degree of fibrosis in CHC and successful CHC treatment effect on these markers. The study comprised 98 CHC patients, qualified for treatment with direct-acting antivirals. Plasma samples were collected prior to and six months post-treatment. iRs were determined by ELISA. sPD-1 levels were significantly higher in more advanced fibrosis (F2 + F3 vs. F0/1). Regardless of the degree of fibrosis, sPD-1 and sLAG-3 levels significantly decreased after therapy. sTIM-3 levels also decreased, however, mostly in patients with no or mild (i.e., F0/1) fibrosis. Furthermore, Gal-3 increased in patients with more advanced fibrosis (F2 + F3). sPD-1 is associated with liver disease stage in CHC and effective treatment is related to the iRs levels reduction.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most prevalent cause of chronic hepatic disease worldwide. Recently, the association between MASLD and renal injury has emerged as an additional factor impacting the clinical course of MASLD.

The present study evaluated the clinical association in patients with obesity.

This study enrolled patients classified as having obesity class II and III (BMI >35 kg/m2) and MASLD from an obesity surgical treatment center. The diagnosis criteria for MASLD included the presence of hepatic steatosis as indicated by histology or imaging assessments. We use Fibrosis-4 (FIB-4) and NAFLD fibrosis score (NSF) to assess and determine the presence of liver fibrosis. The glomerular filtration rate (GRF) was determined using CKD-EPI (chronic kidney disease epidemiology collaboration) equation, with GFR levels ≥90 and <120 mL/min/1,73 m2 considered within the normal range.

The study comprised a total of 560 individuals with obesity grade II and III, 325 individuals with MASLD. Among these, 422 (75.4%) patients were female, and the mean age was 36±10 years. Systemic arterial hypertension (SAH) was present in 162 (41.1%) patients, and 218 (42.8 %) were diagnosed with type 2 Diabetes Mellitus (T2DM). A total of 286 individuals (51.1%) had a GFR below 114 mL/min, with 183 (64%) of them exhibiting a higher degree of liver fibrosis, as indicated by FIB-4 >0.54.

In patients with obesity classified as grades II and III, age emerged as the primary determinant leading to decline in GFR. Furthermore, glomerular hyperfiltration could be an early sign of progression to chronic kidney disease. Nonetheless, the progression of hepatic fibrosis could also be a significant factor contributing to impaired renal function.

Global metabolic dysfunction-associated steatotic liver disease (MASLD) prevalence is estimated at 30% and projected to reach 55.7% by 2040. In the Veterans Affairs (VA) healthcare system, an estimated 1.8 million veterans have metabolic dysfunction-associated steatohepatitis (MASH).

Adult patients at risk for MASLD in a VA healthcare system underwent Fibrosis-4 (FIB-4) and Enhanced Liver Fibrosis (ELF®) testing. Referral rates and cost savings were compared among 6 noninvasive testing (NIT) strategies using these 2 tests independently or sequentially at various cutoffs.

Enrolled patients (N = 254) had a mean age of 65.3 ± 9.3 years and mean body mass index (BMI) of 31.7 ± 6, 87.4% male: 78.3% were non-Hispanic/Latino, and 96.5% had type 2 diabetes mellitus (T2DM). Among the 6 evaluated strategies, using FIB-4 followed by ELF at a 9.8 cutoff yielded the highest proportion of patients retained in primary care without need of referral to hepatology clinic (165/227; 72.7%), and was associated with the lowest costs ($407.62). Compared to the FIB-4 only strategy, FIB-4/ELF with a 9.8 cutoff strategy resulted in 26% fewer referrals and 8.47% lower costs. In the subgroup of patients with BMI >32, there were 25.17% fewer referrals and costs were 8.31% lower.

Our study suggests that sequential use of ELF with a 9.8 cutoff following indeterminate FIB-4 tests results in lower referral rates and lower care costs in a veteran population at risk of MASLD. Adding ELF as a sequential test after indeterminate FIB-4 might help reduce the number of referrals and overall cost of care.

The HFE p.C282Y+/+ (homozygous) genotype and central adiposity both increase liver disease and diabetes risks, but the combined effects are unclear. We estimated waist-to-hip ratio (WHR) associations with incident clinical outcomes in routine care in p.C282Y+/+ participants in the UK Biobank community cohort.

Baseline WHR data available in 1297 male and 1602 female p.C282Y+/+ with 13.3-year mean follow-up for diagnoses. Spline regressions and Cox proportional hazard models were adjusted for age and genetic principal components. Cumulative incidence was from age 40 to 80 years. In p.C282Y+/+ males, there were positive linear WHR relationships for hospital inpatient-diagnosed liver fibrosis/cirrhosis ( p = 2.4 × 10 -5 ), liver cancer ( p = 0.007), non-alcoholic fatty liver disease ( p = 7.7 × 10 -11 ), and type 2 diabetes ( p = 5.1 × 10 -16 ). The hazard ratio for high WHR in p.C282Y+/+ males (≥0.96; 33.9%) was 4.13 for liver fibrosis/cirrhosis (95% CI: 2.04-8.39, p = 8.4 × 10 -5 vs. normal WHR); cumulative age 80 incidence 15.0% (95% CI: 9.8%-22.6%) versus 3.9% (95% CI: 1.9%-7.6%); for liver cancer, cumulative incidence was 9.2% (95% CI: 5.7%-14.6%) versus 3.6% (95% CI: 1.9%-6.6%). Hemochromatosis was diagnosed in 23 (96%) of the 24 high WHR p.C282Y+/+ males with incident fibrosis/cirrhosis. High WHR (≥0.85; 30.0%) p.C282Y+/+ females had raised hazards for liver fibrosis/cirrhosis (hazard ratio = 9.17, 95% CI: 2.51-33.50, p = 3.8 × 10 -7 ) and Non-alcoholic fatty liver disease (hazard ratio = 5.17, 95% CI: 2.48-10.78, p = 1.2 × 10 -5 ). Fibrosis/cirrhosis associations were similar in the subset with additional primary care diagnoses.

In p.C282Y+/+ males and females, increasing WHR is associated with substantially higher risks of liver complications. Interventions to reduce central adiposity to improve these outcomes should be tested.

Lifestyle-induced weight reduction remains crucial for managing type 2 diabetes and steatotic liver disease, but its effectiveness varies. We postulated that the G allele in the rs738409 single nucleotide polymorphism within patatin-like phospholipase domain-containing protein 3 (PNPLA3), which associates with metabolic dysfunction-associated steatotic liver disease, also modulates diet-related metabolic effects.

Participants with type 2 diabetes were randomized to 8-week hypocaloric diets (energy intake: -1,256 kJ/d of, <30 kcal% fat): high in cereal fiber and coffee excluding red meat (HF-RM + C; n = 16), or low in cereal fiber, devoid of coffee, but high in red meat (LF + RM-C; n = 15). Whole-body insulin sensitivity (M value) was assessed using [2H]glucose and hyperinsulinemic-normoglycemic clamps, hepatic lipid content (HCL) and body fat volumes by magnetic resonance spectroscopy/imaging before and after intervention.

Despite comparable weight loss, HCL decreased more in non-carriers (-65 %) than in G-allele carriers (-36 %) upon HF-RM + C diet (both p < 0.05 vs baseline and between groups), but only among non-carriers (-46 %, p < 0.05 vs baseline) upon LF + RM-C. Upon HF-RM + C diet, increase in insulin sensitivity was not different between carriers (+27 % p = 0.051 from baseline) and non-carriers (+21 %, p = 0.032 from baseline), p > 0.05 for between-group comparison. Upon LF + RM-C diet, both groups equally improved their whole-body insulin sensitivity (+42 % for non-carriers and +37 % for carriers, p < 0.05 vs baseline). Upon HF-RM + C diet, non-carriers decreased circulating interleukin-18 from baseline by -31 %, whereas, upon LF + RM-C diet, non-carriers decreased circulating anti-inflammatory interleukin-1 receptor antagonist levels by 14 % (both p < 0.05 vs baseline).

Humans with the PNPLA3 G-allele show modified dietary-induced effects on steatotic liver disease in type 2 diabetes despite body weight reduction. Registration at Clinicaltrials.gov, Identifier number: NCT01409330.

Liver biopsy remains the gold standard for fibrosis staging in patients with chronic hepatitis delta (CHD). Here, we comparatively evaluated the performance of transient elastography (TE) and biomarkers for the diagnosis of liver fibrosis in patients with CHD.

A total of 230 HDV-infected RNA-positive patients from various centers who underwent liver biopsy and liver stiffness measurements (LSMs) using Fibroscan, within a period of 6 months maximum, were investigated retrospectively. Area under the receiver operating characteristic curve and Youden index were used to establish cutoff values of LSM. TE was compared with other noninvasive tests: aspartate aminotransferase to platelet ratio index, Fibrosis-4, and Delta-4 fibrosis scores.

Histologic fibrosis stage distribution was: 20.4% for F0-F1; 27.0% for F2; 18.7% for F3; and 33.9% for F4. TE demonstrated good diagnostic performance for detecting cirrhosis and advanced fibrosis with an Area under the receiver operating characteristic curve of 0.88 and 0.86, which were significantly higher than those obtained with the other noninvasive tests (P = .004 and P < .001). With a cutoff value of >12 kPa for cirrhosis, the sensitivity was 70.5%, specificity was 86.2%, positive predictive value was 72.4%, negative predictive value was 85.1%, and accuracy was 80.9%. Using 10.4 kPa as the cutoff value for F3, the sensitivity was 70.2%, specificity was 83.5%, positive predictive value was 82.5%, negative predictive value was 71.7%, and accuracy was 76.5%. In 89% of patients with LSM ≤6.2 kPa, liver biopsy disclosed only absent or minimal fibrosis.

TE demonstrated good diagnostic performance for advanced fibrosis and cirrhosis in patients with CHD. Advanced fibrosis is highly probable for LSM values ≥10 kPa. LSM values <6 kPa almost totally exclude significant fibrosis. Between 6 and 10 kPa, liver biopsy should be discussed.