Risk Of Hepatocellular Carcinoma Research Articles

Role of biomarkers in the diagnosis and management of HCC.

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

Hepatocellular carcinoma surveillance after HBsAg seroclearance

Hepatitis B surface antigen (HBsAg) seroclearance is considered the functional cure and the optimal treatment endpoint for chronic hepatitis B (CHB). Patients with CHB who cleared HBsAg generally have a favorable clinical course with minimal risk of developing hepatocellular carcinoma (HCC) or cirrhotic complications. Nevertheless, a minority of patients still develop HCC despite HBsAg seroclearance. While patients with liver cirrhosis are still recommended for HCC surveillance, whether other non-cirrhotic patients who achieved HBsAg seroclearance should remain on HCC surveillance remains unclear. This review provides an overview of the incidence of HBsAg seroclearance, the factors associated with the occurrence of HBsAg seroclearance, the durability of HBsAg seroclearance, the risk of developing HCC after HBsAg seroclearance, the risk factors associated with HCC development after HBsAg seroclearance, the role of HCC risk scores, and the implications on HCC surveillance. Existing HCC risk scores have a reasonably good performance in patients after HBsAg seroclearance. In the era of artificial intelligence, future HCC risk prediction models based on artificial intelligence and longitudinal clinical data may further improve the prediction accuracy to establish a foundation of a risk score-based HCC surveillance strategy. As different novel hepatitis B virus (HBV) antiviral agents aiming at HBsAg seroclearance are under active development, new knowledge is anticipated on the natural history and HCC risk prediction of patients treated with new HBV drugs.

Nomogram for preoperative estimation of microvascular invasion risk in hepatocellular carcinoma

Microvascular invasion (MVI) is an adverse prognostic indicator of tumor recurrence after surgery for hepatocellular carcinoma (HCC). Therefore, developing a nomogram for estimating the presence of MVI before liver resection is necessary. We retrospectively included 260 patients with pathologically confirmed HCC at the Fifth Medical Center of Chinese PLA General Hospital between January 2021 and April 2024. The patients were randomly divided into a training cohort (n = 182) for nomogram development, and a validation cohort (n = 78) to confirm the performance of the model (7:3 ratio). Significant clinical variables associated with MVI were then incorporated into the predictive nomogram using both univariate and multivariate logistic analyses. The predictive performance of the nomogram was assessed based on its discrimination, calibration, and clinical utility. Serum carnosine dipeptidase 1 ([CNDP1] OR 2.973; 95 % CI 1.167–7.575; p = 0.022), cirrhosis (OR 8.911; 95 % CI 1.922–41.318; p = 0.005), multiple tumors (OR 4.095; 95 % CI 1.374–12.205; p = 0.011), and tumor diameter ≥3 cm (OR 4.408; 95 % CI 1.780–10.919; p = 0.001) were independent predictors of MVI. Performance of the nomogram based on serum CNDP1, cirrhosis, number of tumors and tumor diameter was achieved with a concordance index of 0.833 (95 % CI 0.771–0.894) and 0.821 (95 % CI 0.720–0.922) in the training and validation cohorts, respectively. It fitted well in the calibration curves, and the decision curve analysis further confirmed its clinical usefulness. The nomogram, incorporating significant clinical variables and imaging features, successfully predicted the personalized risk of MVI in HCC preoperatively.

Hepatocellular carcinoma among patients with chronic hepatitis B in the indeterminate phase.

Hepatitis B virus (HBV) infection is a dynamic disease where patients progress through several stages defined by HBV e-antigen (HBeAg) status, HBV-DNA levels and transaminase elevations, with antiviral therapy indicated only in specific stages. However, some patients cannot be classified into one of the stages and are said to fall into an 'indeterminate phase' or 'grey zone'. Exact definitions of the indeterminate phase vary from guideline to guideline as a result of different cut-off values for biomarker measurements. Data suggest that as many as 50% of HBV patients may be in an indeterminate phase and may not rapidly transition out of this phase. Clinical data that suggest these patients are at increased risk of hepatocellular carcinoma (HCC) are complemented by molecular evidence of integrations of HBV-DNA into the host genome, chromosomal translocations and immune activation despite liver enzymes that may suggest lack of inflammation. Antiviral therapy reduces these hepatocarcinogenic mechanisms and is reflected in a reduction of fibrosis and HCC risk. We review key data on patients in the indeterminate phase, with emphasis on HCC as an outcome. We take a holistic approach and link new biological data with clinical observations as well as examine the potential role of antiviral therapy in reducing HCC risk among patients in the indeterminate phase. With the availability of safe and effective oral antivirals, consideration must be given as to how much residual risk of HCC should be tolerated among patients in the indeterminate phase.

External validation of models to predict hepatocellular carcinoma in Hepatitis C Virus cured F3-F4 patients.

Several hepatocellular carcinoma (HCC) risk-models have been developed to individualise patient surveillance following sustained viral response (SVR) in Hepatitis C Virus patients. Validation of these models in different cohorts is an important step to incorporate a more personalised risk assessment in clinical practice. We aimed at applying these models to stratify the risk in our patients and potentially determine cost-saving associated with individualised HCC risk-stratification screening strategy. Patients with baseline F3-4 fibrosis treated with new oral direct-acting antivirals who had reached a SVR were regularly followed as part of the HCC surveillance strategy. Six models were applied: Pons, aMAP, Ioannou, HCC risk, Alonso and Semmler. Validation of the models was performed based on sensitivity and the proportion of patients labelled as "high risk". After excluding 557 with less than 3 fibrosis, 12 without SVR, 18 with a follow up (FU)<1year, 17 transplant recipients, 16 lost to FU and 31 with HCC at time of antiviral therapy, our cohort consisted of 349 F3-4 SVR patients. Twenty-three patients (6.6%) developed HCC after a median FU of 5.12years. The sensitivity of the different models varied between 0.17 (Semmler7noalcohol) and 1 (Alonso A and aMAP). The lowest proportion of high-risk patients corresponded to the Semmler-noalcohol model (5%). Sixty-three and 90% of the Alonso A and aMAP patients, respectively were labelled as high risk. The most reliable HCC risk-model applied to our cohort to predict HCC development is the Alonso model (based on fibrosis stage assessed by liver stiffness measurements or Fibrosis-4 index (FIB-4) at baseline and after 1year, and albumin levels at 1year) with a-100% sensitivity in detecting HCC among those at high risk and 63% labelled as high risk. The application of the model would have saved the cost of 1290 ultrasound no longer being performed in the 37% low-risk group. In our cohort, the Alonso A model allows the most reliable reduction in HCC screening resulting in safely stopping life-long monitoring in about a third of F3-F4 patients achieving SVR with DAAs.

Evolutionary changes in metabolic dysfunction-associated steatotic liver disease and the risk of hepatocellular carcinoma: a nationwide cohort study.

To determine the association between evolutionary changes in metabolic dysfunction-associated steatotic liver disease (MASLD) status and the risk of hepatocellular carcinoma (HCC) in a nationwide population-based cohort. Information on study participants were derived from the Korea National Health Insurance Service database. The study population consisted of 5,080,410 participants who underwent two consecutive biennial health screenings between 2009 and 2012. All participants were followed up until HCC, death, or 31 December 2020. Association of evolutionary changes in MASLD status as assessed by fatty liver index and cardiometabolic risk factors, including persistent non-MASLD, resolved MASLD, incident MASLD, and persistent MASLD, with HCC risk was evaluated using the multivariable-adjusted Cox proportional hazards regression. Among the 5,080,410 participants with 39,910,331 person-years of follow-up, 4,801 participants developed HCC. The incidence of HCC in participants with resolved, incident, and persistent MASLD was approximately 2.2-, 2.3-, and 4.7-fold higher, respectively, than that in those with persistent non-MASLD among the Korean adult population. When stratifying the participants according to the evolutionary change in MASLD status, persistent (adjusted hazard ratio [aHR], 2.94; 95% confidence interval [CI], 2.68-3.21; P<0.001), incident (aHR, 1.85; 95% CI, 1.63-2.10; P<0.001), and resolved MASLD (aHR, 1.33; 95% CI, 1.18-1.50; P<0.001) had an increased risk of HCC than that of persistent non-MASLD. The evolutionary changes in MASLD were associated with the differential risk of HCC independent of metabolic risk factors and concomitant medications, providing additional information on the risk of HCC stratification in patients with MASLD.

Expanding indications for chronic hepatitis B treatment: Is it really desirable to treat everyone?

Chronic viral hepatitis causes an increased risk of progressive liver disease and hepatocellular carcinoma. On the wave of the World Health Organization’s goal to reduce new cases and deaths from hepatitis B and C by 2030, there is an increasing call to expand the indications for treatment of chronic hepatitis B. Currently, the main goal of treatment is to achieve a functional cure due to the inability of current drugs to completely eradicate the virus. There are still many discrepancies between available guidelines in terms of eligibility for treatment as well as an uncertainty about the appropriate treatment duration. This editorial addresses key questions about the topic and whether indications for treatment should be expanded.

Correlation between CEUS LI-RADS categorization of HCC < 20 mm and clinic-pathological features

ObjectiveTo retrospectively evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) LI-RADS in liver nodules < 20 mm at high risk of hepatocellular carcinoma (HCC) and their correlation with clinic-pathological features.MethodsA total of 432 pathologically proved liver nodules < 20 mm were included from January 2019 to June 2022. Each nodule was categorized as LI-RADS grade (LR)-1 to LR-5 through LR-M according to CEUS LI-RADS. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of CEUS LI-RADS were evaluated using pathological reference standard. Correlations between clinic-pathological features and CEUS LI-RADS categorization, together with major CEUS features, were further explored.ResultsWith LR-5 to diagnose HCC, the sensitivity, specificity, PPV, NPV, and AUC were 50.3%, 70.0%, 91.2%, 18.5%, and 0.601, respectively. The proportion of LR-5 in primary HCCs was significantly higher than that in recurrent ones (p = 0.014). HCC 10–19 mm showed significantly more frequent arterial phase hyper-enhancement (APHE) and late washout (p < 0.05) and less no-washout (p = 0.003) compared with those in HCC < 10 mm. Well-differentiated HCCs showed more frequent non-APHE and no-washout than moderate- and poor-differentiated HCCs (p < 0.05). Upgrading “APHE without washout” LR-4 nodules 10–19 mm with HCC history and “APHE with late mild washout” LR-4 nodules < 10 mm to LR-5 could improve the diagnostic performance of LR-5. The corresponding sensitivity, specificity, PPV, NPV, and AUC are 60.2%, 70.0%, 92.6%, 22.1%, and 0.651, respectively.ConclusionsCEUS LI-RADS is valuable in the diagnosis of HCC < 20 mm and performance can be improved with the combination of clinic-pathological features.Critical relevance statementCEUS LI-RADS was valuable in the diagnosis of HCC < 20 mm and its diagnostic performance can be improved by combining clinic-pathological features. Further research is needed to define its value in this set of lesions.Key PointsContrast-enhanced ultrasound can detect small liver lesions where LI-RADS accuracy is uncertain.Many LI-RADS Grade-4 nodules were upgraded to Grade-5 by combining imaging with clinic-pathological factors.The reclassification of LI-RADS Grade-5 can improve sensitivity without decreasing positive predictive value.Graphical

Causal association between lipid-lowering drugs and cancers: A drug target Mendelian randomization study.

Accumulating evidences have indicated that lipid-lowering drugs have effect for the treatment of cancers. However, causal associations between lipid-lowering drugs and the risk of cancers are still unclear. In our study, we utilized single nucleotide polymorphisms of proprotein convertase subtilis kexin 9 (PCSK9) inhibitors and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitors and performed a drug target Mendelian randomization to explore the causal association between lipid-lowering drugs and the risk of cancers. Five regression methods were carried out, including inverse variance weighted (IVW) method, MR Egger, weighted median, simple mode and weighted mode methods, of which IVW method was considered as the main analysis. Our outcome dataset contained the risk of breast cancer (BC), colorectal cancer, endometrial cancer, gastric cancer (GC), hepatocellular carcinoma (HCC), lung cancer, esophageal cancer, prostate cancer (PC), and skin cancer (SC). Our results demonstrated that PCSK9 inhibitors were significant associated with a decreased effect of GC [IVW: OR = 0.482, 95% CI: 0.264-0.879, P = .017]. Besides, genetic inhibitions of HMGCR were significant correlated with an increased effect of BC [IVW: OR = 1.421, 95% CI: 1.056-1.911, P = .020], PC [IVW: OR = 1.617, 95% CI: 1.234-2.120, P = .0005] and SC [IVW: OR = 1.266, 95% CI: 1.022-1.569, P = .031]. For GC [IVW: OR = 0.559, 95% CI: 0.382-0.820, P = .0029] and HCC [IVW: OR = 0.241, 95% CI: 0.085-0.686, P = .0077], HMGCR inhibitors had a protective risk. Our method suggested that PCSK9 inhibitors were significant associated with a protective effect of GC. Genetic inhibitions of HMGCR were significant correlated with an increased effect of BC, PC and SC. Meanwhile, HMGCR inhibitors had a protective risk of GC and HCC. Subsequent studies still needed to assess potential effects between lipid-lowering drugs and the risk of cancers with clinical trials.

Circulating fatty acids and risk of hepatocellular carcinoma and chronic liver disease mortality in the UK Biobank

Nuclear magnetic resonance (NMR)-based plasma fatty acids are objective biomarkers of many diseases. Herein, we aim to explore the associations of NMR-based plasma fatty acids with the risk of hepatocellular carcinoma (HCC) and chronic liver disease (CLD) mortality in 252,398 UK Biobank participants. Here we show plasma levels of n-3 poly-unsaturated fatty acids (PUFA) and n-6 PUFA are negatively associated with the risk of incident HCC [HRQ4vsQ1: 0.48 (95% CI: 0.33–0.69) and 0.48 (95% CI: 0.28–0.81), respectively] and CLD mortality [HRQ4vsQ1: 0.21 (95% CI: 0.13–0.33) and 0.15 (95% CI: 0.08–0.30), respectively], whereas plasma levels of saturated fatty acids are positively associated with these outcomes [HRQ4vsQ1: 3.55 (95% CI: 2.25–5.61) for HCC and 6.34 (95% CI: 3.68–10.92) for CLD mortality]. Furthermore, fibrosis stage significantly modifies the associations between PUFA and CLD mortality. This study contributes to the limited prospective evidence on the associations between plasma-specific fatty acids and end-stage liver outcomes.

MEG3 rs7158663 genetic polymorphism is associated with the risk of hepatocellular carcinoma

Recently, a meta-analysis has shown that a potentially functional genetic polymorphism (rs7158663 A > G) on the cancer-associated lncRNA MEG3 is associated with the risk of many types of cancer. Given the important role of MEG3 in the development of hepatocellular carcinoma (HCC), the current study evaluated the association of the rs7158663 genetic polymorphism with HCC risk. A total of 271 HCC patients and 267 healthy individuals were included in the current case-control study. Direct sequencing was used to detect the rs7158663 locus genotype of the included individuals. The case-control study showed that the MEG3 rs7158663 genetic polymorphism was associated with the increased risk of developing HCC [GA vs. GG: OR = 1.63, 95% CI = 1.14–2.34, p = 0.009; AA vs. GG: OR = 2.10, 95% CI = 1.10–4.08, p = 0.03; (GA + AA) vs. GG: OR = 1.70, 95% CI = 1.21–2.40, p = 0.003; A vs. G: OR = 1.53, 95% CI = 1.17–2.00, p = 0.002]. In addition, the genotype-tissue expression showed that the rs7158663 AA or GA genotype was associated with reduced MEG3 expression. Bioinformatic analysis showed that the rs7158663 genetic polymorphism not only affects the binding of transcription factors but also interacts with multiple genes through chromatin loops. In summary, the current findings suggest that the rs7158663 genetic polymorphism affecting MEG3 expression is associated with HCC risk and may serve as a marker of genetic susceptibility to HCC. However, the specific molecular mechanisms of the rs7158663 genetic polymorphism in the development of HCC need to be further revealed.

PNPLA3, obesity and heavy alcohol use in cirrhosis patients may exert a synergistic increase hepatocellular carcinoma risk

Background & AimsIn patients with cirrhosis, continued heavy alcohol consumption and obesity may increase risk of hepatocellular carcinoma (HCC). We examined whether germline susceptibility to hepatic steatosis not only independently predisposes to HCC but may also act synergistically with other risk factors. MethodsWe analyzed data from 1911 patients in two multicenter prospective cohort studies in the U.S. We classified patients according to alcohol consumption (current heavy vs. not current heavy), obesity (body mass index [BMI] ≥30 vs. <30), and PNPLA3 I148M variant status (carrier of at least one G risk allele vs. noncarrier). We examined the independent and joint effects of these risk factors on risk of developing HCC using Cox regression with competing risks. ResultsMean age was 59.6y, 64.3% male, 28.7% Hispanic, 18.3% non-Hispanic Black, 50.9% were obese, 6.2% had current heavy alcohol consumption, and 58.4% harbored at least one PNPLA3 G-allele. 116 patients developed HCC. Compared to PNPLA3 noncarriers without heavy alcohol consumption, HCC risk was 2.65-fold higher (hazard ratio [HR], 2.65; 95% confidence interval [CI], 1.20-5.86) for carriers who had current heavy alcohol consumption. Compared to noncarrier patients without obesity, HCC risk was higher (HR, 2.40; 95%CI, 1.33-4.31) for carrier patients who were obese. PNPLA3 and alcohol consumption effect was stronger among patients with viral etiology of cirrhosis (HR, 3.42; 95% CI, 1.31-8.90). PNPLA3 improved 1-year risk prediction for HCC when added to a clinical risk model. ConclusionsThe PNPLA3 variant may help refine risk stratification for HCC in patients with cirrhosis with heavy alcohol consumption or obesity who may need specific preventive measures.

Pre-diagnostic plasma proteomics profile for hepatocellular carcinoma.

Proteomics may discover pathophysiological changes related to hepatocellular carcinoma (HCC), an aggressive and lethal type of cancer with low sensitivity for early-stage diagnosis. We measured 1,305 pre-diagnostic (median 12.7 years) SOMAscan proteins from 54 pairs of healthy individuals who subsequently developed HCC and matched non-HCC controls from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP). In NHS/HPFS, we identified 56 elevated proteins in HCC with absolute fold-change >1.2 and Wald test P < .05 in conditional logistic regression analysis. Ingenuity Pathway Analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins, chitinase-3-like protein 1, growth/differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin, showed strong positive associations with HCC and were thus validated by ELISA (odds ratio ranged 2.48-14.7, all P < .05) in the NHS/HPFS and by Olink platform (hazard ratio ranged 1.90-3.93, all P < .05) in the UKB-PPP. Adding these four proteins to a logistic regression model of traditional HCC risk factors increased the area under the curve (AUC) from 0.67 to 0.87 in the NHS/HPFS. Consistently, model AUC was 0.88 for HCC risk prediction in the UKB-PPP. However, the limited number of HCC cases in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.

A polygenetic risk score combined with environmental factors better predict susceptibility to hepatocellular carcinoma in Chinese population.

This study aimed to investigate environmental factors and genetic variant loci associated with hepatocellular carcinoma (HCC) in Chinese population and construct a weighted genetic risk score (wGRS) and polygenic risk score (PRS). A case-control study was applied to confirm the single nucleotide polymorphisms (SNPs) and environmental variables linked to HCC in the Chinese population, which had been screened by meta-analyses. wGRS and PRS were built in training sets and validation sets. Area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), Akaike information criterion (AIC), and Bayesian information criterion (BIC) were applied to evaluate the performance of the models. A total of 13 SNPs were included in both risk prediction models. Compared with wGRS, PRS had better accuracy and discrimination ability in predicting HCC risk. The AUC for PRS in combination with drinking history, cirrhosis, HBV infection, and family history of HCC in training sets and validation sets (AUC: 0.86, 95% CI: 0.84-0.89; AUC: 0.85, 95% CI: 0.81-0.89) increased at least 20% than the AUC for PRS alone (AUC: 0.63, 95% CI: 0.60-0.67; AUC: 0.65, 95% CI: 0.60-0.71). A novel model combining PRS with alcohol history, HBV infection, cirrhosis, and family history of HCC could be applied as an effective tool for risk prediction of HCC, which could discriminate at-risk individuals for precise prevention.

Does SLC39A8 Ala391Thr confer risk of chronic liver disease?

Manganese is an important co-factor for numerous biological processes, including defense against reactive oxygen species. A common genetic variant in the manganese transporter SLC39A8 (p.Ala391Thr) has been associated with lower blood levels of manganese and with increases in markers of liver cell damage. Whether the variant confers an increased risk of liver disease is unclear. We tested the association of this variant with biochemical, imaging, and clinical hepatic traits and outcomes in large general population cohorts totaling up to one million individuals, including 991 cases with hepatocellular carcinoma (HCC) and 7,191 with cirrhosis. We found that the Thr-allele of p.Ala391Thr was associated with slightly higher plasma alanine transaminase and aspartate transaminase, markedly higher corrected T1 on hepatic magnetic resonance imaging (MRI), a presumed marker of liver inflammation, and with lower hepatic computed tomography attenuation. However, the variant was not associated with hepatic fat content, nor with the risk of HCC or cirrhosis. In conclusion, SLC39A8 p.Ala391Thr is associated with biochemical and imaging markers of hepatic inflammation, but the variant does not confer a higher risk of chronic liver disease. We hypothesize that the associations with hepatic imaging traits are due to lower hepatic manganese levels in carriers of the variant.

Transplantace jater pro chronickou hepatitidu C – význam protivirové léčby v roce 2024

Summary: Liver failure due to cirrhosis and hepatocellular carcinoma (HCC) in hepatitis C (HCV) infection is still one of the main indications for liver transplantation (LTx) in Western countries. In patients with compensated liver cirrhosis C, antiviral therapy should be initiated promptly, as complications, i.e. decompensation of the disease and HCC, can occur in a short time frame. Successful antiviral treatment of HCV in patients with cirrhosis reduces the risk of decompensation, HCC, and death from liver failure, thus reducing the need for LTx in these patients. Treatment in a patient with decompensated liver cirrhosis before LTx aims not only to prevent HCV recurrence in the liver graft but also to improve liver function. In patients on the waiting list, improvement of liver function may lead to removal from the waiting list. LTx should be considered in all patients with chronic liver failure due to HCV in whom we expect prolongation of life expectancy after LTx compared to the natural course of their liver disease or for whom LTx will significantly improve the quality of life. LTx should be considered when life expectancy due to liver disease is one year or less. Before LTx, the patient should be thoroughly examined to exclude comorbidities that substantially complicate or preclude LTx. The advent of direct-acting antivirals into HCV treatment regimens represents a revolutionary step to prevent HCV recurrence in the graft, is either by eradicating HCV before LTx or by early treatment after LTx. Currently, HCV recurrence in the liver graft either by eradicating HCV before LTx or by early treatment after LTx. Currently, HCV recurrence in the liver graft no longer leads to worse survival in patients transplanted for HCV, and outcomes are fully comparable to those of LTx for other diagnoses. Key words: HCV – cirrhosis C – liver failure – hepatocellular carcinoma – liver transplantation – HCV recurrence

Natural History of Indeterminate Liver Nodules in Patients with Advanced Liver Disease: A Multi-Center Retrospective Cohort Study.

Indeterminate liver nodules (ILNs) are frequently encountered on diagnostic imaging after positive hepatocellular carcinoma (HCC) surveillance results, but their natural history remains unclear. We conducted a multi-center retrospective cohort study among patients with ≥1 newly detected LI-RADS 3 (LR-3) lesion ≥1 cm or LI-RADS 4 (LR-4) lesion of any size (per LI-RADS v2018) between January 2018 and December 2019. Patients were followed with repeat imaging at each site per institutional standard of care. Multivariable Fine-Gray models were used to evaluate associations between potential risk factors and patient-level time-to-HCC diagnosis, with death and liver transplantation as competing risks. Of 307 patients with ILNs, 208 had LR-3 lesions, 83 had LR-4 lesions, and 16 had both LR-3 and LR-4 lesions. HCC incidence rates for patients with LR-3 and LR-4 lesions were 110 (95%CI 70 - 150) and 420 (95%CI 310 - 560) per 1000 person-years, respectively. In multivariable analysis, incident HCC among patients with LR-3 lesions was associated with older age, thrombocytopenia (platelet count ≤150 x109/L), and elevated serum alpha-fetoprotein (AFP) levels. Among those with LR-4 lesions, incident HCC was associated with a maximum lesion diameter >1 cm. Although most patients had follow-up CT or MRI, 13.7% had no follow-up imaging and another 14.3% had follow-up ultrasound only. ILNs have a high but variable risk of HCC, with 4-fold higher risk in patients with LR-4 lesions than those with LR-3 lesions, highlighting a need for accurate risk stratification tools and close follow-up in this population.

SGLT2i impact on HCC incidence in patients with fatty liver disease and diabetes: a nation-wide cohort study in South Korea.

This study evaluated the effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on cancer development, particularly in hepatocellular carcinoma (HCC), in individuals with concomitant fatty liver disease (FLD) and type 2 diabetes mellitus (T2DM). Using data from Korea's Health Insurance Review and Assessment Service, we performed Kaplan-Meier and Cox regression analyses in patients with non-alcoholic fatty liver disease (NAFLD) and T2DM (NAFLD-T2DM cohort) and those with chronic viral hepatitis (CVH) alongside FLD and T2DM (FLD-T2DM-CVH cohort). In the propensity score (PS) matched NAFLD-T2DM cohort (N = 107,972), SGLT2i use was not associated with the occurrence of overall cancer, including HCC. However, old age, male sex, liver cirrhosis, and hypothyroidism were identified as independent risk factors for HCC occurrence, whereas statin and fibrate usage were associated with reduced HCC risk in this cohort in multivariate Cox analysis. In the PS-matched FLD-T2DM-CVH cohort (N = 2798), a significant decrease in HCC occurrence was observed among SGLT2i users (P = 0.03). This finding remained consistent in the multivariate Cox regression analysis (Hazard ratio = 2.21, 95% confidence interval = 1.01-4.85, P = 0.048). In conclusion, SGLT2i may be a beneficial option for diabetes management in patients with concomitant T2DM, FLD, and CVH while affirming the overall safety of SGLT2i in other types of cancer.

Reduction of the Risk of Hepatocellular Carcinoma over Time Using Direct-Acting Antivirals: A Propensity Score Analysis of a Real-Life Cohort (PITER HCV)

The treatment of hepatitis C virus (HCV) with direct-acting antivirals (DAA) leads to high sustained virological response (SVR) rates, but hepatocellular carcinoma (HCC) risk persists in people with advanced liver disease even after SVR. We weighted the HCC risk in people with cirrhosis achieving HCV eradication through DAA treatment and compared it with untreated participants in the multicenter prospective Italian Platform for the Study of Viral Hepatitis Therapies (PITER) cohort. Propensity matching with inverse probability weighting was used to compare DAA-treated and untreated HCV-infected participants with liver cirrhosis. Kaplan–Meier analysis and competing risk regression analysis were performed. Within the first 36 months, 30 de novo HCC cases occurred in the untreated group (n = 307), with a weighted incidence rate of 0.34% (95%CI: 0.23–0.52%), compared to 63 cases among SVR patients (n = 1111), with an incidence rate of 0.20% (95%CI: 0.16–0.26%). The 12-, 24-, and 36-month HCC weighted cumulative incidence rates were 6.7%, 8.4%, and 10.0% in untreated cases and 2.3%, 4.5%, and 7.0% in the SVR group. Considering death or liver transplantation as competing events, the untreated group showed a 64% higher risk of HCC incidence compared to SVR patients (SubHR 1.64, 95%CI: 1.02–2.62). Other variables independently associated with the HCC occurrence were male sex, increasing age, current alcohol use, HCV genotype 3, platelet count ≤ 120,000/µL, and albumin ≤ 3.5 g/dL. In real-life practice, the high efficacy of DAA in achieving SVR is translated into high effectiveness in reducing the HCC incidence risk.

Unmet needs in the post-DAA era: the risk and molecular mechanisms of hepatocellular carcinoma after HCV eradication.

Hepatitis C virus (HCV) is one of the major etiologies of hepatocellular carcinoma with approximately 30% of HCC being due to HCV infection worldwide. HCV eradication by antivirals greatly reduces the risk of HCC; nevertheless, HCC remains to occur in CHC patients who have achieved a sustained virological response (SVR). The proportion of post-SVR HCC among newly diagnosed HCC patients is increasing in the DAA era and might be due to preexisting inflammatory and fibrotic liver background, immune dysregulation between host and virus interaction, as well as host epigenetic scar, genetic predispositions and alternations. By means of applying surrogate markers and adopting risk stratification, HCC surveillance should be consistently performed in high-risk populations. In this review, we discuss the possible molecular mechanism, risk factors and surveillance strategy for HCC development after HCV eradication.