Presence of esophageal varices is a risk factor for non-hemorrhagic death of hepatocellular carcinoma patients treated with radiofrequency ablation.

BACKGROUND/AIMS: The presence of esophageal varices (EVs) is believed to be a factor that affects the prognosis of patients with hepatocellular carcinoma (HCC). We examined whether the presence and severity of EVs affected either survival prognosis or the cause of death in HCC patients treated with radiofrequency ablation (RFA). METHODOLOGY: The study included 89 HCC patients treated with RFA who were endoscopically evaluated for EVs before treatment. To determine factors associated with survival, we performed univariate and multivariate analyses of variables including demographics, tumor stage, Child-Pugh class and status of EVs. Furthermore, we investigated the association between the presence of EVs and causes of death. RESULTS: Multivariate analyses showed both Child-Pugh class B (odds ratio: 2.654; p = 0.017) and EVs (odds ratio: 3.18; p = 0.004) to be independent factors of poor prognosis. Of 34 patients who died during the period of observation, one died because of an EV rupture. CONCLUSIONS: The existence of EVs may affect survival prognosis of HCC patients treated with RFA independently of Child-Pugh status, but is not associated with hemorrhagic death.

Interaction between cytochrome P450 1A2 genetic polymorphism and cigarette smoking on the risk of hepatocellular carcinoma in a Japanese population.

Limited epidemiological evidence suggests that genetic polymorphisms of drug-metabolizing enzymes such as cytochrome P450 (CYP), glutathione S-transferase (GST) and N-acetyltransferase (NAT) may be involved in tobacco-related hepatocarcinogenesis. We conducted a case-control study, including 209 incident cases with hepatocellular carcinoma (HCC) and two different control groups [275 hospital controls and 381 patients with chronic liver disease (CLD) without HCC], to investigate whether CYP1A1, CYP1A2, CYP2A6, CYP2E1, GSTM1 and NAT2 polymorphisms are related to the risk of HCC with any interaction with cigarette smoking. Overall, no significant associations with HCC were observed for any genotypes against either control group. However, we found a significant interaction (P = 0.0045) between CYP1A2 -3860G>A polymorphism and current smoking on HCC risk when we compared HCC cases with CLD patients; adjusted odds ratios [ORs; and 95% confidence intervals (CIs)] for G/A and A/A genotypes relative to G/G genotype were 0.28 (0.12-0.66) and 0.18 (0.04-0.94), respectively, among current smokers (P trend = 0.002), as compared with 1.28 (0.80-2.06) and 0.76 (0.34-1.71), respectively, among never/former smokers (P trend = 0.96). Similarly, in CYP1A2 G/G genotype, significant risk increase was observed for current smoking (OR = 4.08, 95% CI = 2.02-8.25) or more recent cigarette use (e.g. pack-years during last 5 years, P trend = 0.0003) but not in G/A and A/A genotypes combined (OR for current smoking = 1.39, 95% CI = 0.63-3.03; P trend for pack-years during last 5 years = 0.40). These results suggest that the CYP1A2 -3860G>A polymorphism modifies the smoking-related HCC risk among CLD patients.

Hepatitis C virus infection enhances insulin resistance induced by visceral fat accumulation.

BACKGROUND/AIMS: To clarify the impact of visceral obesity on hepatitis C virus (HCV)-infected patients, we examined the relationship between insulin resistance development and visceral fat accumulation. METHODS: We analyzed 87 HCV-infected patients with mild fibrosis (stage 1 or 2) in comparison with 125 sex- and age-matched patients with non-alcoholic fatty liver disease (NAFLD). The degree of visceral fat area (VFA; cm(2)) at the umbilical level was measured by abdominal computed tomography and divided into two grades: no visceral obesity, VFA<100 and visceral obesity, VFA>/=100. Insulin resistance was evaluated by homeostasis model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). Pancreatic beta-cell function was evaluated by homeostasis model assessment of beta-cell function (HOMA-beta). Serum soluble tumour necrosis factor (TNF)-receptors 1 and 2 and adiponectin were measured. RESULTS: Insulin resistance evaluated by HOMA-IR and QUICKI was correlated with visceral fat accumulation, and was higher in HCV patients than in NAFLD patients with visceral obesity. HOMA-beta was higher in HCV patients than in NAFLD patients for each VFA grade. Serum-soluble TNF-receptors 1 and 2 were higher in HCV patients than in NAFLD patients with visceral obesity. CONCLUSIONS: Hepatitis C virus infection is a risk factor for development of insulin resistance, particularly in patients with visceral obesity.

Case-control study on cigarette smoking and the risk of hepatocellular carcinoma among Japanese.

Emerging epidemiologic data suggest that cigarette smoking may increase the risk of hepatocellular carcinoma (HCC), yet considerable controversies (e.g. inconsistent dose-response relationships) still exist with this association. We examined whether smoking was associated with HCC risk in a case-control study including 209 incident HCC cases and two different control groups (256 hospital controls and 381 patients with chronic liver disease [CLD] without HCC). Comparison of HCC cases with CLD patients, but not with hospital controls, demonstrated a significantly increased risk of HCC for current smokers. After adjustment for sex, age, heavy drinking history and hepatitis virus markers, odds ratios (and 95% confidence intervals) for former and current smokers relative to never smokers were 1.0 (0.6-1.7) and 2.5 (1.4-4.6), respectively, against CLD patients, as compared with 0.8 (0.3-2.3) and 1.8 (0.6-5.1), respectively, against hospital controls. In terms of pack-years during lifetime, dose-response relationship was not evident against either control group (P trend = 0.43), but it became clearer for more recent cigarette use among CLD patients. For example, regarding cumulative cigarette consumption during the last 5 years, adjusted odds ratios (and 95% confidence intervals) for 1-4 and 5+ pack-years relative to no use were 1.9 (1.1-3.6) and 2.8 (1.5-5.2) (P trend = 0.003), respectively. These results suggest that cigarette smoking may play a crucial role in the late stage of HCC development and that CLD patients may benefit from their earliest smoking cessation.

Menatetrenone, a vitamin K2 analogue, inhibits hepatocellular carcinoma cell growth by suppressing cyclin D1 expression through inhibition of nuclear factor kappaB activation.

PURPOSE: Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2-induced growth inhibition of HCC cells. EXPERIMENTAL DESIGN: HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor kappaB (NF-kappaB) activation was investigated by a NF-kappaB reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated IkappaB, and an in vitro kinase assay for IkappaB kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1. RESULTS: Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF-kappaB binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)-, TNF-alpha-, and interleukin (IL)-1-induced activation of NF-kappaB binding and transactivation. Concomitant with the suppression of NF-kappaB activation, vitamin K2 also inhibited the phosphorylation and degradation of IkappaBalpha and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment. CONCLUSION: Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/IkappaB/NF-kappaB pathway and might therefore be useful for treatment of HCC.

Waist circumference correlates with hepatic fat accumulation in male Japanese patients with non-alcoholic fatty liver disease, but not in females.

BACKGROUND AND AIM: Abdominal obesity, a component of metabolic syndrome, is a major risk factor for non-alcoholic fatty liver disease (NAFLD). In recent worldwide definitions of metabolic syndrome, waist measurement has been proposed as a simple and useful estimate of abdominal obesity, taking into account gender differences in waist circumference. The present cross-sectional study investigated the correlation of hepatic fat accumulation and waist circumference in Japanese NAFLD patients to determine if there are gender differences in this relationship. METHODS: Consecutive patients (n = 2111) who had at least one of two criteria for liver disease (alanine aminotransferase [ALT] level >30 IU/mL and aspartate aminotransferase [AST]/ALT ratio <1) underwent abdominal ultrasonography. Patients positive for hepatitis B virus, hepatitis C virus or autoimmune antibodies and whose alcohol intake was >20 g/day were excluded. Patients with NAFLD underwent abdominal computed tomography. Hepatic fat accumulation was estimated by liver/spleen attenuation ratio (L/S ratio) and visceral adipose accumulation was measured as visceral fat area (VFA) at the umbilical level. RESULTS: Of the 221 NAFLD patients, 103 were females. In males, the relationship between L/S ratio and waist circumference was negative (r =-0.356, P < 0.01), and there was no correlation in the female group. The relationship between L/S ratio and VFA was negative in both groups (males: r = -0.269, P < 0.01; females: r = -0.319, P < 0.01). Subcutaneous fat area/total fat area ratio at the umbilical level was larger in females than in males (P < 0.01). CONCLUSIONS: In NAFLD patients, waist measurement is more susceptible to gender differences than VFA.

High-dose vitamins E and C supplementation prevents ribavirin-induced hemolytic anemia in patients with chronic hepatitis C.

AIM: In combination therapy using interferon (IFN) and ribavirin for chronic hepatitis C, reduced doses should be used due to ribavirin-induced hemolytic anemia. The present study aimed to elucidate whether high-dose vitamins E and C supplementation attenuated ribavirin-induced hemolytic anemia. METHODS: Twenty-one consecutive patients with chronic hepatitis C were enrolled in this study between July 2003 and December 2004, and received high-dose vitamins E (2000 mg) and C (2000 mg) supplementation, daily, in addition to IFN alfa-2b and ribavirin combination therapy (vitamins E/C group). Twenty-one sex- and age-matched patients who received a standard regimen of IFN alfa-2b and ribavirin for chronic hepatitis C between January 2001 and June 2003 were evaluated as the control group. RESULTS: Decrease in hemoglobin level was significantly prevented in the vitamins E and C group compared to that in the control group (P = 0.029). Three (14.3%) patients in the control group discontinued treatment because of anemia, while no treated patient dropped out of the study due to anemia. Sustained virological response was not significantly different between the two groups. CONCLUSION: High-dose vitamins E and C supplementation prevented ribavirin-induced hemolytic anemia during combination therapy with ribavirin and IFN alfa-2b in patients with chronic hepatitis C.

Radiofrequency ablation with the real-time virtual sonography system for treating hepatocellular carcinoma difficult to detect by ultrasonography.

Radiofrequency ablation has been applied to treat hepatocellular carcinoma, with favorable therapeutic outcomes. Nevertheless, practitioners have approached radiofrequency ablation with some reluctance due to the difficulty of identifying isoechoic tumors and recurrent tumors. The aim of the present study is to investigate the efficacy of Real-time Virtual Sonography to treat hepatocellular carcinoma difficult to detect by conventional ultrasonography. Real-time Virtual Sonography is a system generating multiplanar reconstruction images in real-time using the Hitachi medico EUB-8500 equipped with a probe. The system included following components: 1) digital imaging and communications in medicine (DICOM) data from dynamic CT, 2) a magnetic field generator to match the multiplanar reconstruction image on the monitor and the actual ultrasonography image, 3) the cross section with the tumor displayed as a multiplanar reconstruction image. Total twenty-five nodules of twenty-one patients underwent radiofrequency ablation monitored by Real-time Virtual Sonography. All nodules difficult to detect via conventional ultrasonography were clearly visualized in real-time. The average nodule diameter was 2.4 +/- 1.6 cm, and punctures and coagulation were performed an average of 2.2 and 3 times per session. Dynamic CT after session confirmed effective coagulation of each nodule. In conclusion, this study demonstrates that the present system is capable of effectively and accurately treating tumors difficult to detect by conventional ultrasonography.

[Late-onset type ornitine transcarbamirase deficiency (OTCD) with fulminant onset following a fatal prognosis].

A 16-year-old man was admitted to our hospital with nausea, general fatigue, and consciousness disturbance along with extreme hyperammoniemia eight days after the onset of symptoms. Familial history and the high concentration of orotic acid in urine lead us to a diagnosis of OTCD. We immediately initiated intensive treatment such as continuous hemodiafiltration and sodium benzoate administration; however, the patient died twelve days after admission. Since OTCD is not so rare and can be found in all ages, it should be considered fundamental for evaluation of hyperammoniemia. This case suggested that for a better prognosis of OTCD patients it is very important to prevent such an onset, and to make an as early as possible diagnosis and start to treatment.

Visceral fat accumulation and insulin resistance are important factors in nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver diseases are often associated with obesity, insulin resistance, and excessive visceral fat accumulation. The aims of this study were (1) to evaluate the relationship between the severity of fatty liver and visceral fat accumulation in nonalcoholic fatty liver diseases, and (2) to investigate the relationships of fatty liver with biochemical data and insulin resistance. METHODS: One hundred twenty-nine subjects (63 women) with fatty liver diagnosed by ultrasonography were enrolled. Subjects positive for hepatitis B virus, hepatitis C virus, or autoimmune antibodies and those whose alcohol intake was over 20 g/day were excluded. The visceral fat area at the umbilical level and the liver-spleen ratio were evaluated by computed tomography. RESULTS: The severity of fatty liver evaluated by ultrasonography showed a significant positive relationship with the visceral fat area and waist circumstance (fatty liver severity: mild, 92.0 +/- 30.9 cm(2); moderate, 122.1 +/- 32.6 cm(2); severe, 161.0 +/- 48.4 cm(2); P < 0.0001). The visceral fat area and liver-spleen ratio were negatively correlated (r = -0.605, P < 0.0001). The severity of fatty liver showed strong positive relationships with serum aspartate aminotransferase, alanine aminotransferase, fasting plasma glucose, fasting plasma insulin, and insulin resistance. The severity of fatty liver was positively related to the visceral fat area in 49 nonobese subjects (body mass index <25). CONCLUSIONS: The severity of fatty liver was positively correlated with visceral fat accumulation and insulin resistance in both obese and nonobese subjects, suggesting that hepatic fat infiltration in nonalcoholic fatty liver disease may be influenced by visceral fat accumulation regardless of body mass index.

High serum leptin is an independent risk factor for non-response patients with low viremia to antiviral treatment in chronic hepatitis C.

AIM: To determine whether body weight and/or serum leptin were independent predictors of response to antiviral treatment in patients with chronic hepatitis C. METHODS: A retrospective evaluation was performed in 139 patients with chronic hepatitis C treated with interferon (IFN) from 1996 to 2000. Sustained response was defined as negative by hepatitis C virus (HCV) RNA analysis using PCR and normal transaminase at 24 wk after cessation of IFN therapy. Patients who remained positive for HCV RNA at the end of IFN treatment were defined as resistant to IFN therapy. Sex, age, body mass index (BMI) (> or =25 vs <25), complication of diabetes mellitus, serum leptin level (> or =8.0 microg/L vs < 8.0 microg/L), and the stage of liver fibrosis by needle biopsy (F1/F2 vs F3/F4) were examined. RESULTS: Sustained response was achieved in 33 patients (23.7%), while others failed to show a response to IFN therapy. Overall, the factors associated with sustained antiviral effects were HCV-RNA load, HCV genotype, serum leptin level, and stage of liver fibrosis evaluated by univariate analysis. BMI was not associated with any therapeutic effect of IFN. Multivariate analysis indicated that HCV-RNA load was a significant risk factor, but among the patients with low viremia (HCV-RNA <100 MU/L), leptin level was an independent risk factor for IFN resistance. Namely, a high level of serum leptin attenuated the effect of IFN on both male and female patients with low viremia. CONCLUSION: High serum leptin level is a negative predictor of response to antiviral treatment in chronic hepatitis C with low viremia.

Efficacy and safety of telaprevir, pegylated interferon α-2b and ribavirin triple therapy in Japanese patients infected with hepatitis C virus genotype 1b.

Objective This study evaluated the efficacy and safety of triple therapy with telaprevir (TVR), pegylated interferon α-2b (PegIFN-α-2b) and ribavirin (RBV) in Japanese patients chronically infected with hepatitis C virus (HCV) genotype 1b in real-world clinical practice. Methods A total of 106 consecutive patients with HCV genotype 1b were treated with triple therapy for 12 weeks followed by dual therapy with PegIFN-α-2b and RBV for 12 weeks. The primary end point was sustained virological response (SVR), defined as undetectable serum HCV RNA at 24 weeks after the end of treatment. Results The overall SVR rate was 87.7% (93/106 patients). Age and body weight (BW) differed significantly between patients with and patients without SVR. Multivariate analysis showed that age <67 years [odds ratio (OR) 5.03, p=0.014] and BW ≥55 kg (OR 5.87, p=0.008) were independent pretreatment factors predictive of SVR. When posttreatment factors were included, age <67 years (OR 7.30, p=0.041), rapid virological response (OR 10.60, p=0.019) and continuation of therapy (OR 14.45, p=0.012) were each independently associated with SVR. Body weight <55 kg (OR 5.96, p=0.015) and TVR initial dose ≥41 mg/kg/day (OR 5.19, p=0.017) were each independently associated with discontinuation of therapy. Discontinuation rates decreased in inverse proportion to the percentage of patients with an initial TVR dose of 1,500 mg/day. Conclusion For TVR-based triple therapy, continuation of therapy is the most important predictor of SVR. Patients who are likely intolerant of standard-dose TVR should receive reduced initial doses of TVR to avoid discontinuation of therapy.

The relationship between insulin resistance and polymorphisms of the endothelial nitric oxide synthase gene in patients with coronary artery disease.

Nitric oxide (NO) regulates endothelial function and is believed to prevent atherogenesis. In endothelial cells, endothelial nitric oxide synthase (eNOS) is expressed constitutively, and regulates NO synthesis. A mutation of the eNOS gene has been associated with the development of coronary artery disease (CAD). The development of CAD is also influenced by insulin resistance, and recent studies suggest that NO might affect cellular insulin activity. We investigated the association between eNOS polymorphisms and insulin resistance in patients with CAD. We screened 45 patients with a history of myocardial infarction (MI), angina pectoris (AP), or coronary spasm. Genotypes were determined by polymerase chain reaction-restriction fragment-length polymorphism analysis. We examined two polymorphisms of the eNOS gene (The T(-786)-->C variant and the missense Glu298Asp variant). Insulin resistance was measured by determining the plasma immunoreactive insulin concentration at the 120 min time point (IRI 120) of a 75 g oral glucose tolerance test. The IRI 120 of the T(-786)-->C variant group was higher than that for the control group (p<0.05). This finding demonstrates that the T(-786)-->C mutation in the eNOS gene decreases insulin sensitivity.

Induction of multiple matrix metalloproteinase genes in human hepatocellular carcinoma by hepatocyte growth factor via a transcription factor Ets-1.

Matrix metalloproteinases (MMPs) have been implicated in progression of hepatocellular carcinoma (HCC), as have hepatocyte growth factor (HGF) and its c-Met receptor. We investigated regulation of MMP gene expression by HGF in human HCC. Expression of mRNAs encoding MMPs, HGF and c-Met receptor was examined by quantitative reverse transcription-polymerase chain reaction (RT-PCR) in human HCC and in five human HCC cell lines. HCC cells were treated with HGF, and mRNA expression for MMPs and Ets-1 which activates transcription of MMPs was investigated. Ets binding activity was determined by gel mobility shift assay. MMP promoter activities were evaluated by reporter gene assay. Effects of Ets-1 antisense oligonucleotides were also examined. At the mRNA level, MMP-1, -3, -7 as well as c-Met were overexpressed in HCC compared with corresponding nonneoplastic liver tissues, although MMP-2, -9 or HGF were not. HGF dose-dependently induced Ets-1 together with an increased Ets binding activity, followed by transcription of MMP-1, -3, and -7. HGF increased MMP promoter activity, as did cotransfection with Ets-1. Ets-1 antisense oligonucleotide transfection down-regulated the MMP expression, and abolished induction by HGF. In conclusion, certain MMPs and c-Met, overexpressed in HCC cells, are induced by HGF via Ets-1. This pathway may contribute to tumor progression.

Interaction between interleukin-1beta -31T/C gene polymorphism and drinking and smoking habits on the risk of hepatocellular carcinoma among Japanese.

The risk of hepatocellular carcinoma (HCC) increases with the severity of hepatic inflammation. Interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha are proinflammatory cytokines with multiple biological effects and may play essential roles in inflammation-linked tumor development. We conducted a case-control study including 209 incident HCC cases and two control groups (275 hospital controls and 381 patients with chronic liver disease [CLD] without HCC) to investigate whether IL-1B and TNF-A gene polymorphisms influence HCC susceptibility with any interaction with alcohol and tobacco. By comparing HCC cases with CLD patients, we found that IL-1B -31T/C polymorphism was associated with HCC risk among never drinkers and current smokers; adjusted odds ratios (and 95% confidence intervals) for C/T and T/T genotypes compared with C/C genotype were 1.70 (0.76-3.77) and 2.46 (1.05-5.76) (P trend=0.03), respectively, among never drinkers, and 1.53 (0.60-3.99) and 2.54 (0.81-7.95) (P trend=0.11), respectively, among current smokers. Similarly, HCC risk associated with heavy alcohol intake and current smoking differed by this polymorphism among CLD patients. IL-1B -31T/C polymorphism may modify HCC risk in relation to alcohol intake or smoking.

Paternal transmission and slow elimination of mutant alleles associated with late-onset ornithine transcarbamylase deficiency in male patients.

In ten families with late-onset ornithine transcarbamylase (OTC) deficiency in male patients, three mutant alleles-R40H, R277W, and Y55D-were identified. In a total of 20 informative parent-offspring pairs, father-to-daughter transmission and mother-to-offspring transmission occurred in five (25%) and 15 (75%), respectively, indicating that paternal transmission contributes substantially to the pool of these mutant alleles. Relative reproductive fitness of males and females carrying the mutant alleles was calculated to be 0.49 and 0.89, respectively. Comparison of the life span of the mutant alleles, estimated on the basis of these fitness values with those associated with classic phenotype (neonatal onset) in which reproductive fitness of male patients was nil, revealed that mutant alleles associated with the late-onset phenotype were eliminated more slowly. This would allow the late-onset phenotype mutant alleles to be retained more frequently in a population than those associated with classic phenotype. Although heterozygous females carrying the late-onset phenotype mutant alleles were generally asymptomatic, one female carrying the R40H allele died after a hyperammonemic episode at the age of 18 years. Such heterozygous females should be alerted to possible hyperammonemic crisis.

Inverse association between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan.

Coffee use has consistently been associated with lower serum liver enzyme levels and a reduced risk of liver cirrhosis. A limited number of cohort and case-control studies also suggest a decreased risk of hepatocellular carcinoma (HCC) among coffee drinkers, but mostly without consideration of hepatitis virus infection. In the present case-control study, we recruited 209 incident HCC cases and three different controls (1308 community controls, 275 hospital controls, and 381 patients with chronic liver disease [CLD] without HCC), all of whom were aged 40-79 years and residents of Saga Prefecture, Japan. A questionnaire survey elicited information on coffee use during the last 1-2 years and 10 years before, and plasma hepatitis B surface antigen and antibodies to hepatitis C virus were tested for all but community controls. After adjustment for sex, age, heavy alcohol use, smoking status and hepatitis virus markers (except for community controls), coffee use during the last 1-2 years was associated with a decreased risk against any control group. For coffee use 10 years before, comparison between HCC cases and either community controls or CLD patients revealed a decreased risk; adjusted odds ratios for occasional use, 1-2 cups/day and > or =3 cups/day compared with no use were 0.33, 0.27 and 0.22 (P trend < 0.001), respectively, against community controls, and 0.86, 0.62 and 0.53 (P trend = 0.05), respectively, against CLD patients. These results suggest that coffee may protect against the development of HCC, yet further elaborate studies (hopefully, intervention studies) are warranted to corroborate these findings.

The effect of menatetrenone, a vitamin K2 analog, on disease recurrence and survival in patients with hepatocellular carcinoma after curative treatment: a pilot study.

BACKGROUND: The high recurrence rate of hepatocellular carcinoma (HCC) determines the long-term prognosis for patients with HCC. In the current study, the authors tested the effects of menatetrenone, a vitamin K2 analog, on recurrent HCC and survival after curative treatment. METHODS: Sixty-one patients who were diagnosed as free of HCC after surgical resection or percutaneous local ablation were assigned randomly assigned to either a menatetrenone group (n = 32 patients) or a control group (n = 29 patients). Patients in the menatetrenone group received a daily oral dose of 45 mg of menatetrenone. Disease recurrence and survival rates were analyzed in patients with HCC. RESULTS: The cumulative recurrence rates in the menatetrenone group were 12.5% at 12 months, 39.0% at 24 months, and 64.3% at 36 months; and the corresponding recurrence rates in the control group were 55.2%, 83.2%, and 91.6%, respectively (P = 0.0002). Similar results were obtained even for patients who had low baseline levels of serum des-gamma-carboxy-prothrombin. Univariate and multivariate Cox proportional hazard analyses showed that the administration of menatetrenone was the only factor related to the recurrence rate of HCC. The cumulative survival rates for the patients who received menatetrenone were 100% at 12 months, 96.6% at 24 months, and 87.0% at 36 months; and the corresponding survival rates for patients in the control group were 96.4%, 80.9%, and 64.0%, respectively (P = 0.051). CONCLUSIONS: The current study findings suggested that menatetrenone may have a suppressive effect on recurrence of HCC and a beneficial effect on survival, although a larger, placebo-controlled trial will be required to prove these effects.

Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population.

Although alcohol intake as well as hepatitis viruses has been associated with hepatocellular carcinoma (HCC), gene-alcohol interactions on HCC risk remain to be elucidated. We conducted a case-control study to examine whether polymorphisms of alcohol dehydrogenase 2 (ADH2) and aldehyde dehydrogenase 2 (ALDH2) modified the HCC risk depending on the amount of alcohol intake. ADH2 and ALDH2 genotyping was performed by a duplex polymerase chain reaction with confronting two-pair primers in 209 newly diagnosed HCC cases and 2 different controls [275 hospital controls and 381 patients with chronic liver disease (CLD)]. Multiple logistic regression analyses revealed that heavy drinkers consuming >or=3 "go"s/day of sake (69 g of ethanol/day) showed an increased risk of HCC based on comparison of HCC cases with hospital controls [adjusted odds ratio (OR) = 13.5; 95% confidence interval (CI) 3.3-54.3] or CLD patients (adjusted OR = 7.0; 95% CI 2.5-19.2), whereas the overall risk was not elevated among light to moderate drinkers consuming <3 "go"s/day. Interestingly, light to moderate drinking was associated with an increased risk among those with ALDH2*1/*2 (adjusted OR = 4.5 or 2.0), but not among those with ALDH2*1/*1 (adjusted OR = 0.8 or 1.0; p interaction = 0.03 or 0.13). However, this gene-alcohol interaction was not observed for heavy drinking. Among light to moderate drinkers, people with the combination of ALDH2*1/*2 and ADH2*2/*2 revealed the highest risk of HCC. These findings indicate that the ALDH2 polymorphism may modify HCC risk among light to moderate drinkers.

hOGG1 Ser326Cys polymorphism and risk of hepatocellular carcinoma among Japanese.

BACKGROUND: The Ser326Cys polymorphism in human oxoguanine glycosylase 1 (hOGG1), which is involved in the repair of 8-hydroxy-2-deoxyguanine in oxidatively damaged DNA, has been associated with susceptibility to certain cancers, but has not been examined in causation of hepatocellular carcinoma (HCC). METHODS: We conducted a case-control study to investigate whether this polymorphism was related to HCC risk with any interaction with alcohol consumption and cigarette smoking. Genotyping was performed by a polymerase chain reaction with confronting two-pair primers among 209 newly diagnosed HCC cases, 275 hospital controls, and 381 patients with chronic liver disease (CLD) without HCC. RESULTS: Overall, the hOGG1 genotype was not significantly associated with HCC; adjusted odds ratios (and 95% confidence intervals) for the Ser/Cys and Cys/Cys genotypes compared with the Ser/Ser genotype were 0.79 (0.35-1.79) and 0.48 (0.18-1.27) against hospital controls, and 1.51 (0.96-3.37) and 0.86 (0.50-1.47) against CLD patients. We could not detect any significant gene-alcohol interaction (p = 0.95 or 0.16) or gene-smoking interaction (p = 0.70 or 0.69). CONCLUSIONS: These results suggest that the hOGG1 Ser326Cys polymorphism may not play a major role as an independent factor in hepatocarcinogenesis.