non-HCC Group Research Articles

Optimization of risk-predicting models for hepatitis B virus-related hepatocellular carcinoma

Objective The present study aimed to optimize the established predictive models (REACH-B scoring model) for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Methods The hepatitis B surface antigen (HBsAg) positive (> 6 months) patients who were firstly admitted in the Liver Center of First Affiliated Hospital, Fujian Medical University between Oct 1st 2004 and May 1st 2014 were selected as the subjects and divided into two groups, namely, the case group (HCC group) and the control group (non-HCC group). Clinical data of all the subjects were retrospectively collected and analyzed. Receiver operating characteristic curves were used to evaluate the predictive values of the various models. Results To predict the development of HBV-related HCC within 3 years, a total of 627 patients (151 HCC cases and 476 non-HCC controls) were enrolled. Area under curve (AUC) of HBV-related HCC (REACH-B) scoring model was 0.78 (95%CI: 0.74-0.82), with the sensitivity of 73.00% and specificity of 78.70% in predicting 3-year risk of HCC occurrence. By combining alpha-fetoprotein (AFP) and REACH-B, the R-AFP scoring model was constructed. The AUC increased to 0.80 (95%CI: 0.76-0.83, Z=2.50, P=0.01), with the sensitivity of 71.03% and specificity of 79.13% in predicting 3-year HCC development. By combining AFP isoform 3 (AFP-L3%) and REACH-B, the R-AFP-L3% scoring model was constructed. The AUC further increased to 0.83 (95%CI: 0.80-0.87, Z=2.45, P=0.01), with the sensitivity of 75.01% and specificity of 79.32% in predicting 3-year HCC development. To predict the development of HBV-related HCC within 5 years, a total of 159 (65 HCC cases and 94 non-HCC controls) were enrolled. The AUC of REACH-B scoring model was 0.79 (95%CI: 0.72-0.87), with the sensitivity of 73.60% and specificity of 75.43%. The R-AFP scoring model had an AUC of 0.84 (95%CI: 0.77-0.90, Z=2.70, P=0.006), with the sensitivity of 83.12% and specificity of 77.89%. Conclusion Combination of AFP or AFP-L3% may optimize the predictive values of REACH-B scoring model in predicting 3-year and 5-years risks of developing HBV-related HCC. Key words: Hepatitis B virus; Carcinoma, hepatocellular; alpha-Fetoproteins; Forecasting

Aldehyde dehydrogenase 2 polymorphism for development to hepatocellular carcinoma in East Asian alcoholic liver cirrhosis.

We aimed to clarify the influences of aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 1B (ADH1B) polymorphisms, and ethanol consumption profile to hepatocellular carcinoma (HCC) development in alcoholic liver cirrhosis without chronic hepatitis B and C virus infection (non-B non-C). Of 236 freshly diagnosed non-B non-C alcoholic liver cirrhosis patients, 67 were diagnosed as HCC and the remaining 169 as not having HCC. The relationship between the genetic polymorphisms and development to HCC were evaluated in well-matched patients with HCC (HCC group, n = 67) and without HCC (non-HCC group, n = 67) using propensity scores in age, sex, and prevalence of diabetes mellitus. Daily amount of ethanol consumption was significantly lower (P = 0.005), and consumptive period was significantly longer (P = 0.003) in HCC group than non-HCC group. Of 134 well-matched patients, 113 (84.3%) had ALDH2*1/*1 genotype and 21 (15.7%) had ALDH2*1/*2 genotype. In HCC development, consumptive long period (P = 0.007) and carrying ALDH2*1/*2 genotype (P = 0.026) were identified as significant factors independently participated, while there was no relation to ADH1B polymorphism. In addition, consumptive period was significantly longer in HCC group than non-HCC group in ALDH2*1/*1 genotype patients (P = 0.0005), while there was no difference in profile of ethanol consumption in ALDH2*1/*2 genotype patients. Among HCC group, daily (P = 3.78 × 10(-6) ) and cumulative amount (P = 4.89 × 10(-6) ) of ethanol consumption were significantly higher in ALDH2*1/*1 genotype patients than ALDH2*1/*2 genotype patients. In alcoholic liver cirrhosis, investigations of ALDH2 polymorphism and ethanol consumption profile are useful for prediction of HCC development.

Validation study of prediction models of hepatitis B virus-related hepatocellular carcinoma

To validate two previously published models (REACH-B score and CU-HCC score) for predicting the risk of developing hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). In-patients of the Liver Center of First Affiliated Hospital Fujian Medical University who tested positive for hepatitis B surface antigen (HBsAg;more than 6 months) and were admitted for treatment between October 1,2004 and May 1,2014 were enrolled for study. The 627 study participants were grouped according to presence of HCC (151 in the HCC case group, and 476 in the non-HCC control group). Relevant clinical data from 3 and 5 years prior to the current hospital admission were collected retrospectively and assessed using the REACH-B and CU-HCC scoring systems. A subset of the study participants (65 HCC cases, and 94 non-HCC controls) was used for the verification analysis of prediction for 5-year risk of HBV-related HCC.T-test, rank sum test, chisquare test and the receiver operating characteristic curve were used for statistical analyses. For the REACH-B score,prediction of 3-year risk of developing HCC had an area under the curve (AUC) of 0.78,a sensitivity of 73.00% and a specificity of 78.70%.In male patients with alanine aminotransferase (ALT) more than or equal to 45 U/L, the REACH-B score prediction of 3-year risk of developing HCC had an AUC of 0.89, a sensitivity of 87.09% and a specificity of 83.86%. The REACH-B score prediction of 5-year risk of HCC had an AUC of 0.79,a sensitivity of 73.60% and a specificity of 75.53%; the CU-HCC score prediction of 5-year risk of HCC had an AUC of 0.76, a sensitivity of 78.40% and a specificity of 77.40%. Both the REACH-B and CUHCC scoring systems can be used for HCC prediction among patients at the First Affiliated Hospital Fujian Medical University. For male patients with ALT more than or equal to 45 U/L,the REACH-B score may be a more sensitive predictor for 3-year risk of developing HBV-related HCC.

The characteristic changes in hepatitis B virus x region for hepatocellular carcinoma: a comprehensive analysis based on global data.

ObjectivesMutations in hepatitis B virus (HBV) X region (HBx) play important roles in hepatocarcinogenesis while the results remain controversial. We sought to clarify potential hepatocellular carcinoma (HCC)-characteristic mutations in HBx from HBV genotype C-infected patients and the distribution of those mutations in different disease phases and genotypes.MethodsHBx sequences downloaded from an online global HBV database were screened and then classified into Non-HCC or HCC group by diagnosis information. Patients' data of patient age, gender, country or area, and viral genotype were also extracted. Logistic regression was performed to evaluate the effects of mutations on HCC risk.Results1) Full length HBx sequences (HCC: 161; Non-HCC: 954) originated from 1115 human sera across 29 countries/areas were extracted from the downloaded 5956 HBx sequences. Genotype C occupied 40.6% of Non-HCC (387/954) and 89.4% of HCC (144/161). 2) Sixteen nucleotide positions showed significantly different distributions between genotype C HCC and Non-HCC groups. 3) Logistic regression showed that mutations A1383C (OR: 2.32, 95% CI: 1.34-4.01), R1479C/T (OR: 1.96, 95% CI: 1.05-3.64; OR: 5.15, 95% CI: 2.53-10.48), C1485T (OR: 2.40, 95% CI: 1.41-4.08), C1631T (OR: 4.09, 95% CI: 1.41-11.85), C1653T (OR: 2.58, 95% CI: 1.59-4.19), G1719T (OR: 2.11, 95% CI: 1.19-3.73), and T1800C (OR: 23.59, 95% CI: 2.25-247.65) were independent risk factors for genotype C HBV-related HCC, presenting different trends among individual disease phases. 4) Several genotype C HCC risk mutations pre-existed, even as major types, in early disease phases with other genotypes.ConclusionsMutations associated with HCC risk were mainly located in HBx transactivation domain, viral promoter, protein/miRNA binding sites, and the area for immune epitopes. Furthermore, the signatures of these mutations were unique to disease phases leading to HCC, suggesting molecular counteractions between the virus and host during hepatocarcinogenesis.

Interleukin-21 gene polymorphisms and chronic hepatitis B infection in a Chinese population.

To investigate the relationship between interleukin-21 (IL21) gene polymorphisms and chronic hepatitis B virus (HBV) infection in a Chinese population. In this case-control study, 366 Chinese HBV-infected patients were recruited and divided into hepatocellular carcinoma (HCC; n = 94) and non-HCC (n = 272) groups at The First Affiliated Hospital of Sun Yat-Sen University, from April 2009 to December 2012. In the non-HCC group, the patients were classified into three clinical subsets, 76 patients had chronic hepatitis B, 101 were HBV carriers and 95 patients had HBV-related cirrhosis. Two hundred eight unrelated healthy controls were also included. Genomic DNA was extracted from peripheral blood. Single nucleotide polymorphisms (SNPs) rs13143866, rs2221903, and rs907715 were subsequently genotyped using the SNaPshot SNP technique. There were no significant differences in allele and genotype frequencies of SNPs rs13143866, rs2221903, and rs907715 between chronic HBV-infected patients and control subjects. Furthermore, no significant differences were found in the frequencies of all alleles and genotypes between the HCC group and the non-HCC group. However, in the subgroup analysis, IL21 rs13143866 genotype AA frequency in the HBV carrier group was higher than in controls (OR = 6.280, 95%CI: 1.238-31.854; P = 0.019), and the effect of the recessive model (AA vs GG + GA, OR = 6.505, 95%CI: 1.289-32.828) was observed in the HBV carrier group. IL21 rs2221903 genotype TC frequency in the HBV carrier group was higher than in controls (OR = 1.809, 95%CI: 1.043-3.139; P = 0.035). In the haplotype analysis, the ATA haplotype (rs13143866, rs2221903, and rs907715) of IL21 was more frequent in the HCC group than in the non-HCC group (0.165 vs 0.104, P = 0.044; OR = 1.700, 95%CI: 1.010-2.863). Genotypes rs13143866 AA and rs2221903 TC are risk factors for carrying HBV; ATA haplotype increases the risk of HBV-related HCC onset in a Chinese population.

Assessment of thrombin generation using thromboelastometry in cirrhotic patients with hepatocellular carcinoma undergoing liver transplantation

Due to the mixed etiology of liver disease, cirrhotic patients with hepatocellular carcinoma may have either a pro-thrombotic or a bleeding tendency. Haemostatic assessment and blood management represent key issues during liver transplantation (LT) having a significant impact on survival and postoperative outcome. Our aim was to assess haemostatic profile in liver transplant recipients with hepatocellular carcinoma (HCC) and to evaluate its impact on perioperative anaesthetic management. We prospectively included 122 patients that underwent liver transplantation between January and December 2013. Exclusion criteria were incomplete data recall, preoperative anticoagulation treatment, acute liver failure and emergency re-transplantation. Coagulation was assessed using standard coagulation tests and rotational thromboelastometry (ROTEM®) assay performed preoperative and 15 minutes after reperfusion of the liver. We recorded introperative blood loss, transfusion requirements, Post Anaesthesia Care Unit length of stay and incidence of postoperative renal, pulmonary, thrombotic and hemorrhagic complications. After we applied the exclusion criteria, 80 patients were included in the final analysis: 24 patients in the HCC groupand 56 in the non-HCC group. Patients with HCC had increased preoperative thrombin generation demonstrated by a shorter clot formation time (142 vs. 381 sec, p= 0.01, 95% CI[41.9, 292.4] ) and a shorter time to maximum velocity of clot formation (153 vs. 209, p=0.027, 95% CI [6.59, 105.3] ). Intraoperative findings showed no differences in blood loss between the two groups, but lower fresh frozen plasma requirements (11.5 vs. 16.6 units, p =0.031) was observed in the HCC group. Intraoperative ROTEM® variables were similar in both groups measured after reperfusion of the graft. No statistically significant differences in postoperative outcome were observed between groups. In conclusion, patients in HCC group have increased preoperative thrombin generation as demonstrated by ROTEM derived parameters. During major abdominal surgery, like LT, and increased blood loss thrombin generation is similar in patients with and without HCC, demonstrating that haemostatic reserve is limited in HCC group.

Waiting time predicts survival after liver transplantation for hepatocellular carcinoma: a cohort study using the United Network for Organ Sharing registry.

Recipients of liver transplantation (LT) for hepatocellular carcinoma (HCC) have an 8% to 20% risk of HCC recurrence. Single-center studies suggest that a period of waiting after HCC therapy may facilitate the selection of patients at low risk for post-LT HCC recurrence and mortality. We evaluated whether a longer waiting time after Model for End-Stage Liver Disease (MELD) prioritization for HCC predicts longer post-LT survival. From the United Network for Organ Sharing registry, we selected 2 groups registered for LT between March 2005 and March 2009: (1) HCC patients receiving MELD prioritization and (2) non-HCC patients. Patients were stratified by their MELD status at LT (a marker of time on the wait list after HCC MELD prioritization) and were followed from LT until death or censoring through October 2012. By comparing post-LT survival to intention-to-treat (ITT) survival from registration, we assessed predictors of post-LT survival and estimated the benefit of LT. The median MELD scores at LT were 22 (HCC) and 24 (non-HCC). A higher MELD score at LT was independently associated with lower post-LT mortality in the HCC group [hazard ratio (HR) = 0.84, 95% confidence interval (CI) = 0.73-0.98] and higher post-LT mortality in the non-HCC group (HR = 1.20, 95% CI = 1.15-1.25). Compared with the HCC group, the non-HCC group had lower post-LT mortality [relative risk (RR) = 0.85, log-rank P < 0.01] but higher ITT mortality (RR = 1.25, log-rank P < 0.01) because of a 33 percentage point lower probability of undergoing LT. In conclusion, a longer waiting time before LT for HCC predicted longer post-LT survival in a national transplant registry. Delaying LT for HCC may reduce disparities in ITT survival and access to LT among different indications and thereby improve system utility and organ allocation equity for the overall pool of LT candidates.

Association of the gene polymorphisms in sodium taurocholate cotransporting polypeptide with the outcomes of hepatitis B infection in Chinese Han population

ObjectiveIn recent years, sodium taurocholate cotransporting polypeptide (NTCP) was newly identified as a hepatitis B virus (HBV) receptor, which partly shed light on the reason for HBV hepatotropism and its host specificity. However, the related researches were limited to in vitro or animal experiments. Therefore, this study aimed to investigate the association of NTCP polymorphisms with HBV natural course in humans. MethodsAccording to their serological and clinical characteristics, 933 Chinese Han individuals were divided into two major groups, 352 viral clearance controls and 581 persistently infected patients. The latter one included 186 hepatocellular carcinoma (HCC) and 395 non-HCC subjects. A total of five single nucleotide polymorphisms (SNPs) were selected from HapMap dataset and genotyped by high resolution melting (HRM) curve method. ResultsThe rs7154439 AA genotype was observed slightly more common in viral clearance group than in persistently infected group [16 (4.5%) subjects vs. 10 (1.7%) subjects. p=0.008, adjusted odds ratio (AOR)=0.33, 95% confidence interval (CI)=0.15–0.75 in a codominant model; and p=0.006, AOR=0.32, 95% CI=0.14–0.72 in a recessive model]. While the rs4646287 AA genotype was observed slightly more frequent in HCC group than in non-HCC group [6 (3.2%) subjects vs. 1 (0.3%) subject. p=0.018, AOR=15.74, 95% CI=1.59–155.54 in a codominant model; and p=0.018, AOR=15.91, 95% CI=1.61–157.01 in a recessive model]. There were no statistically significant differences of allele or haplotype distribution between any two groups. ConclusionsThis study suggests that polymorphisms in the NTCP region may be associated with the natural course of HBV infection. The rs7154439 AA genotype was associated with HBV clearance, while the rs4646287 AA genotype was associated with HCC occurrence. However, considering the sample size is relatively small, larger studies, especially through multicenter collaboration will be needed to fully validate the significance of these findings.

Serum secreted frizzled-related protein 5 levels differentially decrease in patients with hepatitis B virus-associated chronic infection and hepatocellular carcinoma.

The aim of this study was to investigate the characteristics of serum secreted frizzled-related protein 5 (SFRP5), an inhibitor of Wnt signaling, in hepatitis B virus (HBV)-associated infections and hepatocellular carcinoma (HCC) patients. Serum SFRP5 levels were detected in 147 patients with HBV-associated chronic infection or HCC. Compared with the non-HBV-infected and non-HCC group, the HBV-associated chronic infection and HCC groups exhibited decreased serum SFRP5 levels. A significant inverse correlation between serum SFRP5 levels and HBV DNA levels was identified in the HBV-associated chronic infection and HCC groups. Furthermore, SFRP5 levels differentially decreased in patients with HBV-associated diseases, in a manner which was dependent on liver disease status. Compared with patients exhibiting HBV-associated chronic infection, patients with HCC were found to exhibit lower serum SFRP5 levels. The results of the present study indicated that patients with HBV-associated liver infection and HCC exhibited significantly deceased serum SFRP5 levels, which were found to negatively correlate with HBV DNA levels. Serum SFRP5 levels may present a biomarker for the severity of HBV-associated liver infection, and the risk of HCC initiation and progression.

Wait and Transplant for Stage 2 Hepatocellular Carcinoma With Deceased-Donor Liver Grafts

The method which donor organs are allocated to individuals on the waiting list for transplant is an important topic for research and debate. In recent years, there has been growing interest in applying the concept of utilitarianism to the organ allocation system, seeking the maximum survival benefit of the patient population as a whole, rather than that of an individual patient (1). Ideally, exceptions points were created to allow hepatocellular carcinoma (HCC) patients a fair access to the donor pool. However, the current allocation Model for End-stage Liver Disease exception points seem to overestimate the risk disease progression and dropout in HCC patients, and the likelihood of undergoing a liver transplantation still remains higher for HCC candidates in the United States (2). Therefore, an intention-to-treat analysis, such as that published in Transplantation by Chan et al. (3), is a promising tool to optimize organ donation in a more fair way. Tumor size has been associated with the risk of metastasis and HCC progression (4). Whether or not the Milan criteria could be extended without increasing waiting list mortality for non-HCC candidates depends on the availability of organs in each specific region. Thus, an optimal selection of the HCC patients for liver transplantation has an upmost importance in regions with a low donation rate. The wait-and-transplant policy proposed by Chan et al. provided almost the same chances of being transplanted for HCC and non-HCC patients, and the survival rates of those who were transplanted were almost the same in both groups (40.4% vs. 37.9%, respectively). However, most of the HCC patients in the waiting list died (n=18) or had to be excluded because of disease progression (7), and at the end of study, only 5 patients remained in conditions of being transplanted. As a matter of a fact, liver transplantation could not be offered in 48.2% (25/52) of the HCC patients. On the other hand, only 26.2% (27/103) of the non-HCC patients died in the waiting list during the same period, so 34.9% (35/103) of the non-HCC patients still had chances of receiving a liver graft when the study was ended. According to the intention-to-treat analysis, all alive and active patients should be considered as having a potential for long-term survival, regardless if they were transplanted or not. Although the outcomes of the patients who were still alive in the waiting list are unpredictable, a significant fraction of them probably will be transplanted in the following months, increasing the transplant patient rate and, consequently, the overall survival in the non-HCC group. We agree that wait-and-transplant policy is an interesting idea to avoid unnecessary liver transplant for patients at great risk of early tumor progression and recurrence, like the HCC candidates beyond the Milan criteria. The scenario of organ shortage increases even more the need to improve patient selection, but it seems to us that a shorter waiting period policy (3 months) could also combine the selection benefits of the 6-month wait-and-transplant policy with a lower dropout and mortality rate on the waiting list. Another argument reinforcing this idea is the fact that HCC patients who underwent living donor liver transplantation in the same study also achieved excellent postoperative survival outcomes despite a medium waiting time to transplant of 8.5 days. Cleber Rosito Pinto Kruel Aljamir D. Chedid Tomaz J.M. Grezzana-Filho Serviço de Cirurgia Digestiva Hospital de Clínicas de Porto Alegre Ramiro Barcelos, Porto Alegre RS, Brazil

Serum markers for the early detection of hepatocellular carcinoma in patients with chronic viral hepatitis C infection

ObjectiveThe aim of this study was to identify the serum markers and the use of abdominal ultrasound for early detection of hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis C virus infection.BackgroundHCC meets the criteria of a tumor that would benefit from a surveillance program, but the poor sensitivity and specificity of currently available tools have prevented widespread implementation of surveillance.Patients and methodsThis study included 110 patients, age from 23 to 70 years, from Menoufia University hospitals during the period from July 2011 to November 2013. They were classified into three groups: group I, non-HCC group (50 patients); group II, HCC group (40 patients with chronic hepatitis C virus infection); and group III, healthy controls (20 individuals). Members of the study were subjected to thorough history taking, complete physical examination, liver function testing (serum bilirubin, albumin, prothrombin time, serum transaminases), serum α-fetoprotein (α-FP), and transforming growth factor β1 (TGF-β1) level. Group I was subjected to serum TGF-β1 at 0-, 9-, and 18-month intervals.ResultsThe mean age was 46.72 ± 9.03 years in the non-HCC group (group I), 58.70 ± 5.76 years in the HCC group (group II), and 42.15 ± 11.33 years in the control group (group III). The mean serum level of TGF-β1 was 232.25 ± 70.53 ng/ml in the HCC group, 42.16 ± 13.34 ng/ml in the non-HCC group, and 13.92 ± 7.73 ng/ml in the control group; there was a highly significant difference between all groups (P < 0.001). The mean value of α-FP was 334.40 ± 311.30 ng/ml in group II and 4.82 ± 2.18 ng/ml in group I; the HCC group had a shooting serum level of α-FP with a highly statistically significant difference.ConclusionThis study recommends TGF-β1 as being more accurate than α-FP in differentiating patients with HCC from those with nonmalignant chronic liver disease.

Combinations of eight key mutations in the X/preC region and genomic activity of hepatitis B virus are associated with hepatocellular carcinoma

Accumulation of eight key mutations located in the X/preC regions of the hepatitis B virus (HBV) genome (G1613A, C1653T, T1753V, A1762T, G1764A, A1846T, G1896A and G1899A) is a risk marker for the development of hepatocellular carcinoma (HCC). In this study, we analysed the 8 key mutations in 442 serum samples collected from 310 non-HCC and 132 HCC patients to identify the combinations linked to HCC. After the patients were stratified according to the age groups and mutation combinations, clinical parameters were compared between the HCC and the non-HCC groups. Analyses were focused on patient ≥40years of age infected by HBV genotype C with A1762T and G1764A mutations in the basal core promoter region (BCP double mutation). In patients with ≥6 mutations, the combination of [G1613A+ C1653T+ A1846T+G1896A] mutations was closely linked to HCC, whereas no specific single or double mutation combination was associated with HCC. In patients with ≤5 mutations, HBeAg and HBV DNA serum titres were lower in the HCC group than those in the non-HCC group. Unlike the number of mutations, no specific combination correlated with advanced clinical stage in HCC. Of the BCP double mutation-based HBV mutant types, combinations of ≥6 mutations that include G1613A+C1653T+ A1846T +G1896A, and combinations of ≤5 mutations with reduced HBeAg production, may be more specific indicators of HCC risk than only the number of mutations or any specific combination(s).

Hepatitis B Virus Genetic Variation and TP53 R249S Mutation in Patients with Hepatocellular Carcinoma in Thailand

Chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1) are major risk factors for hepatocellular carcinoma (HCC). The aim of this study was to evaluate the role of HBV genetic variation and the R249S mutation of the p53 gene, a marker of AFB1-induced HCC, in Thai patients chronically infected with HBV. Sixty-five patients with and 89 patients without HCC were included. Viral mutations and R249S mutation were characterized by direct sequencing and restriction fragment length polymorphism (RFLP) in serum samples, respectively. The prevalences of T1753C/A/G and A1762T/G1764A mutations in the basal core promotor (BCP) region were significantly higher in the HCC group compared to the non-HCC group. R249S mutation was detected in 6.2% and 3.4% of the HCC and non-HCC groups, respectively, which was not significantly different. By multiple logistic regression analysis, the presence of A1762T/G1764A mutations was independently associated with the risk of HCC in Thai patients.

PWE-125 Stratification Of Hepatocellular Carcinoma Risk in Primary Biliary Cirrhosis by Biochemical Response to Treatment

Introduction AimsTo review patterns of hepatocellular carcinoma (HCC) presentation in patients with primary biliary cirrhosis (PBC) in the context of disease severity and biochemical response to treatment.MethodsPatients with confirmed PBC...

Phosphorylated Smad2 and Smad3 signaling: Shifting between tumor suppression and fibro‐carcinogenesis in chronic hepatitis C

Insight into hepatic fibrogenesis and carcinogenesis (fibro-carcinogenesis) caused by hepatitis C virus (HCV) infection has come from recent analyses of transforming growth factor (TGF)-β signaling. TGF-β type I receptor and pro-inflammatory cytokine-activated kinases differentially phosphorylate Smad2 and Smad3 to create C-terminally (C), linker (L) or dually (L/C) phosphorylated (p) isoforms. This study aimed to elucidate how HCV infection affected hepatic fibro-carcinogenesis, particularly via phospho-Smad signaling. We first studied phospho-Smad2/3 positivity of 100 patients in different stages of HCV-related chronic liver disease. To examine changes in phospho-Smad2/3 after HCV clearance, we analyzed 32 paired liver biopsy samples obtained before and after sustained virological response (SVR), dividing patients into two groups: 20 patients not developing hepatocellular carcinoma (HCC) after attaining SVR (non-HCC group), and 12 patients who developed HCC despite SVR (HCC group). Hepatocytic tumor-suppressive pSmad3C signaling shifted to carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling as liver diseases progressed. In the non-HCC group, 13 patients (65%) displayed fibrotic regression and inflammation reduction after SVR. Interestingly, SVR restored cytostatic pSmad3C signaling in hepatocytes, while eliminating prior carcinogenic pSmad3L and fibrogenic pSmad2L/C signaling. In the HCC group, seven patients (58%) displayed unchanged or even progressed fibrosis despite smoothened inflammatory activity, reflecting persistently high numbers of hepatocytes with pSmad3L- and pSmad2L/C-signaling and low pSmad3C-signaling. HCV clearance limits fibrosis and reduces HCC incidence by switching inflammation-dependent phospho-Smad signaling from fibro-carcinogenesis to tumor suppression. However, progression to HCC would occur in severely fibrotic livers if an inflammation-independent fibro-carcinogenic process has already begun before HCV clearance.

Risk factors for hepatocellular carcinoma in patients with drug-resistant chronic hepatitis B

To investigate the risk factors and characteristics of hepatocellular carcinoma (HCC) in the patients with drug-resistant chronic hepatitis B (CHB). A total of 432 patients with drug-resistant CHB were analyzed retrospectively from January 2004 to December 2012. The patients were divided into two groups: the HCC group (n = 57) and the non-HCC group (n = 375). Two groups compared using logistic regression for various patients and viral characteristics in order to identify associated risk factors for HCC. Secondarily, patient and tumor characteristics of HCC patients with naïve CHB (N group, n = 117) were compared to the HCC group (R group, n = 57) to identify any difference in HCC characteristics between them. A significant difference was found for age, platelet count, alpha-fetoprotein (AFP), positivity of HBeAg, seroconversion rate of HBeAg, virologic response, the Child-Pugh score, presence of rtM204I, and the duration of antiviral treatment in non-HCC and HCC group. Cirrhosis, age (> 50 years), HBeAg (+), virologic non-responder status, and rtM204I mutants were independent risk factors for the development of HCC. The R group had lower serum C-reactive protein (CRP) and AFP levels, earlier stage tumors, and a shorter mean tumor surveillance period than the N group. However, the total follow-up duration was not significantly different between the two groups. 13.2% of patients with drug-resistant CHB developed HCC. Age, cirrhosis, YIDD status, HBeAg status, and virologic response are associated with risk of HCC. Patients with drug-resistant CHB and these clinical factors may benefit from closer HCC surveillance.

Clinical Significance of Plasma Osteopontin Level as a Biomarker of Hepatocellular Carcinoma

BackgroundBiomarkers of hepatocellular carcinoma (HCC) are helpful in screening, diagnosis and follow up of cases. Osteopontin (OPN) is a glycoprotein secreted by osteoblasts, osteoclasts, macrophages and T cells, and is over-expressed in a variety of tumors, including carcinomas of liver, stomach, breast, lung, colon, and prostate. So, the aim of this study was to verify the possibility of using the plasma Osteopontin level as a biomarker for diagnosis of HCC.MethodsThe study included 70 subjects divided into three groups: group I had 30 patients with HCC (proved by histopathology or combined spiral CT and elevated alpha-fetoprotein) on top of HCV, group II had 30 patients with HCV infection and group III had 10 healthy subjects serving as control. Osteopontin level was measured in plasma of the studied subjects by ELISA, serum alpha fetoprotein (AFP) level was also measured by EIA.ResultsOsteopontin levels were significantly elevated in patients with HCC and in HCV patients in comparison to control group (P: 0.005). There was significant correlation between OPN and AFP levels (P: 0.00). The sensitivity and specificity of OPN for selective detection of HCC group over the non-HCC group (HCV group and healthy control group) were73% and 54%, respectively, at a cut-off value of 128.5 ng/mL. Plasma OPN levels directly correlated with the tumor number but not with the size of the tumor (P: 0.00).ConclusionPlasma OPN level appears to be an additional biomarker for HCC detection.

The Associated Ion between the VDR Gene Polymorphisms and Susceptibility to Hepatocellular Carcinoma and the Clinicopathological Features in Subjects Infected with HBV

Aim. To evaluate the possible association between the vitamin D receptor (VDR), single-nucleotide polymorphisms (SNPs), and hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Method. 968 chronic HBV infection patients were enrolled, of which 436 patients were diagnosed HCC patients, and 532 were non-HCC patients. The clinicopathological characteristics of HCC were evaluated. The genotypes of VDR gene at FokI, BsmI, ApaI, and TaqI were determined. Results. The genotype frequencies of VDR FokI C>T polymorphism were significantly different between HCC and non-HCC groups. HCC patients had a higher prevalence of FokI TT genotype than non-HCC subjects. With FokI CC as reference, the TT carriage had a significantly higher risk for development of HCC after adjustments with age, sex, HBV infection time, α-fetoprotein, smoking status, and alcohol intake. In addition, we also found that the TT genotype carriage of FokI polymorphisms were associated with advanced tumor stage, presence of cirrhosis, and lymph node metastasis. The SNP at BsmI, ApaI, and TaqI did not show positive association with the risk and clinicopathological features of HCC. Conclusion. The FokI C>T polymorphisms may be used as a molecular marker to predict the risk and to evaluate the disease severity of HCC in those infected with HBV.

Lamivudine plus adefovir combination therapy for lamivudine resistance in hepatitis-B-related hepatocellular carcinoma patients

Background/AimsLamivudine (LAM) plus adefovir (ADV) combination therapy has been accepted as one of the best treatments for LAM-resistant chronic hepatitis B (CHB). The aim of this study was to determine the efficacy of this combination therapy in hepatocellular carcinoma (HCC) patients.MethodsThe medical records of CHB patients who developed LAM resistance and were treated with LAM plus ADV combination therapy for more than 6 months were reviewed. Their virological response (VR; undetectable HBV DNA) and biochemical response (BR; alanine aminotransferase normalization) were evaluated, and the findings of HCC and non-HCC patients were compared.ResultsThe data from 104 patients (19 with HCC and 85 without HCC) were analyzed. The VR rates did not differ significantly between the HCC and non-HCC groups: 33.3% vs. 55.6% at 12 months (P=0.119), 58.3% vs. 67.2% at 24 months (P=0.742), 50% vs. 69.8% at 36 months (P=0.280), and 66.7% vs. 71.0% at 48 months (P=1.000). The BR rates also did not differ significantly between the groups: 55.6% vs. 84.0% at 12 months (P=0.021), 58.3% vs. 83.8% at 24 months (P=0.057), 70.0% vs. 77.8% at 36 months (P=0.687), and 66.7% vs. 80.6% at 48 months (P=0.591).ConclusionsThe efficacy of LAM plus ADV combination therapy is comparable in HCC and non-HCC patients.

Relationship of HLA-DRB1 Alleles With Hepatocellular Carcinoma Development in Chronic Hepatitis B Patients

We intended to analyze the relationship between specific human leukocyte antigen (HLA)-DRB1 alleles and development of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. A database of 468 consecutive CHB patients who received lamivudine for more than 12 months between July 1996 and February 2011 was retrospectively analyzed. Sera and buffy coats samples were obtained between April 2008 and April 2010. Six-digit HLA-DRB1 genotyping was performed with sequence-based typing. Serum α fetoprotein levels and ultrasonography or computed tomography image studies were assessed every 3 to 6 months for surveillance of HCC. At baseline, median age was 43 years (range, 16 to 71) [male: 359 (76.7%); HBeAg positivity: 385 (82.3%)]. Among the 27 HLA-DRB1 alleles identified, HLA-DRB1*090102, *080302, and *070101 were the most frequent (>10%). HCC was diagnosed in 36 (7.7%) patients during the median follow-up of 69 months. The frequency of the HLA-DRB1*140101 allele was 9.0% and significantly higher in patients of the HCC group than those of the non-HCC group (19.4 vs. 8.1%, P=0.014). The 2-year, 4-year, and 6-year cumulative rates of HCC development were markedly higher in patients with HLA-DRB1*140101 than those without HLA-DRB1*140101 (2.4, 8.2, and 25.1% vs. 1.9, 4.7, and 7.4%, respectively, P=0.011). No other HLA-DRB1 alleles were associated with HCC development. Baseline clinical characteristics did not differ between patients with and without HLA-DRB1*140101. The HLA-DRB1*140101 allele may be potentially associated with increased risk of HCC development in CHB patients, irrespective of the replicative activity of hepatitis B virus and antiviral responsiveness.