Hepatocellular carcinoma (HCC) is the sixth most common cause of cancer globally, third most common cause of cancer-related death, and most common primary liver malignancy. Whilst nodular well-defined HCC remains the classical phenotype, presentations with infiltrative phenotype, very large HCC, and complications as tumour rupture provide immense diagnostic and therapeutic challenges. Infiltrative HCC is difficult to distinguish against the background cirrhotic liver. They are ill defined on imaging, have poor vascularity, and aggressive biological behaviour. Vascular invasion, metastasis, and poor response to loco-regional, as well as systemic therapy, leads to dismal prognosis. Very large HCCs have a relatively better prognosis than infiltrative HCC and mandate multimodal therapies to downstage for a curative response including liver transplant. Improvement in interventional radiology techniques, emerging evidence with systemic therapies including immunotherapy, and better understanding of tumour biology have opened newer avenues in the management of such complex cases. HCC rupture is a catastrophic moment in the natural history of HCC which has an exponential increase in mortality. Clinical presentation of pain abdomen, hypotension/syncope, new onset, or sudden increase in ascites mandates a strong suspicion of rupture. Presence of hemoperitoneum on diagnostic tap and contrast extravasation in a computed tomography/magnetic resonance imaging are the diagnostic hallmarks. Emergency surgical intervention, locoregional therapies in the form of bland embolisation, or chemoembolisation forms the management cornerstone. The long-term survival and liver transplant as a curative therapy still needs more data as fear of tumour spread is a possibility. This review summarises the clinical challenges with this advance HCC and provides an algorithmic approach for management.

Targeting cholesterol metabolism is a novel direction for tumor therapy. Unfortunately, the current use of statins for hepatocellular carcinoma (HCC) is controversial. Herein, farnesyl-diphosphate farnesyltransferase 1 (FDFT1) is identified as a novel target for treating HCC and a potential alternative to statins. Twenty-three key genes in cholesterol biosynthesis are screened, and FDFT1 is identified via public databases (The Cancer Genome Atlas, International Cancer Genome Consortium and Gene Expression Omnibus). Clinical samples reveal that FDFT1 is highly expressed in HCC tissues, and this phenotype is strongly associated with a poor prognosis. Functionally, FDFT1 knockdown inhibits the proliferation and metastasis of HCC cells and suppresses hepatocarcinogenesis in vitro and in vivo, whereas FDFT1 overexpression promotes HCC cell proliferation and metastasis. Mechanistically, FDFT1 downregulation decreases cholesterol and bile acid levels and then increases hepatocyte nuclear factor 4 alpha (HNF4A) transcriptional activity. Experiments indicate that HNF4A combines with the promoter of aldolase B (ALDOB) and promotes the ALDOB transcription and that ALDOB combines with AKT serine/threonine kinase 1 (AKT1) and inhibits AKT1 phosphorylation. Moreover, FDFT1 knockdown combined with AKT inhibitor (AZD5363) treatment shows remarkable therapeutic potential. FDFT1 inhibition reduces cholesterol and bile acid levels to delay HCC progression through the HNF4A/ALDOB/AKT1 axis. Thus, targeting FDFT1 may be a novel potential strategy for treating HCC.

Recent studies have utilized time-restricted feeding (16/8) (TRF) and dietary approaches to stop hypertension separately to manage metabolic-associated fatty liver disease (MAFLD); however, the effectiveness of combining these two approaches has not been investigated. The objective of this study was to examine the impact of TRF in conjunction with a DASH diet on various factors related to MAFLD. A 12-week randomized controlled trial was conducted to assess the impact of TRF (16/8), along with a DASH diet, compared with a control diet based on standard meal distribution, in patients with MAFLD. An investigation was conducted to examine alterations in anthropometric indices, as well as liver parameters, serum metabolic indices, and an inflammatory marker. The TRF plus DASH diet reduced body mass index (p = 0.03), abdominal circumference (p = 0.005), controlled attenuation parameter (CAP) (p < 0.001), alanine aminotransferase (p = 0.039), and aspartate aminotransferase (0.047) compared to the control group. The levels of insulin and homeostasis model assessment of insulin resistance reduced in both groups significantly (P < 0.05). In MAFLD patients, TRF (16/8) in combination with a DASH diet is superior to a low-calorie diet in promoting obesity indices, and hepatic steatosis and fibrosis. Further long-term investigations are needed to draw definitive conclusions.

NASH-associated liver cancer (NALC) is a significant contributor to global cancer mortality, closely linked to the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). This study comprehensively examines the global burden of NALC from 1990 to 2021.

This study used data from the Global Burden of Disease (GBD) 2021 database to analyze NALC death and age-standardized death rates (ASDR) globally and regionally from 1990 to 2021. We applied Joinpoint regression analysis to assess temporal trends, calculating the annual percent change (APC) and average annual percent change (AAPC). Decomposition analysis was performed to break down mortality changes into contributions from population aging, growth, and epidemiological changes. A frontier analysis was used to evaluate the relationship between NALC burden and sociodemographic development using the Socio-Demographic Index (SDI). Prediction analysis of NALC deaths and ASDR from 2021 to 2045 were estimated using the Nordpred model.

From 1990 to 2021, the global burden of NALC deaths increased significantly, with the ASDR rising from 0.38 per 100,000 in 1990 to 0.48 per 100,000 in 2021. Age-specific data in 2021 revealed that NALC deaths peaked in the 65-69 age group for men and 70-74 age group for women. Decomposition analysis indicated that population growth was the most significant contributor to the global NALC death toll, followed by population aging and epidemiological changes. Frontier analysis showed that countries like Mongolia and Gambia were farthest from the disease burden frontier, while Morocco and Ukraine were closest. Prediction analysis suggest a significant increase in NALC deaths by 2045 compared to 2021, with a larger rise in deaths among women.

Through this study, a data-driven approach is provided to reduce the global disease burden of NALC. Essential data support for public health prevention strategies is offered, helping guide the development of targeted government interventions. Trends across global regions, countries, age groups, and genders have been analyzed, providing valuable insights for the formulation of evidence-based policies aimed at mitigating the impact of NALC worldwide.

The term metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed based on a redefinition of the nonalcoholic fatty liver disease (NAFLD) criteria. Our study aimed to address the knowledge gap by comparing the diagnostic accuracy of MAFLD and NAFLD criteria in identifying significant fibrosis among patients with hepatic steatosis. A cross-sectional study was conducted on 2626 patients with hepatic steatosis treated at Beijing Ditan Hospital between January 2009 and December 2022. Patients with viral hepatitis were excluded. Significant fibrosis was defined as a Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) score F ≥ 2. MAFLD and NAFLD were diagnosed in 478 and 428 patients, respectively. Clinicopathological characteristics were compared between the MAFLD+ NAFLD- group (patients who met the criteria for MAFLD but not NAFLD) and MAFLD- NAFLD+ group (patients who met the criteria for NAFLD but not MAFLD). A total of 743 patients with histologically verified hepatic steatosis were analyzed. The MAFLD+ NAFLD- group comprised 163 (21.9%) and the MAFLD- NAFLD+ group comprised 113 (15.2%) patients. Patients in the MAFLD+ NAFLD- group were older and more likely to be male and had higher body mass index and liver stiffness levels than those in the MAFLD- NAFLD+ group. The prevalence of significant fibrosis was higher in the MAFLD+ NAFLD- group than in the MAFLD- NAFLD+ group (43.6% vs 15.9%, P < .001). The MAFLD criteria may be a better indicator of fibrosis than the NAFLD criteria. Fibrosis in patients with MAFLD can be determined by metabolic disorders, not excessive alcohol consumption.

Liver transplantation for hepatocellular carcinoma (HCC) in metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly being diagnosed and predicted to rise further. We compared outcomes of transplantation for MASLD-related HCC versus other etiologies (OE).

Databases were searched to identify studies comparing outcomes after transplantation MASLD-related HCC with OE-related HCC. Study data were pooled using random-effects modelling. Survival outcomes were analyzed using hazard ratio (HR) for overall survival (OS) and odds ratio (OR) for 1-,3-, and 5-years OS and disease-free survival (DFS).

Ten retrospective comparative studies were identified including a total number of 51'761 patients (MASLD-related HCC=6'793, OE-related HCC=44'968). There were no significant differences in time-to-even survival (HR:0.93, CI95 % 0.81-1.07,p = 0.29), 1-year (87.6% vs 88 %;OR:1.15; CI95 %0.73-1.79,p = 0.55), 3-year (77.2% vs 76 %;OR:1.36;CI95 %0.96-1.94,p = 0.08), or 5-year (67.7% vs 66.3 %;OR:1.08; CI95 %0.77-1.53,p = 0.65) OS rates between the groups. DFS was comparable at 1-year (87.9% vs. 87 %; OR:1.07,p = 0.62), 3-years (77.6% vs. 73.6 %;OR:1.66,p = 0.13) and 5-year (68% vs. 65.6 %;OR:1.37,p = 0.39).

This meta-analysis of the best available evidence (Level 2a) demonstrated that liver transplantation for MASLD-related and OE-related HCC has comparable survival outcomes. Given the global rise in MASLD-related HCC as indication for transplantation, larger studies from other continents, including Europe and Asia, are needed to confirm our findings.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of hepatocellular carcinoma (HCC). In this study, we combine metabolomic and gene expression analysis to compare HCC tissues with non-tumoural tissues (NTT).

A non-targeted metabolomic strategy LC-MS was applied to 52 pairs of human MASLD-HCC and NTT separated into 2 groups according to fibrosis severity F0F1-F2 versus F3F4. The expression of genes related to de Novo lipogenesis (DNL) and fatty acid oxidation (FAO) has been analysed by quantitative RT-PCR and/or interrogation of RNA-seq datasets in 259 pairs of tissues (MASLD-HCC vs. VIRUS-HCC).

Metabolomic analysis revealed that acylcarnitines were the main discriminating metabolites according to fibrosis severity when we compared MASLD-HCC-F0F1-F2 versus NTT and MASLD-HCC-F3F4 versus NTT. Based on these metabolomic data, the analysis of a panel of 15 selected genes related to DNL and FAO indicated that there is no difference between the 2 groups of MASLD-HCC. In contrast the same comparative gene analysis according to the aetiology of HCC: MASLD-HCC versus VIRUS-HCC showed that both aetiologies shared the same upregulation of genes involved in DNL. However, five genes involved in FAO (HADHA, CRAT, CPT1, CPT2 and PPARA) are upregulated exclusively in MASLD-HCC. This result indicates that FAO and DNL pathways are simultaneously activated in MASLD-HCC in contrast to VIRUS-HCC.

These results suggest that, the involvement of adaptive metabolic pathways is different depending on the aetiology of HCC. Moreover, the dogma that simultaneous activation of FAO and DNL is incompatible in cancer would not apply to MASLD-HCC.

Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. We aim to explore the clinical outcomes of NASH cirrhosis compared with other etiologies of cirrhosis.

We utilized an EHR-based database (TriNetX) to study the outcomes of NASH cirrhosis. Patients diagnosed with NAFLD or NASH and cirrhosis between January 2016 and December 2019 were identified utilizing appropriate ICD-10-CM codes. The primary outcome was 3-year overall survival. Secondary outcomes were decompensated cirrhosis, hepatocellular carcinoma, and liver transplantation. The Control group was patients with other etiologies of cirrhosis than NASH. Study and control groups were matched for demographic characters and comorbidities using propensity score matching.

We identified 45,063 patients with NASH cirrhosis. The NASH cirrhosis cohort comprised older (61 vs. 59 y) White (78% vs. 64%) women (58% vs. 38%) with more comorbidities (diabetes mellitus, obesity, ischemic heart disease, history of cancer, chronic kidney disease). After propensity score matching, patients with NASH cirrhosis had a better 3-year survival (78% vs. 74%, HR 0.79, 95% CI 0.77-0.82) compared with patients with non-NASH cirrhosis. Hepatocellular carcinoma was diagnosed less commonly in patients with NASH cirrhosis (6.7% vs. 10.6%, P <0.001), and liver transplantation was performed more often for NASH cirrhosis compared with non-NASH cirrhosis [Risk ratio 1.13 (1.08-1.18)].

Patients with NASH cirrhosis probably have better 3-year overall survival than other etiologies of cirrhosis. This is an interesting finding, as patients with NASH are older and have more comorbidities. Improved survival can be partly explained by a higher probability of liver transplantation and improvements in cardiovascular outcomes.

Viral hepatitis B and C are the leading causes of hepatocellular carcinoma (HCC). With obesity, metabolic-related disorders are increasingly associated with a higher incidence of nonviral HCC. This study aimed to investigate the characteristics, tumor features, treatment outcomes, and survival of patients with viral versus nonviral HCC.

This multicenter cohort study was conducted at six tertiary care centers. Patients were recruited between February 2007 and June 2022 and follow-up was recorded until death or the study end (July 2023). The patients were divided into viral-related and nonviral HCC groups. We studied baseline patient characteristics, tumor characteristics, treatment, and overall survival (OS).

This study included 2233 patients, 1913 patients with viral and 320 patients with nonviral HCC. Patients with nonviral HCC presented with more advanced Barcelona Clinic Liver Cancer (BCLC) stages (BCLC stage C or D were present in 26.3% and 53.8% of patients with viral and nonviral HCC, respectively) that affected the median OS (19.167 vs. 13.830 months, P-value <0.001 for viral and nonviral HCC, respectively). The OS did not differ between patients with viral and nonviral HCC treated with resection, percutaneous ablation, trans-arterial chemoembolization, or Sorafinib. The independent factors affecting the survival of nonviral HCC were albumin-bilirubin score (hazard ratio = 2.323, 95% confidence interval (CI): 1.696-3.181, P-value <0.001), tumor size (hazard ratio = 1.085, 95% CI: 1.019-1.156, P-value 0.011), and alpha-fetoprotein (hazard ratio = 1.000, 95% CI: 1.000-1.000, P-value 0.042).

Patients with nonviral HCC had higher BMI, worse performance status, BCLC stage, and tumor response than those with viral HCC.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the United States. It is characterized by steatosis in the liver and is potentially reversible. Risk factors include obesity, type 2 mellitus, and other metabolic disorders. Metabolic dysfunction-associated steatohepatitis (MASH), a more severe form of MASLD, puts patients at risk for cirrhosis, liver decompensation, and liver cancer. Diet, exercise, and weight loss are the cornerstones of management. Although only 1 medication has been approved for treatment of MASH, other pharmacotherapies and surgeries that aid weight loss and optimize metabolic risk factors can be used. Early diagnosis and intervention are important to prevent progression to cirrhosis and its complications, including cancer.

Steatotic liver disease (SLD) is an emerging liver disease that has been associated with an increased risk for hepatocellular carcinoma (HCC). The impact of concurrent SLD on the prognosis of HCC remains unknown. This study investigates how concurrent SLD affects the outcomes of patients with HCC undergoing curative radiofrequency ablation (RFA) therapy.

A retrospective analysis of patients with early-stage HCC receiving curative RFA at a tertiary medical center was conducted. Laboratory data and HCC characteristics were recorded and analyzed by a Cox proportional hazards regression model to predict recurrence and all-cause mortality after RFA.

A total of 598 patients with HCC were included between 2005 and 2015, with 139 and 459 classified in SLD and non-SLD groups, respectively. The SLD group exhibited a significantly better liver reserve and a lower cumulative incidence of HCC recurrence and liver-related and all-cause mortality after a median follow-up of 51 months. After adjusting for metabolic dysfunction, liver reserve, and HCC characteristics, the presence of SLD reduced all-cause mortality (adjusted hazard ratio [aHR], 0.67; 95% confidence interval [CI], 0.45-0.996; p = .048), which was supported by inverse probability weighting analysis (aHR, 0.65; 95% CI, 0.42-1.00; p = .049). Poor liver functional reserve (high albumin-bilirubin grades) increased all-cause mortality dose dependently. Barcelona Clinic Liver Cancer staging and a higher Fibrosis-4 index were predictors for HCC recurrence, whereas SLD was not.

Among patients with HCC undergoing curative RFA, those with concurrent SLD had a lower risk of all-cause mortality compared to those with poor liver functional reserve.

The present research demonstrated that patients with both liver cancer and steatotic liver disease who received curative radiofrequency ablation for liver cancer survived longer compared to those without steatotic liver disease. Maintaining good liver function is an important prognostic factor for survival.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease with a significant risk of developing hepatocellular carcinoma (HCC). Recent clinical evidence indicates the potential benefits of statins in cancer chemoprevention and therapeutics. However, it is still unclear if these drugs can lower the specific risk of HCC among patients with MASLD.

To investigate the impact of statin use on the risk of HCC development in patients with MASLD.

A systematic review and meta-analysis of all the studies was performed that measured the effect of statin use on HCC occurrence in patients with MASLD. The difference in HCC risk between statin users and non-users was calculated among MASLD patients. We also evaluated the risk difference between lipophilic versus hydrophilic statins and the effect of cumulative dose on HCC risk reduction.

A total of four studies consisting of 291684 patients were included. MASLD patients on statin therapy had a 60% lower pooled risk of developing HCC compared to the non-statin group [relative risk (RR) = 0.40, 95%CI: 0.31-0.53, I 2 = 16.5%]. Patients taking lipophilic statins had a reduced risk of HCC (RR = 0.42, 95%CI: 0.28-0.64), whereas those on hydrophilic statins had not shown the risk reduction (RR = 0.57, 95%CI: 0.27-1.20). The higher (> 600) cumulative defined daily doses (cDDD) had a 70% reduced risk of HCC (RR = 0.30, 95%CI: 0.21-0.43). There was a 29% (RR = 0.71, 95%CI: 0.55-0.91) and 43% (RR = 0.57, 95%CI: 0.40-0.82) decreased risk in patients receiving 300-599 cDDD and 30-299 cDDD, respectively.

Statin use lowers the risk of HCC in patients with MASLD. The higher cDDD and lipophilicity of statins correlate with the HCC risk reduction.

Small intestinal bacterial overgrowth (SIBO), characterized by alterations in both the type and quantity of bacteria in the small intestine, leads to impaired intestinal digestion and absorption that can cause a range of clinical symptoms. Recent studies have identified significant changes in the composition of the small intestinal microbiota and metabolomic profiles of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study systematically reviewed and synthesized the available data to explore the association between SIBO and MASLD. Comprehensive literature searches of the Embase, PubMed, Web of Science, Ovid, and Cochrane databases were conducted. Article quality screening was performed using the Newcastle-Ottawa Quality Assessment Scale. Cross-sectional, cohort, and case-control studies were included. A total of 7,200 articles were initially screened, of which 14 were ultimately included for analysis. Individuals with SIBO in both the MASLD and non-MASLD groups were extracted and a chi-square test was performed to calculate the odds ratio (OR) and 95% confidence interval (CI). The I2 index was used to measure heterogeneity. For heterogeneity >50%, a random effects model was used. There was a clear association between SIBO and MASLD (OR = 3.09; 95% CI 2.09-4.59, I 2 = 66%, p < 0.0001). Subgroup analyses by MASLD stage showed that the probability of SIBO positivity increased with MASLD lesion severity. After stratifying by the diagnostic methods for SIBO and MASLD, the meta-analysis results suggest a reduction in inter-group heterogeneity. For the MASLD subgroup diagnosed via liver biopsy, the OR was 4.89. A subgroup analysis of four studies that included intestinal permeability testing revealed an OR of 3.86 (95% CI: 1.80-8.28, I 2 = 9%, p = 0.0005). A meta-regression analyses revealed that both race and regional development level significantly influenced the relationship between SIBO and MASLD (p = 0.010, p = 0.047). In conclusion, this meta-analyses provides strong evidence that SIBO may contribute to the development and progression of MASLD. The strongest associations were observed between lactulose breath testing, gut microbiota culture, liver biopsy diagnosis of MASLD, and SIBO detected through intestinal permeability testing. The primary sources of heterogeneity are race and developed regions.

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=427040.

Angiogenesis is a critical component of neoplastic progression, and inflammatory cells within the tumor microenvironment contribute to neoangiogenesis. Prostate-specific membrane antigen (PSMA) is expressed in the neovasculature of various solid tumors, including hepatocellular carcinoma (HCC). Also, CXCR2 + inflammatory cells, including CD15 + neutrophils, play crucial roles in HCC progression. We evaluated the associations between PSMA expression and CXCR2 + inflammatory cells in HCC by immunohistochemistry (IHC).

CXCR2 expression and its correlation with PSMA, the PSMA/CD34 ratio, immune markers (CD3, CD15, CD68, and CD163), clinical parameters, and oncologic outcomes were evaluated in 76 HCC and background benign liver tissue.

PSMA and the PSMA/CD34 ratio showed a positive correlation with intratumoral CXCR2, but not with intratumoral CD15. Intratumoral CXCR2 + cell count was positively associated with intratumoral CD3, CD15, CD68, and CD163 expression levels. In the benign compartment, CXCR2 was significantly associated with CD15. Metabolic dysfunction-associated steatotic liver disease (MASLD) risk factors and cirrhosis had an opposite effect on CXCR2 + cell count in benign liver tissue. Higher CD15 + cell count in the benign liver was associated with decreased overall survival (OS) and recurrence-free survival (RFS).

In HCC, intratumoral CXCR2 + cell count is associated with PSMA expression. Intratumoral and benign compartments had different CXCR2 + inflammatory cell makeup. The immune microenvironment of HCC appears to differ depending on underlying risk factors. Further investigations are warranted to elucidate PSMA biology and assess the potential utility of CXCR2 IHC in PSMA-targeted theranostics.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise, making it the leading etiology of chronic liver diseases and a prime cause of liver-related mortality. MASLD can progress into steatohepatitis (termed MASH), fibrosis, cirrhosis, and ultimately cancer. MASLD is associated with increased risks of hepatocellular carcinoma (HCC) and also extrahepatic malignancies, which can develop in both cirrhotic and non-cirrhotic patients, emphasizing the importance of identifying patients with MASLD at risk of developing MASLD-associated malignancies. However, the optimal screening, diagnostic, and risk stratification strategies for patients with MASLD at risk of cancer are still under debate. Individuals with MASH-associated cirrhosis are recommended to undergo surveillance for HCC (e.g. by ultrasound and biomarkers) every six months. No specific screening approaches for MASLD-related malignancies in non-cirrhotic cases are established to date. The rapidly developing omics technologies, including genetics, metabolomics, and proteomics, show great potential for discovering non-invasive markers to fulfill this unmet need. This review provides an overview on the incidence and mortality of MASLD-associated malignancies, current strategies for HCC screening, surveillance and diagnosis in patients with MASLD, and the evolving role of omics technologies in the discovery of non-invasive markers for the prediction and risk stratification of MASLD-associated HCC.

To assess the performance of computed tomography (CT)/magnetic resonance imaging (MRI) Liver Imaging Reporting and Data System (LI-RADS) among patients with non-cirrhotic steatotic liver disease (SLD).

This IRB-approved, retrospective study included 119 observations from 77 adult patients (36 women, 41 men; median 64 years) who underwent liver CT or MRI from 2010 to 2023. All patients had histopathologic evidence of SLD without cirrhosis. Three board-certified abdominal radiologists blinded to tissue diagnosis and imaging follow-up assessed observations with LI-RADS. The positive predictive value (PPV), sensitivity, specificity, accuracy, and inter-reader agreement were calculated.

Seventy-five observations (63%) were benign and 44 (37%) were malignant. PPV for hepatocellular carcinoma (HCC) was 0-0% for LR-1, 0-0% for LR-2, 0-7% for LR-3, 11-20% for LR-4, 75-88% for LR-5, 0-8% for LR-M, and 50-75% for LR-TIV. For LR-5 in identifying HCC, sensitivity was 79-83%, specificity was 91-97%, and accuracy was 89-92%. For composite categories of LR-5, LR-M, or LR-TIV in identifying malignancy, sensitivity was 86-89%, specificity was 85-96%, and accuracy was 86-93%. The most common false positives for LR-5 were hepatocellular adenomas. Only 59-65% of HCCs showed non-peripheral washout at CT versus 67-83% at MRI, though nearly all had an enhancing capsule. PPV and accuracy of LR-5 for HCC did not differ by modality. Inter-reader agreement for major features ranged from 0.667 to 0.830 and was 0.766 for the final category.

Despite challenges such as the lower prevalence of non-peripheral washout at CT and overlapping imaging features between HCC and hepatocellular adenomas, LI-RADS may serve as an effective tool in assessing focal liver lesions in SLD.

LI-RADS in non-cirrhotic steatotic liver disease can effectively diagnose hepatocellular carcinoma and malignancy at computed tomography and magnetic resonance imaging, thereby guiding clinical management decisions and expediting patient care pathways.

Performance of LI-RADS is unknown in non-cirrhotic patients with steatotic liver disease. LI-RADS 5 category showed a high pooled specificity of 91-97% for hepatocellular carcinoma. LI-RADS can non-invasively risk stratify focal liver observations in non-cirrhotic patients with steatotic liver disease.

Introduction Although metabolic dysfunction-associated fatty liver disease (MAFLD) is becoming more common in individuals with hepatocellular carcinoma (HCC), it is still unknown how this condition relates to postoperative complications of HCC. While hepatitis B/C virus (HBV/HCV) infection and alcohol use are primary risk factors, MAFLD has emerged as a significant contributor to HCC incidence. Understanding the prognostic impact of MAFLD on HCC outcomes, particularly post-radical resection, is essential. Objective This study aims to evaluate the prognostic significance of MAFLD on postoperative outcomes in HCC patients, following radical hepatectomy, with a focus on gender-specific mortality differences. Methodology A retrospective cohort study was conducted at Pakistan Navy Station Shifa Hospital, Bahria University Medical and Dental College, Karachi, Pakistan. Consecutive HCC patients who underwent radical resection between May 2023 and April 2024 were included. MAFLD was diagnosed based on hepatic steatosis and metabolic dysfunction criteria. Data on demographics, clinical features, and outcomes were collected from electronic medical records. The primary outcome was overall survival (OS), and the secondary outcomes included recurrence-free survival (RFS). Statistical analyses involved multivariate Cox regression and Kaplan-Meier survival curves using IBM SPSS Statistics for Windows, Version 27 (Released 2020; IBM Corp., Armonk, NY, USA). Results MAFLD patients exhibited higher median body mass index (BMI) (25.3 kg/m² vs. 23.5 kg/m², p < 0.001), increased prevalence of type 2 diabetes mellitus (33.0% vs. 12.0%, p = 0.019), greater metabolic dysregulation (63.0% vs. 17.0%, p < 0.001), and elevated alanine aminotransferase (ALT) levels (38.0 IU/L vs. 32.0 IU/L, p = 0.045) compared to non-MAFLD patients. While OS and RFS rates were marginally better in the MAFLD group, differences were not statistically significant (p > 0.05). Notably, MAFLD significantly increased mortality in female HCC patients, but not in males. Significant predictors of progression included Child-Pugh grade B, tumour size, and microvascular invasion. Conclusion MAFLD does not significantly impact OS or RFS following radical resection of HCC. However, MAFLD is associated with increased mortality in female patients, highlighting the need for gender-specific monitoring and management strategies in MAFLD-related HCC cases. Further large-scale studies are required to confirm these findings and elucidate the underlying mechanisms.

Since its introduction in 1980, fatty liver disease (now termed metabolic dysfunction-associated steatotic liver disease [MASLD]) has grown in prevalence significantly, paralleling the rise of obesity worldwide. While MASLD has been the subject of extensive research leading to significant progress in the understanding of its pathophysiology and progression factors, several gaps in knowledge remain. In this pictorial review, the authors present the latest insights into MASLD, covering its recent nomenclature change, spectrum of disease, epidemiology, morbidity, and mortality. The authors also discuss current qualitative and quantitative imaging methods for assessing and monitoring MASLD. Last, they propose six unsolved challenges in MASLD assessment, which they term the proliferation, reproducibility, reporting, needle-in-the-haystack, availability, and knowledge problems. These challenges offer opportunities for the radiology community to proactively contribute to their resolution. The authors conclude with a call to action for the entire radiology community to claim a seat at the table, collaborate with other societies, and commit to advancing the development, validation, dissemination, and accessibility of the imaging technologies required to combat the looming health care crisis of MASLD.

Dietary rhythms have emerged as a relevant variable in the equation relating nutrition and health. Both experimental and epidemiological studies point to potential beneficial effects of adequate fasting intervals between meals on the evolution of chronic diseases associated with aging. Metabolic dysfunction-associated steatotic liver disease (MASLD) is eminently related to diet and unsurprisingly, diet-based approaches are a mainstay in countering its long-term clinical evolution, including the emergence of hepatocellular carcinoma (HCC). We briefly discuss current evidence linking fasting intervals, MASLD, and HCC and propose a working hypothesis to reconcile some of the apparently conflicting results. This hypothesis relates the beneficial effects of time-restricted eating schedules to the quantity and quality of food, and it is easily amenable to testing.

Hepatocellular carcinoma (HCC) is the fastest-rising and fourth most common cause of cancer death worldwide. Liver cirrhosis is the largest underlying risk factor for HCC. Therefore, patients with cirrhosis should have regular ultrasound and biochemical screening to pick up early HCC. Early HCC can be cured; more advanced HCCs have limited treatment options and poor prognosis. Current screening methods are suboptimal with poor sensitivity in picking up early disease. In this study, the investigators aim to recruit people with liver cirrhosis into a Prospective cohort for early detection of liver cancer-the Pearl cohort. The investigators believe that by using state-of-the-art tests we can improve the detection of early HCC.

This is a UK-based prospective, longitudinal, diagnostic, prognostic, multicentre, non-CTIMP study. Aiming to recruit 3000 patients with liver cirrhosis without a HCC diagnosis, the Pearl cohort will be followed actively for 3 years from recruitment and then passively via registry data for ten years thereafter. Blood and urine samples will be taken and information from routine care will be gathered. These will be used to assess novel diagnostic approaches for the detection early HCC and to develop models to identify those most at risk for developing HCC.Participants will be linked to national UK health registries to ensure long-term capture of HCC incidence and other relevant endpoints. Approximately 75 patients are predicted to develop de novo HCC within the 3-year follow up period. After this period, the study teams will obtain data on participants for at least 10 years after the last contact. This cohort will help develop an understanding of the incidence of HCC in a UK population stratified by underlying cirrhosis aetiology.

Ethical approval has been granted by REC and the trial is registered on ClinicalTrials.gov. The results will be published in peer-reviewed journals and presented at relevant meetings.

NCT05541601.

Detailed subgroup incidence rates for steatotic liver disease (SLD)-related hepatocellular carcinoma (HCC) are critical to inform practice and public health interventions but remain sparse. We aimed to fill in this gap.

In a retrospective cohort study of adults with SLD from the United States (US) Merative Marketscan Research Databases (1/2007 to 12/2021), we estimated HCC incidence stratified by sex, age, cirrhosis, diabetes mellitus (DM), and a combination of all these 4 factors. We excluded patients with significant alcohol use and chronic viral hepatitis. We analyzed data from 741,816 patients with SLD (mean age 51.5 ± 12.8 years, 46% male, 14.7% cirrhosis). During a 2,410,166 person-years (PY) follow-up, 1,740 patients developed HCC. The overall HCC incidence yielded 0.72 per 1,000 PY (95% confidence interval [CI, 0.68, 0.75]). The incidence was higher in males (0.95, 95% CI [0.89, 1.01]) compared to females (0.52, 95% CI [0.48, 0.56]) (p < 0.001). For those with cirrhosis, the incidence was significantly higher at 4.29 (95% CI [4.06, 4.51]) compared to those without cirrhosis (0.14, 95% CI [0.13, 0.16]) (p < 0.001). Additionally, the incidence was higher in patients with DM (1.19, 95% CI [1.12, 1.26]) compared to those without DM (0.41, 95% CI [0.38, 0.44]) (p < 0.001). Chronic kidney disease (CKD) was also associated with a higher HCC incidence of 2.20 (95% CI [2.00, 2.41]) compared to those without CKD (0.58, 95% CI [0.55, 0.62]) (p < 0.001). Similarly, individuals with cardiovascular disease (CVD) had a higher HCC incidence of 1.89 (95% CI [1.75, 2.03]) compared to those without CVD (0.51, 95% CI [0.48, 0.54]) (p < 0.001). Finally, the incidence of HCC was significantly higher in patients with non-liver cancer (3.90, 95% CI [3.67, 4.12]) compared to those without other cancers (0.29, 95% CI [0.26, 0.31]) (p < 0.001). On further stratification, HCC incidence incrementally rose by 10-year age intervals, male sex, cirrhosis, and DM, reaching 19.06 (95% CI [16.10, 22.01]) and 8.44 (95% CI [6.78, 10.10]) in males and females, respectively, but only 0.04 for non-diabetic, noncirrhotic aged <40 years patients in both sexes. The main limitation of this methodology is the potential misclassification of the International Classification of Diseases (ICD) codes inherent in claims database studies.

This nationwide study provided robust granular estimates for SLD-related HCC incidence stratified by several key risk factors. In addition to cirrhosis, future surveillance strategies, prevention, public health initiatives, and future research models should also take into account the impact of sex, age, and DM.

Chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), cirrhosis, and hepatocellular carcinoma (HCC), continue to be a global health burden with a rise in incidence and mortality, necessitating a need for the discovery of novel biomarkers for HCC detection. This study aimed to identify novel non-invasive biomarkers for these different liver disease states. We performed untargeted metabolomics in plasma (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 34) and saliva samples (Healthy = 9, NAFLD = 14, Cirrhosis = 10, HCC = 22) to test for significant metabolite associations with each disease state. Additionally, we identified enriched biochemical pathways and analyzed correlations of metabolites between, and within, the two biofluids. We identified two salivary metabolites and 28 plasma metabolites significantly associated with at least one liver disease state. No metabolites were significantly correlated between biofluids, but we did identify numerous metabolites correlated within saliva and plasma, respectively. Pathway analysis revealed significant pathways enriched within plasma metabolites for several disease states. Our work provides a detailed analysis of the altered metabolome at various stages of liver disease while providing some context to altered pathways and relationships between metabolites.

Hepatocellular carcinoma (HCC) typically develops as a consequence of liver cirrhosis, but HCC epidemiology has evolved drastically in recent years. Metabolic dysfunction-associated steatotic liver disease (MASLD), including metabolic dysfunction-associated steatohepatitis, has emerged as the most common chronic liver disease worldwide and a leading cause of HCC. A substantial proportion of MASLD-associated HCC (MASLD-HCC) also can develop in patients without cirrhosis. The specific pathways that trigger carcinogenesis in this context are not elucidated completely, and recommendations for HCC surveillance in MASLD patients are challenging. In the era of precision medicine, it is critical to understand the processes that define the profiles of patients at increased risk of HCC in the MASLD setting, including cardiometabolic risk factors and the molecular targets that could be tackled effectively. Ideally, defining categories that encompass key pathophysiological features, associated with tailored diagnostic and treatment strategies, should facilitate the identification of specific MASLD-HCC phenotypes. In this review, we discuss MASLD-HCC, including its epidemiology and health care burden, the mechanistic data promoting MASLD, metabolic dysfunction-associated steatohepatitis, and MASLD-HCC. Its natural history, prognosis, and treatment are addressed specifically, as the role of metabolic phenotypes of MASLD-HCC as a potential strategy for risk stratification. The challenges in identifying high-risk patients and screening strategies also are discussed, as well as the potential approaches for MASLD-HCC prevention and treatment.

Metabolic dysfunction-associated steatotic liver disease (MASLD)-and its worse form, metabolic-associated steatohepatitis (MASH), characterised by inflammation and liver damage-corresponds to the liver's involvement in metabolic syndrome, which constitutes an economic burden for healthcare systems. However, the biomolecular pathways that contribute to steatotic liver disease are not completely clear. Abnormalities of bone metabolism are frequent in people affected by metabolic liver disease, with reduced bone density and an increased risk of fracture. Receptor activator of NF-κB (RANK), receptor activator of NF-κB ligand (RANKL), and osteoprotegerin(OPG) are critical regulators of bone metabolism, performing pleiotropic effects, and may have potential involvement in metabolic disorders like MASLD, resulting in a topic of great interest and intrigue. This narrative review aims to investigate this potential role and its implications in MASLD development and progression and in hepatocellular carcinoma, which represents its worst complication.

Deaths from the majority of cancers are falling globally, but the incidence and mortality from hepatocellular carcinoma (HCC) is increasing in the United Kingdom and in other Western countries. HCC is a highly fatal cancer, often diagnosed late, with an incidence to mortality ratio that approaches 1. Despite there being a number of treatment options, including those associated with good medium to long-term survival, 5-year survival from HCC in the UK remains below 20%. Sex, ethnicity and deprivation are important demographics for the incidence of, and/or survival from, HCC. These clinical practice guidelines will provide evidence-based advice for the assessment and management of patients with HCC. The clinical and scientific data underpinning the recommendations we make are summarised in detail. Much of the content will have broad relevance, but the treatment algorithms are based on therapies that are available in the UK and have regulatory approval for use in the National Health Service.

The global proportion of hepatocellular carcinoma (HCC) attributable to metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. The MAFLD diagnostic criteria allows objective diagnosis in the presence of steatosis plus defined markers of metabolic dysfunction, irrespective of concurrent liver disease. We aimed to determine the total global prevalence of MAFLD in HCC cohorts (total-MAFLD), including the proportion with MAFLD as their sole liver disease (single-MAFLD), and the proportion of those with concurrent liver disease where MAFLD was a contributary factor (mixed-MAFLD).

This systematic review and meta-analysis included studies systematically ascertaining MAFLD in HCC cohorts, defined using international expert panel criteria including ethnicity-specific BMI cut-offs. A comparison of clinical and tumour characteristics was performed between single-MAFLD, mixed-MAFLD, and non-MAFLD HCC.

22 studies (56,565 individuals with HCC) were included. Total and single-MAFLD HCC prevalence was 48.7% (95% confidence interval [CI] 34.5-63.0%) and 12.4% (95% CI 8.3-17.3%), respectively. In HCC due to chronic hepatitis B, C, and alcohol-related liver disease, mixed-MAFLD prevalence was 40.0% (95% CI 30.2-50.3%), 54.1% (95% CI 40.4-67.6%) and 64.3% (95% CI 52.7-75.0%), respectively. Mixed-MAFLD HCC had significantly higher likelihood of cirrhosis and lower likelihood of metastatic spread compared to single-MAFLD HCC, and a higher platelet count and lower likelihood of macrovascular invasion compared to non-MAFLD HCC.

MAFLD is common as a sole aetiology, but more so as a co-factor in mixed-aetiology HCC, supporting the use of positive diagnostic criteria.

Metabolic syndrome (MS) is a growing epidemic and a risk factor for the development of hepatocellular carcinoma (HCC). This study investigated the long-term outcomes of liver resection (LR) for HCC in patients with MS. Rates, timing, patterns, and treatment of recurrences were investigated, and cancer-specific survivals were assessed.

Between 2001 and 2021, data from 24 clinical centers were collected. Overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival were analyzed as well as recurrence patterns and treatment. The analysis was conducted using a competing-risk framework. The trajectory of the risk of recurrence over time was applied to a competing risk analysis. For post-recurrence survival, death resulting from tumor progression was the primary endpoint, whereas deaths with recurrence relating to other causes were considered as competing events.

In total, 813 patients were included in the study. Median OS was 81.4 months (range 28.1-157.0 months), and recurrence occurred in 48.3% of patients, with a median RFS of 39.8 months (range 15.7-174.7 months). Cause-specific hazard of recurrence showed a first peak 6 months (0.027), and a second peak 24 months (0.021) after surgery. The later the recurrence, the higher the chance of receiving curative intent approaches (p = 0.001). Size >5 cm, multiple tumors, microvascular invasion, and cirrhosis were independent predictors of recurrence showing a cause-specific hazard over time. RFS was associated with death for recurrence (hazard ratio: 0.985, 95% CI: 0.977-0.995; p = 0.002).

Patients with MS undergoing LR for HCC have good long-term survival. Recurrence occurs in 48% of patients with a double-peak incidence and time-specific hazards depending on tumor-related factors and underlying disease. The timing of recurrence significantly impacts survival. Surveillance after resection should be adjusted over time depending on risk factors.

Metabolic syndrome (MS) is a growing epidemic and a significant risk factor for the development of hepatocellular carcinoma (HCC). The present study demonstrated that patients who undergo surgical resection for HCC on MS have a good long-term survival and that recurrence occurs in almost half of the cases with a double peak incidence and time-specific hazards depending on tumor-related factors and underlying liver disease. Also, the timing of recurrence significantly impacts survival. Clinicians should therefore adjust follow-up after surgery accordingly, considering timing of recurrence and specific risk factors. Also, the results of the present study might help design future trials on the use of adjuvant therapy following resection.

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause of mortality. This review examines the role of lipid-lowering therapies in MASLD, with a particular focus on bempedoic acid, a recently approved cholesterol-lowering agent for hypercholesterolemia and high cardiovascular-risk patients. It explores its potential in liver disease by modulating lipid metabolism and inflammatory pathways based on the most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol and fatty acid synthesis while activating AMP-activated protein kinase to suppress gluconeogenesis and lipogenesis. Animal studies indicate its efficacy in reducing hepatic steatosis, inflammation, and fibrosis. Bempedoic acid holds promise as a therapeutic for MASLD, offering dual benefits in lipid metabolism and inflammation. Further clinical trials are required to confirm its efficacy and safety in MASLD patients, potentially addressing the multifaceted nature of this disease.