Lower Risk Of Hepatocellular Carcinoma Research Articles

Synergistic association of sodium-glucose cotransporter-2 inhibitor and metformin on liver and non-liver complications in patients with type 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease

ObjectiveType 2 diabetes mellitus and metabolic dysfunction-associated steatotic liver disease (diabetic MASLD) frequently coexist and worsen liver and non-liver outcomes, but effective pharmacological therapies are limited. We aimed to evaluate...

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 >3x normal and bilirubin >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.

Age of hepatitis B e antigen loss in Aboriginal, Torres Strait Islander and non-Indigenous residents of tropical Australia; implications for clinical care.

This study determined the hepatitis B e antigen (HBeAg) status of people living with chronic hepatitis B (CHB) in Far North Queensland (FNQ), Australia and their age of HBeAg loss. It was hoped that this would provide data to explain the stark difference in the incidence of hepatocellular carcinoma (HCC) between Aboriginal and Torres Strait Islander individuals living with CHB in FNQ, a finding that has been hypothesised to relate to differences in hepatitis B virus genotype. We identified every FNQ resident with CHB, determined their country of birth, their HBeAg status, the age they lost HBeAg and whether they identified as an Aboriginal, a Torres Strait Islander or a non-Indigenous individual. We then ascertained whether these demographic and virological variables were correlated. Of 1,474 individuals living with CHB in FNQ, 278 (19%) were Aboriginal, 507 (34%) were Torres Strait Islanders and 689 (47%) were non-Indigenous. Aboriginal individuals were less likely to be HBeAg positive (26/278, 9%) than Torres Strait Islander (91/507, 18%) and non-Indigenous (126/689, 18%) individuals, p < 0.0001. Aboriginal individuals lost HBeAg at an earlier age (median (interquartile range): 30 (23-39) years) than Torres Strait Islander (38 (29-49) years) and non-Indigenous (36 (29-47) years) individuals, p < 0.0001. Aboriginal individuals with CHB in FNQ are more likely to be HBeAg negative than Torres Strait Islander and non-Indigenous individuals and lose HBeAg at a younger age. This provides a biological basis for local clinicians' observation that Aboriginal individuals with CHB in FNQ are at a lower risk of HCC and data to support the principle of genotype-based care in the region.

Blood Magnesium Level and Risk of Hepatocellular Carcinoma in a Prospective Liver Cirrhosis Cohort.

Higher magnesium intake was linked to a lower risk of hepatocellular carcinoma (HCC). However, the relationship between blood magnesium level and HCC has not been fully characterized, especially among patients with liver cirrhosis who are at a higher risk for HCC. In the Mass General Brigham Biobank, we developed a new prospective cohort of 1,430 patients with liver cirrhosis without liver cancer history using the validated International Classification of Diseases codes. We used Cox proportional hazards models to generate hazard ratios (HRs) with 95% confidence intervals (CI) for incident HCC and used generalized estimating equations to compare changes in liver biomarkers according to baseline blood magnesium, adjusting for age, sex, race, lifestyles, body mass index, type 2 diabetes, model for end-stage liver disease score, and hepatitis infection. During a median follow-up period of 4.26 years, 109 patients developed HCC. Magnesium deficiency (<1.70 mg/dL; N = 158) was associated with a higher risk of HCC (HR = 1.93; 95% CI, 1.12-3.30) compared with magnesium sufficiency (≥1.70 mg/dL;N= 1282). This association remained robust in the 1-year lag analysis (HR = 2.18; 95% CI, 1.11-4.28) and in sensitivity analysis excluding patients with alcoholic liver disease (HR = 2.41; 95% CI, 1.23-4.74). Magnesium in the lowest quartile was associated with a faster increase in alanine transaminase (β = 4.35; 95% CI, 1.06-7.63), aspartate aminotransferase(β = 6.46; 95% CI, 0.28-12.6), direct bilirubin (β = 0.18; 95% CI, 0.01-0.35), and total bilirubin (β = 0.21; 95% CI, 0.03-0.39), compared with the highest quartile. Lower blood magnesium level is associated with higher HCC risk and unfavorable liver biomarker changes. If confirmed, our findings may potentially enable better identification of high-risk patients for HCC and inform better management strategies for liver cirrhosis.

Association of physical activity, including amount and maintenance, with the risk of HCC among patients with type 2 diabetes

Background & AimsWe investigated the association of the amount and change of physical activity (PA) with the risk of HCC in patients with type 2 diabetes. MethodsPatients with type 2 diabetes who had undergone health examinations in 2009 and 2011 were enrolled. In total, 1,439,152 patients were included in the analysis. The level of PA was classified as inactive (<500 metabolic equivalent task [MET]-min/week), moderately active (500-1500 MET-min/week), and active (≥1500 MET-min/week). Change in PA was categorized as persistently no active PA, newly active PA, active PA quitter, and persistently active PA according to change of active PA between 2009 and 2011. ResultsDuring a median of 5.2 years of follow-up, 22,686 patients developed HCC. Compared to the inactive group, the risk of HCC was significantly lower in the moderately active (adjusted hazard ratio [aHR]=0.96, 95% confidence interval [CI]=0.93–0.99), and in active group (aHR=0.95, 95% CI=0.91–0.99). The patients in the persistently active PA group had a significantly lower risk of HCC than those in the persistently no active PA group (aHR=0.91, 95% CI=0.84–0.98). ConclusionsPhysical activity showed a dose-response preventive effect against HCC in patients with diabetes. Impact and implicationsOur study investigated the impact of physical activity (PA) levels and changes on the risk of hepatocellular carcinoma (HCC) in patients with type 2 diabetes. PA was associated with a dose-response preventive effect against HCC. Patients in the persistently active PA group had a significantly lower risk of HCC than those in the persistently inactive PA group, while newly active patients and PA quitters had similar risks to the persistently inactive group. Our study highlighted the importance of maintaining regular PA as a preventive strategy against HCC.

Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy.

Chronic hepatitis C (CHC) patients who failed antiviral therapy are at increased risk for hepatocellular carcinoma (HCC). This study assessed the potential role of metformin and statins, medications for diabetes mellitus (DM) and hyperlipidemia (HLP), in reducing HCC risk among these patients. We included CHC patients from the T-COACH study who failed antiviral therapy. We tracked the onset of HCC 1.5 years post-therapy by linking to Taiwan's cancer registry data from 2003 to 2019. We accounted for death and liver transplantation as competing risks and employed Gray's cumulative incidence and Cox subdistribution hazards models to analyze HCC development. Out of 2,779 patients, 480 (17.3%) developed HCC post-therapy. DM patients not using metformin had a 51% increased risk of HCC compared to non-DM patients, while HLP patients on statins had a 50% reduced risk compared to those without HLP. The 5-year HCC incidence was significantly higher for metformin non-users (16.5%) versus non-DM patients (11.3%; adjusted sub-distribution hazard ratio [aSHR]=1.51; P=0.007) and metformin users (3.1%; aSHR=1.59; P=0.022). Statin use in HLP patients correlated with a lower HCC risk (3.8%) compared to non-HLP patients (12.5%; aSHR=0.50; P<0.001). Notably, the increased HCC risk associated with non-use of metformin was primarily seen in non-cirrhotic patients, whereas statins decreased HCC risk in both cirrhotic and non-cirrhotic patients. Metformin and statins may have a chemopreventive effect against HCC in CHC patients who failed antiviral therapy. These results support the need for personalized preventive strategies in managing HCC risk.

A Meta-Analysis of Cumulative Incidence of Hepatocellular Carcinoma After the Fontan Operation.

Hepatic complications are increasingly recognized after the Fontan operation. The development of hepatocellular carcinoma (HCC) is associated with high mortality when diagnosed, but its incidence and risk factors are poorly understood. We conducted a systematic review and meta-analysis of the cumulative incidence of HCC after Fontan and associated risk factors. We searched PubMed, CINAHL, and MEDLINE databases for articles reporting the cumulative incidence of HCC after Fontan operation on March 21, 2023. A single-arm random effects meta-analysis was conducted to assess cumulative incidence at 10, 20, and 30 years after Fontan. Meta-analysis of the difference of the medians was used to assess the influence of risk factors on the development of HCC. Four studies including a total of 1320 patients reported cumulative incidence. The cumulative incidence of HCC at 10, 20, and 30 years after Fontan was 0% (95% CI 0.00-0.01), 2% (0.01-0.06), and 7% (0.03-0.17) respectively. Seven studies including 6,250 patients reported overall incidence of HCC and associated risk factors. At a median 18.4 (IQR 11.9-24.9) years of follow-up, incidence of HCC was 2% (0.01-0.04). Only use of anticoagulation was associated with a lower risk of HCC (RR 0.3, 95% CI 0.1-0.88). By 30years after Fontan, cumulative incidence of HCC is high (7%). Risk of HCC development prior to 10 years post-Fontan is low (0%), though the decision to defer HCC surveillance in this period may require future investigation based on larger studies. Screening with ultrasound every 6 months starting 20 years post-Fontan is reasonable, however, further research regarding timing, cost-effectiveness, additional risk factors associated with HCC risk, and different screening modalities is required.

Lower Risks of New-Onset Hepatocellular Carcinoma in Patients With Type 2 Diabetes Mellitus Treated With SGLT2 Inhibitors Versus DPP4 Inhibitors.

Type 2 diabetes mellitus (T2DM) may be a risk factor for development of hepatocellular carcinoma (HCC). The association between risk of developing HCC and treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP4i) is currently unknown. This study aimed to compare the risk of new-onset HCC in patients treated with SGLT2i versus DPP4i. This was a retrospective cohort study of patients with T2DM in Hong Kong receiving either SGLT2i or DPP4i between January 1, 2015, and December 31, 2020. Patients with concurrent DPP4i and SGLT2i use were excluded. Propensity score matching (1:1 ratio) was performed by using the nearest neighbor search. Multivariable Cox regression was applied to identify significant predictors. A total of 62,699 patients were included (SGLT2i, n=22,154; DPP4i, n=40,545). After matching (n=44,308), 166 patients (0.37%) developed HCC: 36 in the SGLT2i group and 130 in the DPP4i group over 240,269 person-years. Overall, SGLT2i use was associated with lower risks of HCC (hazard ratio [HR], 0.42; 95% CI, 0.28-0.79) compared with DPP4i after adjustments. The association between SGLT2i and HCC development remained significant in patients with cirrhosis or advanced fibrosis (HR, 0.12; 95% CI, 0.04-0.41), hepatitis B virus (HBV) infection (HR, 0.32; 95% CI, 0.17-0.59), or hepatitis C virus (HCV) infection (HR, 0.41; 95% CI, 0.22-0.80). The results were consistent in different risk models, propensity score approaches, and sensitivity analyses. SGLT2i use was associated with a lower risk of HCC compared with DPP4i use after adjustments, and in the context of cirrhosis, advanced fibrosis, HBV infection, and HCV infection.

FRI-387 Similarly low risk of hepatocellular carcinoma and cirrhotic complications in patients in the HBeAg-negative indeterminate phase compared with chronic infection

FRI-387 Similarly low risk of hepatocellular carcinoma and cirrhotic complications in patients in the HBeAg-negative indeterminate phase compared with chronic infection

Abstract 4865: Income dynamics and the risk of hepatocellular carcinoma in individuals with type 2 diabetes: A nationwide population-based cohort study

Abstract Introduction: Type 2 diabetes (T2D) is associated with over 2 times increased risk of hepatocellular carcinoma (HCC). Low-income status is associated with a higher risk of developing HCC, more advanced stage, and mortality. Evidence is limited on whether income dynamics are associated with the risk of developing HCC in individuals with T2D who are susceptible to income changes. We examined whether income levels and income changes are associated with HCC risk. Methods: Using representative data from the Korean National Health Insurance Service (NHIS), 2,227,893 adults with T2D (aged ≥ 20 years) without a cancer history were included between 2015-2016. Income levels were measured based on health insurance premiums and categorized into 4 levels (quartiles [Q], 1 [low income], to 4 [high income]). These quartiles excluded the very low-income individuals who qualified as Medical Aids beneficiaries (MAB), which comprised a 5th income category. To identify income change, income levels were collected annually from the baseline year backward 4 years. The incident HCC, defined based on ICD-10 codes and special reimbursement codes, was identified until December 2020. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated to assess the association between income parameters and HCC after adjusting for sociodemographic factors, comorbidities, and diabetes duration and treatment. Income parameters included 1) the baseline income status, 2) the cumulative number of years being in each income level, and 3) changes in income level between the two time points (4 years ago vs. baseline). Results: During follow-up (median, 3.9 years), 9,887 HCC cases developed. Individuals who had experienced at least one episode of MAB during the five years showed a significantly higher HCC risk than those who had never qualified as MAB (HRs ranging from 1.52 to 2.01). In contrast, individuals who had experienced high-income status (Q4) during the five years had a lower HCC risk than those who had never experienced (HRs ranging from 0.79 to 0.92; HRn=5 years vs. n=0 years 0.79, 95% CI 0.75-0.83; P for trend &amp;lt;0.05). Individuals in the low-income status (MAB-Q1) at the first assessment (4 years ago) but experienced increased income had a reduced risk of HCC, which linearly declined with increasing income rise. Also, those who experienced a substantial increase in income up to the top quartile (Q4) had the lowest HCC risk (HR 0.73, 95% CI 0.60-0.88; P for trend&amp;lt;0.05) than those who maintained the low-income status. Conclusions: Experiencing any very low- or high-income state was independently associated with increased or decreased HCC risk. Improved income levels among those in the low-income status had an inverse linear association with reduced HCC risk. Our findings underline the need for increased public policy awareness of the impact of income dynamics on HCC risk in adults with T2D. Citation Format: Jongha Baek, Benjamin C. Amick III, Clare C. Brown, Mario Schootman, Marie-Rachelle Narcisse, Seung-Hyun Ko, Pearl A. McElfish, Michael R. Thomsen, Seong-Su Lee, Kyungdo Han, Yong-Moon Mark Park. Income dynamics and the risk of hepatocellular carcinoma in individuals with type 2 diabetes: A nationwide population-based cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4865.

Persistently high HBsAg levels during HBeAg-seropositive stage predict lower risk of hepatocellular carcinoma in chronic hepatitis B patients.

High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown. HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HRadj) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant. A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥104 IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <104 IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HRadj [95% CI] = 4.11 [2.26-7.48]), genotype C (HRadj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HRadj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HRadj [95% CI] = 32.75 [5.41-198.42]). Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development.

Statin Use and Hepatocellular Carcinoma Risk: A Comprehensive Meta- Analysis and Systematic Review.

Hepatocellular Carcinoma (HCC) is a public health problem around the world. Several studies have investigated the association between statin use and the risk of HCC, however, more studies are needed in this field. This systematic review and meta-analysis aimed to investigate the relationship between statin use and HCC risk. Systematic searches of Web of Science, Scopus, PubMed, Cochrane, Science Direct, and Embase were conducted for studies published between 1980 and September 2023. Metaanalyses were performed using Stata 15 with a significance level of 0.05. The search retrieved 8,125 articles, of which 40 were included in the meta-analysis after applying eligibility criteria. The total sample was 5,732,948 participants, including 68,698 HCC cases. Statin use was associated with a 44% lower risk of HCC compared to non-use (RR 0.56, 95% CI 0.50-0.63, p < 0.001). The RR was 0.54 (0.42-0.69) in American countries, 0.52 (0.44-0.62) in Asian countries, and 0.63 (0.48-0.84) in European countries. The RR was 0.50 (0.42-0.60) in studies with a mean age <50 years and 0.61 (0.53-0.70) in studies with a mean age ≥50 years. No evidence of publication bias was found (Begg's test p = 0.718). This meta-analysis found statin use is associated with a significantly lower HCC risk. Statins may be a promising preventive intervention against HCC.

Effects of N-acetylcysteine on hepatocellular carcinoma in chronic hepatitis C.

Hepatitis C virus (HCV) infection significantly contributes to global hepatocellular carcinoma (HCC) incidence. N-Acetylcysteine (NAC), known for its antioxidant properties, is a potential therapeutic agent. However, evidence on its efficacy in reducing HCC risk among HCV patients is limited. A retrospective cohort analysis using Taiwan's National Health Insurance Research Database (2008-2018) included ≥18-year-old HCV patients. NAC usage (≥28 cumulative defined daily doses [cDDDs]) was assessed for its association with HCC risk using Cox regression models and propensity score matching. The study comprised 269,647 HCV patients, with detailed NAC dosage characterization and hazard ratios (HRs) for HCC risk. Post-matching, NAC usage emerged as the significant predictor of reduced HCC risk (adjusted HR: 0.39, 95% CI: 0.37-0.41, P<0.0001). Dose-response analysis showed reduced HCC risk with increasing cDDDs of NAC (P<0.0001). Higher daily NAC dosage (≥1 DDD) was associated with significantly lower HCC risk (adjusted HR: 0.33, 95% CI: 0.31-0.36, P<0.0001). The study provides compelling evidence for NAC's potential in reducing HCC risk among HCV patients. Insights into dose-dependent effects and optimal daily intensity thresholds offer valuable directions for future therapeutic strategies and clinical trials targeting HCC burden in HCV-infected individuals.

Liver Stiffness Measurement and Risk Prediction of Hepatocellular Carcinoma After HCV Eradication in Veterans With Cirrhosis

Background & AimsPatients with cirrhosis secondary to chronic hepatitis C virus (HCV) are at risk for hepatocellular carcinoma (HCC) despite a sustained virological response (SVR). We examined whether post-SVR liver stiffness measurement (LSM) could be used to stratify HCC risk. MethodsThis was a retrospective cohort study of 1850 participants identified from the Veterans Health Administration, with HCV cirrhosis and SVR, followed up over 5099 person-years, from the time of post-SVR elastography until death, HCC, or the end of the study. ResultsThe risk of HCC increased by 3% with every 1-kPa increase in LSM (adjusted hazard ratio [aHR], 1.03, 95% confidence interval [CI], 1.01–1.04; P < .001) and decreased with the number of years from SVR (aHR, 0.79; 95% CI, 0.70–0.90; P = .0003). The adjusted annual risk of HCC was 2.03% among participants with post-SVR LSM <10 kPa, 2.48% in LSM 10–14.9 kPa (aHR, 1.71; 95% CI, 1.01–2.88; P = .046), 3.22% for LSM 15–19.9 kPa (aHR, 1.59; 95% CI, 0.78–3.20; P = .20), 5.07% among LSM 20–24.9 kPa (aHR, 2.55; 95% CI, 1.30–5.01; P = .01), and 5.44% in LSM ≥25 kPa (aHR, 3.03; 95% CI, 1.74–5.26; P < .0001). The adjusted annual risk of HCC was < 0.4% in participants with LSM <5 kPa and without diabetes mellitus. ConclusionsLSM predicts rates of HCC in patients with HCV cirrhosis after SVR at multiple cutoff levels and offers a single test to predict portal hypertension–related complications and HCC. Patients with LSM <5 kPa in the absence of diabetes mellitus had a low risk of HCC in which surveillance could be discontinued.

Dietary intake and serum levels of copper and zinc and risk of hepatocellular carcinoma: A matched case-control study.

Copper and zinc are involved in the development of multiple malignancies; yet, epidemiological evidence on hepatocellular carcinoma (HCC) is limited. This study aimed to investigate the association between dietary intake and serum levels of copper and zinc with the risk of HCC. A total of 434 case-control pairs matched for sex and age (±1 year) were included in this study. Cases with newly diagnosed HCC were from the Guangdong Liver Cancer Cohort (GLCC) study, and healthy controls were from the Guangzhou Nutrition and Health Study (GNHS). A semi-quantitative 79-item food frequency questionnaire (FFQ) was used to assess habitual dietary intakes of copper and zinc. Serum levels of copper and zinc were measured by using inductively coupled plasma mass spectrometry. The copper (Cu)/ zinc (Zn) ratio was computed by dividing copper levels by zinc levels. Conditional logistic regression models were performed to calculate the odds ratio (OR) and 95% confidence intervals (CI) for per 1 standard deviation increase (per-SD increase) in copper and zinc levels. Higher dietary intake (OR per-SD increase = 0.65, 95% CI: 0.44, 0.96, Ptrend = 0.029) and serum levels of zinc (OR per-SD increase = 0.11, 95% CI: 0.04, 0.30, Ptrend <0.001) were both associated with a lower risk of HCC. Subgroup analyses showed that the inverse association was only pronounced in men but not in women ( Pinteraction = 0.041 for dietary zinc intake and 0.010 for serum zinc levels). Serum copper levels (OR per-SD increase = 2.05, 95% CI: 1.39, 3.03, Ptrend = 0.020) and serum Cu/Zn ratio (OR per-SD increase = 6.53, 95% CI: 2.52, 16.92, Ptrend <0.001) were positively associated with HCC risk, while dietary copper intake and dietary Cu/Zn ratio were not associated with HCC risk. Zinc may be a protective factor for HCC, especially among men, but the effects of copper on HCC risk are not clear.

Hepatocellular carcinoma risk decreases as time accrues following hepatitis C virus eradication.

It is unclear whether the risk of hepatocellular carcinoma (HCC) decreases over time following hepatitis C virus (HCV) eradication. To determine if patients who have accrued longer time since sustained virologic response (SVR) have a lower risk of HCC than those with less time since SVR METHODS: We conducted a retrospective cohort study of all HCV-infected Veterans Affairs patients who achieved SVR before 1 January 2018 and remained alive without a diagnosis of HCC as of 1 January 2019 (n = 75,965). We ascertained their baseline characteristics as of 1 January 2019 (time zero), including time accrued since SVR and followed them for the subsequent 12 months for incident HCC. We used multivariable Cox proportional hazards regression to determine the association between time since SVR and HCC risk after adjusting for age, race/ethnicity, sex, diabetes, hypertension, body mass index, alcohol use, Charlson Comorbidity Index, Fibrosis-4 score, HCV genotype, hepatitis B virus co-infection and HIV co-infection. 96.0% were male; mean age was 64.6 years. Among those with cirrhosis (n = 19,678, 25.9%), compared to patients who had accrued only ≥1 to 2 years since SVR (HCC incidence 2.71/100 person-years), those who had accrued >2 to 4 years (2.11/100 person-years, aHR 0.80, 95% CI 0.63-1.01) and >4 to 6 years (1.65/100 person-years, aHR 0.61, 95% CI 0.41-0.90) had progressively lower HCC risk. However, HCC risk appeared to plateau for those with >6 years since SVR (1.68/100 person-years, aHR 0.70, 95% CI 0.46-1.07). Among those without cirrhosis, HCC risk was 0.23-0.27/100 person-years without a significant association between time since SVR and HCC risk. Among patients with cirrhosis and cured HCV infection, HCC risk declined progressively up to 6 years post-SVR-although it remained well above thresholds that warrant screening. This suggests that time since SVR can inform HCC surveillance strategies in patients with cured HCV infection and can be incorporated into HCC risk prediction models.

Low-density lipoprotein cholesterol and risk of hepatocellular carcinoma: a Mendelian randomization and mediation analysis

BackgroundA previous study demonstrated that low-density lipoprotein cholesterol (LDL-C) is associated with hepatocellular carcinoma (HCC); however, the causality between them has not been proven due to conflicting research results and the interference of confounders. This study utilized Mendelian randomization (MR) to investigate the causal relationship between LDL-C and HCC and identify the mediating factors.MethodsLDL-C, HCC, and coronary artery disease (CAD) genome-wide association study (GWAS) data were obtained from a public database. To investigate causality, inverse variance weighting (IVW) was the main analysis approach. MR‒Egger, simple mode, weighted median (WM), and weighted mode were employed as supplementary analytic methods. In addition, horizontal pleiotropy and heterogeneity were tested. To evaluate the stability of the MR results, a "leave-one-out" approach was used. Multivariate MR (MVMR) was utilized to correct the confounders that might affect causality, and mediation analysis was used to investigate the potential mediating effects. Finally, we used HCC risk to infer the reverse causality with LDL-C level.ResultsRandom effects IVW results were (LDL-C-HCC: odds ratio (OR) = 0.703, 95% confidence interval (CI) = [0.508, 0.973], P = 0.034; CAD–HCC: OR = 0.722, 95% CI = [0.645, 0.808], P = 1.50 × 10–8; LDL-C–CAD: OR = 2.103, 95% CI = [1.862, 2.376], P = 5.65 × 10–33), demonstrating a causal link between LDL-C levels and a lower risk of HCC. Through MVMR, after mutual correction, the causal effect of LDL-C and CAD on HCC remained significant (P < 0.05). Through mediation analysis, it was proven that CAD mediated the causative connection between LDL-C and HCC, and the proportion of mediating effect on HCC was 58.52%. Reverse MR showed that HCC could affect LDL-C levels with a negative correlation (ORIVW = 0.979, 95% CI = [0.961, 0.997], P = 0.025).ConclusionThis MR study confirmed the causal effect between LDL-C levels and HCC risk, with CAD playing a mediating role. It may provide a new view on HCC occurrence and development mechanisms, as well as new metabolic intervention targets for treatment.

Incidence of hepatocellular carcinoma and mortality in chronic viral hepatitis in an Asian population with and without HIV infection.

It is uncertain whether people with HIV infection have a higher incidence of hepatocellular carcinoma (HCC) than the general population. To compare the incidence of HCC between people infected with HBV and/or HCV with and without HIV METHODS: We performed a retrospective population-based cohort study, involving people with HBV and/or HCV infection from 2001 to 2018. The primary endpoint was incidence of HCC; secondary endpoint was all-cause mortality. We performed Cox proportional hazard regression models to estimate the hazard ratios (HR) of HIV for the primary and secondary endpoints. We identified 1374 people infected with HIV and 39,908 people without HIV with HBV and/or HCV infection. Among those with HIV, 654 (47.6%) had HBV, 649 (47.2%) HCV and 71 (5.2%) HBV-HCV-co-infection; they were younger, and had a higher prevalence of HCV and a lower prevalence of cirrhosis. The incidence rate estimates of HCC were, respectively,1.5 (95% CI: 0.8-2.5) and 7.6 (95% CI 7.3-8.0) per 1000 person-years for those with and without HIV infection. Using multivariate Cox proportional hazard regression models, among people with HBV, HIV was associated with lower risk of HCC (adjusted HR: 0.376, 95% CI: 0.201-0.704, p = 0.01) and death (adjusted HR: 0.692, 95% CI: 0.552-0.867, p = 0.007). Risks of HCC were similar for HCV and HBV-HCV co-infection for people with and without HIV. Among individuals with HBV infection, the Incidence of HCC was lower in those with HIV. For HCV infection, incidence of HCC was similar between those with and without HIV.

TRIM16 E121D variant affects the risk and prognosis of hepatocellular carcinoma by modulating the Wnt/β-catenin pathway.

TRIM16 has been identified as a tumor suppressor in hepatocellular carcinoma (HCC). This study aimed to investigate whether there are genetic variants in TRIM16 influencing HCC risk and/or prognosis and explore the mechanisms. We performed a gene-wide single-nucleotide polymorphism (SNP) mining in TRIM16. The associations of SNPs with both HCC risk and prognosis were assessed through two independent cohorts respectively. Functional experiments were performed to investigate the underlying mechanisms. A missense variant rs2074890 (G > T, resulting in an amino acid substitution from glutamate to aspartate at code 121, E121D) of TRIM16 was found to be associated with both HCC risk (odds ratio = 0.806, p = 0.023) and prognosis (hazard ratio = 0.44, p = 0.034). Compared to the rs2074890 G allele (corresponding to TRIM16121E ) homozygote carriers, the rs2074890 T allele (corresponding to TRIM16121D ) carriers showed lower HCC risk and better overall survival. Mechanistically, TRIM16121D has stronger ability to inhibit proliferation, migration, and invasion of HCC cells. Furthermore, TRIM16121D could bind to β-catenin better and mediate K48-linked ubiquitination to degrade β-catenin, which leads to inhibition of Wnt/β-catenin pathway. In conclusion, TRIM16 E121D variant impacts both risk and prognosis of HCC via regulation of Wnt/β-catenin pathway, which may lead to better understanding the pathogenesis of HCC.

Tenofovir alafenamide and tenofovir disoproxil fumarate reduce incidence of hepatocellular carcinoma in patients with chronic hepatitis B

Antiviral therapy may attenuate the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). We aimed to explore how tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) affect HCC risk in patients with CHB. The REACH-B, aMAP, and mPAGE-B models were utilized to assess HCC risk in patients with CHB from two global randomized-controlled trials evaluating the impact of TAF vs. TDF treatment. Standard incidence ratios (SIRs) were calculated using data from the REACH-B model as a ratio of observed HCC cases in the TAF- or TDF-treated patients vs. predicted HCC cases for untreated historical controls. Proportions of treated patients shifting aMAP and mPAGE-B risk categories between baseline and Week 240 were calculated. Of the 1,632 patients (TAF, n= 1,093; TDF, n= 539) followed for up to 300 weeks, 22 HCC cases developed. Those receiving TAF had an SIR that was lower compared to the SIR of individuals receiving TDF: 0.32 (p <0.001) vs. 0.56 (p= 0.06). In the general study population, individuals without cirrhosis at baseline had an SIR that was lower compared to the SIR of individuals with cirrhosis at baseline: 0.37 (p <0.001) vs. 0.58 (p= 0.15). Of the patients at low risk of HCC at baseline, the majority (97%) remained low risk by mPAGE-B and aMAP scoring at Week 240. Among those at medium or high risk at baseline, substantial portions shifted to a lower risk category by Week 240 (mPAGE-B: 22% and 42%; aMAP: 39% and 63%, respectively). This evaluation provides evidence that treatment with TAF or TDF can reduce HCC risk in patients with CHB, particularly in patients without cirrhosis. Despite the substantial impact of HCC on long-term outcomes of patients with CHB, the differential risk of HCC development among those receiving treatment with TAF vs. TDF has not been well elucidated. Using three validated risk prediction models, we found that TAF is at least as effective as TDF in reducing HCC risk in patients with CHB. While TDF is well-studied in the context of HCC risk reduction, our novel findings underscore the effectiveness of TAF as a treatment option for patients with CHB. NCT01940341; NCT02836249; NCT01940471; NCT02836236.