A novel risk score for hepatocellular carcinoma in Asian cirrhotic patients: a multicentre prospective cohort study.
ABSTRACT: Liver cirrhotic patients suffer from a seemingly unpredictable risk of hepatocellular carcinoma (HCC). Here, an HCC risk score R (0???R???1) was derived from commonly tested haematological and biochemical parameters. In the score-derivation Taiwanese cohort (144 cirrhosis versus 48 HCC-remission patients), the score had an area-under-the-curve (AUC) of 0.70 (95% confidence interval [CI], 0.61-0.78, P?
Project description:Whether tenofovir disoproxil fumarate (TDF) is superior to entecavir in lowering the risk of hepatocellular carcinoma (HCC) development remains controversial. This retrospective study compared the incidences of HCC, cirrhotic events, and mortality between patients treated with entecavir and TDF. The study enrolled 1560 chronic hepatitis B (CHB) patients with cirrhosis from 2008 through 2018. All patients received entecavir or TDF monotherapy for at least 12 months before enrollment. Patients who had HCC or liver transplantation at initial treatment or within the first year of entecavir or TDF therapy were excluded. In the entire cohort, the cumulative incidence rates of HCC at 3, 5, and 10 years were 9.5%, 15.2%, and 25.4%, respectively. The entecavir group had a higher cumulative incidence of HCC than the TDF group (<i>P</i> = 0.001). A Cox regression analysis showed that entecavir group, old age, male sex, hepatic decompensation, diabetes mellitus, lower albumin levels, and platelet count were independent predictors of HCC. TDF treatment was significantly associated with a lower risk of HCC compared to entecavir treatment after adjustment with propensity score matching or inverse probability of treatment weighting in all patients. However, this association was not observed in patients with compensated cirrhosis at entry or patients enrolled after 2011, including after adjustment with propensity score matching or inverse probability of treatment weighting. No significant differences were observed in cirrhotic events and mortality or liver transplantation between the entecavir and TDF groups. In conclusion, the incidences of HCC did not differ significantly between patients with compensated cirrhosis or those enrolled over the same period treated with entecavir or TDF.
Project description:With the availability of potent antiviral therapies, complete suppression of hepatitis B virus (HBV) replication and total eradication of hepatitis C virus (HCV) can now be achieved. Despite these advances, hepatocellular carcinoma (HCC) still develops in a substantial proportion of cirrhotic patients, suggesting that host factors remain critical. Dysregulation of miRNAs is noted in many cancers, and circulating miRNAs can be readily assayed. In this study, we aimed to develop a circulating miRNA signature to assess the risk of HCC in cirrhotic patients. We first discovered that HBV- and HCV-related cirrhotic patients had distinguishable circulating miRNA profiles. A cohort of 330 cirrhotic patients was then compared against a cohort of 42 early HCC patients with complete remission. A score comprising 5 miRNAs and a binary etiology variable was established that was capable of differentiating between these two groups (AUC?=?72.5%, P?<?0.001). The 330 cirrhotic patients were further stratified into high- and low-risk groups, and all patients were longitudinally followed for 752 (11-891) days. Of them, 19 patients developed HCC. The high-risk group had significantly higher cumulative HCC incidence (P?=?0.038). In summary, a circulating miRNA-based score was developed that is capable of assessing HCC risks in cirrhotic patients.
Project description:The relation between aflatoxin B1 (AFB1 ) and cirrhosis in chronic carriers of hepatitis B virus (HBV) remains inconclusive. This case-control study nested in a large community-based cohort aimed to assess the effect of AFB1 exposure on cirrhosis and HCC in chronic HBV carriers. Serum AFB1 -albumin adduct levels at study entry were measured in 232 cirrhosis cases, 262 HCC cases and 577 controls. Multivariate-adjusted odds ratios (aORs) and 95% confidence intervals (95% CIs) were estimated using logistic regression. Among all chronic HBV carriers, the time intervals between study entry and diagnosis of HCC, cirrhosis, cirrhotic HCC, and non-cirrhotic HCC were all significantly (p?<?0.0001) shorter in participants with high serum levels of AFB1 -albumin adducts than those with low/undetectable levels. There were significant dose-response relations with serum AFB1 -albumin adduct level at study entry for cirrhosis (p-trend?=?0.0001) and cirrhotic HCC (p-trend?<?0.0001) newly diagnosed within 9 years after entry as well as non-cirrhotic HCC (p-trend?=?0.021) newly diagnosed within 4 years after entry. The aORs (95% CIs) for high versus undetectable serum AFB1 -albumin adduct levels were 2.45 (1.51-3.98) for cirrhosis (p?=?0.0003), 5.47 (2.20-13.63) for cirrhotic HCC (p?=?0.0003), and 5.39 (1.11-26.18) for non-cirrhotic (p?=?0.0368) HCC, respectively. There remained a significant dose-response relation between serum AFB1 -albumin adduct level and HCC risk (p-trend?=?0.0291) in cirrhosis patients, showing an aOR (95% CI) of 3.04 (1.11-8.30) for high versus undetectable serum levels (p?=?0.0299). It is concluded that AFB1 exposure may increase the risk of cirrhosis and HCC in a dose-response manner among chronic HBV carriers.
Project description:<h4>Background and aims</h4>Prognosis after liver transplantation differs between hepatocellular carcinoma (HCC) arising in cirrhotic and non-cirrhotic livers and aetiology is poorly understood. The aim was to investigate differences in mortality after liver transplantation between these patients.<h4>Methods</h4>We included patients from the European Liver Transplant Registry transplanted due to HCC from 1990 to November 2016 and compared cirrhotic and non-cirrhotic patients using propensity score (PS) calibration of Cox regression estimates to adjust for unmeasured confounding.<h4>Results</h4>We included 22,787 patients, of whom 96.5% had cirrhosis. In the unadjusted analysis, non-cirrhotic patients had an increased risk of overall mortality with a hazard ratio (HR) of 1.37 (95% confidence interval [CI] 1.23-1.52). However, the HR approached unity with increasing adjustment and was 1.11 (95% CI 0.99-1.25) when adjusted for unmeasured confounding. Unadjusted, non-cirrhotic patients had an increased risk of HCC-specific mortality (HR 2.62, 95% CI 2.21-3.12). After adjustment for unmeasured confounding, the risk remained significantly increased (HR 1.62, 95% CI 1.31-2.00).<h4>Conclusions</h4>Using PS calibration, we showed that HCC in non-cirrhotic liver has similar overall mortality, but higher HCC-specific mortality. This may be a result of a more aggressive cancer form in the non-cirrhotic liver as higher mortality could not be explained by tumour characteristics or other prognostic variables.
Project description:Nonalcoholic fatty liver disease (NAFLD) represents an emerging cause of hepatocellular carcinoma (HCC), especially in non-cirrhotic individuals. The rs641738 C?>?T MBOAT7/TMC4 variant predisposes to progressive NAFLD, but the impact on hepatic carcinogenesis is unknown. In Italian NAFLD patients, the rs641738 T allele was associated with NAFLD-HCC (OR 1.65, 1.08-2.55; n?=?765), particularly in those without advanced fibrosis (p?<?0.001). The risk T allele was linked to 3'-UTR variation in MBOAT7 and to reduced MBOAT7 expression in patients without severe fibrosis. The number of PNPLA3, TM6SF2, and MBOAT7 risk variants was associated with NAFLD-HCC independently of clinical factors (p?<?0.001), but did not significantly improve their predictive accuracy. When combining data from an independent UK NAFLD cohort, in the overall cohort of non-cirrhotic patients (n?=?913, 41 with HCC) the T allele remained associated with HCC (OR 2.10, 1.33-3.31). Finally, in a combined cohort of non-cirrhotic patients with chronic hepatitis C or alcoholic liver disease (n?=?1121), the T allele was independently associated with HCC risk (OR 1.93, 1.07-3.58). In conclusion, the MBOAT7 rs641738 T allele is associated with reduced MBOAT7 expression and may predispose to HCC in patients without cirrhosis, suggesting it should be evaluated in future prospective studies aimed at stratifying NAFLD-HCC risk.
Project description:Background & Aims. Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is growing in incidence but treatment options remain limited, particularly for late stage disease. As liver cirrhosis is the principal risk state for HCC development, markers to detect early HCC within this patient population are urgently needed. Perturbation of epigenetic marks, such as DNA methylation (5mC), is a hallmark of human cancers, including HCC. Identification of regions with consistently altered 5mC levels in circulating cell free DNA (cfDNA) during progression from cirrhosis to HCC could therefore serve as markers for development of minimally-invasive screens of early HCC diagnosis and surveillance. Methods. To discover DNA methylation derived biomarkers of HCC in the background of liver cirrhosis, we profiled genome-wide 5mC landscapes in patient cfDNA using the Infinium HumanMethylation450k BeadChip Array. We further linked these findings to primary tissue data available from TCGA and other public sources. Using biological and statistical frameworks, we selected CpGs that robustly differentiated cirrhosis from HCC in primary tissue and cfDNA followed by validation in an additional independent cohort. Results. We identified CpGs that segregate patients with cirrhosis, from patients with HCC within a cirrhotic liver background, through genome-wide analysis of cfDNA 5mC landscapes. Lasso regression analysis pinpointed a panel of probes in our discovery cohort that were validated in two independent datasets. A panel of five CpGs (cg04645914, cg06215569, cg23663760, cg13781744, and cg07610777) yielded AUROCs of 0.9525, 0.9714, and 0.9528 in cfDNA discovery and tissue validation cohorts 1 and 2, respectively. Conclusions. 5mC markers derived from cfDNA robustly identify HCC within a cirrhotic liver background indicating that further validation is warranted. Our finding that 5mC markers derived from primary tissue did not perform well in cfDNA, compared to those identified directly from cfDNA, reveals potential advantages of starting with cfDNA to discover high performing markers for liquid biopsy development. Overall design: Infinium 450k profiling of cfDNA for DNA methylation-based biomarkers of HCC in cirrhotic patients
Project description:Epidemiological data indicate that type 2 diabetes is associated with increased risk of hepatocellular carcinoma (HCC). However, risk stratification for HCC has not been fully elucidated in diabetic population. The aim of this study was to identify potential predictors of HCC in diabetic patients without chronic viral hepatitis. A cohort of 3,544 diabetic patients without chronic viral hepatitis or alcoholic cirrhosis was established and subjects were randomly allocated into a derivation and a validation set. A scoring system was developed by using potential predictors of increased risk of HCC from the Cox proportional hazards model. The performance of the scoring system was tested for validation by using receiver operating characteristics analysis. During median follow-up of 55 months, 36 cases of HCC developed (190 per 100,000 person-years). The 5- and 10-year cumulative incidences of HCC were 1.0%, and 2.2%, respectively. Multivariate Cox regression analysis showed that age > 65 years, low triglyceride levels and high gamma-glutamyl transferase levels were independently associated with an increased risk of HCC. DM-HCC risk score, a weighted sum of scores from these 3 parameters, predicted 10-year development of HCC with area under the receiver operating characteristics curve of 0.86, and discriminated different risk categories for HCC in the derivation and validation cohort. In conclusion, old age, low triglyceride level and high gamma-glutamyl transferase level may help to identify individuals at high risk of developing HCC in diabetic patients without chronic viral hepatitis or alcoholic cirrhosis.
Project description:BACKGROUND:Given the lack of long-term prospective studies, it is challenging for clinicians to make informed decisions about screening and treatment decisions regarding the risk of hepatocellular carcinoma (HCC) in patients with non-alcoholic steatohepatitis (NASH) who do not have cirrhosis. AIM:To characterise the pooled risk of HCC in the non-cirrhosis population. METHODS:Published studies were identified through April 2016 in MEDLINE, Scopus, Science Citation Index, AMED and the Cochrane Library. Two independent reviewers screened citations and extracted data. Random effect odds ratios (OR) were calculated to obtain aggregate estimates of effect size between NASH and non-NASH groups. Between-study variability and heterogeneity were assessed. RESULTS:Nineteen studies with 168 571 participants were included. Eighty-six per cent of included subjects had cirrhosis. The prevalence of HCC in non-cirrhotic NASH was 38.0%; among other aetiologies in non-cirrhotics, it was 14.2% (P < 0.001). Non-cirrhotic NASH subjects were at greater odds of developing HCC than non-cirrhotic subjects of other aetiologies (OR 2.61, 95% CI 1.27-5.35, P = 0.009). When examining all NASH subjects either with or without cirrhosis, those with NASH as the underlying liver disease did not have a significantly increased risk of HCC (OR 1.43, 95% CI 0.77-2.65, P = 0.250). CONCLUSIONS:In non-cirrhotic subjects, those with NASH have a higher risk of HCC compared to other aetiologies of liver disease. Further study investigating the risk factors of HCC among non-cirrhotic NASH patients is needed.
Project description:Alcohol increases the risk of both hepatocellular carcinoma (HCC) and colorectal neoplasia. In this hospital-based case-control and retrospective cohort study, we sought to determine whether development of colorectal neoplasia increases the risk of HCC in patients with alcoholic liver disease (ALD). In the phase I case-control analysis, the association between history of colorectal cancer (CRC) and HCC development was assessed in patients with ALD by logistic regression modeling (n = 1,659). In the phase II retrospective cohort analysis, the relative risk of HCC development was compared in ALD patients with respect to the history of CRC by a Cox model (n = 1,184). The history of CRC was significantly associated with HCC in the case-control analysis (adjusted odds ratio, 1.82; 95% CI, 1.06-3.15; P < 0.05). ALD patients with CRC had higher risk of developing HCC compared to those without CRC (adjusted hazards ratio [HR], 5.48; 95% CI, 1.63-18.36; P = 0.006) in the cohort analysis. Presence of CRC, liver cirrhosis, elevated baseline alpha-fetoprotein level, and low platelet counts were independent predictors of HCC development in ALD patients. Patients with history of CRC had an increased risk of HCC in both cirrhotic (HR, 3.76; 95% CI, 1.05-13.34, P = 0.041) and non-cirrhotic (HR, 23.46; 95% CI, 2.81-195.83, P = 0.004) ALD patients. In conclusion, ALD patients with CRC are at increased risk of developing HCC.
Project description:Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. While cirrhosis is the main risk factor for HCC, the factors influencing progression from cirrhosis to HCC remain largely unknown. Gut microbiota plays a key role in liver diseases; however, its association with HCC remains elusive. This study aimed to elucidate microbial differences between patients with HCC-associated cirrhosis (HCC-cirrhosis) and cirrhotic patients without HCC and healthy volunteers and to explore the associations between diet, lifestyle, and the microbiome of these patients. Fecal samples and food frequency questionnaires were collected from 95 individuals (30 HCC-cirrhosis patients, 38 cirrhotic patients without HCC, and 27 age- and body mass index [BMI]-matched healthy volunteers). 16S rRNA gene sequencing was performed. Bacterial richness in cirrhosis and HCC-cirrhosis patients was significantly lower than in healthy controls. The HCC-cirrhosis group was successfully classified with an area under the curve (AUC) value of 0.9 based on the dysbiotic fecal microbial signature. The HCC-cirrhosis group had a significant overrepresentation of <i>Clostridium</i> and <i>CF231</i> and reduced <i>Alphaproteobacteria</i> abundance compared to cirrhotic patients without HCC. Patients with HCC-cirrhosis who were overweight displayed significantly decreased bacterial richness and altered microbiota composition compared to their normal-weight counterparts. There was a significant correlation in the HCC-cirrhosis group between intake of artificial sweeteners and the presence of <i>Akkermansia muciniphila</i> A unique microbial signature was observed in patients with HCC-cirrhosis, irrespective of cirrhosis stage, diet, or treatment. BMI, dietary sugar, and artificial sweeteners were significantly associated with alterations in the microbiome of HCC-cirrhosis patients. However, the increased abundance of <i>Clostridium</i> and <i>CF231</i> observed in HCC-cirrhosis patients was not influenced by environmental factors, implying that this change was due to development of HCC.<b>IMPORTANCE</b> Development of hepatocellular carcinoma in patients with cirrhosis is associated with alterations in intestinal microbiota, including an escalation of dysbiosis and reduced bacterial richness. This study demonstrates that reduced bacterial richness and dysbiosis escalate with the progression of cirrhosis from compensated to decompensated cirrhosis and to HCC-associated cirrhosis (HCC-cirrhosis). Moreover, we report for the first time the effect of environmental factors on HCC-cirrhosis. Excess weight was associated with increased dysbiosis in patients with HCC compared to their normal-weight counterparts. Moreover, fatty liver, consumption of artificial sweeteners, and high-sugar foods were associated with altered microbial composition, including altered levels of <i>Akkermansia muciniphila</i> in HCC-cirrhosis. We have successfully determined that levels of <i>Alphaproteobacteria</i> and the two genera <i>CF231</i> and <i>Clostridium</i> are significantly altered in cirrhotic patients who develop hepatocellular carcinoma, independently of cirrhosis severity and dietary habits.