Intrahepatic cholangiocarcinoma (ICC) is a malignant tumour associated with a poor prognosis. Recent studies have suggested that ribonucleotide reductase subunit M2 (RRM2) could promote tumour progression. This study aims to explore the expression, function and mechanism of RRM2 in ICC by regulating ferroptosis through the HIF-1α signalling pathway. The expression of RRM2 and HIF-1α was detected in ICC patients, and the relationship between RRM2 and prognosis was analysed. CCK-8, clone formation assay, wound healing assay, transwell invasion experiment, cell apoptosis detection and tumorsphere formation assay were conducted to evaluate the effect of RRM2 on the progression of ICC. Transcriptomics was used to explore the mechanism of RRM2 promotion of ICC. Ferroptosis inducer (Ferrostatin-1) and inducer (RSL3), HIF-1α inhibitor (LW6) and inducer (CoCl2) were applied to investigate the effects of RRM2 on reactive oxygen species (ROS), ferroptosis-related indicators and HIF-1α expression. The effects of RRM2 on tumour growth were validated using subcutaneous tumours in nude mice. RRM2 was significantly upregulated in ICC tissues and was associated with a poor prognosis in patients. Overexpression of RRM2 promoted the proliferation, colony formation, invasion, metastasis, stemness, and inhibited apoptosis of ICC cells. Transcriptomics clarified that the HIF-1α signalling pathway was a key downstream pathway. The expression of HIF-1α was significantly positively correlated with the expression of RRM2 and was associated with poor prognosis in patients. Overexpression of RRM2 upregulated HIF-1α and reduced ROS levels. RRM2 upregulated SLC7A11 and GPX4 and downregulated ACSL4 by regulating the HIF-1α signalling pathway, inhibiting intracellular iron ion accumulation and lipid peroxidation, thus suppressing ferroptosis. Under hypoxic conditions, the anti-tumour effect of knocking down RRM2 was weakened. HIF-1α inhibitor could reverse the ferroptosis inhibition caused by RRM2 overexpression, and the HIF-1α inducer could alleviate the enhanced ferroptosis caused by knocking down RRM2. In vivo experiments also confirmed that overexpression of RRM2 promoted tumour growth, upregulated Ki-67, GPX4, HIF-1α, and N-cadherin, and downregulated E-cadherin. RRM2 inhibited ferroptosis by regulating the HIF-1α signalling pathway, thereby promoting the progression of ICC. The RRM2/HIF-1α/ferroptosis axis may become a potential target for ICC therapy.
Cirrhosis favours infections that can lead to liver decompensation and death. Some of these infections can be prevented by vaccination. This study aimed to evaluate the immune response after HBV, pneumococcal, diphtheria, and tetanus vaccination in cirrhotic patients. Patients with cirrhosis were prescribed 3 doses of hepatitis B vaccine, a tetanus-diphtheria booster and/or a 13-valent pneumococcal conjugate vaccine followed by a 23-valent polysaccharide vaccine. HBs seroconversion was assessed 6 months after the last booster dose. Antibody concentrations for seven pneumococcal serotypes, tetanus and diphtheria were measured by ELISA before (V0) and 4 to 6 months after vaccination (V1). Of the 125 patients enrolled, 83 were analysed for HBs seroconversion, 119 for pneumococcal vaccine response and 117 for tetanus and diphtheria vaccine response. The anti-HBs seroconversion rate was 31%. A doubling of the antibody was observed in 19% of cases for tetanus and in 26% of cases for diphtheria. For the pneumococcal vaccine, the global protection (at least 5 antibodies with a concentration ≥ 1.3 mg/L against the 7 serotypes of pneumococcus tested) increased from 39% before vaccination to 80% after vaccination. However, only 48% of patients had a 2-fold increase in IgG antibody for at least five of the seven serotypes tested. Our study highlights a weak response to the hepatitis B, tetanus, and diphtheria vaccines and an acceptable immunological response to the pneumococcal vaccine, although lower than in healthy subjects. There is a real need to optimise vaccination in cirrhotics. Cirrhotic patients are at very high risk of infection, which is why vaccination is recommended. Our study is the first to evaluate the response to different vaccines in these patients. It shows a very weak response to vaccination against hepatitis B, tetanus and diphtheria, and an acceptable response to the pneumococcal vaccine. There is a need to optimise vaccination schedules and to vaccinate earlier, well before the onset of cirrhosis.
The World Federation for Ultrasound in Medicine and Biology (WFUMB) guidance update 2024 proposed a 'rule-of-4' using ARFI liver stiffness measurement (LSM) to stratify the risk of decompensation events. This rule identifies advanced chronic liver disease (ACLD) at a threshold of ≥ 13 kPa and indicates a high probability of clinically significant portal hypertension (CSPH) above 21 kPa. We prospectively enrolled 187 patients undergoing same-day SSI-2D-LSM (Aixplorer SuperSonic Imagine) and hepatic venous pressure gradient (HVPG) measurement. Patients were stratified into three LSM groups < 13 kPa, 13-21 kPa and > 21 kPa and followed for decompensation events for 1 year (Y1). The cohort comprised 31 (16.6%) patients with LSM < 13 kPa (non-ACLD); 33 (17.6%) LSM 13-21 kPa (ACLD) and 123 (65.8%) LSM > 21 kPa (high CSPH probability). The corresponding median HVPG values were 5 [IQR: 3-7] vs. 10 [7-14] vs. 17 [13-21] mmHg, respectively, and the corresponding CSPH prevalence was 6.5%, 54.5% and 91.9%. In ROC analysis to predict CSPH, SSI-2D-LSM demonstrated high accuracy (AUC: 0.83). Validating the new WFUMB extension of the 'rule-of-4', the recommended > 21 kPa threshold identified CSPH with a specificity of 80.0% and a PPV of 83.1%. In competing risk analysis, the Y1-decompensation rate was 0%, 10% and 24.7% of patients in the < 13 kPa, 13-21 kPa and > 21 kPa groups, respectively. For prediction of Y1-decompensation risk in the compensated ACLD (cACLD) subgroup, HVPG demonstrated the highest predictive accuracy (AUC: 0.92), while SSI-2D-LSM (AUC: 0.75) performed similarly to vibration-controlled transient elastography (VCTE: AUC: 0.77; AUC-comparison: p = 0.837). The WFUMB 'rule-of-4' for ARFI-LSM allows for accurate and point-of-care non-invasive risk stratification of patients with liver disease. Specifically, the short-term risk of decompensation starts at SSI-2D-LSM ≥ 13 kPa and becomes considerable at SSI-2D-LSM > 21 kPa (indicating high CSPH probability). These findings support the broader implementation of ARFI-LSM for risk assessment in clinical routine.
Systemic therapies have been widely applied in the first-line treatment of patients with unresectable hepatocellular carcinoma (uHCC). Regimens based on programmed cell death 1/ligand 1 (PD-1/PD-L1) inhibitors combined with either bevacizumab or lenvatinib have become first-line treatments, yet the optimal strategy remains controversial. This systematic review and meta-analysis aimed to compare the efficacy and safety of lenvatinib versus bevacizumab, both in combination with PD-1/PD-L1 inhibitors, as first-line therapy for uHCC. A thorough literature search was performed in PubMed, Web of Science, Embase, CNKI and Wanfang from their inception to August 1, 2025. The primary endpoints were overall survival (OS) and progression-free survival (PFS), whereas secondary endpoints included objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). A meta-analysis using a random effects model was performed to obtain hazard ratio (HRs) and 95% confidence intervals. Statistical analyses were conducted using Stata software. A total of 10 retrospective cohort studies involving 1659 patients were included. The analysis demonstrated that, compared with the bevacizumab-based regimen, the lenvatinib-based regimen was associated with significantly prolonged OS (I2 = 55.9%, HR: 0.69, 95% CI: 0.5-0.95, p = 0.023) and PFS (I2 = 45.7%, HR: 0.73, 95% CI: 0.59-0.9, p = 0.004). No significant differences were observed between the two groups in terms of ORR (I2 = 65%, RR: 1.09, 95% CI: 0.91-1.31, p = 0.304) or DCR (I2 = 77%, RR: 0.99, 95% CI: 0.92-1.06, p = 0.532). Regarding safety, the overall incidence of AEs was comparable between the two groups. However, the lenvatinib-based regimen was associated with a higher incidence of hand-foot skin reaction and neutropenia, whereas the bevacizumab-based regimen carried a higher risk of gastrointestinal haemorrhage. In this meta-analysis of retrospective studies, lenvatinib plus PD-1/PD-L1 inhibitor regimens were associated with superior OS and PFS compared with bevacizumab plus PD-1/PD-L1 inhibitor regimens as first-line regimen for uHCC in East Asian populations. These findings require confirmation in large-scale, prospective, multinational randomized controlled trials in other populations. We systematically compared the efficacy of lenvatinib or bevacizumab combined with anti‐PD‐1/PD‐L1 in the treatment of uHCC and found that lenvatinib combined with anti‐PD‐1/PD‐L1 was more effective in prolonging PFS and OS, with a manageable safety profile.
Liver-related sarcopenia is a devastating systemic complication of chronic liver disease (CLD) driven by mechanisms extending beyond nutritional deficiency. However, the role of liver-derived humoral factors remains unclear. We utilised a unique cohort of human skeletal muscle biopsies to test the hypothesis that serum conjugated bile acids (C-BAs) act as key mediators of this liver-muscle cross-talk. Serum and rectus abdominis muscle samples were meticulously collected from 36 CLD patients and 6 non-CLD controls during elective surgery. Multifidus-erector spinae and psoas muscle areas were quantified from CT images. Comprehensive correlations were analysed between C-BAs and molecular markers of muscle inflammation and fibre-type composition. These findings were supplemented by in vitro validation using GCDCA treatment of C2C12 myotubes. Serum C-BAs levels were significantly elevated in CLD patients. The liver cirrhosis (LC) group exhibited a significantly smaller multifidus-erector spinae area (32.06 ± 8.05 cm2) compared to controls (39.78 ± 4.38 cm2, p = 0.019). Muscle area loss was strongly correlated with hepatic reserve deterioration (ALBI/ALB) and systemic inflammation (serum IL-6). Crucially, muscle area was negatively correlated with the ratio of tauro-C-BAs (p < 0.05). Muscle biopsies showed a molecular shift: enrichment of the slow-twitch fibre marker myosin-heavy chain 7 (MYH7, type I) and a concomitant reduction of the fast-twitch marker MYH4 (type IIb), alongside signs of local chronic inflammation (p < 0.05). The reduction in MYH4 was correlated with glyco-C-BAs, a finding replicated in GCDCA-treated C2C12 myotubes. Elevated C-BAs may represent a critical, liver-derived humoral factor associated with the pathological features of liver-related sarcopenia. C-BA-associated muscle mass loss and systemic inflammation are reflected at the molecular level by a shift toward a slow-twitch phenotype, accumulation of macrophages and altered energy metabolism in muscle biopsies. These findings suggest that C-BAs may serve as a potentially actionable therapeutic target for mitigating muscle catabolism and improving clinical outcomes in CLD patients.
Strong non-invasive tests (NITs) are needed to predict decompensation in patients with compensated advanced chronic liver disease (cACLD) and improve personalized patient care. We conducted a comprehensive review of the studies evaluating the effectiveness of NITs in predicting decompensation or liver-related death in patients with cACLD. A literature search was conducted in the PubMed database up to August 2025. Prospective or retrospective studies that included patients with cACLD and evaluated NITs for predicting decompensation or death or liver transplantation were included. Studies evaluating elastography and blood-based tests were analysed separately. The majority of studies assessed liver stiffness measurement (LSM), primarily using transient elastography (TE-LSM). There is a strong association between higher LSM values and an increased risk of decompensation, allowing classification of patients at low risk of decompensation from those with a higher risk. However, none of the studies reported data calibration, thereby limiting the ability to accurately predict the individual risk of decompensation. Higher FIB-4, ELF, and MELD values have been associated with an increased occurrence of decompensation. However, their performance was modest, with an area under the curve (AUC) below 0.75. Innovative approaches to improving the non-invasive prediction of decompensation may include levels of extracellular vesicles, genetic polymorphisms, or imaging-derived variables. Furthermore, since decompensation is the result of numerous interacting factors, artificial intelligence has the potential to improve the clinical relevance of predictive models by incorporating and processing a high-dimensional set of variables that reflect the underlying pathophysiological complexity.
While cirrhosis is a primary risk factor for hepatocellular carcinoma (HCC), a significant proportion of HCC cases attributed to metabolic dysfunction-associated steatotic liver disease (MASLD) develop in the absence of cirrhosis. MASLD is strongly linked to obesity, a known risk factor for multiple cancers. Whether the effect of obesity on HCC is mediated via cirrhosis or other factors is unknown. We used univariable Mendelian randomization (MR) to test the total effect of a higher body mass index (BMI), a proxy for obesity, on HCC, and multivariable MR to test the direct effect. We estimated that the effect of BMI was a 1.65-fold higher risk of HCC per standard deviation increase (95% confidence interval (CI): 1.28-2.12, p-value = 1.0 × 10-5). The BMI effect became indistinguishable from zero when taking liability to cirrhosis into account with multivariable MR (odds ratio = 1.12, 95% CI: 0.84-1.50, p-value = 0.44). We investigated additional potential pathways linking BMI to HCC-such as inflammation and type 2 diabetes-and explored the direct effect of childhood obesity on the risk of HCC. We found no direct effect of inflammation or type 2 diabetes (p-values > 0.05). Childhood body size increased the risk of HCC (odds ratio = 1.78, 95% CI: 1.27-2.49, p-value = 8 × 10-4), but the effect disappeared when we took adult body size into account using multivariable MR. Cirrhosis liability is the primary mediator of the causal effect of obesity on HCC.
Diabetes mellitus (DM) affects a substantial proportion of individuals with cirrhosis, with the highest prevalence observed in those with metabolic dysfunction-associated steatotic liver disease (MASLD). Its frequency increases in parallel with declining hepatic function, irrespective of the underlying aetiology. In this setting, both classical type 2 diabetes mellitus (T2DM) and hepatogenous diabetes, which arises secondary to hepatic dysfunction, may occur. T2DM and insulin resistance play key roles in the pathogenesis of MASLD, in the progression of hepatic fibrosis, and in the onset of cirrhosis-related complications through mechanisms encompassing systemic inflammation, endothelial dysfunction, and worsening of portal hypertension. Indeed, DM has been shown to be associated with worse prognosis, including increased rates of hepatic decompensation, higher mortality, and poorer post-liver transplantation outcomes. Achieving adequate glycaemic control may therefore reduce the risk of decompensation and improve overall prognosis. This narrative review examines DM in the context of decompensated cirrhosis, addressing diagnostic challenges, clinical implications, and therapeutic strategies. Particular attention is given to the complexities of antidiabetic management in the presence of impaired liver function, including drug repurposing and the development of agents with potential hepatoprotective effects.
Metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant health burden and impacts quality of life (QoL). This study evaluates the effects of essential phospholipids (EPL) on liver steatosis, QoL, and other liver and metabolic parameters in patients with MASLD and associated comorbidities. In this multicenter, double-blind, randomised, placebo-controlled phase 4 clinical trial, patients with MASLD and type 2 diabetes, hyperlipidemia, or obesity received either EPL or placebo, alongside standard of care. change in hepatic steatosis from baseline to 6 months (measured by Controlled Attenuation Parameter [CAP] score); secondary endpoints: changes in QoL (measured by the Chronic Liver Disease Questionnaire [CLDQ-MASLD]), symptom changes; other endpoints: other liver, metabolic, and lipid parameters, and safety. Of 193 randomised patients, 165 constituted the modified intention-to-treat population (median age: 56.5 years [EPL arm], 55.0 years [placebo arm]). More than ¾ of patients were obese and had CAP score ≥ 280 dB/m. At 6 months, EPL treatment significantly reduced CAP (p = 0.0269) versus placebo. This effect was evident at 3 months (p = 0.0049) and sustained until 3 months post treatment (p = 0.0234). QoL total score showed numerical improvement, with statistically significant improvement in fatigue subscore (p = 0.0229) with EPL versus placebo at 6 months. EPL significantly improved HbA1c levels (p = 0.0069) over 6 months. No safety concerns arose. The beneficial effects of EPL on hepatic steatosis, QoL and glycemic control, and its favourable safety profile make it a promising candidate for managing steatosis and enhancing overall liver health in MASLD patients with cardiometabolic risk. The trial was registered in the EudraCT (2021-006069-39). Essential phospholipids (EPLs) can be used along with standard treatments to reduce liver fat in patients with fatty liver disease linked to metabolic health issues. However, strong evidence from well‐controlled studies is limited. The present phase 4 clinical study (EXCEL) found that EPLs, when added to standard care, significantly reduced liver fat, tiredness and blood sugar levels within 6 months in such patients. These results suggest that EPLs could be a safe and effective option to improve liver health in patients with fatty liver disease with conditions like diabetes, high cholesterol, or obesity.
Microplastics (MPs) or nanoplastics (NPs) are emerging environmental pollutants, but current studies predominantly focus on the hepatotoxicity of high-dose MPs, whereas the health effects of low-dose MPs under high-fat diet (HFD) conditions remain unclear. We aimed to investigate the hepatotoxicity induced by combined exposure to high-fat diet and low-dose microplastics. Male Wistar rats were administered a high-fat diet (HFD) without (HFD) or with polystyrene nanoparticles (PS-NPs) (HFD-NP) for consecutive 90 days. In vitro experiments were conducted using primary hepatocytes treated with PS-NPs and palmitic acid (PA) in the presence or absence of AMPK or an autophagy inhibitor for 24 h. H&E staining revealed significant lipid accumulation, inflammation, and hepatic fibrosis in livers from HFD group, whereas no obvious pathological changes were observed in NP group. Notably, these effects were greatly diminished in HFD-NP group, compared with HFD group. In vitro experiments also showed that PS-NPs displayed no apparent effect on the viability of primary hepatocytes, while significantly alleviated palmitic acid (PA)-induced hepatocyte apoptosis and lipid droplet accumulation. These observations indicate that low-dose PS-NPs mitigate hepatotoxicity induced by HFD. Furthermore, hepatic lipid oxidation and utilization were enhanced in HFD-NP rats, suggesting that PS-NPs may modulate lipid metabolism upon HFD. Transcriptomic analysis revealed the mechanism might involve the activated AMPK signalling pathway and inhibited mTOR signalling pathway, important regulators for autophagy, implying the involvement of lipophagy in this process. Furthermore, in vitro experiments showed the inhibition of lipid droplet autophagy exacerbated HFD-induced hepatotoxicity. Our results indicate low-dose PS-NPs can activate the AMPK pathway and lipophagy, thereby alleviating liver injury through a stress adaptation response under high-fat diet conditions. Our findings elucidate the context-dependent interaction between microplastics and dietary patterns in liver diseases development and provide novel insights into the health effects of microplastics. This study found that low‐dose polystyrene nanoplastics, at levels relevant to human exposure, do not cause liver damage on their own. However, in rats fed a high‐fat diet, these nanoplastics unexpectedly helped reduce liver injury by activating a natural cellular process called lipophagy, which breaks down excess fat. These findings suggest that the health effects of microplastics may depend on dose and dietary context, offering new insights into their interaction with metabolic diseases.
One third of patients with cirrhosis experience an early readmission, and predicting such an event is challenging. We developed and validated a scoring system to predict non-elective readmissions in patients with cirrhosis. An observational and multicenter retrospective study enrolled 1382 consecutive non electively admitted patients with cirrhosis and acute decompensation from 20 centers in Spain and were categorized as derivation and validation cohorts. The cohorts were followed for 90 days after discharge. The rate of 7-day, 30-day and 90-day readmission was 5.3%, 19.9% and 36.7%, respectively, while 12.3% of patients died during the study. History of decompensation [HR 1.31 (95% CI 1.04-1.64); p = 0.022], Charlson index [HR 1.08 (95% CI 1.02-1.14); p = 0.012], large-volume paracentesis [HR 1.37 (95% CI 1.09-1.73); p = 0.007], INR [HR 1.52 (95% CI 1.17-1.97); p = 0.001] and bilirubin [HR 1.03 (95% CI 1.001-1.05); p = 0.045] at prior discharge were associated with early readmission. REACT score distinguished patients at high versus low risk of readmission: (a) derivation cohort 19.6% vs. 0% for 7-day, 70.6% vs. 2.5% for 30-day, 91.1% vs. 20.2% for 90-day; (b) internal validation 20.6% vs. 0% for 7-day, 58.8% vs. 0.5% for 30-day, 72.1% vs. 11.8% for 90-day; (c) external validation 5.8% vs. 0% for 7-day, 24.6% vs. 0% for 30-day, 44.2% vs. 12% for 90-day. Also, high-risk patients were more likely to be readmitted before their scheduled follow-up appointment (51.9% vs. 5.7%). Cirrhosis readmission rate was 20% within the first 30 days after discharge. REACT score effectively predicted the risk of non-elective readmission in patients with decompensated cirrhosis. Prospective studies are needed to fully assess the usefulness of this scoring system in predicting non-elective readmissions and in developing strategies to prevent them. Hospital readmissions are a major issue in cirrhosis, with about a third of patients experiencing a 30‐day readmission. Currently, there are no models in clinical practice to accurately predict hospital readmissions. We derived and externally validated a new scoring system (REACT score) to predict 7‐ day, 30‐day and 90‐day non‐elective readmissions. REACT score, which combines factors of a history of prior decompensation, Charlson comorbidity index, large‐volume paracentesis during hospitalization and INR and bilirubin levels at discharge. Implementing a readmission prediction score for liver cirrhosis for non‐elective readmissions, such as the REACT score, which is easy and quick to use, is clinically relevant as it would help identify high‐risk patients, enabling personalized care and targeted interventions to prevent complications.
Cirrhosis is a major contributor to disease burden in the Middle East and North Africa (MENA) region, with variations in outcomes across socioeconomic contexts and etiologies. The primary aim of this study was to assess the temporal trends in cirrhosis-related mortality and disability across the MENA region, with a focus on variations by aetiology and Socio-demographic Index (SDI). By identifying patterns and disparities in disease burden, the study seeks to support evidence-based policymaking and optimise regional liver health planning efforts. We analysed age-standardised data from the Global Burden of Disease Study to evaluate cirrhosis burden in the MENA region by SDI level in 2021 and by etiologic subtype in 1990 and 2021. Burden metrics included disability-adjusted life years (DALYs), years of life lost (YLLs), years lived with disability (YLDs), and the YLL-to-YLD ratio, applied as a novel epidemiologic indicator to illustrate evolving patterns in disease mortality versus chronicity. Aetiology-specific trends were quantified using Estimated Annual Percentage Change (EAPC) and stratified by SDI to assess variability across countries and over time. In 2021, cirrhosis burden varied markedly by SDI in the MENA region. Low-SDI countries experienced the highest YLL-to-YLD ratio (122.2), reflecting a predominantly fatal disease course, whereas high-middle and high-SDI countries demonstrated lower ratios (51.3 and 56.1, respectively), indicating improved survival but with more patients living longer with disability. From 1990 to 2021, the total age-standardised DALY rate for cirrhosis decreased from 18498.2 in 1990-9749.3 in 2021, with the YLL-to-YLD ratio dropping from 123.6 to 71, signalling a transition toward less fatal and more manageable disease. Aetiology-specific trends showed consistent decreases in YLL-to-YLD ratios across all causes: chronic hepatitis C (186.6-108.5), chronic hepatitis B (180.4-105.1), alcohol-related cirrhosis (188.4-116.1), and non-alcoholic fatty liver disease (166.6-94.4). Cirrhosis from other causes remained the most disability-predominant subtype (YLL-to-YLD ratio 25.6 in 2021). Cirrhosis in the MENA region is undergoing a transition from fatal disease to a chronically disabling condition. These changes reflect advances in detection, treatment, and survival, but also underscore the need for policy adaptation to improve awareness, prevention, early diagnosis, expand long-term care infrastructure, and reduce disparities across SDI levels.
Long-term albumin (LTA) is effective for treating ascites in decompensated cirrhosis. This study aims to analyse the clinical courses of patients receiving LTA and provide a 3 month stratification to personalise management integrating LTA with other options. Patients receiving LTA included in the multicentre, retrospective, observational Real-ANSWER study were stratified into three categories according to the response of ascites after 3 months of treatment: 'responders' (grade 0-1 ascites), 'partial responders' (at least grade 2 ascites not receiving therapeutic paracentesis) and 'non-responders' (at least grade 2 ascites receiving therapeutic paracentesis). Clinical trajectories and outcomes of the different categories were compared. Of the 252 patients included (median Child-Pugh 9, MELDNa 18), 36% were responders, 29% partial responders and 35% non-responders. Responders differed significantly from the other groups, with higher cumulative incidence of LTA discontinuation for clinical improvement (33%) and transplantation (26%), a lower 18 month mortality (13%) and minimal use of TIPS. Partial and non-responders showed similar trajectories with high mortality (35% and 42%) and low incidence of transplantation (12% and 11%). TIPS was performed predominantly among non-responders (15%). Both groups had a few patients (12% and 8%) able to stop LTA for clinical improvement frequently related to an effective etiologic treatment. Using a 3 month stratification according to the ascites response of LTA, patients can be grouped into three categories with different clinical courses and outcomes. This may help to stratify prognosis and inform clinical discussions on the management of ascites by integrating LTA with other available options. Long‐term albumin should be considered an additional weapon on top of diuretics for treatment of clinically evident grade 2 and 3 ascites in patients with decompensated cirrhosis. The response of ascites after 3 months of long‐term albumin (responders, partial responders and non‐responders) stratifies patients with different trajectories and outcomes. This stratification may help to guide long‐term albumin treatment at the individual level and integrate this approach with the other options available for the management of difficult‐to‐treat ascites.
Despite advancements in the detection and treatment of hepatocellular carcinoma (HCC), the overall survival remains poor. Traditional survival analyses, such as the Cox model, are limited in capturing the dynamic progression across different clinical states. Our paper proposes the utilization of a continuous-time multi-state Markov model to inform risk stratification and management strategies for HCC by accounting for transitions between disease states. This cohort study included 934 adult patients (25.0% female) with HCC who underwent curative treatment, defined as liver transplantation, resection or ablation, across eight tertiary centres in Australia, China, Japan, Singapore, South Korea and the United States. The primary objective was to assess the risk of HCC recurrence and survival following curative treatment. The median (IQR) age of the cohort was 65 (IQR 58-74), and 72% had known cirrhosis. Distinct clinical trajectories were identified: recurrence, death without recurrence and death after recurrence. The median (IQR) time from curative treatment to recurrence, from recurrence to death, and from curative treatment to death without recurrence was 15.40 months (4.78-26.01), 51.27 months (20.04-82.50), and 23.13 months (9.26-37.01), respectively. Analyses revealed that advancing age and HCV were associated with recurrence risk, while liver transplantation was protective against recurrence. Ablation, non-curative locoregional therapy, and systemic therapies were associated with higher risks of recurrence and post-recurrence death. Alpha-fetoprotein, tumour size, INR, bilirubin and advanced BCLC stage were key predictors of recurrence and mortality. By modelling disease as a sequence of interlinked transitions, we provide updated estimates for the time spent within each transition state and predictors for disease progression within a dynamic framework. Most studies of liver cancer use statistical methods that estimate risk from the time of treatment and assume this risk remains constant over time. In reality, a patient's outlook changes markedly after events such as cancer recurrence. By using a step‐by‐step modelling approach that follows patients as they move between being cancer‐free, recurrence and death, we show that different factors matter at different stages, which are not captured by traditional single‐risk estimates.
Differentiating between malignant and benign biliary strictures remains a clinical challenge because current diagnostic tools have limited sensitivity. The detection of tumour-related biomarkers directly in bile, which is in close contact with the lesion, may enhance diagnostic accuracy. This study aimed at evaluating the diagnostic and prognostic values of biliary concentrations of VEGF, PDGF-AA, IGF and MMPs in patients with extrahepatic cholangiocarcinoma (CCA), pancreatic ductal adenocarcinoma (PDAC), or benign obstruction. A total of 100 consecutive patients undergoing ERCP for obstructive jaundice were enrolled and categorised into benign (n = 48), CCA (n = 23) and PDAC (n = 29) groups. Bile samples collected during ERCP were analysed. The diagnostic and prognostic performance of several biomarkers was assessed and, when appropriate, their incremental diagnostic value was assessed in comparison with standard bile cytology. Biliary concentrations of VEGF, MMP-1, MMP-2, MMP-7 and MMP-9 were significantly higher in malignant cases than in benign cases. VEGF demonstrated the best diagnostic accuracy (AUROC 0.86, sensitivity 87%, specificity 81%). MMP-1 and MMP-7 also showed good diagnostic values (AUROCs 0.79 and 0.81 respectively). In the multivariate analysis, VEGF was independently associated with the diagnosis of malignancy and PDAC, whereas both VEGF and MMP-2 were independently associated with CCA diagnosis. Using a predefined cut-off, bile VEGF showed a higher sensitivity than bile cytology, and their combination markedly reduced false-negative results. Regarding prognosis, higher PDGF-AA levels were independently associated with better survival rates. Biliary VEGF is a strong independent biomarker for the diagnosis of malignant biliary obstruction, both in PDAC and CCA. MMP-2 was independently associated with CCA diagnosis. PDGF-AA is a promising prognostic biomarker for malignant biliary strictures. These findings support the clinical potential of bile-based biomarkers for improving the diagnosis and assessing the prognosis of malignant biliary strictures.
Primary sclerosing cholangitis (PSC) is a progressive cholestatic liver disease with a high risk of malignancy and limited therapeutic options. Both the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) recommend structured baseline evaluation, fibrosis staging and longitudinal surveillance. However, real-world adherence to these practices in North America remains unclear. We conducted a retrospective cohort study of 1300 patients with PSC enrolled in the Consortium for Autoimmune Liver Diseases (CALiD) registry between 2018 and 2024 across 19 centres in North America. Guideline adherence was assessed for diagnostic measures at baseline (colonoscopy to establish IBD status and noninvasive fibrosis staging) and longitudinal surveillance (colonoscopy in PSC-IBD, abdominal imaging for hepatobiliary cancer surveillance and CA 19-9 testing). Prescribing patterns for ursodeoxycholic acid (UDCA) were also characterised. Multivariable logistic regression was used to evaluate demographic, clinical and socioeconomic predictors of adherence. At diagnosis, 78.8% of eligible patients with available data underwent colonoscopy to establish IBD status, and 45% underwent noninvasive fibrosis staging. During follow-up, only 30%-35% of patients with PSC-IBD underwent colonoscopy annually, while abdominal imaging for hepatobiliary cancer surveillance declined from 74% at Year 1 to 51% by Year 4. CA 19-9 testing was documented in 47% over 5-year period. UDCA was prescribed in 51% at baseline, with median dose of 12.5 mg/kg/day. Socioeconomic factors, including lower education and household income, were associated with reduced adherence, while cirrhosis strongly predicted completion of surveillance imaging. Adherence to guideline-based care in PSC remains suboptimal in North America Suboptimal adherence was observed for strongly recommended practices with longstanding guideline support (colonoscopy to establish IBD status; annual CRC surveillance in PSC-IBD) as well as practices where guideline consensus has evolved more recently or where societies differ (baseline fibrosis assessment; hepatobiliary cancer imaging). Efforts to standardise care and address socioeconomic barriers are urgently needed to improve outcomes. Primary sclerosing cholangitis (PSC) is a serious liver disease that increases the risk of liver failure and cancer, making regular monitoring essential. In a large North American study of 1300 patients, we found that many recommended tests—both at diagnosis and during follow‐up—are not consistently performed, and cancer surveillance decreases over time. Socioeconomic factors also influence whether patients receive recommended care. Improving adherence to guidelines may help detect complications earlier and improve outcomes.
Placental growth factor (PGF) is associated with the progression of hepatocellular carcinoma (HCC), but current research on this relationship remains limited. This study aims to establish a pathomics model for predicting PGF expression levels in H&E-stained HCC sections, and to explore its prognostic relevance and underlying molecular mechanisms. Retrospective analysis utilised H&E images and clinical data from TCGA and an external cohort. Prognostic significance of PGF was assessed via survival analysis. Image segmentation employed the OTSU algorithm, followed by PyRadiomics-based feature extraction. Key features were selected using mRMR and RFE algorithms, with a gradient boosting machine (GBM) model constructed for PGF prediction. Model performance was validated through ROC and Precision-Recall (PR) curves, calibration analysis along with Brier score, and decision curve analysis. Prognostic stratification, Cox regression, and subgroup analyses were conducted for high/low pathomics score (PS: a continuous score derived from a machine learning model based on H&E image features to predict PGF expression) groups. Bioinformatics approaches identified differentially expressed genes (DEGs) and immune infiltration patterns. PGF expression was identified as an independent prognostic factor for poor survival in HCC (HR = 1.922, 95% CI: 1.217-3.036, p = 0.005). A pathomics model integrating seven PGF-associated features demonstrated strong predictive accuracy, achieving an AUC of 0.811 (95% CI: 0.749-0.873) in the training set, 0.747 (95% CI: 0.639-0.855) in the internal validation set, and 0.740 (95% CI: 0.632-0.849) in the external test set. Patients classified into the high-pathomics score (PS) subgroup had significantly poorer survival (HR = 1.667, 95% CI: 1.024-2.713, p = 0.040). Functional analysis of DEGs in high-PS tumours revealed enrichment in ribosome- and coagulation-related pathways, upregulation of the inflammatory gene HBEGF, and increased infiltration of γδT cells. Moreover, TP53 mutations were frequently observed in this subgroup, with a mutation rate exceeding 20%. PGF may serve as an independent prognostic biomarker in HCC. The developed pathomics model enables non-invasive PGF expression prediction through H&E image analysis. Mechanistically, PGF-associated molecular alterations involve inflammatory signalling, immune microenvironment remodelling, and frequent TP53 mutations, providing insights into HCC pathogenesis. We developed a novel machine learning‐based pathomics model that accurately predicts placental growth factor (PGF) expression in hepatocellular carcinoma using routine H&E‐stained tissue slides, and confirmed PGF as an independent prognostic biomarker for poor survival in liver cancer patients with high pathomics scores linked to significantly worse outcomes. This non‐invasive model further uncovered that high PGF expression is associated with perturbed inflammatory signalling, altered immune cell infiltration, and frequent TP53 mutations in liver cancer, providing key mechanistic insights into tumour progression and a practical, low‐cost tool for clinicians to stratify high‐risk patients and guide personalised treatment strategies.
Life-long treatment is critical in Wilson disease (WD), a rare genetic disease leading to copper accumulation with hepatic and extrahepatic manifestations. Poor adherence is a well-known contributor to unfavourable clinical outcomes. Measuring adherence in these chronic patients may be challenging, as no gold standard method is available. We aimed at evaluating adherence in a well-characterised WD cohort and ultimately designing individualised nursing interventions. Prospective, single-centre study, including adult WD patients. Adherence to medication was assessed by a three-dimensional approach: (1) self-reported ARMSe questionnaire; (2) pharmacy service dispensing records and (3) physician-based evaluation. Concordance between methods was assessed, and variables associated with low adherence were evaluated. Inclusion of 54 WD patients (54% female, median age 39 years, median time since diagnosis 20 years). According to ARMSe, 39% of the patients reported low adherence, which was significantly associated with younger age at evaluation, higher ALT and higher exchangeable copper levels. Although a trend towards a positive association between methods was observed, concordance was low and patients were not classified in a constant manner, as only 12% were noncompliant by the three methods. Despite the critical role of adherence for adequate control of WD, one-third of our cohort exhibited low adherence. The limited agreement among the different assessment methods reinforces the need for a combined strategy. The ARMSe questionnaire proved useful for guiding individualised educational nursing interventions by enabling the identification of patient-specific barriers to adherence.
Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) is a growing clinical challenge, necessitating effective diagnostic strategies to identify advanced liver fibrosis while minimising unnecessary referrals of mild cases. Current clinical guidelines recommend care pathways utilising non-invasive tests (NITs) to stratify patients, but the optimal diagnostic algorithm across care settings remains unclear. This state-of-the-art review systematically examines studies describing clinical care pathways for detecting advanced fibrotic MASLD and stratifying patients at risk. A comprehensive literature search of MEDLINE, Embase, Cochrane Library, and Scopus, finalised in January 2026, identified nine relevant studies that met predefined criteria including structured care plans and applicability beyond diagnosis alone. Pathway populations included patients at risk for MASLD (type 2 diabetes (n = 4) or broad range cardiometabolic risk factors (n = 1)) or confirmed MASLD (n = 4). The most frequently employed NITs were FIB-4 and vibration-controlled transient elastography (VCTE). Numbers needed to screen (NNS) for hepatology referral and advanced fibrosis detection varied considerably across pathways and populations, reflecting heterogeneity in design and fibrosis assessment methods. All studies reported improved patient risk stratification; attendance rates declined at each pathway step. Findings suggest that NIT-based clinical care pathways can effectively align patient management and optimise transmural care for MASLD. Nonetheless, heterogeneity in pathway design and fibrosis determination highlights the need for standardised protocols and validation in larger, at-risk cohorts to strengthen evidence supporting widespread adoption. This review contributes to advancing MASLD management within evolving clinical frameworks.
Redox-active iron (Fe) overload and antioxidant zinc (Zn) deficiency are hallmarks of chronic liver fibrosis, yet their upstream regulatory mechanisms remain elusive. Here, we identify the redox-sensitive metallothionein (MT) as a critical regulator in the injured liver that integrates trace-metal homeostasis with Hippo-Yap signalling. MT expression was transiently induced in early-stage murine and human liver fibrosis but declined sharply in advanced disease. Genetic deletion of MT in mice exacerbated CCl4-induced liver injury, characterized by severe Zn depletion, pathological Fe accumulation, and aggravated fibrosis. Mechanistically, MT loss impaired the activity of Zn-dependent matrix metalloproteinases and unleashed pathological Fe deposition, which amplified lipid peroxidation and oxidative damage. We revealed that MT deficiency suppressed the upstream Hippo kinase Mst1, promoting the nuclear translocation and activation of the transcriptional coactivator Yap. Crucially, pharmacological inhibition of Yap with verteporfin rescued the Fe overload and attenuated fibrosis in MT-deficient livers but did not correct the Zn depletion, establishing Yap as a key downstream driver of Fe dysregulation. The analysis of human fibrotic and cirrhotic livers confirmed a conserved inverse correlation between MT levels and nuclear Yap accumulation, accompanied by severe Fe deposition. These findings reveal MT as a key hepatocyte integrator of trace-metal homeostasis and Yap signalling and suggest that therapeutic strategies enhancing MT activity or combining Zn supplementation with Yap inhibition may offer new avenues to prevent or reverse chronic liver fibrosis.