Search Results (194)

Aflatoxins, particularly aflatoxin B₁ (AFB₁), are among the most potent naturally occurring carcinogens and remain a major food-borne hazard in parts of Asia and Africa. China has generated a uniquely cohesive body of evidence connecting aflatoxin contamination to hepatocellular carcinoma (HCC), especially in settings where chronic hepatitis B virus (HBV) infection is highly prevalent and acts synergistically with aflatoxin exposure. Over five decades, field investigations and laboratory innovations—exemplified by long-term work in Qidong—have assembled a multi-layered causal chain spanning the following: (i) contamination monitoring in staple foods; (ii) quantification of internal dose and biologically effective dose using validated biomarkers (e.g., urinary AFB₁–N⁷–guanine, AFM₁, and serum AFB₁–lysine albumin adducts); (iii) a characteristic molecular fingerprint in tumors and circulation (TP53 R249S); (iv) reversibility demonstrated through randomized intervention trials and policy-driven natural experiments. Chemoprevention and dietary interception studies (e.g., oltipraz, chlorophyllin, and broccoli sprout beverages) showed that enhancing detoxication pathways can lower biomarker burdens in exposed populations. At the population level, a sustained dietary transition from maize to rice, together with strengthened food governance, was accompanied by marked decreases in biomarker distributions and subsequent declines in HCC mortality in endemic regions. Nevertheless, regional heterogeneity, multi-mycotoxin co-exposure, and climate variability are expected to increase exposure volatility and complicate surveillance. Here, we translate and synthesize the Chinese evidence base, highlight biomarker-enabled monitoring and policy evaluation, and propose an integrated “5+1” prevention framework spanning source control, process detoxification, tiered governance, short-course interception, precision follow-up of high-risk individuals, and climate-sensitive early warning along the climate–agriculture–storage–processing–population (CAT–CSPP) chain. Full article

Background: Hepatocellular carcinoma (HCC) poses a significant public health challenge in Australia, with poorer survival observed in non-metropolitan populations. This study investigated whether survival disparities persist between non-metropolitan and metropolitan patients if only those with early-stage HCC treated at metropolitan tertiary referral centres are considered. Methods: We performed a retrospective cohort study across ten Australian tertiary centres involving patients with a new diagnosis of Barcelona Clinic Liver Cancer (BCLC) stage 0 or A, recorded from 1 January 2016 to 31 December 2020. Residential postcodes were entered using the Modified Monash (MM) model to define metropolitan versus non-metropolitan residence. The primary endpoint was adjusted for all-cause mortality. Results: Our study included 854 patients (metropolitan n = 612, and non-metropolitan n = 242) with a median follow-up of 42.6 months. We found no significant survival or mortality differences between the two groups with the unadjusted Kaplan–Meier survival analysis (log-rank test p = 0.612) and with the Cox proportional hazards regression analysis (adjusted HR 0.93, 95% CI 0.64–1.34, p = 0.690). As expected, tumour burden, Child–Pugh Score, and Charlson Comorbidity Index (CCI) were significant predictors of mortality. Conclusions: Our findings suggest that previously observed survival disparities may stem from delayed diagnosis and reduced access to tertiary care in non-metropolitan regions and highlight the need for improved HCC surveillance and referral pathways, particularly for rural and Indigenous communities, to mitigate geographic inequities. Full article

Background: Hepatocellular carcinoma (HCC) is a major global health burden, with poor outcomes largely due to diagnosis at an advanced stage and the limited performance of current surveillance tools. Ultrasound with alpha fetoprotein (AFP) provides insufficient sensitivity for early-stage detection, highlighting the need to better identify the at-risk population. Focus of the review: Many HCC risk scores have been proposed; however, some depend on specialized laboratory data that are not widely available. This review summarizes risk scores that show reliable discrimination and rely on demographic, clinical, or molecular information that can be readily obtained in routine care. Conclusions: Advances in HCC risk scores support the move toward surveillance approaches based on individual risk. These tools can improve risk stratification, increase the likelihood of early detection, and potentially support better outcomes for people who belong to the at-risk population for HCC. Full article

Conventional ultrasound (US) has long been central to hepatocellular carcinoma (HCC) surveillance in cirrhotic patients, due to its low cost, wide availability, non-invasiveness, and adequate sensitivity for detecting small nodules. However, its specificity in distinguishing HCC from other lesions is limited. Contrast-enhanced ultrasound (CEUS) has significantly improved the characterization of nodules first identified on conventional US. Yet, when CEUS is performed using sulfur hexafluoride (SonoVue)—the only contrast agent available in Western countries—assessment remains restricted to a single nodule per examination, and enhanced CT or MRI is still required for full characterization and staging. In clinical settings, such as hepatology, internal medicine, infectious diseases, and surgery, CEUS offers the advantage of immediate availability, enabling rapid characterization of suspicious nodules in cirrhotic livers and facilitating timely therapeutic decisions. Although the introduction of direct-acting antivirals (DAAs) has substantially reduced HCV-related HCC, HCC incidence is increasingly driven by metabolic dysfunction-associated steatohepatitis (MASH). Evidence on surveillance strategies for MASH patients remains limited, and current EASL guidelines recommend monitoring only patients with >F2 fibrosis. Additionally, the effectiveness of US in obese or diabetic/obese populations is under ongoing investigation; abbreviated non-contrast MRI has been proposed as an alternative surveillance tool, but its adoption would entail significant economic implications for healthcare systems. HCC arising from MASH—sometimes even without cirrhosis—exhibits different sonographic and pathological features. Instead of small, hypoechoic nodules, typically seen in HCV-related cirrhosis, clinicians increasingly encounter larger or multiple lesions, often accompanied by macrovascular invasion, limiting access to curative treatments. Furthermore, typical CEUS LI-RADS patterns are less frequently observed. This review summarizes the evolving US findings in the era of MASH-related HCC and underscores the continued importance of US as the primary imaging tool in routine clinical practice. Full article

Chronic hepatitis C virus (HCV) infection remains a major global health burden, responsible for substantial morbidity and mortality despite the advent of curative antiviral therapy. HCV induces hepatic injury and carcinogenesis through direct viral effects, persistent inflammation, oxidative stress, and metabolic disturbance. The introduction of direct-acting antivirals (DAAs) has revolutionized therapy, achieving sustained virologic response rates exceeding 95% and transforming HCV from a chronic, progressive disease into a curable infection. Nevertheless, viral eradication does not fully normalize hepatic or systemic risk. Patients with advanced fibrosis or cirrhosis continue to face an elevated incidence of hepatocellular carcinoma (HCC) and other complications, reinforcing the need for long-term monitoring. This review summarizes current knowledge of the molecular mechanisms underlying HCV-mediated carcinogenesis, the partial restoration of hepatic homeostasis following DAA-induced cure, and the clinical implications for surveillance and management in the post-HCV era. By integrating insights from molecular virology, immunopathogenesis, and clinical hepatology, the review highlights how persistent epigenetic and inflammatory footprints may sustain oncogenic potential even after viral clearance. A comprehensive understanding of these processes is essential for optimizing HCC prevention strategies, guiding surveillance policies, and advancing future therapeutic innovations aimed at complete hepatic recovery. Full article

Background: Abdominal ultrasound is prone to hepatocellular carcinoma (HCC) surveillance failure, particularly in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) or alcohol-associated liver disease (ALD), prompting growing interest in blood-based biomarkers as an alternative strategy. Methods: We conducted a case–control study evaluating two blood-based biomarker panels, GAAD and GALAD, for detection of early-stage HCC (Barcelona Clinic Liver Cancer (BCLC) stage 0 or A) in patients with MASLD or ALD cirrhosis. Blood specimens were collected within 6 months of HCC diagnosis (cases); controls were patients with cirrhosis but without HCC. GAAD and GALAD scores were measured using the Roche Elecsys platform, applying validated cutoffs of 2.57 and 2.47, respectively. Sensitivity and specificity were compared between the panels and versus ultrasound plus alpha fetoprotein (AFP) using McNemar’s chi square test. Results: Of 152 patients (56.6% men), 46.7% had HCC (54.9% BCLC 0/A) and 53.3% had cirrhosis without HCC. GAAD and GALAD each achieved a sensitivity of 87.2% for early-stage HCC, with specificities of 69.1% and 67.9%, respectively. In paired analyses (n = 90), GAAD had higher sensitivity for any-stage HCC (89.5% vs. 68.4%, p = 0.046) but lower specificity (71.8% vs. 93.0%, p = 0.006) than ultrasound plus AFP. GAAD and GALAD demonstrated consistently higher sensitivity than ultrasound plus AFP across subgroups by age, sex, cirrhosis etiology, and Child Pugh class. Conclusion: In this case–control study of patients with non-viral cirrhosis, GAAD and GALAD demonstrated high sensitivity for early-stage HCC. These findings highlight the potential of blood-based biomarkers to improve HCC surveillance in contemporary populations. Full article

Background: Social determinants of health critically impact outcomes along the care continuum of patients with hepatocellular carcinoma (HCC). This systematic review summarizes the effect of socioeconomic status (SES) factors on HCC outcomes in the United States. Methods: Electronic databases were queried for the concepts of “liver cancer”, “health disparities”, and “socioeconomic factors” on 1 March 2021. Eligible studies included an individual- or area-level SES measure such as income, education, employment, and insurance and one of the following outcomes across the clinical continuum of HCC care: incidence, screening/surveillance, diagnosis, treatment, survival, and end-of-life. Results: Of 3331 studies screened, a total of 63 studies encompassing 179 separate analyses were included in our narrative synthesis: 13 on incidence, 5 on surveillance, 19 on diagnosis, 79 on treatment, 61 on survival, and 2 on end-of-life. Insurance was the most frequent SES measure represented (50%), followed by mostly area-level income (39%), education (9%), and employment (2%). The included studies were heterogeneous regarding both SES definitions (e.g., individual vs. area-level measures) and outcome reporting. Trends of worse outcomes were generally observed with lower indicators across all SES domains and HCC outcomes, particularly in analyses using national cancer registry data (e.g., SEER and NCDB). Unadjusted racial and ethnic disparities in outcome were attenuated in six out of 23 analyses that adjusted for an SES measure. Conclusions: Our findings highlight the need for social risk screening and interventions early in the HCC care pathway. Future research should focus on HCC surveillance and end-of-life/survivorship, with greater emphasis on examination of modifiable individual-level social determinants. Full article

Background/Objectives: Late presentations of advanced hepatocellular carcinoma (HCC) indicate a lack of detection of underlying cirrhosis and a need to identify clinical and socioeconomic risk factors contributing to early-stage HCC recognition. This study tested associations between early diagnostics of HCC and demographic, socioeconomic, clinical, and healthcare-related indicators. Methods: A retrospective analysis of clinical data accumulated between February 2018 and February 2024 was completed at a quaternary care centre (South Australia). Results: We identified 388 cases of newly diagnosed HCC during a six-year period. There were 131 (33.7%) patients with early-stage (Barcelona clinic liver cancer (BCLC) stage 0–A) and 257 (66.3%) patients with late-stage (BCLC B–D) HCC. Late-stage HCC was found in 66.3% of patients, with half of the cohort not having a diagnosis of cirrhosis at the time of HCC detection. A retrospectively calculated Fibrosis Index (FIB-4) of >3.25 was present in nearly half of patients with newly diagnosed HCC with no prior diagnosis of cirrhosis. Engagement with healthcare (p < 0.05), a history of liver cirrhosis (p < 0.001), and gastroenterologist-led care with surveillance programmes (p < 0.001) was associated with early-stage presentation and curative treatment. Late-stage HCC was associated with male sex (p = 0.041), failing to attend appointments (p < 0.001), and liver function tests ordered by general physicians (p = 0.002) or non-gastroenterologist specialists (p = 0.023). Logistic regression analysis indicated that engaging in a surveillance programme, assessment by a gastroenterologist, and Model for End-Stage Liver Disease scores were important factors contributing to early detection of HCC; the area under the curve for this model on the ROC analysis was 0.892 (95% CI 0.855–0.929). Conclusions: Better cirrhosis detection is required, given that 60% of patients had a retrospectively calculated FIB-4 > 3.25. Routine use of non-invasive scores by all healthcare providers may increase engagement with surveillance and improve HCC screening. Full article

Background: Hepatocellular carcinoma (HCC) frequently develops in patients with chronic hepatitis B and C. Early detection is critical, but current methods, including ultrasound and AFP, have suboptimal accuracy. Objectives: This study aimed to evaluate the predictive performance of protein induced by vitamin K absence or antagonist-II (PIVKA-II) and alpha-fetoprotein (AFP) testing, alone and in combination, for HCC development. Methods: A retrospective cohort study at a single university center included 242 CHB and 181 CHC patients. Data on demographics, clinical status, laboratory parameters, and imaging were collected, with fibrosis and steatosis assessed by FibroScan^®. Serum AFP and PIVKA-II were measured, but measurements of PIVKA-II in patients receiving vitamin K antagonists were excluded from the analysis. HCC diagnosis and staging followed clinical guidelines. Cox regression and ROC analyses identified independent predictors and evaluated biomarker accuracy for HCC detection. Results: HCC incidence was comparable between cohorts (5.0% in CHB vs. 5.5% in CHC). Both AFP and PIVKA-II independently predicted HCC development in multivariate models adjusted for age and sex. The combined biomarker score (AFP × PIVKA-II) showed superior predictive accuracy with hazard ratios of 1.38 (CHB) and 1.36 (CHC). ROC analyses demonstrated high discriminative ability for PIVKA-II (AUC ~0.81) and AFP (AUC ~0.83) in both cohorts. Additional independent predictors were chronic alcohol abuse, cirrhosis, and higher liver stiffness measurements. Specific viral factors such as HBeAg positivity and HCV subgenotype 1b were also associated with increased HCC risk. Conclusions: AFP and PIVKA-II are independent, valuable biomarkers for HCC risk in chronic hepatitis B and C. Combined use improves early detection, aiding timely treatment. These results support adding PIVKA-II to AFP in surveillance, but larger studies are needed to confirm the findings and refine cut-off values. Full article

Virus-associated hepatocellular carcinoma (HCC) remains a major global health burden despite effective antiviral therapies. Chronic infection with hepatitis B (HBV), hepatitis C (HCV), and hepatitis D (HDV) promotes malignant transformation through overlapping pathways of fibrosis, immune dysregulation, and microenvironmental remodeling. YKL-40, a glycoprotein secreted by hepatic stellate cells, hepatocytes under stress, macrophages, and endothelial cells, has emerged as a marker that reflects stromal activation rather than direct hepatocyte injury. Its expression is reinforced by profibrotic and angiogenic circuits, and circulating concentrations correlate with advanced fibrosis, residual risk after viral suppression, and oncologic outcomes. This review synthesizes current evidence on YKL-40 across HBV, HCV, and HDV cohorts, with emphasis on its role in bridging molecular mechanisms to clinical applications. We examine its utility in non-invasive fibrosis assessment, longitudinal monitoring after antiviral therapy, and prognostic modeling in HCC. Particular attention is given to its potential in the liver transplant pathway, where YKL-40 may refine eligibility beyond morphology, inform bridging therapy response, and predict post-transplant recurrence or graft fibrosis. Remaining challenges include its lack of disease specificity, assay variability, and limited multicenter validation. Future integration of YKL-40 into multimarker, algorithm-based frameworks could enable risk-adaptive strategies that align surveillance and transplant decisions with the evolving biology of virus-associated liver disease. Full article

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, in part due to late diagnosis and limited prognostic tools. In recent years, microRNAs, small, non-coding regulators of gene expression, have emerged as key modulators of tumor metabolism, microenvironmental crosstalk, and therapeutic response in HCC. This narrative review synthesizes evidence published from January 2000 through April 2025, focusing on four interrelated themes: (1) miRNA-driven metabolic rewiring; (2) circulating and exosomal miRNAs as diagnostic and (3) predictive biomarkers; (4) miRNA-based therapeutic strategies. We conducted a targeted PubMed search using terms related to HCC, miRNA biology, biomarkers, metabolism, and therapy, supplemented by manual reference mining. Preclinical and clinical studies reveal that loss of tumor-suppressor miRNAs and gain of oncomiRs orchestrate glycolysis, lipid and glutamine metabolism, and stromal-immune remodeling. Circulating miRNA signatures, including single- and multimarker panels, demonstrate diagnostic AUCs up to 0.99 for early-stage HCC and distinguish HCC from cirrhosis more accurately than alpha-fetoprotein. Predictively, miRNAs such as miR-21 and miR-486-3p correlate with sorafenib resistance, while tissue and exosomal miRNAs forecast recurrence and survival after curative therapy. Therapeutic manipulation, restoring tumor-suppressor miRNAs via mimics or AAV vectors and inhibiting oncomiRs with antagomirs or LNA oligonucleotides, yields potent anti-tumor effects in models, affecting cell cycle, apoptosis, angiogenesis, and immune activation. Despite technical and delivery challenges, early-phase trials validate target engagement and inform safety optimization. In this review, we highlight opportunities to integrate miRNA biomarkers into surveillance algorithms and combine miRNA therapeutics with existing modalities, charting a roadmap toward precision-guided management of HCC. Full article

Background and Aims: Glecaprevir/pibrentasvir achieves sustained virologic response (SVR) rates above 95% in chronic hepatitis C (CHC). Nevertheless, the residual risk of hepatocellular carcinoma (HCC) after SVR, especially in patients with advanced liver disease, has not been fully defined. We prospectively evaluated longitudinal changes in liver function and fibrosis and sought predictors of post-SVR HCC in a real-world multicenter cohort. Methods: A total of 395 CHC patients who attained SVR with glecaprevir/pibrentasvir were followed prospectively. Liver function tests, noninvasive fibrosis indices, and clinical outcomes were recorded at predefined intervals. Cox proportional hazards regression identified factors associated with incident HCC. Results: Over a median follow-up of 31.1 months, HCC occurred in 16 patients (4.1%). From univariate analysis, baseline FIB-4 > 3.25, APRI > 1.5, MELD ≥ 10, Child–Pugh score ≥ 6, and clinically significant portal hypertension were associated with HCC. Multivariate analysis retained FIB-4 > 3.25 (p = 0.003) and MELD ≥ 10 (p = 0.032) as independent predictors. Cumulative incidence rose stepwise with the number of risk factors. Conclusions: Despite a virologic cure, patients with advanced fibrosis or impaired liver function remain susceptible to HCC. Risk stratification using FIB-4 and MELD and continued surveillance are therefore warranted. Full article

Background: Hepatocellular carcinoma (HCC) remains a major cause of cancer-related mortality worldwide, with survival outcomes influenced by a range of demographic and pathological factors. While cirrhosis is a well-established risk factor, recent evidence shows that HCC can also develop in patients with only mild to moderate liver fibrosis. However, there is limited understanding of how fibrosis severity interacts with other clinical variables, such as patient age, to affect mortality. This study aims to explore how fibrosis scores relate to both overall and cancer-specific mortality in US HCC patients, with an emphasis on how this relationship may shift across different age groups. Methods: We utilized data from the Surveillance, Epidemiology, and End Results (SEER) database to identify 15,796 adult patients diagnosed with HCC between 2010 and 2021. Baseline demographics, disease characteristics, and treatment variables were examined. Mortality outcomes were evaluated using Cox proportional hazard regression. Variables significant at p < 0.1 in univariate analysis were included in multivariate models to identify independent predictors of mortality (with hazard ratios [HRs] > 1 signifying increased risk). A secondary analysis assessed how age modifies the association between fibrosis score and mortality. Results: The study population was predominantly male (77.2%), with most patients aged 60–79 (59.6%) and presenting with localized disease (61%). A majority had advanced liver fibrosis or cirrhosis (81.7%) and lived in large urban areas (62.9%). Crude comparisons indicated that male sex, older age, single status, advanced tumor stage, lower income, and cirrhosis were linked to worse outcomes. In adjusted models, independent predictors of increased mortality included male sex, older age, unmarried status, and more advanced disease stage. Receipt of surgery or chemotherapy was associated with a lower risk of death. Notably, the influence of fibrosis on mortality was found to be greater in older patients than in their younger counterparts. Conclusions: This analysis identifies key prognostic indicators in HCC and suggests that the relationship between fibrosis and survival is not uniform across age groups. These findings support the need for age-specific clinical management strategies and highlight the potential benefit of early detection and appropriate interventions, even in non-cirrhotic patients. Full article

Hepatocellular carcinoma (HCC) critically lacks reliable biomarkers for early detection. By mining the TCGA_LIHC and two GEO cohorts, we identified the liver-specific long non-coding RNA CTC-537E7.3 as the most consistently down-regulated transcript in tumors. This finding was validated in 97 paired tissues, with CTC-537E7.3 expression lost in 95% of cases (*** p < 0.0001). It demonstrated excellent diagnostic performance in discriminating tumor from non-tumor tissue (AUC = 0.95), which was maintained in early-stage (I/II) disease. Low CTC-537E7.3 expression correlated with shorter overall and disease-free survival and was inversely associated with serum α-fetoprotein (AFP) levels, highlighting its complementary clinical value. Mechanistic investigation revealed a potential competing endogenous RNA (ceRNA) axis. The microRNA miR-190b-5p was highly expressed in tumors and predicted to bind CTC-537E7.3, while its target, PLGLB1, was significantly suppressed. Survival analysis confirmed that concurrent high expression of CTC-537E7.3 and PLGLB1 conferred superior outcomes. These findings establish CTC-537E7.3 as a liver-specific, ceRNA-mediated tumor suppressor with robust diagnostic and prognostic potential. It represents a promising adjunct to existing HCC surveillance strategies, such as ultrasound and AFP measurement, for high-risk populations. Full article

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide, but its molecular drivers remain underexplored in Latin American populations. This study investigated the prevalence, co-occurrence, and tissue distribution of somatic mutations in the TERT promoter (C228T/C250T) and CTNNB1 exon 3, as well as TERT gene expression, in liver tissues from Brazilian patients. A total of 85 samples (42 HCC, 21 cirrhosis, and 22 hepatitis) were analysed using Sanger sequencing and RT-qPCR. TERT promoter mutations were detected in 47.6% of HCC tissues, including C228T (45.2%) and C250T (2.4%), and were also present in 19% of cirrhotic tissues but absent in hepatitis samples, supporting their emergence in early hepatocarcinogenesis. CTNNB1 exon 3 mutations occurred in 17.2% of HCCs and significantly co-occurred with TERTp mutations (66.7%, p = 0.0485), although the number of CTNNB1-mutated cases was limited. TERT expression was significantly upregulated in HCC tissues regardless of mutation status (p < 0.001). This is the first study to characterise these mutations in Brazilian HCC patients, highlighting the C228T mutation as a promising biomarker for early detection and molecular surveillance in cirrhotic individuals. Despite the genetic admixture of the studied population, the mutational patterns were comparable to those reported in more homogeneous populations, reinforcing the global relevance of these molecular alterations. Full article