Hepatocellular Carcinoma In Subjects Research Articles

Effect of entecavir and tenofovir disoproxil fumarate on hepatocellular carcinoma in subjects with chronic hepatitis B: a meta-analysis

BackgroundA meta-analysis was made to assess the impact of entecavir comparison with tenofovir disoproxil fumarate as nucleos(t)ide analogue on hepatic cellular carcinoma (HCC). The study had subjects with chronic hepatitis B virus (HBV). Systemic research was done for all studies concerned with our topic till the date (March 2022). We included 19 studies in which 27,618 subjects participated. All subjects included were diagnosed with chronic HBV at the beginning of the study. A total of 15,734 subjects from the overall 27,618 were medicated with entecavir; however, 11,884 subjects were on tenofovir disoproxil fumarate. We calculated the odds ratio (OR) with confidence intervals (CIs) of 95% to evaluate the impact of entecavir and tenofovir disoproxil fumarate on HCC in subjects with chronic HBV by applying a dichotomous approach with a random or fixed-effect model.ResultsChronic HBV subjects treated with entecavir showed a higher significant biochemical response than those treated with tenofovir disoproxil fumarate (OR 1.39; 95% CI 1.21–1.60, at p < 0.001). Also, no significant difference was detected with entecavir compared to tenofovir disoproxil fumarate concerning the occurrence of hepatic cells cancer (OR 1.26; 95% CI 0.96–1.67, p = 0.10), virological response (OR 0.89; 95% CI 0.63–1.25, p = 0.49), and seroconversion (OR 1.27; 95% CI 0.76–2.14, p = 0.37).ConclusionsThe use of entecavir resulted in a significantly higher biochemical response; nevertheless, it did not show any significant variation concerning the occurrence of hepatic cancer, virological response, or serological conversion compared to tenofovir disoproxil fumarate in chronic HBV subjects. So, results interpretation needs to be carried out carefully owing to the limited number of studies included in specific comparisons, e.g., serological conversion.

Incidence of hepatocellular carcinoma in chronic hepatitis B virus infection in those not meeting criteria for antiviral therapy.

Chronic hepatitis B virus (HBV) infection is the leading risk factor for hepatocellular carcinoma (HCC). The aim of this study was to explore the incidence of HCC in a cohort of subjects with HBV and correlate with HBV treatment current guidance. We identified 2846 subjects with HBV over the study period. HCC was diagnosed in 386 of 2846 (14%) subjects; 209 of 386 (54%) were on nucleos(t)ide analogue (NA) therapy at time of HCC diagnosis, and 177 of 386 (46%) were not on NA therapy. Of the 177 subjects not on NAs who developed HCC during follow‐up, 153 of 177 (86%) had cirrhosis. Within the 177 subjects not on NAs, 158 of 177 (89%) had undetectable HBV DNA, 10 of 177 (6%) had detectable HBV DNA < 2000 IU/L, and 9 of 177 (5%) had HBV DNA > 2000 IU/L. Of those with cirrhosis and undetectable HBV DNA, 115 of 141 had compensated cirrhosis, and 26 of 141 had decompensated cirrhosis. Significant predictors of HCC on time to event analysis included cirrhosis (hazard ratio [HR] 10, 95% confidence interval [CI] 5.8–17.5; p < 0.001), alanine aminotransferase level (HR 1.004, 95% CI 1.002–1.006; p < 0.001), age (HR 1.04, 95% CI 1.03–1.06; p < 0.001), (HR 1.9, 95% CI 1.2–3.1; p 0.007), and nonalcoholic fatty liver disease (HR 1.7, 95% CI 1.1–2.8; p 0.02). Kaplan–Meier analysis demonstrated the cumulative incidence of HCC in subjects with compensated cirrhosis receiving NA therapy was significantly lower compared to subjects with compensated cirrhosis outside current HBV treatment practice guidance (undetectable HBV DNA) (32% vs. 51%; p < 0.001). Conclusion: Those with untreated compensated cirrhosis with undetectable HBV DNA who do not meet current guidance for treatment had higher rates of HCC than those with compensated cirrhosis and suppressed HBV DNA by NA therapy. This study highlights the need for earlier diagnosis and treatment of HBV.

Prevalence of the Absence of Cirrhosis in Subjects with NAFLD-Associated Hepatocellular Carcinoma.

Background. Hepatocellular carcinoma (HCC) is most commonly considered as a complication of cirrhosis. However, an increasing number of HCC in subjects with non-alcoholic fatty liver disease (NAFLD) without cirrhosis is being reported. We conducted a meta-analysis to assess the prevalence of the absence of cirrhosis in NAFLD-associated HCC. Methods. Four databases were searched until March 2021 (CRD42021242969). The original articles included were those reporting data on the presence or absence of cirrhosis among at least 50 subjects with NAFLD-associated HCC. The number of subjects with absent cirrhosis in each study was extracted. For statistical pooling of data, a random-effects model was used. Subgroup analyses according to the continent, target condition and reference standard for the diagnosis of cirrhosis were conducted. Results. Thirty studies were included, evaluating 13,371 subjects with NAFLD-associated HCC. The overall prevalence of cases without cirrhosis was 37% (95%CI 28 to 46). A higher prevalence was reported in Asia versus Europe, North America and South America (45, 36, 37 and 22%, respectively) as well as in studies adopting histology only as the reference standard for the diagnosis of cirrhosis versus histology and other modalities (e.g., radiology, endoscopy, biochemistry or overt clinical findings) (53 and 27%, respectively). No difference was found between studies including subjects with non-alcoholic steatohepatitis (NASH) only, versus NAFLD with or without NASH (p = 0.385). One in three subjects with NAFLD-associated HCC presented without cirrhosis. This should be reflected in future guidelines and surveillance programs adapted to allow for the early detection of these cancers too.

BRAZILIAN SOCIETY OF HEPATOLOGY UPDATED RECOMMENDATIONS FOR DIAGNOSIS AND TREATMENT OF HEPATOCELLULAR CARCINOMA.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. The Brazilian Society of Hepatology (SBH) published in 2015 its first recommendations about the management of HCC. Since then, new data have emerged in the literature, prompting the governing board of SBH to sponsor a single-topic meeting in August 2018 in São Paulo. All the invited experts were asked to make a systematic review of the literature reviewing the management of HCC in subjects with cirrhosis. After the meeting, all panelists gathered together for the discussion of the topics and the elaboration of updated recommendations. The text was subsequently submitted for suggestions and approval of all members of the Brazilian Society of Hepatology through its homepage. The present manuscript is the final version of the reviewed manuscript containing the recommendations of SBH.

The role of ERCC1 and AFP gene polymorphism in hepatocellular carcinoma.

The aim of this study was to evaluate the effects of polymorphisms in excision repair cross-complementation group 1 (ERCC1) and alpha-fetoprotein (AFP) genes and their haplotypes on the susceptibility to hepatocellular carcinoma (HCC), and to decipher the association between single-nucleotide polymorphisms (SNPs) and clinicopathologic characteristics of HCC.Peripheral blood DNA was extracted from 206 subjects. SNaPshot technique was used for genotyping 5 SNP sites of the ERCC1 rs735482, rs1046282, rs3212948, and AFP rs737241, rs4024 genotypes. Chi-squared test and logistic regression model were used to analyze the relationship of different genotypes or haplotype and the susceptibility and clinicopathologic characteristics of HCC.The frequency of GG.GA and AA genotypes at the AFP rs737241 site in the case and control groups showed statistically significant differences (P < .05). The risk of HCC in subjects carrying mutated allele A (GA+AA) was increased by 0.543-times (P < .05) compared to that in the subjects with the GG genotype. Significant differences were observed in the linkage disequilibrium between 2 of the five SNPs (P < .05); the frequency of ERCC1 C-C and AFP A-A haplotypes was significantly lower in the case group than in the control group (P < .05). The results of clinicopathologic analysis showed that A allele at the rs737241 locus could increase the expression level of AFP (P = .007), the rs1046282 mutation C allele could increase the AFP expression level (P = .011), rs4024 locus mutation A allele could reduce the risk of vascular invasion (P = .013), rs3212948 locus mutation T allele could reduce the differentiation of liver cancer (P = .022), rs1046282 locus C allele could reduce the DNA load of hepatitis B virus (P = .035), and rs735482 A allele could increase the tumor size in HCC (P = .037).The SNPs in rs737241 for AFP gene may correlate with the occurrence of HCC. The SNPs in ERCC1 and AFP genes may affect the prognosis of HCC, offering reliable information for early prediction of tumor progression and diagnosis of HCC.

Type 2 diabetes mellitus increases the risk of hepatocellular carcinoma in subjects with chronic hepatitis B virus infection: a meta-analysis and systematic review

BackgroundType 2 diabetes mellitus has been proved to be a risk factor of hepatocellular carcinoma, but how diabetes affects incidence of hepatocellular carcinoma among patients with chronic hepatitis B virus infection remains controversial.MethodsA comprehensive search of Medline and Embase was performed. Incidence of hepatocellular carcinoma in chronic hepatitis B patients was the primary outcome. Pooled HRs and 95% CIs were calculated to assess the correlation between diabetes and incidence of hepatocellular carcinoma.ResultsFive cohort studies and two case–control studies were identified, with a total of 21,842 chronic hepatitis B patients. The diabetes mellitus cohort was found to have increased incidence of hepatocellular carcinoma (pooled HR 1.77, 95% CI 1.28–2.47; fixed effect) and worse overall mortality (pooled RR 1.93, 95% CI 1.64–2.27; fixed effect) in comparison with those without diabetes. In case–control studies, hepatocellular carcinoma cases were found to have an insignificantly elevated diabetes mellitus rate in comparison with the control group.ConclusionType 2 diabetes mellitus is significantly associated with increased risk of hepatocellular carcinoma among patients with chronic hepatitis B virus infection, and aggressive management of diabetes mellitus is strongly suggested.

Prevalence of Aflatoxin-Associated TP53R249S Mutation in Hepatocellular Carcinoma in Hispanics in South Texas.

We aimed to determine whether aflatoxin dietary exposure plays a role in the high incidence of hepatocellular carcinoma (HCC) observed among Hispanics in South Texas. We measured TP53R249S somatic mutation, hallmark of aflatoxin etiology in HCC, using droplet digital PCR and RFLP. TP53R249S mutation was detected in 3 of 41 HCC tumors from Hispanics in South Texas (7.3%). We also measured TP53R249S mutation in plasma cell-free DNA (cfDNA) from 218 HCC patients and 96 Hispanic subjects with advanced fibrosis or cirrhosis, from South Texas. The mutation was detected only in Hispanic and Asian HCC patients, and patients harboring TP53R249S mutation were significantly younger and had a shorter overall survival. The mutation was not detected in any Hispanic subject with advanced fibrosis or cirrhosis. Genes involved in cell-cycle control of chromosomal replication and in BRCA1-dependent DNA damage response were enriched in HCCs with TP53R249S mutation. The E2F1 family members, E2F1 and E2F4, were identified as upstream regulators. TP53R249S mutation was detected in 5.7% to 7.3% of Hispanics with HCC in South Texas. This mutation was associated with a younger age and worse prognosis. TP53R249S was however not detected in Hispanics in South Texas with cirrhosis or advanced fibrosis. Aflatoxin exposure may contribute to a small number of HCCs in Hispanics in South Texas, but the detection of TP53R249S mutation in plasma cfDNA is not a promising biomarker of risk assessment for HCC in subjects with cirrhosis or advanced fibrosis in this population. Cancer Prev Res; 11(2); 103-12. ©2017 AACR.

Des-γ carboxyprothrombin may not be a good biomarker for hepatocellular carcinoma in those chronically infected with hepatitis B virus with basal core promoter double mutations (T^{1762}, A^{1764}), a prospective study.

The accuracy of des-γ -carboxyprothrombin (DCP) in the detection of hepatocellular carcinoma (HCC) in those infected hepatitis B virus (HBV) from cross-sectional or case-control studies is contradictory. To resolve this contradiction using a prospective study. Three hundred male individuals persistently infected with HBV were recruited from the Chinese cohort and followed up once per year from 2012 to 2015. Each subject was screened for HCC by measurements of serum alpha-fetoprotein (AFP), lectin-bound α -fetoprotein (AFP-L3), DCP concentrations and ultrasonographic examinations. Nineteen HCC cases were identified. The area under receiver operating characteristic (AUROC) at first, second and third visit for AFP, AFP-L3 and DCP ranges from 0.710-0.897, 0.566-0.637 and 0.520-0.595, respectively. The rate of elevated DCP is not significantly different between the HCC cases and controls (52.6% vs. 47.4%) (P > 0.05). The incidence of HCC in subjects with elevated DCP is not significantly higher than that of those with normal DCP (9.5% vs. 4.6%) (P > 0.05). The AUROC of combinations of these biomarkers was higher than that of AFP alone at the first visit. However, it was reduced at the second visit. At the third visit, the AUROCs of AFP + DCP and AFP + AFP-L3 + DCP, but not that of AFP + AFP-L3, were higher than that of AFP alone. AFP but DCP or AFP-L3 remains a valuable biomarker for HCC in those chronically infected with HBV. The combination with AFP-L3 and DCP may not increase the accuracy of AFP in differentiating HCC cases from controls, among those infected with HBV.

Genetic variations in microRNA genes and susceptibility to hepatocellular carcinoma.

We conducted a hospital-based case-control study to investigate the effect of the miR-146aG>C and miR-499A>G polymorphisms on the risk of hepatocellular carcinoma (HCC) in a Chinese population. This study was 1:1 matched case-control study consisting of 184 HCC patients and 184 control subjects. miR-146aG>C and miR-499A>G polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism. Multivariate regression analyses showed that subjects carrying the miR-146a G allele and miR-499 G allele were associated with a non-significant increased risk of HCC compared with subjects with the homozygous allele, with adjusted odds ratios (95% confidence interval) of 1.38 (0.97-1.84) and 1.40 (0.99-2.08), respectively. Moreover, subjects carrying the miR-499 A allele showed a greatly increased risk of HCC in subjects infected with HBV compared with subjects carrying the miR-499 A allele, with an adjusted odds ratio (95% confidence interval) of 1.53 (1.34-2.41). In conclusion, the miR-146aG>C and miR-499A>G polymorphisms do not have a role in the genetic susceptibility to HCC.

Impact of occult HBV infection in HCC presentation in HCV-related cirrhosis

Introduction: The role of the occult HBV infection (OBI) as an additional risk factor for hepatocellular carcinoma (HCC) has not been fully investigated. Aims: To evaluate the impact of OBI (HBV DNA in liver tissue in HBsAg negative patients) in the clinical presentation of HCC in subjects with HCV-related cirrhosis. Methods and results: 46 consecutive patients with HCC were enrolled at two centers from June 2013 to April 2014: 7 HBsAg positive (positive control group; 6 males, mean age 68±1.53 years); 7 HBsAg/anti-HBc/anti-HCV negative (negative control group; all males, mean age 68±1.41 years); 32 anti-HCV positive and HBsAg negative (Case group; 19 males, mean age 71±5.9 years; 16 positive for anti-HBc and 16 negative). Of these 16 anti-HBc positive patients, 9 were anti-HBs/antiHBc positive and 7 anti-HBs negative/antiHBc positive. For each patient a sample of plasma and HCC-liver tissue were collected. The liver HBV DNA was identified by real-time PCR and quantified in relation to DNA -globin. The 7 positive controls were all positive for HBV-DNA in liver (range 7.5×102 to 5.8×105 IU/cells), while all the 7 negative controls negative. In the case group, liver HBV-DNA was positive in 6 (37.5%) of 16 anti-HBc positive patients (range: 1.8×101 IU/cells to 4.06×103 IU/cells) and only in 1 of 16 anti-HBc negative (2.16×102 IU/cells). All the 6 anti-HBc positive patients with positivity for HBV-DNA in liver tissue were anti-HBs negative. The demographic (sex, age, BMI), biochemical (AST/ALT/ALP/total bilirubin/ FP/albumin/PLT/PT) and clinical (unifocal or multifocal HCC, diameter of HCC, HCC localization) were similar in the 7 patients with occult HBV infection and in the 25 without. Conclusions: OBI was found in 22% of the patients with HCVrelatedHCC; it is rare (1/25) in subjects anti-HBs/anti-HBc negative and frequent (37.5%) in those anti-HBcpositive, particularly (85.7%) in those with isolated anti-HBc, without impact on the clinical presentation of HCC.

Role of Leptin Receptor (LEPR) Gene Polymorphisms and Haplotypes in Susceptibility to Hepatocellular Carcinoma in Subjects with Chronic Hepatitis B Virus Infection

The reported association of the leptin receptor (LEPR) protein with hepatocellular carcinoma (HCC) carcinogenesis prompted us to evaluate whether genetic polymorphisms of the LEPR gene affect susceptibility to HCC and its clinicopathologic characteristics. A total of 417 subjects who were diagnosed with HCC and 551 age- and sex-matched subjects without HCC were enrolled in this study. All subjects had chronic hepatitis B virus (HBV) infection. Three single nucleotide polymorphisms (SNPs) of the LEPR gene were determined. The genotype frequencies of Lys109Arg and Gln223Arg differed significantly between HCC and non-HCC subjects (both p < 0.001). For the Lys109Arg polymorphism, HCC subjects had a higher prevalence of 109Arg/Arg than non-HCC subjects. The 109Arg/Arg carriers had a significantly higher adjusted risk of HCC than the 109Lys/Lys carriers. For the Gln223Arg polymorphism, subjects with the 223Arg/Arg genotype had a significantly higher risk of HCC than those with the 223Gln/Gln genotype. The Lys656Asn SNP did not affect the HCC risk. Haplotype analyses showed that subjects with 109Lys-656Lys-223Arg and 109Arg-656Asn-223Arg haplotypes had an increased HCC risk, while the 109Lys-656Lys-223Gln and 109Lys-656Asn-223Gln haplotypes had protective effects against HCC development. None of these polymorphisms were related to the clinicopathologic features of HCC. The Lys109Arg and Gln223Arg polymorphisms of the LEPR gene are associated with susceptibility to HCC but not with its clinicopathologic features. These polymorphisms may represent genetic markers for the risk of HCC in the context of chronic HBV infection.

Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma

Most cases of hepatocellular carcinoma (HCC) are associated with cirrhosis related to chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Changes in the time trends of HCC and most variations in its age-, sex-, and race-specific rates among different regions are likely to be related to differences in hepatitis viruses that are most prevalent in a population, the timing of their spread, and the ages of the individuals the viruses infect. Environmental, host genetic, and viral factors can affect the risk of HCC in individuals with HBV or HCV infection. This review summarizes the risk factors for HCC among HBV- or HCV-infected individuals, based on findings from epidemiologic studies and meta-analyses, as well as determinants of patient outcome and the HCC disease burden, globally and in the United States.

Liver stiffness measurement by magnetic resonance elastography is not associated with developing hepatocellular carcinoma in subjects with compensated cirrhosis

Liver stiffness assessed using transient elastography is described as a potential risk factor for hepatocellular carcinoma (HCC) in cirrhosis. However, the strict assessment of hepatic parenchymal areas uninvolved with HCC has not been investigated. To determine if liver stiffness of nonmalignant hepatic parenchyma using magnetic resonance elastography (MRE) is higher in patients with HCC compared with controls. Cases were defined by compensated cirrhosis with a Child-Turcotte-Pugh score <7 and HCC by radiological criteria or histology. Control subjects with compensated cirrhosis were frequency matched with cases by gender and disease aetiology. Overt manifestations of portal hypertension and previous therapy for liver disease or HCC were exclusion criteria. Region of interest analyses were performed on hepatic parenchyma regions distant to HCC location among cases. Thirty patients with HCC and 60 matched controls comprised the study cohort. The mean age for cases was 64±10 years (range, 45-85) with 70% being men. Major disease aetiologies were chronic viral hepatitis (57%), non-alcoholic fatty liver disease (33%) and alcohol (10%). Twenty-eight (93%) patients had solitary HCC lesions with a mean size of 5.2 cm (range, 2-14 cm). However, patients with HCC had similar liver stiffness among uninvolved areas distant to HCC lesions, when compared with controls without HCC (mean, 6.1±2.0 vs. 6.3±2.5 kPa, P=0.7). In contrast to previous studies with transient elastography, we did not observe a systematic association between liver stiffness assessed using MRE and the presence of HCC in patients with compensated cirrhosis.

Failure of islet β‐cell compensation for insulin resistance causes type 2 diabetes: What causes non‐alcoholic fatty liver disease and non‐alcoholic steatohepatitis?

See article in J. Gastroenterol. Hepatol. 2010; 25: 1687–1691.

Combined effect of socioeconomic status, viral hepatitis, and lifestyles on hepatocelluar carcinoma risk in Korea

Background:The independent and combined effects of socioeconomic status (SES), viral hepatitis, and other lifestyle factors on hepatocellular carcinoma (HCC) risk have not been investigated among Koreans.Methods:From the National Cancer Center Hospital, 207 HCC cases and 828 age- and gender-matched controls aged 30 years or older were recruited. Socio-demographic and behavioural risk factors were ascertained through personal interview, and infection with hepatitis B and C viruses was determined by their serologic markers. Multivariate logistic regression and synergy index methods were applied for statistical analysis.Results:HB surface antigen (HbsAg) and anti-HCV-positive rates were 149.3 and 185.1 times higher in cases than controls, respectively. Lifetime alcohol consumption (odds ratio: 2.96, 95% CI: 1.29–6.79), cigarette smoking (OR: 3.53, 95% CI: 1.31–9.52), and family income (OR: 17.07, 95% CI: 4.27–68.25) were independently associated with the risk of HCC in subjects with or without viral hepatitis. Synergistic interaction on HCC risk was observed between low income and HBsAg positivity (SI: 3.12, 95% CI: 1.51–6.47) and between low income and heavy alcohol intake (SI: 2.93, 95% CI: 1.24–6.89).Conclusion:The inverse association with SES suggests SES as an independent and synergistic predictor of HCC. Heavy alcohol intake also showed a combined effect with low SES on HCC risk.

Gene expression in nontumoral liver tissue and recurrence-free survival in hepatitis C virus-positive hepatocellular carcinoma

BackgroundThe goal of this study was to understand gene expression signatures of hepatocellular carcinoma (HCC) recurrence in subjects with hepatitis C virus (HCV) infection. Recurrence-free survival (RFS) following curative resection of HCC in subjects with HCV is highly variable. Traditional clinico-pathological endpoints are recognized as weak predictors of RFS. It has been suggested that gene expression profiling of HCC and nontumoral liver tissue may improve prediction of RFS, aid in understanding of the underlying liver disease, and guide individualized patient management. Frozen samples of the tumors and nontumoral liver were obtained from 47 subjects with HCV-associated HCC. Additional nontumoral liver samples were obtained from HCV-free subjects with metastatic liver tumors. Gene expression profiling data was used to determine the molecular signature of HCV-associated HCC and to develop a predictor of RFS.ResultsThe molecular profile of the HCV-associated HCC confirmed central roles for MYC and TGFβ1 in liver tumor development. Gene expression in tumors was found to have poor predictive power with regards to RFS, but analysis of nontumoral tissues yielded a strong predictor for RFS in late-recurring (>1 year) subjects. Importantly, nontumoral tissue-derived gene expression predictor of RFS was highly significant in both univariable and multivariable Cox proportional hazard model analyses.ConclusionsMicroarray analysis of the nontumoral tissues from subjects with HCV-associated HCC delivers novel molecular signatures of RFS, especially among the late-recurrence subjects. The gene expression predictor may hold important insights into the pathobiology of HCC recurrence and de novo tumor formation in cirrhotic patients.

Associations Between Hepatitis B Virus Mutations and the Risk of Hepatocellular Carcinoma: A Meta-Analysis

BackgroundThe association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis remains controversial because of conflicting data in the literature. We conducted a meta-analysis of case–control and cohort studies to examine HBV PreS, enhancer II (EnhII), basal core promoter (BCP), and precore mutations in relation to the risk of hepatocellular carcinoma (HCC).MethodsWe searched databases for studies of these associations that were published in English or Chinese up to August 31, 2008. HBV mutation–specific odds ratios and relative risks were pooled by use of a random-effects model and stratified by potential confounders. All statistical tests were two-sided.ResultsOf the 43 studies included in this meta-analysis, 40 used a case–control design. The 43 studies evaluated a total of 11 582 HBV-infected participants, of whom 2801 had HCC. Statistically significant summary odds ratios of HCC were obtained for any PreS mutation (3.77, 95% confidence interval [CI] = 2.57 to 5.52), C1653T in EnhII (2.76, 95% CI = 2.09 to 3.64), T1753V (2.35, 95% CI = 1.63 to 3.40), and A1762T/G1764A in BCP (3.79, 95% CI = 2.71 to 5.29). PreS mutations were more strongly associated with an increased risk of HCC in subjects who were infected with HBV genotype C than in those who were infected with HBV genotype B, whereas the opposite was true for A1762T/G1764A. C1653T, T1753V, and A1762T/G1764A were more strongly associated with an increased risk of HCC in hepatitis B e antigen (HBeAg)–positive subjects than in HBeAg-negative subjects. PreS mutations, C1653T, T1753V, and A1762T/G1764A accumulated during the progression of chronic HBV infection from the asymptomatic carrier state to HCC (Ptrend < .001 for each mutation). PreS mutations, C1653T, C1653T + T1753V, and A1762T/G1764A-based combinations of mutations had specificities greater than 80% for the prediction of HCC. The precore mutations G1896A and C1858T were not associated with the risk of HCC, regardless of HBeAg status and HBV genotype.ConclusionsHBV PreS mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. These mutations alone and in combination may be predictive for hepatocarcinogenesis.

The MTHFR 677C &gt; T polymorphism is associated with an increased risk of hepatocellular carcinoma in patients with alcoholic cirrhosis

Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, plays a major role in the provision of methyl groups for DNA methylation and in the production of dTMP for DNA synthesis. Different polymorphisms have been described for this enzyme, the most studied being the C677T, which has been shown to be associated with predisposition to colorectal cancer in patients who consume a high alcohol diet. The aim of this study was to determine whether the MTHFR polymorphism is related to hepatocellular carcinoma (HCC) in patients with alcoholic cirrhosis. MTHFR genotypes were determined in 300 liver transplant patients, 72 of whom had alcoholic cirrhosis with HCC and 122 of whom had alcoholic cirrhosis without HCC. The remaining patients were transplanted for HCC on normal liver (n = 27) or viral cirrhosis with HCC (n = 49) or without HCC (n = 30). We also tested 80 healthy subjects. Among the group of patients transplanted for alcoholic cirrhosis, the frequency of MTHFR variants CC versus CT and TT was significantly higher in patients with HCC than in patients without macroscopic evidence of HCC (P = 0.02). This difference was not observed between patients with and without HCC developed either on viral cirrhosis or on non-cirrhotic liver. If we considered all the patients transplanted for HCC, the MTHFR CC genotype was significantly higher in patients who had developed HCC on alcoholic cirrhosis rather than on viral cirrhosis (P = 0.002) or on non-cirrhotic livers (P = 0.02). The relative risk for HCC in subjects with alcoholic cirrhosis and the CC genotype was 2.03. These results suggest that the MTHFR CC genotype increases the risk to develop HCC in patients who consume a high alcohol diet.

Iron and hepatocellular carcinoma.

The high prevalence of hepatocellular carcinoma (HCC) in genetic hemochromatosis (GH) and the association between increased body iron stores and occurrence of HCC in subjects with iron overload unrelated to GH, and the experimental evidence of a co-carcinogenic role of iron strongly support that iron is involved in the development of HCC.

Dietary iron overload as a risk factor for hepatocellular carcinoma in Black Africans.

Although the iron-loading disease, hereditary hemochromatosis, has a strong causal association with hepatocellular carcinoma (HCC), the carcinogenic potential of dietary iron overload in Black Africans is not known. We investigated this potential by evaluating iron status, alcohol consumption, markers for hepatitis B (HBV) and C virus (HCV) infections, and exposure to dietary aflatoxin B1 in 24 rural patients with this tumor, 48 race-, sex-, and age-matched hospital-based controls, and 75 related or unrelated close family members of the cancer patients. Iron overload was defined as a raised serum ferritin concentration in combination with a transferrin saturation > or = 60%, and was confirmed histologically when possible. Among 24 patients and 48 hospital controls, the risk of developing HCC in the iron-loaded subjects was 10.6 (95% confidence limits of 1.5 and 76.8) relative to individuals with normal iron status, after adjusting for alcohol consumption, chronic HBV and HBC infections, and exposure to aflatoxin B1. The risk of HCC in subjects with HBV infection was 33.2 (7.2, 153.4) (odds ratio [95% confidence limits]), HCV infection 6.4 (0.3, 133.5), and alcohol consumption 2.0 (0.5, 8.2). Aflatoxin B1 exposure did not appear to increase the risk of HCC. The population attributable risk of iron overload in the development of HCC was estimated to be 29%. Among 20 cancer patients and 75 family members, the risk of developing HCC with iron overload was 4.1 (0.5, 32.2). We conclude that dietary iron overload may contribute to the development of HCC in Black Africans.