Hepatocellular carcinoma is the seventh most common kind of cancer worldwide and the second largest cause of cancer-related deaths in males, behind lung cancer. Globally, 866,000 people were diagnosed with hepatocellular carcinoma (HCC) in 2022, and nearly 42,240 new cases will be identified in 2025 in the United States. Using stem cells obtained from bone marrow can effectively reduce the number of malignant tumor cells through the induction of an epigenetic impact. We obtained bone marrow-derived mesenchymal stem cells (BM-MSCs) from mice and collected the conditioned medium (CM) from cultured cells with 90% confluency. The effect of the CM was identified using both 2D and 3D sphere cultures of wild-type human liver cancer cell line (HepG2), considering variations in sphere size and percentage. A cell death study was conducted using the cell cytotoxicity (MTT) kit, while the quantity of stem cells was determined by immunohistochemistry and gene expression analysis. The effectiveness of our therapy was demonstrated by an in vivo assessment of BM-MSCs through intravenous injection and the currently available anticancer drug cisplatin. In vitro, the combination treatment resulted in a synergetic effect, leading to 74% cell death in both adherent and spherical cultures when treated with 25 µM of cisplatin and 90%CM. In vivo, the histological study indicated a decrease in tumor size and number following treatment with cisplatin and BM-MSCs. The study lasted 18 weeks and revealed that the body weight of mice improved across all treatment groups, with the combination group exhibiting the most significant improvement. Both in vitro and in vivo studies showed the synergetic effect of cisplatin and isolated conditioned medium. Our study aimed to identify more efficient therapeutic approaches utilizing stem cells and existing marketed medications to minimize adverse effects with better efficacy.

Alcohol-related liver disease is the third leading cause of hepatocellular carcinoma worldwide and the leading cause in Europe. Additionally, the recent definition of metabolic dysfunction-associated steatotic liver disease with increased alcohol intake (MetALD) will enrich this population with a more nuanced phenotype, reflecting recent epidemiological trends. In these patients, the hepatocellular carcinoma diagnosis is often delayed and less frequently detected through screening programmes. Moreover, at the time of diagnosis, patients with alcohol-related hepatocellular carcinoma tend to have a poorer general condition, more severely impaired liver function, and a higher prevalence of comorbidities, leading to increased competitive mortality. However, when hepatocellular carcinoma is diagnosed during surveillance programmes in patients with alcohol-related liver disease or MetALD, the rate of allocation to first-line curative treatments is high (56%) and comparable to that of patients with virus-related hepatocellular carcinoma. As a consequence, the aetiology of the underlying cirrhosis cannot be considered an independent prognostic factor in patients with hepatocellular carcinoma. Instead, prognosis is driven by liver function, general condition, and tumour burden. This underscores the crucial role of early diagnosis through periodic surveillance in patients with alcohol- or MetALD-related cirrhosis.

Despite increasing incidence of hepatocellular carcinoma (HCC) in vulnerable populations, accurate early detection tools are lacking. We aimed to investigate the associations between prediagnostic plasma metabolites and incident HCC in a diverse population. In a prospective, nested case-control study within the Southern Community Cohort Study, we conducted prediagnostic LC/MS metabolomic profiling in 150 incident HCC cases (median time to diagnosis, 7.9 years) and 100 controls with cirrhosis. Logistic regression assessed metabolite associations with HCC risk. Metabolite set enrichment analysis identified enriched pathways, and a random forest classifier was used for risk classification models. Candidate metabolites were validated in the UK Biobank (N = 12 incident HCC cases and 24 cirrhosis controls). In logistic regression analysis, seven metabolites were associated with incident HCC (MeffP < 0.0004), including N-acetylmethionine (OR = 0.46; 95% confidence interval, 0.31-0.66). Multiple pathways were enriched in HCC, including histidine and CoA metabolism (FDR P < 0.001). The random forest classifier identified 10 metabolites for inclusion in HCC risk classification models, which improved HCC risk classification compared with clinical covariates alone (AUC = 0.66 for covariates vs. 0.88 for 10 metabolites plus covariates; P < 0.0001). Findings were consistent in the UK Biobank (AUC = 0.72 for covariates vs. 0.88 for four analogous metabolites plus covariates; P = 0.04), assessed via nuclear magnetic resonance spectroscopy. Prediagnostic metabolites, primarily amino acid and sphingolipid derivatives, are associated with HCC risk and improve HCC risk classification beyond clinical covariates. These metabolite profiles, detectable years before diagnosis, could serve as early biomarkers for HCC detection and risk stratification if validated in larger studies. Prevention Relevance: Our findings support the need for larger prospective studies examining the role of prediagnostic plasma metabolomics for the preventive management of HCC in diverse patients across multiple etiologies of liver disease. This approach could improve HCC care by identifying metabolic changes years before diagnosis, potentially enhancing screening and early detection practices.

For many cancers, biomarkers have served as an important tool across the cancer care continuum from risk stratification and early detection to diagnosis and treatment. Alpha-fetoprotein (AFP) remains one of the few validated biomarkers for patients with HCC. Although AFP has shown potential for each of these steps, its performance, when used alone, has often been suboptimal. There continue to be discordant recommendations about AFP's value when combined with ultrasound for surveillance, as well as its role in diagnostic algorithms. Conversely, high AFP levels are associated with aggressive tumor biology and survival, so it remains a key factor for the selection of candidates for liver transplant. There have been immense efforts to identify and validate additional biomarkers for each of these steps in the HCC care continuum. Indeed, biomarker panels have shown promising data for HCC risk stratification and surveillance among patients with cirrhosis, as well as prognostication and detection of minimal residual disease in patients undergoing HCC treatment. Several large prospective studies are currently ongoing to evaluate the role of these emerging biomarkers in clinical practice.

Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), significantly contribute to the increasing incidence of liver cancer due to NASH (NALC), emphasizing the urgent need to address the associated global health burden.

Using the Global Burden of Disease 2021 dataset, we analyzed the incidence, mortality, and disability-adjusted life year (DALY) rates of NALC and NAFLD from 1990 to 2021 across 204 countries. The Joinpoint model, age-period-cohort modeling, decomposition analysis, and frontier analysis were used to assess trends, identify contributing factors, and evaluate health inequities. Projections for future incidence were made using Nordpred and Bayesian age-period-cohort models.

The global incidence and mortality rates of NALC have increased significantly. Incidence rose from 14,413.92 cases (95% CI 11,470.95-17,854.24) in 1990 to 42,291.37 (95% CI 34,032.64-51,129.45) in 2021. This trend was particularly evident in low-middle SDI countries, while high SDI countries exhibited declining mortality rates despite rising incidence. Population growth was a primary driver of the increased burden in most regions. Projections suggest that NALC incidence may reach 43,525.53 (95% CI 14,169.28-72,881.77) by 2039, particularly among the elderly, highlighting the serious future risks associated with NALC globally.

The findings highlight the growing global burden of NALC driven by NAFLD, especially in low- to middle-income regions. Targeted interventions, alongside a deeper understanding and better resource allocation, are essential to mitigate the rising incidence and address the health disparities associated with this expanding public health challenge.

We investigated associations between body mass index (BMI) and hepatocellular carcinoma (HCC) in patients with hepatitis B (HBV) C (HCV) virus infection, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and liver cirrhosis (LC).

We followed 350,608 Korean patients with liver disease who underwent routine health examinations from 2003-2006 until December 2018 via national hospital discharge records. Multivariable adjusted hazard ratios (HRs) per 5-kg/m2 BMI increase (BMI ≥25 kg/m2) for HCC risk were calculated using Cox models. HCC developed in 17,752 patients.

The HRs (95% CI) were 1.17 (1.06-1.28), 1.08 (0.87-1.34), 1.34 (1.14-1.58), 1.51 (1.17-1.94), and 1.11 (1.00-1.23) for HBV, HCV, ALD, NAFLD, and LC, respectively. The HRs for HBV were 1.45 (1.23-1.70) and 1.06 (0.95-1.19) in women and men, respectively; the corresponding HRs for LC were 1.27 (1.07-1.50) and 1.02 (0.90-1.16), respectively. In patients <65 years old with HBV, HCV, and NAFLD, the HRs were 1.17 (1.07-1.29), 1.33 (1.03-1.73), and 1.20 (0.87-1.64), respectively; the corresponding HRs were 1.05 (0.70-1.59), 0.74 (0.50-1.10), and 2.40 (1.62-3.54), respectively, in patients ≥65 years old. A BMI of 27.5-29.9 kg/m2 showed significantly higher HCC risks in patients with HBV, ALD, NAFLD, and LC.

Higher BMIs were associated with increased HCC risks in patients with HBV, ALD, NAFLD, and LC. Overweight status increased HCC risk. Women with HBV and LC had stronger BMI-HCC associations than men. The effect of high BMI was stronger in older patients with NAFLD and younger patients with viral hepatitis.

Hepatocellular carcinoma (HCC) is the most common form of liver (LC) with a high mortality rate, driven by risk factors including viral hepatitis, alcoholic liver disease, and nonalcoholic steatohepatitis. The incident of HCC increases 2-4% of the worldwide population each year which would most certainly exceed one million per year by 2025. Despite advances in our knowledge, 25% of HCC tumors have actionable mutations which demands for innovative treatments strategies. In this perspective, we are providing a comprehensive summary of nanoparticles (NPs) based therapeutic approaches for HCC. We begin with an overview of HCC, concentrating on its pathogenesis, current conventional therapies, and their limitations. Then we delve into the therapeutic application of various nanoparticles (NPs) platforms for HCC, including polymeric micelles, dendrimers, liposomes, solid-lipid nanoparticles, nanostructured lipid carriers, exosomes, niosomes, mesoporous silica nanoparticles, carbon nanotubes. Special attention is given to the application of NPs in photothermal and photodynamic treatment was also investigated, with a focus on their effectiveness in targeted cancer ablation. Additionally, the review discusses recent patents and clinical studies that demonstrate the promise of NPs-based therapies in improving HCC treatment outcomes. This article underscores the potential of NPs based technologies to address the challenges faced by traditional therapies and offers insights into future directions for HCC management.

Hepatocellular carcinoma (HCC) risk prediction models may provide a more personalised approach to surveillance for HCC among patients with cirrhosis. This systematic review aims to summarise the performance of HCC prediction models in patients with non-viral chronic liver disease.

The study was prospectively registered with PROSPERO (ID: CRD42022370078) and reported in accordance with PRISMA guidelines. MEDLINE and Embase databases were searched using a validated search filter for prediction model studies. Two reviewers independently assessed studies for inclusion and risk of bias. Measures of model performance (discrimination and calibration) to assess the risk of HCC at specified time points were identified. A random effects meta-analysis was performed on a subset of studies that reported performance of the same model.

A total of 7,854 studies were identified. After review, 14 studies with a total of 94,014 participants were included; 45% of patients had viral hepatitis, 27% ALD (alcohol-related liver disease) and 19% MASLD (metabolic dysfunction-associated steatotic liver disease). Follow-up ranged from 15.1-138 months. Only one model was developed using a competing risk approach. Age (7 models) and sex (6 models) were the most frequently included predictors. Model discrimination (AUROC or c-statistic) ranged from 0.61-0.947. Only the 'aMAP' score (age, male sex, albumin, bilirubin, and platelets) had sufficient external validation for quantitative analysis, with a pooled c-statistic of 0.81 (95% CI 0.80-0.83). Calibration was reported in only 9 of 14 studies. All studies were rated at high risk of bias.

Studies describing risk prediction of HCC in non-viral chronic liver disease are poorly reported, have a high risk of bias and do not account for competing risk events. Patients with ALD and MASLD are underrepresented in development and validation cohorts. These factors remain barriers to the clinical utility and uptake of HCC risk models for those with the most common liver diseases.

The recent EASL policy statement emphasises the potential of risk-based surveillance to reduce both hepatocellular carcinoma (HCC)-related deaths and surveillance costs. This study addresses the gap in understanding the performance of current HCC risk models in patients with non-viral liver diseases, reflecting the epidemiological landscape of liver disease in Western countries. In our review of these models we identified several key concerns regarding reporting standards and risk of bias and confirmed that patients with alcohol-related liver disease and metabolic dysfunction-associated steatotic liver disease are underrepresented in model development and validation cohorts. Additionally, most models fail to account for the significant risk of competing events, leading to potential overestimation of true HCC risk. This study highlights these critical issues that may hinder the implementation of risk models in clinical practice and offers key recommendations for future model development studies.

Hepatocellular carcinoma (HCC) is a relevant complication occurring in individuals with advanced Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD). Recent epidemiological data suggest an alarming increase in the HCC burden worldwide, with a relevant proportion attributable to MASLD (up to 38 %), either in cirrhotic or non-cirrhotic livers. In view of the changing landscape of metabolic syndrome as "silent pandemic", this narrative review aims to provide an updated picture of the burden of HCC in individuals with MASLD. In the complex pathophysiological pathways linking insulin resistance to MASLD and cardiometabolic syndrome, metabolic inflammation appears a relevant driver of systemic as well as organ-specific complications. Novel insights from the field of immunology, gut-derived liver damage, and association with extra-hepatic cancers will be discussed. Finally, strategies for risk-based HCC surveillance (circulating biomarkers, prognostic models and polygenic risk scores) will be provided and the potential impact of novel drug targeting fibrosing Metabolic dysfunction-Associated Steatohepatitis (MASH) on incident HCC will be discussed.

Hepatocellular carcinoma (HCC) in young patients is rare, and the most common cause is hepatitis B viral infection. We report a case of ruptured HCC in a man in his 30s with a body mass index of 33 kg/m² without hepatitis viral infection. He had multiple HCC with distant metastases at the first visit. On the 6th day after admission, he underwent transcatheter arterial embolisation for HCC rupture, but died the following day. Pathological autopsy revealed moderately to poorly differentiated HCC without evidence of fibrolamellar carcinoma, which is common in young patients with HCC. Based on his history of obesity and fatty liver, we presumed that he had metabolic dysfunction-associated steatohepatitis. However, his non-neoplastic liver was normal. The HCC might have developed from metabolic dysfunction-associated steatotic liver disease, followed by regression of the underlying hepatic steatosis as the patient lost weight owing to HCC progression.

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) has been introduced as a superior term to describe steatosis on a background of metabolic dysregulation and is slated to become the leading cause of HCC worldwide, as the incidence of metabolic comorbidities is increasing. As such, MASLD has evolved into an important public health issue, potentially leading to higher rates of liver mortality and end-stage liver disease. To this end, understanding the association between MASLD and HCC may allow for the identification of better interventions and novel therapeutic strategies.

The authors provide a review of current knowledge on HCC development among patients with MASLD, with insights into molecular pathways and current and future therapeutic strategies.

MASLD has a strong association with the risk of HCC development, as metabolic comorbidities induce dysregulation in molecular pathways, leading to insulin-resistance, oxidative stress, and chronic inflammation, thus causing progression to cirrhosis and eventually to HCC. Therapeutic strategies focused on reducing diabetes-associated complications, as well as the prevalence of obesity and smoking can improve patient outcomes and reduce HCC incidence. Future studies on the molecular background of metabolic alterations may help devise new therapeutic approaches aiming to improve the current management of MASLD-HCC.

Although the burden of alcohol-associated hepatocellular carcinoma (HCC) is increasing with rising alcohol consumption, clinical presentation and outcomes of alcohol-associated HCC have not been systematically assessed. We aimed to determine the prevalence, clinical characteristics, surveillance rates, treatment allocation, and outcomes of alcohol-associated HCC.

Medline and Embase were searched from inception to January 2023. Proportional data were analyzed using a generalized linear mixed model. The odds ratio (OR) or mean difference comparing alcohol-associated HCC and other causes was obtained with pairwise meta-analysis. Survival outcomes were evaluated using a pooled analysis of hazard ratios.

Of 4824 records identified, 55 articles (86,345 patients) were included. Overall, 30.4% (95% confidence interval [CI], 24.0%-37.7%) of HCC was alcohol associated, with the highest proportion in Europe and the lowest in the Americas. People with alcohol-associated HCC were more likely male but were similar in age and comorbidities compared with other causes. A total of 20.8% (95% CI, 11.4%-34.9%) of people with alcohol-associated HCC underwent surveillance compared with 35.0%, 31.6%, and 21.4% in hepatitis B virus, hepatitis C virus, and metabolic dysfunction-associated HCC, respectively (all P < .05). Alcohol-associated HCC had a lower likelihood of Barcelona Clínic Liver Cancer C stage (0/A) (OR, 0.7; 95% CI, 0.6-0.9; P = .018) and curative therapy (24.5% vs 33.9%; OR, 0.7; 95% CI, 0.5-0.9; P = .003), and higher mortality (HR, 1.3; 95% CI, 1.1-1.5; P = .012) when compared with other causes.

Alcohol-associated HCC is associated with lower surveillance rates, more advanced BCLC stage, lower likelihood of receiving curative therapy, and poorer survival. These data call for measures to reduce heavy alcohol consumption and improve strategies for effective HCC surveillance in high-risk individuals.

Hepatocellular carcinoma (HCC) is typically detected only at advanced stages when treatment options are limited. Most of the current HCC risk models focus on patients with viral hepatitis or diagnosed cirrhosis or require variables not routinely available in clinical care.

To identify modifiable HCC risk factors in the general population and to develop a risk score to inform HCC screening and risk-factor modification interventions for high-risk individuals without viral hepatitis or decompensated cirrhosis.

This cohort study analyzed demographic, clinical, laboratory, and diagnostic data from the US Department of Veterans Affairs (VA) electronic health records. Data were divided into development and validation samples. Veterans aged 30 to 95 years were included, and those with hepatitis B or C virus infection, hepatic decompensation, or prevalent HCC were excluded. Patients were followed up until the occurrence of HCC diagnosis, death, or December 31, 2021. A Cox proportional hazards regression model for 10-year risk of HCC was developed and used to create an HCC risk score, and performance in development and validation samples and in patient subgroups was evaluated. One outpatient visit date per person at least 18 months after VA entry, between October 1, 2007, and March 31, 2020, was randomly selected and used as the index date for the start of follow-up. Analyses were performed from March 2023 to May 2024.

Age, sex, race and ethnicity, body mass index, liver fibrosis (detected with Fibrosis-4 Index [FIB-4]), diabetes status, smoking status, and alcohol use.

First HCC diagnosis during follow-up. This information was ascertained from VA national cancer registry topography and histology codes and from International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes for the inpatient or outpatient visits.

This study of 6 509 288 veterans included 6 048 917 males (92.9%), with a median (IQR) age of 65 (54-74) years, who identified as being of Hispanic (5.3%), non-Hispanic Black (15.0%), non-Hispanic White (68.9%), or other (4.6%) race and ethnicity. Overall, 15 142 patients (0.2%) developed HCC, 69.5% of whom had FIB-4 of 3.25 or lower at baseline. While FIB-4 was the most important variable, age, sex, race and ethnicity, body mass index, diabetes, smoking, and alcohol use were also informative. Discrimination in the development sample was better than FIB-4 alone (C statistic, 0.83 [95% CI, 0.82-0.85] vs 0.79 [95% CI, 0.77-0.80]). The HCC risk score performed consistently well in the validation sample and in all subgroups. A FIB-4 threshold of 3.25 would screen 5.0% of the cohort at a cost of 28 false-positives for every true-positive; a model risk score of 58 would screen 4.7% of the cohort at a cost of 23 false-positives for every true-positive.

Results of this study suggest that a multivariable risk score that uses routinely available clinical data outperforms FIB-4 alone in identifying patients at risk of HCC who do not have viral hepatitis or hepatic decompensation at baseline.

Alcohol-associated liver disease (ALD) poses a significant risk for hepatocellular carcinoma (HCC), comprising various liver conditions from steatosis to cirrhosis. Despite accounting for a third of global HCC cases and deaths, ALD-related HCC lacks characterization compared to viral hepatitis-related HCC. Proposed mechanisms for ALD-related HCC include acetaldehyde toxicity, increased reactive oxygen species, and inflammation. This review examines ALD-associated HCC epidemiology, co-factors like viral hepatitis and metabolic syndrome, surveillance, and treatment challenges. Despite advances in screening and management, ALD-related HCC often presents at advanced stages, limiting treatment options and survival.

Liver is the most common organ affected by alcohol misuse. The spectrum of alcohol-associated liver disease (ALD) ranges from simple steatosis to cirrhosis and its complications. The unique clinical phenotype of alcohol-associated hepatitis has a risk for high short-term mortality. Several gaps exist with respect to epidemiology, noninvasive testing, prognostication, and treatment of ALD. Most studies focus on short-term survival as the ideal endpoint and ignore other aspects of alcohol-use disorder and ALD. In this review, the authors discuss the existing knowledge gaps, enumerate ongoing clinical trials, and highlight the research priorities and future landscape of clinical trials.

Hepatocellular carcinoma (HCC) is one of the few cancers with a 5-year survival that has remained below 20%; however, prognosis differs by tumor stage at diagnosis. Curative treatment options among patients with early-stage HCC afford a median survival of 5-10 years. Accordingly, international society guidelines recommend semi-annual HCC surveillance in at-risk patients, including those with cirrhosis or high-risk chronic hepatitis B infection. Surveillance is associated with increased early-stage HCC detection and curative treatments, leading to reduced HCC-related mortality. Abdominal ultrasound has been the cornerstone for HCC surveillance for the past two decades, but recent data have highlighted its suboptimal sensitivity for early-stage HCC detection, particularly in patients with obesity and those with non-viral etiologies of liver disease. The combination of ultrasound plus alpha fetoprotein (AFP) has higher sensitivity for early-stage HCC detection than ultrasound alone, although the combination still misses over one-third of HCC at an early stage. Emerging imaging and blood-based biomarker strategies have promising data in biomarker phase 2 (case-control) and phase 3 (cohort) studies. Beyond ultrasound, Magnetic resonance imaging (MRI) is the best-studied imaging strategy, with superior sensitivity and specificity compared to ultrasound in a cohort study. Abbreviated MRI protocols have been proposed to address concerns about MRI radiological capacity, costs, and patient acceptance. Of biomarker strategies, GALAD (a panel including gender, age, AFP, AFP-L3, and DCP) is the best validated, with promising sensitivity for early-stage HCC detection in a national multi-center cohort study. Liquid biopsy biomarkers, including methylated DNA markers, have also shown promising accuracy in case-control studies. Abbreviated MRI and GALAD are now entering prospective trials that examine clinical outcomes such as early-stage HCC detection and screening-related harms, which are essential data to understand for adoption in clinical practice. As additional surveillance strategies become available, it will allow an era of precision surveillance in which optimal surveillance modalities are tailored to individual patient risk and expected test performance.

Higher magnesium intake was linked to a lower risk of hepatocellular carcinoma (HCC). However, the relationship between blood magnesium level and HCC has not been fully characterized, especially among patients with liver cirrhosis who are at a higher risk for HCC.

In the Mass General Brigham Biobank, we developed a new prospective cohort of 1,430 patients with liver cirrhosis without liver cancer history using the validated International Classification of Diseases codes. We used Cox proportional hazards models to generate hazard ratios (HRs) with 95% confidence intervals (CI) for incident HCC and used generalized estimating equations to compare changes in liver biomarkers according to baseline blood magnesium, adjusting for age, sex, race, lifestyles, body mass index, type 2 diabetes, model for end-stage liver disease score, and hepatitis infection.

During a median follow-up period of 4.26 years, 109 patients developed HCC. Magnesium deficiency (<1.70 mg/dL; N = 158) was associated with a higher risk of HCC (HR = 1.93; 95% CI, 1.12-3.30) compared with magnesium sufficiency (≥1.70 mg/dL; N = 1282). This association remained robust in the 1-year lag analysis (HR = 2.18; 95% CI, 1.11-4.28) and in sensitivity analysis excluding patients with alcoholic liver disease (HR = 2.41; 95% CI, 1.23-4.74). Magnesium in the lowest quartile was associated with a faster increase in alanine transaminase (β = 4.35; 95% CI, 1.06-7.63), aspartate aminotransferase (β = 6.46; 95% CI, 0.28-12.6), direct bilirubin (β = 0.18; 95% CI, 0.01-0.35), and total bilirubin (β = 0.21; 95% CI, 0.03-0.39), compared with the highest quartile.

Lower blood magnesium level is associated with higher HCC risk and unfavorable liver biomarker changes.

If confirmed, our findings may potentially enable better identification of high-risk patients for HCC and inform better management strategies for liver cirrhosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

The diagnosis of hepatocellular carcinoma (HCC) often experiences latency, ultimately leading to unfavorable patient outcomes due to delayed therapeutic interventions. Our study is designed to develop and validate a model that employs triple-phase computerized tomography (CT)-based deep learning radiomics and clinical variables for early warning of HCC in patients with cirrhosis.

We studied 1858 patients with cirrhosis primarily from the PreCar cohort (NCT03588442) between June 2018 and January 2020 at 11 centres, and collected triple-phase CT images and laboratory results 3-12 months prior to HCC diagnosis or non-HCC final follow-up. Using radiomics and deep learning techniques, early warning model was developed in the discovery cohort (n = 924), and then validated in an internal validation cohort (n = 231), and an external validation cohort from 10 external centres (n = 703).

We developed a hybrid model, named ALARM model, which integrates deep learning radiomics with clinical variables, enabling early warning of the majority of HCC cases. The ALARM model effectively predicted short-term HCC development in cirrhotic patients with area under the curve (AUC) of 0.929 (95% confidence interval 0.918-0.941) in the discovery cohort, 0.902 (0.818-0.987) in the internal validation cohort, and 0.918 (0.898-0.961) in the external validation cohort. By applying optimal thresholds of 0.21 and 0.65, the high-risk (n = 221, 11.9%) and medium-risk (n = 433, 23.3%) groups, which covered 94.4% (84/89) of the patients who developed HCC, had significantly higher rates of HCC occurrence compared to the low-risk group (n = 1204, 64.8%) (24.3% vs 6.4% vs 0.42%, P < 0.001). Furthermore, ALARM also demonstrated consistent performance in subgroup analysis.

The novel ALARM model, based on deep learning radiomics with clinical variables, provides reliable estimates of short-term HCC development for cirrhotic patients, and may have the potential to improve the precision in clinical decision-making and early initiation of HCC treatments.

This work was supported by National Key Research and Development Program of China (2022YFC2303600, 2022YFC2304800), and the National Natural Science Foundation of China (82170610), Guangdong Basic and Applied Basic Research Foundation (2023A1515011211).

Alcohol use leads to disabilities and deaths worldwide. It not only harms the liver but also causes alcohol use disorder (AUD) and heart disease. Additionally, alcohol consumption contributes to health disparities among different socio-economic groups.

We estimated global and regional trends in the burden of AUD, liver disease, and cardiovascular disease from alcohol using the methodology of the Global Burden of Disease study.

In 2019, the highest disability-adjusted life years rate per 100,000 population was due to AUD (207.31 [95% Uncertainty interval (UI) 163.71-261.66]), followed by alcohol-associated liver disease (ALD) (133.31 [95% UI 112.68-156.17]). The prevalence rate decreased for AUD (APC [annual percentage change] -0.38%) and alcohol-induced cardiomyopathy (APC -1.85%) but increased for ALD (APC 0.44%) and liver cancer (APC 0.53%). Although the mortality rate for liver cancer from alcohol increased (APC 0.30%), mortality rates from other diseases decreased. Between 2010 and 2019, the burden of alcohol-associated complications increased in countries with low and low-middle sociodemographic index (SDI), contributing more significantly to the global burden.

The global burden of AUD, liver, and cardiovascular disease has been high and increasing over the past decade, particularly for liver complications. Lower SDI countries are contributing more to this global burden. There is a pressing need for effective strategies to address this escalating burden.

Gamma-glutamyltransferase (GGT) is known as an oxidative stress marker, induced by alcohol consumption and metabolic disorders, and is reported as a predictor of hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) elimination. However, it is not clear whether GGT serves simply as a surrogate marker for overlapping metabolic diseases or reflects HCV-specific carcinogenicity. We investigated the association between GGT and hepatocarcinogenesis after achieving a sustained viral response (SVR), accounting for drinking habits or diabetes, and examined predisposing factors associated with GGT levels after SVR.

This is a prospective, multicenter, and observational study using the database of 1001 patients after HCV eradication with direct-acting antiviral agents. The association of GGT at SVR with cumulative HCC development was examined in a multivariate analysis using Cox proportional hazard models after adjustment for covariates including alcohol and diabetes. The association between oxidative stress markers or genetic factors and GGT levels was analyzed.

High GGT levels at SVR were associated with HCC development (HR] 2.38, 95% CI 1.10-5.17). This association was also significant when restricted to patients without alcohol consumption or diabetes (HR 8.38, 95% CI 2.87-24.47). GGT levels were correlated with serum growth differentiation factor 15 levels, a marker of mitochondrial dysfunction. Single-nucleotide polymorphisms of ZNF827 and GDF15 were associated with high GGT levels.

High GGT levels at SVR were associated with HCC development after accounting for alcohol consumption and diabetes. GGT levels are influenced by genetic predisposition and may reflect mitochondrial dysfunction after HCV eradication.

Hepatocellular carcinoma (HCC) patients with compensated cirrhosis typically face a high prevalence and unfavorable prognosis. However, there is currently a deficiency in prediction models to anticipate the prognosis of these patients. Therefore, our study included the Gamma-glutamyl transpeptidase-to-platelet ratio (GPR) in analysis and aimed to develop a nomogram for HCC patients with compensated cirrhosis after local ablation.

Enrolling 669 patients who underwent local ablation at Beijing You'an Hospital during the period from January 1, 2014, to December 31, 2022, this study focused on individuals with compensated cirrhotic HCC. In a ratio of 7:3, patients were allocated to the training cohort (n=468) and the validation cohort (n=201). Lasso-Cox regression was employed to identify independent prognostic factors for overall survival (OS). Subsequently, a nomogram was constructed using these factors and was validated through receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).

GPR, age, and hemoglobin were identified by Lasso-Cox regression as independent prognostic factors of the nomogram. The area under the ROC curves (AUCs) for 3-, 5-, and 8-year OS (0.701, 0.755, and 0.768 for the training cohort; 0.684, 0.707, and 0.778 for the validation cohort), and C-indices (0.695 for training cohort; 0.679 for validation cohort) exhibited the excellent predictive ability of the nomogram. Calibration curves and DCA curves indicated favorable calibration performance and clinical utility. Patients were further stratified into two risk groups according to the median nomogram score. There existed an obvious distinction between the two groups both in the training cohort and validation cohort.

In summary, this research established and validated a novel nomogram to predict OS, which had good predictive power for HCC patients with compensated cirrhosis after local ablation.

In the US, hepatocellular carcinoma (HCC) has been the most rapidly increasing cancer since 1980, and metabolic dysfunction-associated steatotic liver disease (MASLD) is expected to soon become the leading cause of HCC.

To develop a prediction model for HCC incidence in a cohort of patients with MASLD.

This prognostic study was conducted among patients aged at least 18 years with MASLD, identified using diagnosis of MASLD using International Classification of Diseases, Ninth Revision (ICD-9) or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes; natural language processing of radiology imaging report text, which identified patients who had imaging evidence of MASLD but had not been formally diagnosed; or the Dallas Steatosis Index, a risk equation that identifies individuals likely to have MASLD with good precision. Patients were enrolled from Kaiser Permanente Northern California, an integrated health delivery system with more than 4.6 million members, with study entry between January 2009 and December 2018, and follow-up until HCC development, death, or study termination on September 30, 2021. Statistical analysis was performed during February 2023 and January 2024.

Data were extracted from the electronic health record and included 18 routinely measured factors associated with MASLD.

The cohort was split (70:30) into derivation and internal validation sets; extreme gradient boosting was used to model HCC incidence. HCC risk was divided into 3 categories, with the cumulative estimated probability of HCC 0.05% or less classified as low risk; 0.05% to 0.09%, medium risk; and 0.1% or greater, high risk.

A total of 1 811 461 patients (median age [IQR] at baseline, 52 [41-63] years; 982 300 [54.2%] female) participated in the study. During a median (range) follow-up of 9.3 (5.8-12.4) years, 946 patients developed HCC, for an incidence rate of 0.065 per 1000 person-years. The model achieved an area under the curve of 0.899 (95% CI, 0.882-0.916) in the validation set. At the medium-risk threshold, the model had a sensitivity of 87.5%, specificity of 81.4%, and a number needed to screen of 406. At the high-risk threshold, the model had a sensitivity of 78.4%, a specificity of 90.1%, and a number needed to screen of 241.

This prognostic study of more than 1.8 million patients with MASLD used electronic health record data to develop a prediction model to discriminate between individuals with and without incident HCC with good precision. This model could serve as a starting point to identify patients with MASLD who may need intervention and/or HCC surveillance.

Liver cirrhosis due to nonalcoholic steatohepatitis (NASH) is a life-threatening condition with increasing incidence world-wide. Although its symptoms are unspecific, it can lead to decompensation events such as ascites, hepatic encephalopathy, variceal hemorrhage, and hepatocellular carcinoma (HCC). In addition, an increased risk for cardiovascular events has been demonstrated in patients with NASH. Pharmacological treatments for NASH cirrhosis are not yet available, one of the reasons being the lack in surrogate endpoints available in clinical trials of NASH cirrhosis. The feasibility of non-invasive prognostic biomarkers makes them interesting candidates as possible surrogate endpoints if their change following treatment would result in better outcomes for patients in future clinical trials of NASH cirrhosis. In this systematic literature review, a summary of the available literature on the prognostic performance of non-invasive biomarkers in terms of cardiovascular events, liver-related events, and mortality is outlined. Due to the scarcity of data specific for NASH cirrhosis, this review includes studies on NAFLD whose evaluation focuses on cirrhosis. Our search strategy identified the following non-invasive biomarkers with prognostic value in studies of NASH patients: NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI), enhanced liver fibrosis (ELF™), BARD (BMI, AST/ALT (alanine aminotransferase) ratio, diabetes), Hepamet Fibrosis Score (HFS), liver enzymes (AST + ALT), alpha-fetoprotein, platelet count, neutrophil to lymphocyte ratio (NLR), Lysyl oxidase-like (LOXL) 2, miR-122, liver stiffness, MEFIB (liver stiffness measured with magnetic resonance elastography (MRE) + FIB-4), and PNPLA3 GG genotype. The aim of the present systematic literature review is to provide the reader with a summary of the non-invasive biomarkers with prognostic value in NASH cirrhosis and give an evaluation of their utility as treatment monitoring biomarkers in future clinical trials.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver disease. Its prevalence is increasing with the epidemic of obesity and metabolic syndrome. MASLD progression into metabolic dysfunction-associated steatohepatitis (MASH) and advanced fibrosis may lead to decompensated cirrhosis and development of liver-related events, hepatocellular carcinoma and death. Monitoring disease progression is critical in decreasing morbidity, mortality, need for transplant and economic burden. Assessing for treatment response once FDA-approved medications are available is still an unmet clinical need.

To explore the most up-to-date literature on testing used for monitoring disease progression and treatment response METHODS: We searched PubMed from inception to 15 August 2023, using the following MeSH terms: 'MASLD', 'Metabolic dysfunction-associated steatotic liver disease', 'MASH', 'metabolic dysfunction-associated steatohepatitis', 'Non-Alcoholic Fatty Liver Disease', 'NAFLD', 'non-alcoholic steatohepatitis', 'NASH', 'Biomarkers', 'clinical trial'. Articles were also identified through searches of the authors' files. The final reference list was generated based on originality and relevance to this review's broad scope, considering only papers published in English.

We have cited 101 references in this review detailing methods to monitor MASLD disease progression and treatment response.

Various biomarkers can be used in different care settings to monitor disease progression. Further research is needed to validate noninvasive tests more effectively.

Microvascular invasion (MVI) is a significant pathological feature in hepatocellular carcinoma (HCC), adjuvant hepatic arterial infusion chemotherapy (a-HAIC) and adjuvant transcatheter arterial chemoembolization (a-TACE), are commonly used for HCC patients with MVI. This study aims to evaluate the efficacies of two adjuvant therapies after surgical treatment for HCC, compare them, and identify the significant factors.

Clinical data from two randomized controlled trials involving HCC patients with MVI after surgical treatment were retrospectively reviewed. Propensity score matching (PSM) analysis was performed to balance baseline differences between patients who received a-HAIC or a-TACE, and control groups who underwent hepatectomy alone. Disease-free survival (DFS) and overall survival (OS) rates were compared.

In total of 549 patients were collected from two randomized controlled trials. Using the PSM and Kaplan-Meier method, the median DFS of the a-HAIC, a-TACE, and control groups was 63.2, 21.7, and 11.2 months (P<0.05). The a-HAIC group show significantly better 1-, 3-, and 5-year OS rates compared to the a-TACE and control groups (96.3%, 80.0%, 72.8% vs 84.4%, 57.0%, 29.8% vs 84.5%, 62.8%, 53.4%, P<0.05). But the OS rates of a-TACE and control groups showed no significant difference (P=0.279). Multivariate analysis identified a-HAIC (HR=0.449, P=0.000) and a-TACE (HR=0.633, P=0.007) as independent protective factors. For OS, a-HAIC (HR=0.388, P=0.003) was identified as an independent protective factor, too.

Compared to a-TACE and the control group, a-HAIC demonstrated greater benefits in preventing tumor recurrence and improving survival in HCC patients with MVI.

Diabetes mellitus (DM) is a disease that affects millions of individuals worldwide and is characterized by abnormal glucose metabolism that can induce severe damage to numerous organs throughout the body. Sex differences have been demonstrated in a number of factors associated with diabetes and its complications, such as diabetic kidney disease and diabetic liver disease. To investigate the sex differences in DM further, the changes in the weight, food and water intake, and blood sugar of mice were recorded for 8 weeks in the present study. Hematoxylin and eosin staining, Masson's trichrome staining and transmission electron microscopy were used to observe the pathological changes of liver and kidney tissues. There is no significant difference in the water intake and blood glucose concentration between db/db female and male mice was observed. However, sex differences in liver and kidney damage including glomerular injury and hepatic fibrosis were found. In conclusion, the present study characterized the features of liver and kidney damage in db/db mice and indicated that sex differences should be taken into account in experiments using female and male experimental animals. Furthermore, sex differences should be taken into account in the selection of drug interventions in experiments and in clinical drug therapy.

The prevalence of metabolic-associated fatty liver disease (MAFLD) is increasing globally due to factors such as urbanization, obesity, poor nutrition, sedentary lifestyles, healthcare accessibility, diagnostic advancements, and genetic influences. Research on MAFLD and HCC risk factors, pathogenesis, and biomarkers has been conducted through a narrative review of relevant studies, with a focus on PubMed and Web of Science databases and exclusion criteria based on article availability and language. Steatosis marks the early stage of MASH advancement, commonly associated with factors of metabolic syndrome such as obesity and type 2 diabetes. Various mechanisms, including heightened lipolysis, hepatic lipogenesis, and consumption of high-calorie diets, contribute to the accumulation of lipids in the liver. Insulin resistance is pivotal in the development of steatosis, as it leads to the release of free fatty acids from adipose tissue. Natural compounds hold promise in regulating lipid metabolism and inflammation to combat these conditions. Liver fibrosis serves as a significant predictor of MASH progression and HCC development, underscoring the need to target fibrosis in treatment approaches. Risk factors for MASH-associated HCC encompass advanced liver fibrosis, older age, male gender, metabolic syndrome, genetic predispositions, and dietary habits, emphasizing the requirement for efficient surveillance and diagnostic measures. Considering these factors, it is important for further studies to determine the biochemical impact of these risk factors in order to establish targeted therapies that can prevent the development of HCC or reduce progression of MASH, indirectly decreasing the risk of HCC.

The existing hepatocellular carcinoma (HCC) risk scores have modest accuracy, and most are specific to chronic hepatitis B infection. In this study, we developed and validated a liver stiffness-based machine learning algorithm (ML) for prediction and risk stratification of HCC in various chronic liver diseases (CLDs).

MLs were trained for prediction of HCC in 5155 adult patients with various CLDs in Korea and further tested in 2 prospective cohorts from Hong Kong (HK) (N = 2732) and Europe (N = 2384). Model performance was assessed according to Harrell's C-index and time-dependent receiver operating characteristic (ROC) curve.

We developed the SMART-HCC score, a liver stiffness-based ML HCC risk score, with liver stiffness measurement ranked as the most important among 9 clinical features. The Harrell's C-index of the SMART-HCC score in HK and Europe validation cohorts were 0.89 (95% confidence interval, 0.85-0.92) and 0.91 (95% confidence interval, 0.87-0.95), respectively. The area under ROC curves of the SMART-HCC score for HCC in 5 years was ≥0.89 in both validation cohorts. The performance of SMART-HCC score was significantly better than existing HCC risk scores including aMAP score, Toronto HCC risk index, and 7 hepatitis B-related risk scores. Using dual cutoffs of 0.043 and 0.080, the annual HCC incidence was 0.09%-0.11% for low-risk group and 2.54%-4.64% for high-risk group in the HK and Europe validation cohorts.

The SMART-HCC score is a useful machine learning-based tool for clinicians to stratify HCC risk in patients with CLDs.

Although non-alcoholic fatty liver disease (NAFLD) is becoming a leading cause of hepatocellular carcinoma (HCC), HCC risk in non-cirrhotic NAFLD received little attention. We aimed to develop and validate an HCC risk prediction model for non-cirrhotic NAFLD.

A nationwide cohort of non-cirrhotic NAFLD patients in Korea was recruited to develop a risk prediction model and validate it internally (n = 409 088). A model using a simplified point system was developed by Cox proportional hazard model. K-fold cross-validation assessed the accuracy, discrimination and calibration. The model was validated externally using a hospital cohort from Asan Medical Center (n = 8721).

An 11-point HCC risk prediction model for non-cirrhotic NAFLD was developed using six independent factors of age, sex, diabetes, obesity, serum alanine aminotransferase level and gamma-glutamyl transferase level (c-index 0.75). The average area under receiver operating curves (AUROCs) of the model was 0.72 at 5 years and 0.75 at 10 years. In the external validation cohort, the AUROCs were 0.79 [95% confidence interval [CI], 0.59-0.95] at 5 years and 0.84 (95% CI, 0.73-0.94) at 10 years. The calibration plots showed the expected risks corresponded well with the observed risks. Risk stratification categorized patients into the low (score 0-6), moderate (7, 8) and high (9-11; estimated incidence rate >0.2%/year) risk groups.

A novel HCC risk prediction model for non-cirrhotic NAFLD patients was developed and validated with fair performance. The model is expected to serve as a simple and reliable tool to assess HCC risk and assist precision screening of HCC.

The surveillance of hepatocellular carcinoma (HCC) using semi-annual liver ultrasound (US) is justified in patients with cirrhosis. In this context, US has a low sensitivity (<30%) for the detection of HCC at the very early stage (ie, Barcelona clinic liver cancer (BCLC) 0, uninodular tumour <2 cm). The sensitivity of abbreviated liver MRI (AMRI) is reported to exceed 80%, but its use is hampered by costs and availability. Our hypothesis is that AMRI used as a screening examination in patients at high risk of HCC (>3% per year) could increase the rates of patients with a tumour detected at an early stage accessible to curative-intent treatment, and demonstrate its cost-effectiveness in this population.

The FASTRAK trial is a multicentre, randomised controlled trial with two parallel arms, aiming for superiority and conducted on patients at high risk for HCC (yearly HCC incidence >3%). Randomisation will be conducted on an individual basis with a centralised approach and stratification by centre. After inclusion in the trial, each patient will be randomly assigned to the experimental group (semi-annual US and AMRI) or the control group (semi-annual US alone). The main objective is to assess the cost/quality-adjusted life year and cost/patient detected with a BCLC 0 HCC in both arms. A total of 944 patients will be recruited in 37 tertiary French centres during a 36-month period and will be followed-up during 36 months.

The FASTRAK trial received ethical approval on 4 April 2022. Results will be disseminated via publication in peer-reviewed journals as well as presentation at international conferences.

Clinical trial number (ClinicaTrials.gov) NCT05095714.

Liver cancer is globally the third leading cause of death from cancer. Hepatocellular carcinoma (HCC) develops in patients with underlying liver disease. The fraction of HCC attributed to nonalcoholic fatty liver disease (NAFLD) shows an accelerated increase in the last decades, being already responsible for 15% of all HCC cases. Similar to other causes of liver cirrhosis, patients with NAFLD-associated cirrhosis should be enrolled in HCC-screening programs, yet these patients are under-screened, and currently are less than half likely to be proposed for HCC screening as compared to patients with HCV-associated cirrhosis. NAFLD-associated HCC has the peculiarity of occurring in precirrhotic phases in 20-50% of the cases. Currently, HCC screening in precirrhotic NAFLD patients is not routinely recommended, since the risk of developing HCC is very low. However, because NAFLD affects one-third of the worldwide population, noncirrhotic NAFLD already accounts for 6% of HCC cases. As such, it is pressing to develop stratification tools, in order to personalize the individual risk of HCC development in a patient with NAFLD, allowing precision HCC-screening programs. This review summarizes the epidemiology of NAFLD-associated HCC with a critical analysis of current HCC-screening recommendations.

Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease (NAFLD)) represents a rapidly increasing cause of chronic liver disease and hepatocellular carcinoma (HCC), mirroring increasing rates of obesity and metabolic syndrome in the Western world. MASLD-HCC can develop at an earlier stage of fibrosis compared to other causes of chronic liver disease, presenting challenges in how to risk-stratify patients to set up effective screening programmes. Therapeutic decision making for MASLD-HCC is also complicated by medical comorbidities and disease presentation at a later stage. The response to treatment, particularly immune checkpoint inhibitors, may vary by the aetiology of the disease, and, in the future, patient stratification will be key to optimizing the therapeutic pathways.

The value of HCC surveillance is determined by the balance between benefits and harms; however, no studies have enumerated psychological harms.

We fielded surveys measuring psychological harms to patients with cirrhosis in a multicenter randomized trial of HCC surveillance outreach. All patients with positive or indeterminate surveillance results and matched patients with negative results were invited to complete surveys measuring (1) depression through the Patient Health Questionnaire-ninth version, (2) anxiety through State-Trait Anxiety Inventory, (3) HCC-specific worry through Psychological Consequences Questionnaire, and (4) decisional regret. Patients were classified into 4 groups: true positive (TP), false positive (FP), indeterminate, and true negative (TN). Multivariable longitudinal regression analysis using the generalized estimating equation method was performed to compare the means of measures across groups. We conducted 89 semistructured interviews in a subset of patients stratified by health system and test results. Of 2872 patients in the trial, 311 completed 1+ follow-up survey (63 FP, 77 indeterminate, 38 TP, and 133 TN). Moderate depression decreased in TN patients, increased in TP, and had intermittent but mild increases in those with FP and indeterminate results. High anxiety temporarily increased in patients with TP results but resolved over time and was stable in those with FP and indeterminate results. Decisional regret was low and did not differ across groups. In semistructured interviews, patients reported apprehension, anxiety, emotional distress, and coping related to HCC surveillance.

Psychological harms of HCC surveillance appear mild but differ by test result. Future research should determine the impact of psychological harms on the value of HCC surveillance programs.

Hepatocellular carcinoma (HCC) surveillance is recommended by professional society guidelines given a consistent association with reduced HCC-related mortality. HCC surveillance should be performed using semiannual abdominal ultrasound and alpha-fetoprotein, although this combination has suboptimal sensitivity and can miss more than one-third of HCC at an early stage. There are promising emerging blood-based and imaging-based strategies, including abbreviated MRI and biomarker panels; however, these require further validation before routine use in clinical practice. HCC surveillance is underused in clinical practice due to patient-related and provider-related barriers, highlighting a need for interventions to improve surveillance utilization in clinical practice.

During fibrosis, (myo)fibroblasts deposit large amounts of extracellular matrix proteins, thereby replacing healthy functional tissue. In liver fibrosis, this leads to the loss of hepatocyte function, portal hypertension, variceal bleeding, and increased susceptibility to infection. At an early stage, liver fibrosis is a dynamic and reversible process, however, from the cirrhotic stage, there is significant progression to hepatocellular carcinoma. Both liver-resident macrophages (Kupffer cells) and monocyte-derived macrophages are important drivers of fibrosis progression, but can also induce its regression once triggers of chronic inflammation are eliminated. In liver cancer, they are attracted to the tumor site to become tumor-associated macrophages (TAMs) polarized towards a M2- anti-inflammatory/tumor-promoting phenotype. Besides their role in thrombosis and hemostasis, platelets can also stimulate fibrosis and tumor development by secreting profibrogenic factors and regulating the innate immune response, e.g., by interacting with monocytes and macrophages. Here, we review recent literature on the role of macrophages and platelets and their interplay in liver fibrosis and hepatocellular carcinoma.