Risk Of Hepatocellular Carcinoma Research Articles

Low level of hepatitis B viremia is associated with increased risk of hepatocellular carcinoma in compensated cirrhotic patients

BACKGROUND Whether patients with compensated cirrhosis and low-level viremia (LLV) of hepatitis B should receive antiviral therapy (AVT) is still controversial, and published results are inconsistent. AIM To investigate the link between LLV in compensated cirrhosis and prognosis concerning hepatocellular carcinoma (HCC), decompensation, and liver-related events. METHODS The PubMed, EMBASE, and Cochrane Library databases were searched up to March 5, 2023. Outcomes of interest were assessed by pooled hazard ratios (HRs). The study was registered with PROSPERO (CRD42023405345). RESULTS Six cohort studies representing 3155 patients were included. Compared with patients with undetectable HBV DNA, patients with LLV was associated with increased risk of HCC (HR: 2.06, 95%CI: 1.36-3.13; Q -statistic-P = 0.07, I 2 = 51%) regardless of receiving AVT or not (AVT group: HR: 3.14; 95%CI: 1.73-5.69; Q -statistic-P = 0.60, I 2 = 0%; un-AVT group: HR: 1.73, 95%CI: 1.09-2.76; Q -statistic-P = 0.11, I 2 = 50%). The pooled results showed no statistical association between LLV and decompensation of cirrhosis (HR: 2.06, 95%CI: 0.89-4.76; Q -statistic-P = 0.04, I 2 = 69%), and liver-related events (HR: 1.84, 95%CI: 0.92-3.67; Q -statistic-P = 0.03, I 2 = 72%), respectively. Grading of Recommendations Assessment, Development and Evaluation assessment indicated moderate certainty for HCC, very low certainty for decompensation of cirrhosis and liver-related clinical events. CONCLUSION LLV in compensated cirrhotic patients is associated with increased risk of HCC, higher tendency for hepatic decompensation and liver-related events. Closer screening of HCC should be conducted in this population.

Risk of Hepatocellular Carcinoma with Glucagon-like Peptide-1 receptor agonist treatment in patients: a systematic review and meta-analysis

Risk of Hepatocellular Carcinoma with Glucagon-like Peptide-1 receptor agonist treatment in patients: a systematic review and meta-analysis

Abstract A050: Early detection of liver cancer from diverse populations using cfDNA fragmentome and protein biomarkers

Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer death world-wide. In the US, liver cancer has increased in incidence and mortality due to a growing population from South and Central America, which faces higher risk of disease in part due to aflatoxin exposure. Recently, we showed that the DELFI (DNA evaluation of fragments for early interception) approach using genome-wide cell free DNA (cfDNA) fragmentation profiles and machine learning can be used for detection of liver and other cancers. Having previously demonstrated that a DELFI classifier accurately detects HCC in populations from the US and Hong Kong, we evaluated the classifier in other clinically relevant cohorts worldwide. Here we show that approach generalizes to diverse populations, and that including other genomic and protein features from the same blood draw improves performance. We examined plasma samples from 377 individuals, including 244 individuals with HCC and 133 without cancer, including 85 with cirrhosis. Plasma samples were collected from individuals with or without HCC in a case-control study in Guatemala (n=203) and from a prospective collection in Romania (n=174) and cfDNA was analyzed by whole- genome sequencing at ∼10x coverage. The median DELFI scores using a locked classifier (Foda et al., Cancer Discovery, 2023) were higher in both cohorts for patients with cancer across all stages compared to individuals without cancer, regardless of the presence of cirrhosis. Using the locked model with a threshold that corresponded to 80% specificity in prior work, DELFI detected individuals with HCC with sensitivities of 90% and 69% in the two cohorts at specificities of 92% and 86%, respectively. For early-stage HCC within Milan Criteria for liver transplantation, sensitivities were 85% in the case-control cohort and 64% in the prospective cohort. In these cohorts, the fixed DELFI model outperformed AFP at the clinically used threshold of 20 ng/mL with a sensitivity in the combined cohorts of 78% at 91% specificity, compared to 63% sensitivity at 91% specificity for AFP. A combined approach using either DELFI at a threshold that corresponded to a 90% specificity in our previous study or AFP at the clinical threshold resulted in 82% sensitivity (74% in early stage) at 92% specificity and was superior to estimates of AFP and ultrasound for early-stage disease (63% sensitivity at 84% specificity). Individuals who tested positive with DELFI had a significantly shorter overall survival (p=0.002, log rank test), even amongst individuals at the earliest stage, while AFP alone did not stratify survival for patients with early-stage disease. Single-molecule analyses from low coverage WGS of cfDNA revealed genome-wide mutational profiles that were similar to those of HCC and in individuals from Guatemala that were characteristic of aflatoxin exposure. Overall, this work provides insight into the origins of cfDNA in populations at risk for HCC and validates our genome-wide fragmentome approach for non-invasive cancer detection that may facilitate liver cancer screening. Citation Format: Zachariah H Foda, Daniel Bruhm C Bruhm, Akshaya V Annapragada, Shashikant Koul, Sarah Short, Keerti Boyapati, Adrianna Bartolomucci, Vilmos Adleff, Nicholas A Vulpescu, Hope Orjuela, Andrei Sorop, Razvan Iacob, Liana Gheorghe, Simona Dima, Katherine A McGlynn, Manuel Ramírez-Zea, Jillian Phallen, John Groopman, Robert B Sharpf, Victor E Velculescu. Early detection of liver cancer from diverse populations using cfDNA fragmentome and protein biomarkers [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A050.

Beyond the Liver: A Comprehensive Review of Strategies to Prevent Hepatocellular Carcinoma

Background/Objectives: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, primarily developing in the context of chronic liver disease. Traditional prevention has focused on liver-specific interventions like antiviral therapies and surveillance. However, extrahepatic factors also significantly contribute to HCC risk. This review explores comprehensive strategies for HCC prevention, including both hepatic and extrahepatic factors. Methods: An extensive literature search of peer-reviewed articles up to October 2024 was conducted, focusing on studies addressing HCC prevention strategies. Studies that focused on both hepatic and extrahepatic factors were included. Data were extracted and synthesized to provide an overview of current prevention strategies and their effectiveness in reducing HCC incidence. Results: Hepatitis B vaccination and antiviral treatments for hepatitis B and C significantly reduce HCC incidence. Lifestyle modifications—such as reducing alcohol consumption, maintaining a healthy weight through diet and exercise, and smoking cessation—are crucial in lowering HCC risk. Environmental measures to limit exposure to aflatoxins and other hazards also contribute to prevention. Regular surveillance of high-risk groups enables early detection and improves survival rates. Emerging strategies like immunotherapy and gene therapy show potential for further reducing HCC risk. Conclusions: A comprehensive approach combining medical interventions, lifestyle changes, and environmental controls is essential for effectively decreasing HCC incidence globally. Implementing these combined measures could significantly reduce the global burden of HCC.

An overview of pathogenesis of metabolic dysfunction-associated steatotic liver disease

Steatotic liver disease (SLD) has been known for a long time, but our understanding of this disease has remained poor until the past decade. Despite extensive research, our ability to comprehend the etiopathogenesis and natural course of SLD is far from the desired level of comprehension. This is required to develop a universally effective novel therapeutic agent. This review aims to concisely elaborate the conceptual approach and advancement in the understanding of global disease burden and etiopathogenic process, identifying the gaps and the pathophysiologic mechanism behind developing novel therapeutic agents. We searched two major databases, PubMed and Google Scholar, to identify publications related to the abovementioned topics. All publications, including original papers, reviews, and commentaries, were reviewed. Findings: Metabolic dysfunction-associated steatotic liver disease (MASLD) is not limited to obese individuals, rather, it may develop in any individual independent of weight. Visceral adiposity is strongly associated with MASLD and subsequent risks of cirrhosis, hepatocellular carcinoma, and cardiovascular disease. MASLD is associated with diabetes mellitus independent of underlying pathogenic mechanisms, and there is a bidirectional connection between MASLD and diabetes mellitus, making the situation quite challenging. Not all patients with MASLD exhibit atherogenic dyslipidemia and thus do not have a higher risk of cardiovascular disease. The overlap of these metabolic risk factors is not straightforward. There is a differential contribution of these risk factors based on age, gender, race, ethnicity, alcohol consumption, and microbiota composition. Poor dietary habits and lifestyle directly affect the microbiota, modulators, and mediators, thereby affecting the final biochemical processes leading to steatosis, steatohepatitis, fibrosis, and oncogenesis. In conclusion, MASLD is a complex and pathogenically heterogeneous disease with significant interpatient variation in the natural course and outcome. Understanding the precise mechanism of variability is the key gap and a limiting factor in the development of a novel therapeutic agent.

Causal relationship between gout and liver cancer: A Mendelian randomization and transcriptome analysis.

Gout is an inflammatory arthritis resulting from urate crystal deposition, now recognized as part of metabolic syndrome. Hyperuricemia, a hallmark of gout, is associated with various health complications, including liver cancer. Observational studies indicate a link between gout and increased cancer incidence. However, the causal relationship between gout and hepatocellular carcinoma remains uncertain. This study utilizes Mendelian randomization (MR) to explore this connection, minimizing confounding factors commonly present in observational studies. Genome-wide association study data for gout and liver cancer were sourced from the UK Biobank. We selected single nucleotide polymorphisms that are strongly associated with gout and liver cancer as instrumental variables for the analysis. We conducted 2-sample MR analysis using multiple MR methods (MR-Egger, weighted median, inverse variance weighting, and weighted mode) to evaluate causality. Co-localization and transcriptomic analyses were employed to identify target genes and assess their expression in hepatocellular carcinoma tissues. The 2-sample MR analysis indicated a significant causal relationship between gout and heightened liver cancer risk (P_IVW = .014). Co-localization analysis identified phosphatidylethanolamine N-methyltransferase (PEMT) as a crucial gene associated with gout (pH4 = 0.990). Transcriptomic data showed that PEMT expression was significantly higher in normal liver tissues compared to malignant samples (P < .001), and higher PEMT levels correlated with improved survival outcomes (P = .045). Immunohistochemical analysis revealed lower PEMT expression in hepatocellular carcinoma from patients with concurrent gout compared to those without (P < .05). The results indicate that gout increases the risk of hepatocellular carcinoma, with PEMT potentially playing a key role. Although this study focused on European populations, indicating a need for further research in diverse groups, the results emphasize the potential for liver cancer screening in newly diagnosed gout patients. Understanding the relationship between these conditions may inform future clinical practices and cancer prevention strategies.

Phase 3 validation of PAaM for hepatocellular carcinoma risk stratification in cirrhosis

Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis. Molecular (Prognostic Liver Secretome signature with alpha-fetoprotein) and clinical (aMAP score) variable-based scores were integrated to develop PAaM, which was subsequently validated in two phase 3 biomarker validation studies: the statewide Texas HCC Consortium (THCCC) and nationwide HCC Early Detection Strategy (HEDS) prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation (PRoBE) design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events. Of 2,156 cirrhosis patients in THCCC, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared to low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios (sHRs) for incident HCC of 7.51 (95% confidence interval [CI], 4.42-12.8) and 4.20 (95%CI, 2.52-7.01), respectively. Of 1,328 cirrhosis patients in HEDS, PAaM identified 201 (15%) high-risk, 540 (41%) intermediate-risk, and 587 (44%) low-risk patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate risk groups were associated with sHRs for incident HCC of 6.54 (95%CI, 3.85-11.1) and 1.77 (95%CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease (MASLD) and cured hepatitis C infection. PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.

Risk Score for Hepatocellular Cancer in Adults Without Viral Hepatitis or Cirrhosis

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.

Risk of Hepatocellular Carcinoma in Asian Patients with Primary Biliary Cholangitis: A Nationwide and Hospital Cohort Study

Background & AimsLarge-scale studies on the association between primary biliary cholangitis (PBC) and hepatocellular carcinoma (HCC) in Asians are scarce. This study aimed to evaluate the incidence of HCC and its risk factors in a nationwide cohort. MethodsThe data of 4,882 patients with PBC and 38,603 matched controls were extracted from the Korean National Health Insurance Service (2007–2020) and analyzed. The incidence of HCC and its risk factors in patients with PBC were assessed and compared with those in the matched controls. The results were validated in a multi-center hospital cohort of 862 patients with PBC, recruited from Asan Medical Center (n=815) and Yeouido St. Mary’s Hospital (n=47) in Korea. ResultsIn total,105 patients with PBC developed HCC over the median follow-up period of 5.42 years, yielding an incidence rate of 3.7/1,000 person-years (PYs), which was significantly higher than that in the controls (0.5/1,000 PYs; adjusted hazard ratio: 9.07; 95% confidence interval [CI]: 6.71–12.27). PBC, older age, male sex, diabetes, and smoking were identified as significant risk factors for HCC. Twenty-three of the 862 patients with PBC developed HCC in the multi-center hospital cohort, yielding an incidence of 4.0/1,000 PYs (95% CI: 2.4–5.7). Older age (subdistribution hazard ratio [SHR]: 1.05, 95% CI: 1.00–1.10), male sex (SHR: 3.00, 95% CI: 1.11–8.13), current alcohol consumption (SHR: 3.70, 95% CI: 1.08–12.59), and cirrhosis (SHR: 5.17, 95% CI: 2.07–12.93) were identified as risk factors in the hospital cohort. ConclusionPatients with PBC were at a significantly higher risk of developing HCC. Older age and male sex were consistent risk factors in both cohorts. Impact and implicationsNotable heterogeneity has been observed among different studies in terms of the incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cholangitis (PBC). Large-scale studies on the association between PBC and HCC in Asians are scarce. In our nationwide cohort study, patients with PBC exhibited a significantly heightened risk of developing HCC and mortality than the age- and sex-matched controls. Individuals with PBC had a 9.1-fold higher risk of developing HCC than their matched counterparts, with an incidence rate of 3.7 per 1,000 person-years. Older age, male sex, smoking, and diabetes were identified as prominent risk factors for HCC in patients with PBC in the nationwide cohort. Older age, male sex, and alcohol consumption were identified as the factors significantly contributing to the elevated risk of HCC in patients with PBC in validation multicenter hospital cohort.

Double Trouble: Metabolic Dysfunction-Associated Fatty Liver Disease in Fraternal Twins

Pediatric cases of metabolic dysfunction-associated fatty liver disease (MASLD, formerly termed non-alcoholic fatty liver disease (NAFLD) are a troubling new outcome of the pediatric obesity epidemic. Advising patients and families with this condition is challenging considering the nutrition needed to sustain developmentally appropriate growth in youth. Describing risk factors, comorbidities, management, and referrals for MASLD could improve surveillance and outcomes for this condition. MASLD is commonly seen with other comorbidities such as dyslipidemia, obstructive sleep apnea, type 2 diabetes, hypothyroidism, anxiety, and depression. Considerations of epigenetics, diabetes, and adverse childhood experiences will be explored as additional underlying contributors to MASLD. Screening patients for this condition in conjunction with other comorbidities is essential to preventing the progression to non-alcoholic steatohepatitis (NASH) and cirrhosis, as well as lowering the risk for hepatocellular carcinoma. This fraternal twin case report describes pertinent diagnostics, recommendations for referrals, follow-up consultations, and red flags for more advanced liver disease.

Lower Incidence of Hepatocellular Carcinoma with Tenofovir Alafenamide in Chronic Hepatitis B: Evidence from a Large-Scale Cohort

Background & AimsThe newer tenofovir alafenamide (TAF) lacks extensive research regarding its impact on hepatocellular carcinoma (HCC). This study aims to evaluate and compare the effects of TAF, tenofovir disoproxil fumarate (TDF), and entecavir (ETV) on HCC incidence using nationwide claim data. MethodsA total of 75,816 treatment-naïve chronic hepatitis B patients were included and divided into TAF (n=25,680), TDF (n=26,954), and ETV (n=23,182) groups after exclusions. Propensity score matching (1:1:1) resulted in 17,537 patients per group, and HCC incidence rates were compared. ResultsBefore matching, the incidence of HCC was significantly lower in the TAF group compared to the TDF and ETV groups (11.47 vs. 15.04 and 14.24 per 1,000 person-years). The incidence rate ratio for TDF was 1.31 (1.19-1.44) and for ETV was 1.24 (1.12-1.37). Before matching, the TAF group had a significantly lower HCC compared to TDF and ETV in both cirrhotic and non-cirrhotic patients. After matching, the TAF group had a lower HCC incidence compared to TDF (12.38 vs. 15.39, incidence rate ratio 1.24, p<0.001) but not ETV (incidence rate ratio 1.08, p=0.219). In cirrhotic patients, TAF had lower HCC incidence than TDF and ETV (30.25 vs. 39.56 and 38.51). In non-cirrhotic patients, TAF had lower HCC incidence than TDF (incidence rate ratio 1.19, p=0.030) but not ETV (incidence rate ratio 0.85, p=0.066). Cox regression analysis showed TAF had a significantly lower HCC incidence compared to TDF (hazard ratio 1.335, p<0.001) and ETV (hazard ratio 1.162, p=0.011), after adjusting for age, gender, and cirrhosis status. ConclusionsThe TAF group consistently demonstrated a lower incidence of HCC compared to the TDF and ETV groups, especially in patients with cirrhosis. IMPACT and IMPLICATIONSThe scientific justification for this work lies in its potential to fill the knowledge gap regarding the comparative efficacy of Tenofovir Alafenamide (TAF), Tenofovir Disoproxil Fumarate (TDF), and Entecavir (ETV) in reducing the incidence of hepatocellular carcinoma (HCC) in chronic hepatitis B patients. The study's findings are particularly crucial for healthcare providers and policymakers, as they highlight the significantly lower incidence of HCC associated with TAF, especially in patients with cirrhosis. These results suggest that TAF could be a preferable antiviral therapy option to mitigate HCC risk, thus influencing clinical decision-making and healthcare guidelines. Practically, these findings can guide physicians in prescribing more effective treatments, assist researchers in designing further studies to explore the mechanisms behind TAF's effectiveness, and inform policymakers in crafting healthcare policies that optimize patient outcomes while considering potential limitations such as the observational nature of the study and residual confounding factors.

Prevalence, Risk Factors, and Clinical Profiles of Hepatitis D Virus in Nigeria: A Systematic Review, 2009–2024

Background: The World Health Organization (WHO) recommends hepatitis D virus (HDV) screening among hepatitis B virus (HBV) infected individuals, with a focus on priority populations in resource-limited settings like Nigeria. HDV infection is a growing public health challenge, particularly among individuals with chronic hepatitis B virus (HBV) infection. HDV accelerates liver disease progression and significantly increases the risk of cirrhosis and hepatocellular carcinoma. Despite this, the epidemiology of HDV in Nigeria remains inadequately documented. This scoping review critically evaluates the prevalence, risk factors, and clinical outcomes of HDV co-infection among HBV patients in Nigeria. Method: We conducted a systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. The review included observational cross-sectional studies published between 2009 and 2024. We focused on studies that used Immunoglobulin G (IgG) antibody testing or RNA-based diagnostics to assess HDV prevalence. We included PubMed, Google Scholar, and Dimensions databases due to their broad indexing and coverage of peer-reviewed articles and accessibility. We screened the studies for their relevance to HDV prevalence, risk factors, and clinical outcomes, while excluding those that only tested for IgM or HDV antigen. Eleven studies, with a combined sample size of 2308 participants, were included in the final analysis. We performed a narrative synthesis of the findings, considering geographic, gender, and age-based variations in HDV prevalence and clinical impact. Results: HDV prevalence among HBV-infected individuals in Nigeria ranged from 2.0% to 31.6%. The highest prevalence was reported in the Southwest (31.6%) among malaria patients, while lower rates were observed in the Southeast (2.8%). Prevalence was higher in males, particularly those aged 21–30 years in the Southwest and 31–40 years in other regions. RNA-based testing provided more accurate data on active viremia, with viremic HDV prevalence rates ranging from 3.2% to 16%. Triple infection with HIV/HBV/HDV was associated with significantly lower CD4+ cell counts and worse clinical outcomes, including elevated liver enzymes and rapid progression to liver cancer. Key risk factors for HDV co-infection included multiple sexual partners, sharing of needles, and unsafe medical practices. Co-infected patients demonstrated worse clinical outcomes, such as elevated liver enzymes, decompensated cirrhosis, and higher rates of hepatocellular carcinoma. Conclusions: Our review underscores the urgent need for routine HDV screening among HBV patients in Nigeria, especially given the severe clinical consequences of co-infection. The recent WHO guidelines recommending HDV screening align with our findings, which emphasize the importance of RNA-based HDV testing among HBV-positive patients to improve diagnostic accuracy. Public health efforts should prioritize tailored interventions based on geographic, age, and gender disparities in HDV prevalence. Triple infection with HIV/HBV/HDV requires integrated care models to address both immune suppressions as indicated by diminished CD4 cell count and liver disease progression, as these patients face worse outcomes. Targeted HDV screening in mostly affected demographics and geographies and improved Nigeria capacity for cheaper HDV RNA/PCR diagnostics can reduce liver-related morbidity and mortality caused by HBV, which can be worsened and accelerated by HDV coinfection.

Therapeutic targets for hepatocellular carcinoma identified using proteomics and Mendelian randomization.

Hepatocellular carcinoma (HCC) emerges as a formidable malignancy marked by elevated morbidity and mortality rates, coupled with a dismal prognosis. The revelation of gene-protein associations has presented an avenue for the exploration of novel therapeutic targets. Pooling plasma proteomic data (seven published GWAS) and HCC data (DeCODE cohort), we applied MR to identify potential drug targets, which were further validated in the FinnGen cohort and UK Biobank. Subsequent colocalization and summary-data-based Mendelian randomization analyses were performed for potential associations of this set of proteins. In addition, enrichment information pathways were investigated in depth by KEGG pathway analysis, single-cell sequencing, PPI and DGIdb, ChEMBL, and DrugBank database analyses, specific cell types enriched for expression were identified, interacting proteins were identified, and finally, druggability was assessed. In summary, the levels of 10 proteins are linked to HCC risk. Elevated levels of TFPI2 as well as decreased levels of ALDH1A1, KRT18, ADAMTS13, TIMD4, SCLY, HRSP12, TNFAIP6, FTCD, and DDC are associated with increased HCC risk. Notably, HRSP12 show the strongest evidence. These genes are primarily expressed in specific cell types within the HCC TME. Moreover, intricate protein-protein interactions, involving key players like ALDH1A1 and RIDA, ALDH1A1 and DDC, and ALDH1A1 and KRT18, contribute significantly to the amino acid metabolism and dopaminergic neurogenesis pathway. Proteins such as ALDH1A1, KRT18, TFPI2, and DDC are promising targets for HCC therapy and broader cancer drug development. Targeting these proteins offers substantial potential in advancing HCC treatment strategies. This research delineates 10 protein biomarkers linked to HCC risk and offers novel perspectives on its etiology, as well as promising avenues for the screening of HCC protein markers and therapeutic agents.

Night shift-induced circadian disruption: links to initiation of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and risk of hepatic cancer.

The circadian system plays a crucial role in regulating metabolic homeostasis at both systemic and tissue levels by synchronizing the central and peripheral clocks with exogenous time cues, known as zeitgebers (such as the light/dark cycle). Our body's behavioral rhythms, including sleep-wake cycles and feeding-fasting patterns, align with these extrinsic time cues. The body cannot effectively rest and repair itself when circadian rhythms are frequently disrupted. In many shift workers, the internal rhythms fail to fully synchronize with the end and start times of their shifts. Additionally, exposure to artificial light at night (LAN), irregular eating patterns, and sleep deprivation contribute to circadian disruption and misalignment. Shift work and jet lag disrupt the normal circadian rhythm of liver activity, resulting in a condition known as "circadian disruption". This disturbance adversely affects the metabolism and homeostasis of the liver, contributing to excessive fat accumulation and abnormal liver function. Additionally, extended working hours, such as prolonged night shifts, may worsen the progression of non-alcoholic fatty liver disease (NAFLD) toward non-alcoholic steatohepatitis (NASH) and increase disease severity. Studies have demonstrated a positive correlation between night shift work (NSW) and elevated liver enzymes, indicative of hepatic metabolic dysfunction, potentially increasing the risk of hepatocellular carcinoma (HCC) related to NAFLD. This review consolidates research findings on circadian disruption caused by NSW, late chronotype, jet lag, and social jet lag, drawing insights from studies involving both humans and animal models that investigate the effects of these factors on circadian rhythms in liver metabolism.

Impact of SGLT2 inhibitors on liver-related outcomes in patients with heart failure - a population-based study in HK

Abstract Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now recommended for heart failure with preserved ejection fraction (HFpEf). While their side effects on respiratory and renal outcomes in patients with type 2 diabetes have been studied, the impact on liver-related diseases within HF patients is not well-established. Purpose This study aims to evaluate the association between SGLT2 inhibitor use and the risks of adverse liver events among HF patients. Methods We conducted a retrospective cohort study using the Hong Kong Clinical Data Analysis and Reporting System (CDARS) to identify 80,248 HF patients (mean age 73.37 ± 12.88 years; 49.2% male) between 2013 and 2022. Propensity score matching was applied to achieve a 1:3 ratio of SGLT2 users to non-users, ensuring balanced baseline characteristics. Competing risk regression within Cox proportional hazards frameworks quantified the risks for cirrhosis, hepatocellular carcinoma, liver-related death, and significant elevations in liver enzymes (ALT or AST &amp;gt;3x normal and bilirubin &amp;gt;2x normal). Results During a median follow-up of 6.02 years (interquartile range: 3.48–9.25 years), there were 12,103 liver-related deaths. SGLT2 was associated with a 52% reduced risk of cirrhosis (adjusted subdistribution hazard ratio [SHR]: 0.48; 95% confidence interval [CI]: 0.36-0.65), a 61% lower risk of hepatocellular carcinoma (SHR: 0.39; 95% CI: 0.26-0.42), a 13% decreased risk of liver-related death (SHR: 0.87; 95% CI: 0.77-0.98), and a 19% risk reduction in elevated liver enzymes (SHR: 0.81; 95% CI: 0.68-0.96). 5-year cumulative incidences were 1.7%, 0.62%, 13%, and 5.4%, respectively, for SGLT2 users compared to 3.7%, 1.9%, 16%, and 7.0% for SGLT2 nonusers. Conclusion SGLT2 use is associated with a decreased risk of adverse liver outcomes in HF patients. This suggests a potential protective role for SGLT2 in liver health within this population.

Influence of recipient KRAS gene rs712 polymorphisms on the overall survival rate of hepatocellular carcinoma after hepatic transplantation

Hepatocellular carcinoma (HCC) recurrence appears commonly after liver transplantation (LT), and it severely affected the long-term survival of patients. Previous studies have proved that Rap1A is involved in hepatocarcinogenesis and metastasis, and demonstrated the significant association between KRAS rs712 polymorphism and HCC. However, the relationship between KRAS rs712 polymorphism and HCC recurrence after LT remained unclear. A total of 93 HCC patients who underwent LT from March 2008 to Dec 2015 was analyzed. The genotypes of both donors and recipients had been confirmed as KRAS rs712. The independent risk factors that associated with HCC recurrence were investigated with univariate and multivariate logistic regression analysis. The recurrence-free (RFS) and overall survival (OS) were calculated with Cox regression analysis. The KRAS rs712 genotype frequencies were determined using the Χ2 test and the minor allele frequencies (MAFs) of KRAS rs712 genotypes were calculated by Hardy–Weinberg equilibrium. We found that the recipient KRAS rs712 polymorphism was significantly associated with HCC recurrence after LT. Moreover, the Milan criteria, microvascular invasion and recipient KRAS rs712 genotype were proved to be independent risk factors for HCC recurrence after LT. Patients with donor TG/TT genotypes had a significantly higher RFS and OS than TT genotype. The TNM stage, microvascular invasion, Milan criteria, treatment and recipient KRAS rs712 genotype were independent factors for the RFS of LT patients. Recipient KRAS rs712 polymorphism is associated with HCC recurrence after liver transplantation and plays as a promising bio-predictor of overall survival rate of HCC risks after hepatic transplantation.

Non-Targeted Metabolomics Reveal Apomorphine’s Therapeutic Effects and Lysophospholipid Alterations in Steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH), characterized by progressive inflammation and fibrosis, evolves from metabolic dysfunction-associated steatotic liver disease and significantly heightens the risk of cirrhosis and hepatocellular carcinoma. Understanding metabolic pathways that influence MASH progression is crucial for developing targeted therapies. Non-targeted metabolomics offer a comprehensive view of metabolic alterations, enabling identification of novel biomarkers and pathways without preconceived ideas. Conversely, targeted metabolomics deliver precise and reproducible measurements, focusing on predefined metabolites to accurately quantify established pathways. This study utilized hepatocyte-specific PTEN knockout mice as a model to explore metabolic shifts associated with MASH. By integrating non-targeted metabolomics and targeted metabolomics, we analyzed liver samples from three groups: normal, pathological (MASH-affected), and MASH-affected, but treated with apomorphine, an antioxidant and recently reported ferroptosis inhibitor with potential therapeutic effects. Metabolic profiling identified lysophospholipids (LPLs) as significantly altered metabolites, with elevated levels in the MASH model and a notable reduction after apomorphine treatment. This suggests that LPLs are central to the etiology of MASH and may serve as targets for therapeutic intervention. Our findings underscore the effectiveness of apomorphine in modulating disease-specific metabolic disruptions, offering insights into its potential as a treatment for human MASH.

Serum laminin γ2 monomer as a predictive biomarker for hepatocellular carcinoma in patients with chronic hepatitis B virus infection: a retrospective cohort study

This retrospective study evaluated the use of laminin γ2 monomer (LG2m) as a predictive biomarker for hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Serum LG2m levels were measured in two cohorts of patients: cohort 1 comprised 56 patients with chronic liver disease for assessing LG2m stability, whereas cohort 2 included 89 patients with chronic HBV infection who did not have HCC for evaluating the usefulness of LG2m measurement in HCC prediction. LG2m was highly stable in cryopreserved serum, and an increased LG2m level was significantly associated with a higher risk of HCC in chronically HBV-infected patients (P = 0.012). Multivariable Cox regression analysis revealed that high LG2m was an independent significant risk factor for HCC (hazard ratio, 7.16; 95% confidence interval, 1.31–39.2; P = 0.023). These findings suggest that LG2m may serve as a useful biomarker for the prediction of future HCC in patients with chronic HBV infection.

Rifaximin prophylaxis in MASLD‑hepatocellular carcinoma: Lessons from a negative animal model.

The incidence of hepatocellular carcinoma (HCC) has been rising, particularly among individuals diagnosed with metabolic dysfunction-associated steatotic liver disease. In the present study, the prophylactic effects of rifaximin (RIF) on HCC, inflammatory markers and cardiovascular risk (CVR) were investigated in an animal model. Adult Sprague-Dawley rats were randomly allocated into three groups (n=10, each): Control [standard diet/water plus gavage with vehicle (Veh)], HCC [high-fat choline deficient diet (HFCD)/diethylnitrosamine (DEN) in drinking water/Veh gavage] and RIF [HFCD/DEN/RIF (50 mg/kg/day) gavage] groups. After euthanasia at week 16, biochemical/inflammatory markers and the liver histology were assessed. The results demonstrated that the HCC and RIF animals had a significant increase in fresh liver weight, liver weight/body weight ratio, serum total cholesterol (TC), high-density lipoprotein-cholesterol, triglycerides, hepatic lipid accumulation and hepatic concentration of triglycerides and TC, relative to the controls (P<0.001, for all). Additionally, the HCC and RIF animals had higher plasminogen activator inhibitor, intercellular adhesion molecule-1, E-selectin and CVR scores than the controls (P<0.001, for all). The HCC animals had higher interleukin (IL)-1β (P=0.011), IL-10 (P<0.001), toll-like receptor-2 (P=0.012), lipopolysaccharide-binding protein (P=0.018) and metalloproteinase-2 (P=0.003) levels than the RIF animals. Furthermore, liver steatosis, inflammation and fibrosis, along with increased collagen fiber deposition occurred in the HCC and RIF groups. However, HCC occurred only in 2 RIF rats. In conclusion, although most animals did not develop HCC in the present study, RIF positively affected liver inflammation markers involved in steatohepatitis pathogenesis.

Lessons learned: strategies for implementing and the ongoing use of LI-RADS in your practice.

The establishment of the Liver Imaging Reporting and Data System (LI-RADS) in 2011 provided a comprehensive approach to standardized imaging, interpretation, and reporting of liver observations in patients diagnosed with or at risk for hepatocellular carcinoma (HCC). Each set of algorithms provides criteria pertinent to the various components of HCC management including surveillance, diagnosis, staging, and treatment response supported by a detailed lexicon of terms applicable to a wide range of liver imaging scenarios. Before its widespread adoption, the variability in the terminology of diagnostic criteria and definitions of imaging features led to significant challenges in patient management and made it difficult to replicate findings or apply them consistently. The integration of LI-RADS into the clinical setting has enhanced the efficiency and clarity of communication between radiologists, referring providers, and patients by employing a uniform language that averts miscommunications. LI-RADS has been strengthened with its integration into the American Association for Study of Liver Diseases practice guidelines. We will provide the background on the initial development of LI-RADS and reasons for development to serve as a starting point for conveying the system's benefits and evolution over the years. We will also suggest strategies for the implementation and maintenance of a LI-RADS program will be discussed.