Significant Risk Factor For Hepatocellular Carcinoma Research Articles

Development of machine learning-based personalized predictive models for risk evaluation of hepatocellular carcinoma in hepatitis B virus-related cirrhosis patients with low levels of serum alpha-fetoprotein

Introduction and ObjectivesThe increasing incidence of hepatocellular carcinoma (HCC) in China is an urgent issue, necessitating early diagnosis and treatment. This study aimed to develop personalized predictive models by combining machine learning (ML) technology with a demographic, medical history, and noninvasive biomarker data. These models can enhance the decision-making capabilities of physicians for HCC in hepatitis B virus (HBV)-related cirrhosis patients with low serum alpha-fetoprotein (AFP) levels. Patients and MethodsA total of 6,980 patients treated between January 2012 and December 2018 were included. Pre-treatment laboratory tests and clinical data were obtained. The significant risk factors for HCC were identified, and the relative risk of each variable affecting its diagnosis was calculated using ML and univariate regression analysis. The data set was then randomly partitioned into validation (20 %) and training sets (80 %) to develop the ML models. ResultsTwelve independent risk factors for HCC were identified using Gaussian naïve Bayes, extreme gradient boosting (XGBoost), random forest, and least absolute shrinkage and selection operation regression models. Multivariate analysis revealed that male sex, age >60 years, alkaline phosphate >150 U/L, AFP >25 ng/mL, carcinoembryonic antigen >5 ng/mL, and fibrinogen >4 g/L were the risk factors, whereas hypertension, calcium <2.25 mmol/L, potassium ≤3.5 mmol/L, direct bilirubin >6.8 μmol/L, hemoglobin <110 g/L, and glutamic-pyruvic transaminase >40 U/L were the protective factors in HCC patients. Based on these factors, a nomogram was constructed, showing an area under the curve (AUC) of 0.746 (sensitivity = 0.710, specificity=0.646), which was significantly higher than AFP AUC of 0.658 (sensitivity = 0.462, specificity=0.766). Compared with several ML algorithms, the XGBoost model had an AUC of 0.832 (sensitivity = 0.745, specificity=0.766) and an independent validation AUC of 0.829 (sensitivity = 0.766, specificity = 0.737), making it the top-performing model in both sets. The external validation results have proven the accuracy of the XGBoost model. ConclusionsThe proposed XGBoost demonstrated a promising ability for individualized prediction of HCC in HBV-related cirrhosis patients with low-level AFP.

Exposure to Agent Orange and Hepatocellular Carcinoma Among US Military Personnel

Hepatocellular carcinoma (HCC) and its mortality are on the rise. Viral hepatitis and alcohol are leading risk factors; however, other risk factors among veterans are less defined, including Agent Orange (AO), an herbicide linked to several cancers. To assess the association of AO exposure and HCC in a national cohort of Vietnam veterans. This retrospective cohort study included Vietnam veterans who served between 1966 and 1975, were male, were older than 18 years at the time of deployment, and had established follow-up in the Veterans Affairs (VA) between 2000 and 2019. Veterans with AO exposure were identified in the disability data via validated clinical surveys. Relevant clinical risk factors for cirrhosis and HCC were collected. Patients were stratified based on cirrhosis status, as defined by consecutive diagnosis found by documented International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision scores or calculated Fibrosis-4 scores. Data were collected from January 1, 2019, to December 31, 2020, and analyzed from December 2020 to October 2023. Incident HCC was the primary outcome. AO and HCC association was estimated using a multivariable Cox regression analysis, with death and liver transplant as competing events. Of the 296 505 eligible veterans (222 545 [75.1%] White individuals and 44 342 [15.0%] Black individuals), 170 090 (57%) had AO exposure (mean [SD] age, 21.62 [3.49] years; 131 552 White individuals [83.2%] and 22 767 Black individuals [14.4%]) and 35 877 (12.1%) had cirrhosis. Veterans who were not exposed to AO were more likely to smoke (109 689 of 126 413 [86.8%] vs 146 061 of 170 090 [85.9%]); use alcohol (54 147 of 126 413 [42.8%] vs 71 951 of 170 090 [42.3%]) and have viral hepatitis (47 722 of 126 413 [37.8%] vs 58 942 of 170 090 [34.7%]). In a multivariable competing risk model, AO exposure was not associated with HCC. Among veterans with cirrhosis, self-identification as Hispanic individuals (aHR, 1.51; 95% CI, 1.30-1.75; P <.001) or Black individuals (aHR, 1.18; 95% CI, 1.05-1.32; P = .004), and having a diagnosis of viral hepatitis (aHR, 3.71; 95% CI, 3.26-4.24; P <.001), alcohol-associated liver disease (aHR, 1.32; 95% CI, 1.19-1.46; P <.001), and nonalcoholic fatty liver disease (NAFLD) (aHR, 1.92; 95% CI, 1.72-2.15; P <.001) were associated with HCC. Among veterans without cirrhosis, hypertension (aHR, 1.63; 95% CI, 1.23-2.15; P <.001) and diabetes (aHR, 1.52; 95% CI, 1.13-2.05; P = .005) were also associated with HCC. Early smoking and alcohol use were significant risk factors for HCC. In this large nationwide cohort study of Vietnam veterans, AO exposure was not associated with HCC. Smoking, alcohol, viral hepatitis, and NAFLD were the most important clinical risk factors for HCC.

Risk factors of hepatocellular carcinoma in non-alcoholic fatty liver disease: a systematic review and meta-analysis.

This study aimed to systematically review and quantitatively synthesize the existing evidence to better identify the high-risk population of hepatocellular carcinoma (HCC) in nonalcoholic fatty liver disease (NAFLD). We searched databases including MEDLINE, EMBASE, Web of Science, Cochrane Library, and ClinicalTrials.gov up to February 2023. The meta-analysis was performed using RevMan5.3 software, and we calculated the estimated combined effect using inverse variance weighting of OR. I2 statistics were used to quantify the inter-study heterogeneity. Funnel plots and Egger test were used to assess publication bias, and sensitivity analysis was carried out through the transformation effect model or the removal of literature one by one. Finally, 29 articles were included in the study, which involved a total of 726,656 patients with NAFLD. A total of 15 major risk factors were evaluated. Statistically significant risk factors were: advanced liver fibrosis (OR=6.40), diabetes (OR=2.38), obesity (OR=1.46), hypertension (OR=1.75), older age (OR=3.57), male (OR=2.45), alcohol intake (OR=2.98), smoking (OR=1.44), PNPLA3 genotype variation (OR=1.76), elevated liver enzymes (OR=2.92), low platelet counts (OR=4.61), and low albumin levels (OR=2.11). Our results showed that advanced liver fibrosis, diabetes, obesity, hypertension, older age, male, alcohol intake, smoking, PNPLA3 genotype variation, elevated liver enzymes, low platelet counts, and low albumin levels were all significant risk factors for HCC in NAFLD. However, dyslipidemia was not found to be a risk factor. Further exploration is needed to confirm whether Hispanic ethnicity and high ferritin levels are also risk factors.

Serum resistin and the risk for hepatocellular carcinoma in diabetic patients.

Hepatocellular carcinoma (HCC), the predominant type of liver cancer, is a major contributor to cancer-related fatalities across the globe. Diabetes has been identified as a significant risk factor for HCC, with recent research indicating that the hormone resistin could be involved in the onset and advancement of HCC in diabetic individuals. Resistin is a hormone that is known to be involved in inflammation and insulin resistance. Patients with HCC have been observed to exhibit increased resistin levels, which could be correlated with more severe disease stages and unfavourable prognoses. Nevertheless, the exact processes through which resistin influences the development and progression of HCC in diabetic patients remain unclear. This article aims to examine the existing literature on the possible use of resistin levels as a biomarker for HCC development and monitoring. Furthermore, it reviews the possible pathways of HCC initiation due to elevated resistin and offers new perspectives on comprehending the fundamental mechanisms of HCC in diabetic patients. Gaining a better understanding of these processes may yield valuable insights into HCC's development and progression, as well as identify possible avenues for prevention and therapy.

Predicting Hepatocellular Carcinoma Risk in Chronic Hepatitis B Patients Receiving Finite Periods of Antiviral Therapy

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most severe complications in chronic hepatitis B virus (HBV) infection. HCC can still develop in patients with chronic HBV (CHB) infection undergoing antiviral therapy. Several effective scoring systems for the prediction of HCC risk in CHB patients have been established. However, very few of them are designed for CHB patients receiving nucleos(t)ide analogues (NAs) therapy. Furthermore, none are available for HCC risk prediction in CHB patients receiving finite periods of antiviral therapy. METHODS: This study enrolled 790 consecutive treatment-naïve patients with CHB infection who had visited our liver clinics from 2008 to 2012 for pretreatment assessment before receiving antiviral therapies. The treatments were provided at finite periods according to the National Health Insurance Policy in Taiwan. The last follow-up date was 31 December 2021. We analyzed the virological and clinical factors in these 790 CHB patients receiving finite periods of NA treatments and identified the most significant risk factors for HCC to establish a novel predictive scoring system. By using stepwise selection in a multivariate Cox proportional hazards model, we divided the patients into three risk groups. RESULTS: Our predictive scoring system included five independent variables: genotype C (adjusted HR [aHR] = 2.23), NA-withdraw-related hepatitis relapse (aHR = 6.96), male (aHR = 4.19), liver cirrhosis (aHR = 11.14), and T1768A core promoter mutation (aHR = 3.21). This model revealed significant differences in HCC incidence among the three risk groups. The 5-year cumulative HCC risk significantly differed among the three risk groups (low risk: 1.33%, moderate risk: 4.99%, and high risk: 17.46%), with log-rank test p &lt; 0.001. CONCLUSION: Our predictive scoring system is a promising tool for the prediction of HCC in CHB patients receiving finite NA treatments. Genotype C, NA-withdraw-related hepatitis relapse, male gender, liver cirrhosis, and the T1768A HBV core promoter mutation were significant independent risk factors.

Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma: Experimental and clinical scenarios.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Viral hepatitis is a significant risk factor for HCC, although metabolic syndrome and diabetes are more frequently associated with the HCC. With increasing prevalence, there is expected to be > 1 million cases annually by 2025. Therefore, there is an urgent need to establish potential therapeutic targets to cure this disease. Peroxisome-proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that plays a crucial role in the patho-physiology of HCC. Many synthetic agonists of PPARγ suppress HCC in experimental studies and clinical trials. These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC. However, some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy. Thus natural PPARγ agonists can be an alternative to exploit this potential target for HCC treatment. In this review, the regulatory role of PPARγ in the pathogenesis of HCC is elucidated. Furthermore, the experimental and clinical scenario of both synthetic and natural PPARγ agonists against HCC is discussed. Most of the available literature advocates PPARγ as a potential therapeutic target for the treatment of HCC.

Prevalence and Risk Factor for Hepatocellular Carcinoma in Individuals with Hemophilia in the Era of Direct-Acting Antiviral Agents: A National Inpatient Sample Study

▪Background: Hepatocellular carcinoma (HCC) is a major complication of chronic hepatitis C virus (HCV) infection. HCV is the leading cause of liver disease in hemophilia population and was acquired with their first transfusion. While direct-acting antiviral agents (DAAs) are effective in HCV eradication, its impact on preventing HCC remains unclear. Few data on HCC in hemophilia after DAA are available. We undertook an observational study to determine the prevalence of and risk factors for HCC in hemophilia since the introduction of DAAs.Methods: We conducted an observational study including adult male discharges in the National Inpatient Sample (NIS) database from 2016-2018. Status of hemophilia (H) and non-hemophilia (NH), HCV, HCC, and other relevant medical conditions were identified using ICD-10 codes. Analysis included NIS-provided discharge-level weights to reflect national estimates. Categorical and continuous variables were assessed by Rao-Scott Chi-Square and weighted simple linear regression, respectively. Weighted multivariable logistic regression was performed to determine HCC risk factors. Variables included were age, race, HCV, HIV, alcoholism, smoking, obesity, hyperlipidemia (HLD), non-alcoholic steatohepatitis (NASH), substance abuse, transfusion, and Charlson comorbidity index (CCI).Results: In total, 7,674,969 adult male discharges, including 3,370 with H (0.04%), were identified between 2016 and 2018. Between 2016 and 2018, the diagnosis rates of HCV were 10.06% (95%CI 8.97%-11.26%) in H vs. 1.22% (95%CI 1.19%-1.25%) in NH, and the rates of HCC were 1.07% (95%CI 0.76%-1.51%) in H vs. 0.27% (95%CI 0.26%-0.28%) in NH. The diagnosis rates of HCV and HCC were similar in 2016, 2017 and 2018, for both H and NH populations. Compared with H without HCC, H with HCC were older (58.6 vs. 50.9 years-old, p<0.001), had higher CCI (mean : 6.5 ± 0.6 vs. 2.0 ± 2.0, p<0.001), and higher prevalence of HCV (36.11% vs. 9.78%, p<0.001), HBV (11.11% vs. 0.45%, p<0.001), NASH (5.56% vs. 0.12%, p<0.001), end-stage liver disease (88.89% vs. 8.61%, p<0.001), portal hypertension (27.78% vs. 2.61%, p<0.001), and platelet transfusion (11.11% vs. 1.44%, p<0.001). The prevalence of HIV infection between H with and without HCC was similar (8.33% vs. 8.82%, p=0.919). Among these with HCC, H were more likely to be younger (58.6 vs. 64.1 years-old, p=0.001), HIV (+) (8.33% vs. 1.64%, p=0.002), and less likely to have alcoholism (11.1% vs. 33.2%, p=0.018) and HLD (2.78% vs. 20.8%, p=0.008), than NH. The rates of cirrhosis, NASH, autoimmune hepatitis, and biliary cirrhosis were similar between groups. Multivariable logistic regression analysis among H patients indicated that NASH (OR 21.6, 95%CI 4.63-100.6), HCV (OR 3.96, 95%CI 1.55-10.2), and CCI (OR 1.54, 95%CI 1.39-1.72) were significant risk factors for HCC, while HIV (OR 0.02, 95% CI 0.00-0.13) and HLD (H: OR 0.07, 95% CI 0.01-0.39) were protective.Conclusion: From 2016 to 2018, the rate of HCC did not significantly decrease in discharges with hemophilia in the NIS database. Chronic HCV infection remains a significant risk factor of HCC in hemophilia despite availability of DAA therapy. NASH and Charlson comorbidity contribute to HCC risk, while HIV and hyperlipidemia appear protective. DisclosuresRagni: Takeda Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioMarin Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Bioverativ (Sanofi): Membership on an entity's Board of Directors or advisory committees; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees; Alnylam (Sanofi): Membership on an entity's Board of Directors or advisory committees; University of Pittsburgh: Research Funding.

Risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis B virus (HBV) infection: a systematic review and meta-analysis.

Hepatocellular carcinoma (HCC) is one of the leading contributors to cancer mortality worldwide and is a leading cause of death in individuals with chronic hepatitis B virus (HBV) infection. It is uncertain how the presence of other metabolic factors and comorbidities influences HCC risk in HBV. Therefore, we performed a systematic literature review and meta‐analysis to seek evidence for significant associations. MEDLINE, EMBASE and Web of Science databases were searched from 1 January 2000 to 24 June 2020 for studies investigating associations of metabolic factors and comorbidities with HCC risk in individuals with chronic HBV infection, written in English. We extracted data for meta‐analysis and generated pooled effect estimates from a fixed‐effects model. Pooled estimates from a random‐effects model were also generated if significant heterogeneity was present. We identified 40 observational studies reporting on associations of diabetes mellitus (DM), hypertension, dyslipidaemia and obesity with HCC risk. Only DM had a sufficient number of studies for meta‐analysis. DM was associated with >25% increase in hazards of HCC (fixed‐effects hazards ratio [HR] 1.26, 95% confidence interval (CI) 1.20–1.32, random‐effects HR 1.36, 95% CI 1.23–1.49). This association was attenuated towards the null in a sensitivity analysis restricted to studies adjusted for metformin use. In conclusion, in adults with chronic HBV infection, DM is a significant risk factor for HCC, but further investigation of the influence of antidiabetic drug use and glycaemic control on this association is needed. Enhanced screening of individuals with HBV and diabetes may be warranted.

Risk Scores for Hepatocellular Carcinoma in Chronic Hepatitis B: A Promise for Precision Medicine.

In the past 10 years, there have been over a dozen risk scores to predict the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). Many of the scores were derived in untreated CHB patients, while others were based on patients receiving antiviral therapy. In review of a total of 17 prediction scores, the variables included in these scores may be categorized into three groups: (1) liver fibrosis and cirrhosis, (2) hepatitis activities, and (3) host factors including comorbid conditions. HCC scores in untreated patients tended to include variables from all three categories, whereas of those derived in patients on therapy, few included variables representing hepatitis activities. Some variables which are well accepted as significant risk factors for HCC, such as family history, are not included in the majority of the scores. While the effects on HCC development of variables that represent hepatitic and inflammatory activities are relatively easily controlled by antiviral therapy, impact of fibrosis/cirrhosis as well as host and comorbidity factors are more difficult to modify. More work is needed for precision scores that comprehensively consider all of the relevant variables and provide individualized prediction which then may be applied to broad CHB populations. In the meantime, the existing scores are helpful for the clinician to counsel their patients of their risk of HCC, to determine candidacy for surveillance and to strategize to mitigate the risk of HCC by intervening in modifiable factors such as controlling viral/hepatitic activities and optimizing medical management of comorbidity.

A Diagnostic Dilemma of Hepatocellular Carcinoma on a Background of Thalassemia

Purpose: Thalassemia (HbH) is a chronic condition that may have potential complications of liver cirrhosis secondary to iron overload or hepatitis. Iron deposition in the liver can mask the classic imaging findings of hepatocellular carcinoma. We report an interesting case with similar nature with diagnostic dilemma, where multiple imaging modalities were unable to delineate the nature of the liver nature, and the patient was eventually diagnosed with hepatocellular carcinoma, after percutaneous biopsy was performed. Method: A 61-year-old male, with background history of HbH disease and transfusion dependent, presented with an incidental finding of 2 liver nodules on an ultrasound scan after complaints of right hypochondrium pain. A computed tomography (CT) scan diagnosed one nodule as a flash-filling haemangioma but was inconclusive about the other larger nodule. A magnetic resonance imaging (MRI) scan was also inconclusive but gave the differentials of extramedullary haematopoiesis. A sulphur colloid scan did not show uptake, making extramedullary haematopoiesis less likely. Results: A percutaneous biopsy of the indeterminate liver nodule was performed, and the histology showed hepatocellular carcinoma. The patient underwent wedge resection of the hepatocellular carcinoma and recovered well post-operatively. Conclusion: In the event of inconclusive imaging in patients with significant risk factors for hepatocellular carcinoma, a percutaneous biopsy should be performed for definitive diagnosis.

Long-term prospective study of development of hepatocellular carcinoma in compensated cirrhosis

Background and Aims: Hepatocellular carcinoma (HCC) is the 5th incident solid tumor in males and the 2nd for mortality. With the aim of identifying clinical/biologic risk factors for HCC development, we started in 2013 a prospective study in patients with liver cirrhosis undergoing hepatic venous pressure gradient (HVPG) measurement (ClinicalTrials.gov:NCT03083002). Method: 445 consecutive patients with liver cirrhosis prospectively enrolled from July 2013 (66.5% CP-A, 23.2% CP-B, 10.3% CP-C) when undergoing HVPG/transjugular liver biopsy, were followed-up every 6 months with US and blood tests. Etiology, portal vein thrombosis, HVPG,esophageal varices, Child-Pugh,MELD Score, time to HCC development were recorded. Incident cases of HCC were biopsied for pathological and transcriptomic characterization. Independent risk factors for HCC were evaluated by Cox regression analysis. Results: Median follow-up was 40 months. 61 patients died during follow-up, 34 developed HCC (incidence 4-5% per year). Preliminary results of analysis of hepatic and circulating biomarkers of angiogenesis, portal hypertension and fibrosis as predictive factors for HCC development indicate marked activation of angiogenesis as related with HCC risk. At univariate analysis HVPG>15 (but not HVPG>10 or >20 mmHg), F2/F3 esophageal varices, viral vs. non-viral etiology,and albumin were statistically associated with HCC development (HVPG/F2-F3 varices collinear). In HVPG>15 multivariate model, none of these factors was significantly associated with HCC development while in F2/F3 esophageal varices model,the latter were independently linked with it (HR 2.258,95% CI:1.135-4.494). Albumin only had borderline significance (.586, CI% .337-1.018). Conclusion: Neither HVPG>10,>15 or >20 was independently associated with HCC development. Previous data indicating HVPG>10 as a significant risk factor for HCC were influenced by the cohort studied, which was free of varices at enrollment. In a cohort of compensated patients with liver cirrhosis not selected for absence of varices, more severe portal hypertension as indicated by F2/F3 varices was the only independent risk factor for HCC development.

Hepatocellular carcinoma surveillance: An evidence-based approach.

Hepatocellular carcinoma (HCC) makes up 75%-85% of all primary liver cancers and is the fourth most common cause of cancer related death worldwide. Chronic liver disease is the most significant risk factor for HCC with 80%-90% of new cases occurring in the background of cirrhosis. Studies have shown that early diagnosis of HCC through surveillance programs improve prognosis and availability of curative therapies. All patients with cirrhosis and high-risk hepatitis B patients are at risk for HCC and should undergo surveillance. The recommended surveillance modality is abdominal ultrasound (US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with non-alcoholic fatty liver disease (NAFLD). With the current obesity epidemic and rise in the prevalence of NAFLD, abdominal computed tomography or magnetic resonance imaging may be indicated as the primary screening modality in these patients. The addition of alpha-fetoprotein to a surveillance regimen is thought to improve the sensitivity of HCC detection. Further investigation of serum biomarkers is needed. Semiannual screening is the suggested surveillance interval. Surveillance for HCC is underutilized and low adherence disproportionately affects certain demographics such as non-Caucasian race and low socioeconomic status.

Usefulness of Gd-EOB-DTPA-enhanced MRI for evaluating the potential for early development of hepatocellular carcinoma after HCV eradication by direct-acting antiviral treatment.

Objective: The development of hepatocellular carcinoma (HCC) is not uncommon in patients who achieve eradication of the hepatitis C virus through direct-acting antiviral (DAA) treatment. The aim of this study was to identify the patients at high risk for novel HCC development after a sustained virologic response (SVR) by DAA treatment.Patients and Methods: A total of 518 patients with no history of HCC treatment and who achieved SVR by DAA treatment were evaluated retrospectively. The correlations between HCC development and the patients’ characteristics were evaluated. For patients who underwent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) or dynamic contrast-enhanced computed tomography, the relationship between the imaging findings and subsequent HCC development was also assessed.Results: HCC developed newly in 22 patients, and the 1-year and 3-year cumulative HCC rates were 2.0% and 8.5%, respectively. In multivariate analysis, a FIB-4 index >4.0 and a post-treatment α-fetoprotein >4.0 ng/ml were significant risk factors for HCC. In 26 of 118 patients who underwent an MRI before DAA treatment, a non-hypervascular hypo-intense nodule was seen in the hepatobiliary phase, and in 6 of 182 patients who underwent a CT, a non-hypervascular hypo-enhanced nodule was seen in the delayed phase. The sensitivity and specificity of the MRI-positive findings for the subsequent development of HCC were 0.92 and 0.87, respectively, and those of the CT were 0.40 and 0.99, respectively. In multivariate analysis of patients who underwent an MRI, a non-hypervascular hypo-intense nodule was the only factor that was significantly related to HCC development (HR 32.4, p = 0.001).Conclusion: Gd-EOB-DTPA-enhanced MRI was found to be reliable for risk evaluation of subsequent HCC development in patients after SVR by DAA treatment. Patients with a non-hypervascular hypo-intense nodule need more careful observation for incident HCC.

Exosomes released by hepatocarcinoma cells endow adipocytes with tumor-promoting properties

BackgroundThe initiation and progression of hepatocellular carcinoma (HCC) are largely dependent on its local microenvironment. Adipocytes are an important component of hepatic microenvironment in nonalcoholic fatty liver disease (NAFLD), which is a significant risk factor for HCC. Given the global prevalence of NAFLD, a better understanding of the interplay between HCC cells and adipocytes is urgently needed. Exosomes, released by malignant cells, represent a novel way of cell-cell interaction and have been shown to play an important role in cancer cell communication with their microenvironment. Here, we explore the role of HCC-derived exosomes in the cellular and molecular conversion of adipocytes into tumor-promoting cells.MethodsExosomes were isolated from HCC cell line HepG2 and added to adipocytes. Transcriptomic alterations of exosome-stimulated adipocytes were analyzed using gene expression profiling, and secretion of inflammation-associated cytokines was detected by RT-PCR and ELISA. In vivo mouse xenograft model was used to evaluate the growth-promoting and angiogenesis-enhancing effects of exosome-treated adipocytes. Protein content of tumor exosomes was analyzed by mass spectrometry. Activated phospho-kinases involved in exosome-treated adipocytes were detected by phospho-kinase antibody array and Western blot.ResultsOur results demonstrated that HCC cell HepG2-derived exosomes could be actively internalized by adipocytes and caused significant transcriptomic alterations and in particular induced an inflammatory phenotype in adipocytes. The tumor exosome-treated adipocytes, named exo-adipocytes, promoted tumor growth, enhanced angiogenesis, and recruited more macrophages in mouse xenograft model. In vitro, conditioned medium from exo-adipocytes promoted HepG2 cell migration and increased tube formation of human umbilical vein endothelial cells (HUVECs). Mechanistically, we found HepG2 exosomes activated several phopho-kinases and NF-κB signaling pathway in exo-adipocytes. Additionally, a total of 1428 proteins were identified in HepG2 exosomes by mass spectrometry.ConclusionsOur results provide new insights into the concept that tumor cell-derived exosomes can educate surrounding adipocytes to create a favorable microenvironment for tumor progression.

Review article: the prevention of hepatitis B-related hepatocellular carcinoma.

Ample evidence indicates an aetiological association of persistent hepatitis B virus (HBV) infection with hepatocellular carcinoma (HCC). Several viral, host and external risk factors for the development of HBV-related HCC have been documented. To summarise and discuss the risk stratification and the preventive strategies of HBV-related HCC. Recent published studies identified from PubMed were comprehensively reviewed. The key words included chronic hepatitis B, HBV, hepatocellular carcinoma, prevention and antiviral therapy. The incidence of HCC is extremely high in HBV hyperendemic areas. For HBV patients left untreated, significant risk factors for HCC include male gender, aging, advanced hepatic fibrosis, persistent serum transaminase elevation, specific HBV entry receptor (NTCP) genotype, PM2.5 exposure, HBeAg positivity, HBV genotype C/D/F, high proportion of core promoter mutation, pre-S deletion, high serum levels of HBV DNA and HBsAg as well as co-infection with HCV, HDV and HIV. Primary prevention of HBV-related HCC can be achieved through universal HBV vaccination and anti-viral prophylaxis for high viraemic mothers. The goal of secondary prevention has been reached by effective anti-viral therapy to reduce the risk of HCC development in chronic hepatitis B patients. However, whether HCC is prevented or delayed deserves further examination. Finally, several studies confirmed the tertiary preventive effect of anti-viral therapy in reducing risk of HCC recurrence after curative therapies. Through the strategies of three-level prevention, the global burden of HBV-related HCC should decline over time and even be eliminated in conjunction with HBV cure.

Outcome of All-Oral Direct-Acting Antiviral Regimens on the Rate of Development of Hepatocellular Carcinoma in Patients with Hepatitis C Virus Genotype 1-Related Chronic Liver Disease

Objectives: There is little information on the risk factors for hepatocellular carcinoma (HCC) and outcome of treatment with an all-oral combination of direct-acting antiviral regimens following eradication of hepatitis C virus (HCV) RNA. Methods: The study subjects were 1,170 patients with HCV genotype 1-related chronic liver disease treated with either NS5A inhibitor plus NS3/4A protease inhibitor (n = 707), NS5A inhibitor plus NS5B polymerase inhibitor (n = 345), or NS5A inhibitor, NS3/4A protease inhibitor plus ritonavir (n = 118), for 12-24 weeks. All patients were free of HCC before and during therapy. Results: In this retrospective study, 22 patients developed HCC during the follow-up (time from the end of antiviral therapy until the last visit: 1.3 years). At 1 and 2 years after completion of the treatment, the cumulative HCC rates for the whole group were 1.8 and 2.3%, respectively, and 1.4 and 1.8%, respectively, for 1,065 patients who showed sustained virological response (SVR). The risk factors for HCC identified by multivariate analysis were hypoalbuminemia, thrombocytopenia, a high α-fetoprotein level, and non-SVR for all patients, and hypoalbuminemia and a high α-fetoprotein level for patients with SVR. Conclusion: Eradication of HCV RNA by direct-acting antiviral regimens might reduce the risk of HCC. Albumin and α-fetoprotein levels are significant risk factors for HCC.

Rapid Alanine Aminotransferase Normalization with Entecavir and Hepatocellular Carcinoma in Hepatitis B Virus-Associated Cirrhosis.

Sustained abnormal serum alanine aminotransferase (ALT) levels can increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. This study is aimed to confirm the impact of rapid ALT normalization (≤30IU/L) on HCC risk in patients with hepatitis B virus (HBV)-associated cirrhosis after entecavir (ETV) commencement. A total of 578 treatment-naïve patients with HBV-associated cirrhosis (mean age 51±9years, male sex 63.3%) were treated with ETV for more than 1year. Serum ALT and HBV DNA levels were measured at three time points (baseline, 6, and 12months after ETV commencement) and subjected to risk factor analysis. Median follow-up after ETV commencement was 43 (12-98) months. Cumulative incidences of HCC at 1, 3, 5, and 7years were 0.3, 8.5, 19.5, and 30.6%, respectively. Univariate Cox regression analysis showed that older age, abnormal ALT at 6months or 12months, and lower platelet count were significant risk factors for HCC. However, gender, HBeAg positivity, abnormal ALT levels or HBV DNA levels at baseline, and detectable HBV DNA at 6 or 12months were not risk factors. Multivariate analysis showed that older age (P<0.001), abnormal ALT at 12months (P=0.006), and lower platelet count (P=0.034) were the risk factors for HCC. Abnormal serum ALT levels after ETV commencement are significant risk factor for HCC. Therefore, ALT should be rapidly normalized to minimize the risk of HCC development in patients with HBV-associated cirrhosis.

Obesity Early in Adulthood Increases Risk but Does Not Affect Outcomes of Hepatocellular Carcinoma

Despite the significant association between obesity and several cancers, it has been difficult to establish an association between obesity and hepatocellular carcinoma (HCC). Patients with HCC often have ascites, making it a challenge to determine body mass index (BMI) accurately, and many factors contribute to the development of HCC. We performed a case-control study to investigate whether obesity early in adulthood affects risk, age of onset, or outcomes of patients with HCC. We interviewed 622 patients newly diagnosed with HCC from January 2004 through December 2013, along with 660 healthy controls (frequency-matched by age and sex) to determine weights, heights, and body sizes (self-reported) at various ages before HCC development or enrollment as controls. Multivariable logistic and Cox regression analyses were performed to determine the independent effects of early obesity on risk for HCC and patient outcomes, respectively. BMI was calculated, and patients with a BMI of 30 kg/m(2) or greater were considered obese. Obesity in early adulthood (age, mid-20s to mid-40s) is a significant risk factor for HCC. The estimated odds ratios were 2.6 (95% confidence interval [CI], 1.4-4.4), 2.3 (95% CI, 1.2-4.4), and 3.6 (95% CI, 1.5-8.9) for the entire population, for men, and for women, respectively. Each unit increase in BMI at early adulthood was associated with a 3.89-month decrease in age at HCC diagnosis (P < .001). Moreover, there was a synergistic interaction between obesity and hepatitis virus infection. However, we found no effect of obesity on the overall survival of patients with HCC. Early adulthood obesity is associated with an increased risk of developing HCC at a young age in the absence of major HCC risk factors, with no effect on outcomes of patients with HCC.

A Polymorphism in Interferon L3 Is an Independent Risk Factor for Development of Hepatocellular Carcinoma After Treatment of Hepatitis C Virus Infection

Polymorphisms in interferon (IFN)L3 (encodes IFNλ3 or interleukin 28B) are associated with outcomes of treatment for hepatitis C virus (HCV) infection. However, there is controversy regarding how polymorphisms in IFNL3 affect the risk for development of hepatocellular carcinoma (HCC) in patients treated with pegylated interferon and ribavirin. In a retrospective study, we analyzed data from 1118 patients with HCV infection (589 men; median age, 60 y; 49.9% infected with genotype 1; 51.3% with advanced fibrosis) treated with pegylated interferon and ribavirin from March 2000 through October 2009 at the Chang Gung Memorial Hospital in Kaohsiung, Taiwan (71.64% achieved sustained virologic response [SVR]). Baseline samples were collected before therapy. Starting 24 weeks after treatment, clinical and biochemical features were assessed every 3 to 6 months and patients underwent ultrasound examinations. Lesions detected were examined by computed tomography, angiography, or fine-needle aspiration biopsy analyses. Patients were followed up from the initiation of HCV therapy until a diagnosis of HCC (based on published guidelines), death, or March 31, 2013 (median, 60 mo). DNA samples from each patient were analyzed for rs12979860 in IFNL3. Kaplan-Meier analysis was used to determine the risk for development of HCC. The percentages of patients with the IFNL3 rs12979860 CC, CT, and TT genotypes were 86.4%, 13.2%, and 0.3%, respectively. A total of 108 patients (9.66%) developed HCC. The IFNL3 rs12979860 CT and TT genotypes correlated with high baseline levels of α-fetoprotein (AFP; ≥20 ng/mL), advanced stage of fibrosis, diabetes, or lack of an SVR (all P < .05). Based on multivariate Cox regression analysis, age 60 years and older, low platelet count (<15 × 10(9) cells/L), AFP level of 20 ng/mL or greater, advanced stage fibrosis, diabetes, lack of an SVR, and the IFNL3 rs12979860 CT and TT genotypes were significant risk factors for HCC (P < .05). Age 60 years and older, low numbers of platelets or high AFP level, and advanced fibrosis were risk factors for HCC among patients with a SVR. The IFNL3 rs12979860 genotype did not have a significant effect on risk for HCC among patients with SVRs, although some of these patients (with the CT or TT genotype) did develop HCC. Among patients without SVRs, only fibrosis stage and the IFNL3 rs12979860 CT and TT genotypes (hazard ratio, 1.80; 95% confidence interval, 1.06-3.07; P = .030) were independent risk factors for HCC. Based on a retrospective study of patients treated for HCV infection, the IFNL3 rs12979860 CT and TT polymorphisms are associated with a risk for HCC, especially in patients without a SVR.

Post-treatment Levels of α-Fetoprotein Predict Incidence of Hepatocellular Carcinoma After Interferon Therapy

In patients with chronic hepatitis C virus (HCV) infection, lack of sustained virologic response (SVR) 24 weeks after the end of interferon therapy is a significant risk factor for hepatocellular carcinoma (HCC). Although many pretreatment factors are known to affect HCC incidence, less is known about post-treatment factors-many change during the course of interferon therapy. We performed a prospective study, collecting data from 2659 patients with chronic hepatitis C without a history of HCC who had been treated with pegylated interferon (Peg-IFN) plus ribavirin from 2002 through 2008 at hospitals in Japan. Biopsy specimens were collected before treatment; all patients received Peg-IFN plus ribavirin for 48 to 72 weeks (HCV genotype 1) or 24 weeks (HCV genotype 2). Hematologic, biochemical, and virologic data were collected every 4 weeks during treatment and every 6 months after treatment. HCC was diagnosed based on angiography, computed tomography, and/or magnetic resonance imaging findings. HCC developed in 104 patients during a mean observation period of 40 months. Older age, male sex, lower platelet counts and higher levels of α-fetoprotein at baseline, and lack of an SVR were significant risk factors for HCC. The cumulative incidence of HCC was significantly lower in patients without SVRs who relapsed than those with no response to treatment. Levels of α-fetoprotein 24 weeks after the end of treatment (AFP24) were significantly lower than levels of α-fetoprotein at baseline in patients with SVRs and those who relapsed, but not in nonresponders. Post-treatment risk factors for HCC among patients with SVRs included higher AFP24 level and older age; among those without SVRs, risk factors included higher AFP24 level, integrated level of alanine aminotransferase, older age, and male sex. AFP24 (≥10 ng/mL, 10-5 ng/mL, and then <5 ng/mL) was a better predictor of HCC incidence than pretreatment level of AFP among patients with and without SVRs. In patients with chronic HCV infection, levels of α-fetoprotein decrease during interferon therapy. High post-treatment levels of α-fetoprotein predict HCC, regardless of whether patients achieve an SVR. University Hospital Medical Information Network Clinical Trials Registry: C000000196, C000000197.