Diabetes mellitus,metabolic syndrome and obesity are not significant risk factors for hepatocellular carcinoma in an HBV- and HCV-endemic area of Southern Taiwan

A prominent factor in hepatocellular carcinoma (HCC) is chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). Diabetes mellitus (DM), metabolic syndrome (MetS), and obesity have also been implicated in HCC development, but these associations are not observed in all HBV- and HCV-endemic areas. We attempted to clarify the role of these factors in HCC development in an HBV- and HCV-endemic area in southern Taiwan. A community-based health examination was conducted in 2004 in Tainan County. After individuals with incomplete data and those with known HCC were excluded, there were 56,231 participants who were over 40 years of age. A further 262 HCC cases were identified from the National Cancer Registration Database records from 2005 to 2007. The hepatitis B surface antigen (HBsAg) seropositivity, anti-HCV seropositivity, platelet count, serum biochemical data, blood pressure, sociodemographic information, and anthropometric measurements were analyzed. Survival analyses were used to identify the associations between these factors and HCC. For the 262 HCC cases, male gender and age greater than 65 years were risk factors. Furthermore, a high alanine aminotransferase level, chronic HBV and/or HCV infection, and liver cirrhosis were also risk factors for HCC. However, DM, MetS and obesity were not associated with HCC development in the non-HBV-/non-HCV-infected, HBV, HCV, or dual B/C groups. In this HBV- and HCV- endemic area, DM, MetS and obesity were not risk factors for developing HCC.     

Association of metabolic health phenotypes,obesity, and hepatocellular carcinoma risk

BackgroundThe obesity and hepatocellular carcinoma (HCC) risk association may differ by individuals’ metabolic health status.AimTo investigate the association between obesity categories and HCC risk among individuals with different metabolic health phenotypes.MethodsA case-control study among 518 HCC cases and 1,036 frequency-matched controls was conducted. Body mass index (BMI) was assessed before diagnosis. Pre-diagnosis data on dyslipidemia, hypertension, and diabetes were used to categorize participants as metabolically healthy or metabolically unhealthy. Participants were further categorized into metabolically healthy normal weight (MHNW), metabolically healthy overweight (MHOW), metabolically healthy obese (MHO), metabolically unhealthy normal weight (MUNW), metabolically unhealthy overweight (MUOW), and metabolically unhealthy obese (MHO). We used logistic regression to calculate multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs).ResultsBeing overweight (OR=1.68, 95%CI=1.21–2.34) or obese (OR=1.49, 95%CI=1.11–1.89) was associated with higher HCC risk. Among metabolically healthy participants, no association was found between being overweight or obese and HCC risk. However, among the metabolically unhealthy participants, being overweight (OR=1.89, 95%CI=1.31–2.72) or obese (OR=1.50, 95%CI=1.07–2.09) was associated with higher HCC risk. Compared to the MHNW phenotype, no association was found between the MHOW and MHO phenotypes and HCC risk, but the MUNW (OR=1.94, 95%CI=1.09–3.43), MUOW (OR=3.78, 95%CI=2.15–6.65), and MUO (OR=2.93, 95%CI=1.70–5.05) phenotypes were associated with higher HCC risk.ConclusionThe association between BMI and HCC appears to be restricted to individuals with underlying metabolic abnormalities.     

Mycotoxins are conventional and novel risk biomarkers for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common malignant disease with poor prognosis. To improve the clinical outcome, early diagnosis of HCC arising from nonviral agents and hepatitis virus is important. Among several etiological factors, mycotoxins defined as carcinogens by the International Agency for Research in Cancer (IARC) might be one of the critical risk factors for nonviral HCC. Aflatoxin B1 is the most well-known carcinogenic mycotoxin for HCC, but the role of the other types of mycotoxin remains unclear. Several studies have reported that a chromatographic separation technique based on high-performance liquid chromatography can successfully detect the concentration of mycotoxins in plasma. Recently, serum level of ochratoxin A (OTA), a widely distributed mycotoxin classified as Group 2B by IARC, was evaluated in HCC patients in Egypt. The results suggested that serum OTA levels might be a good biomarker for HCC. In this article, we review recent studies of OTA, and discuss its possible significance as a biomarker of HCC.     

Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma

Primary liver cancer is the third most common cause of cancer-related death worldwide, with a rising incidence in Western countries. Little is known about the genetic etiology of this disease. To identify genetic factors associated with hepatocellular carcinoma (HCC) and liver cirrhosis (LC), we conducted a comprehensive, genome-wide variation analysis in a population of unrelated Asian individuals. Copy number variation (CNV) and single nucleotide polymorphisms (SNPs) were assayed in peripheral blood with the high-density Affymetrix SNP6.0 microarray platform. We used a two-stage discovery and replication design to control for overfitting and to validate observed results. We identified a strong association with CNV at the T-cell receptor gamma and alpha loci (P < 1 × 10(-15)) in HCC cases when contrasted with controls. This variation appears to be somatic in origin, reflecting differences between T-cell receptor processing in lymphocytes from individuals with liver disease and healthy individuals that is not attributable to chronic hepatitis virus infection. Analysis of constitutional variation identified three susceptibility loci including the class II MHC complex, whose protein products present antigen to T-cell receptors and mediate immune surveillance. Statistical analysis of biologic networks identified variation in the "antigen presentation and processing" pathway as being highly significantly associated with HCC (P = 1 × 10(-11)). SNP analysis identified two variants whose allele frequencies differ significantly between HCC and LC. One of these (P = 1.74 × 10(-12)) lies in the PTEN homolog TPTE2. Conclusion: Combined analysis of CNV, individual SNPs, and pathways suggest that HCC susceptibility is mediated by germline factors affecting the immune response and differences in T-cell receptor processing.     

乙型肝炎病毒相关性肝癌的高危因素分析

慢性乙型肝炎病毒(HBV)感染是我国肝细胞肝癌的主要致病因素,乙肝相关性肝癌的高危因素众多,包括乙肝病毒的传播方式、HBeAg的状态、病毒载量、基因型和亚型、基因变异和蛋白变异等。监测这些高危因素有助于筛查原发性肝癌的易感人群,有利于肝癌的早期发现、早期治疗。本文就与乙肝病毒相关的因素作一综述。     

Glycated hemoglobin and antidiabetic strategies as risk factors for hepatocellular carcinoma

AIM: To evaluate the relationship between glycemic control [assessed by glycated hemoglobin (HbA1c)], antidiabetic therapies and the risk of hepatocellular carcinoma (HCC).METHODS: We recruited 465 patients with HCC, 618 cases with liver cirrhosis and 490 controls with no liver disease. Among subjects with type 2 diabetes mellitus (DM2), the associations between the antidiabetic strategies and HbA1c level with HCC were determined through 2 series of multivariate logistic regression models using cirrhotic pa...     

Independent risk factors for hepatocellular carcinoma in French drinkers.

The aim of this study was to assess whether markers of hepatitis B virus or hepatitis C virus infection are independent risk factors for hepatocellular carcinoma in drinkers after adjustment for three known risk factors: cirrhosis, age and male sex. Among 2,015 consecutive drinkers admitted, hepatitis C virus antibodies were found by sensitive radioimmunoassay in 1,259. The following five factors have been identified and ranked as risk factors for hepatocellular carcinoma in unidimensional and regression analysis: cirrhosis (p less than 0.001), age (p less than 0.001), male sex (p less than 0.001), presence of HBsAg (p less than 0.001) and presence of hepatitis C virus antibodies (p less than 0.03). Among drinkers with cirrhosis, the patients with hepatocellular carcinoma were older (64 +/- 11 yr vs. 56 +/- 9 yr; p less than 0.001), were more often male (93% vs. 65%; p less than 0.0001) and had higher prevalence of HBsAg (9% vs. 2%; p = 0.02) and hepatitis C virus antibodies (41% vs. 26%; p = 0.02). A simple algorithm permitted us to identify a high-risk population of drinkers: the male cirrhotic patient older than 50 yr. The relative risk of hepatocellular carcinoma in this selected population was 17.7 (95% confidence interval = 9.0 to 37.5; p less than 0.0001). From a pragmatic point of view, the detection of HBsAg or hepatitis C virus antibodies, although independently associated with hepatocellular carcinoma, is not useful in increasing the diagnostic value of this algorithm because of the poor sensitivity of these tests. The weak relationships observed between hepatitis C virus antibodies and hepatocellular carcinoma needs confirmation by more accurate tests.     

Incidence and risk factors for hepatocellular carcinoma in 967 patients with cirrhosis

Purpose: To determine the incidence of hepatocellular carcinoma in cirrhosis and to examine the influence of age and sex, and the contribution of etiological factors. Methods: 967 patients with liver cirrhosis and free of hepatocellular carcinoma were enrolled in this longitudinal, retrospective and observational study. Monitoring for hepatocellular carcinoma was scheduled at 3- to 6-month intervals. The mean (±SD) length of follow-up was 60.3 ± 51.7 months (range 6–258). Results: During the observation period, hepatocellular carcinoma developed in 64 patients. The calculated annual incidence was 2.1%. The probability of being free of liver cancer was 92% at 5 years, 80% at 10 years, and 69% at 15 years. Age was the only independent risk factor for the development of malignancy in the multivariate analysis. There were no differences according to male sex, alcohol abuse, and chronic hepatitis B and C virus infection. Conclusions: The annual incidence of hepatocellular carcinoma was 2.1%. These results, although confirming that age is a risk factor for hepatocellular carcinoma in cirrhosis, indicate that alcohol abuse, male sex, and concurrent hepatitis B and C virus infection do not involve a higher risk of developing liver cancer.     

Clarification of risk factors for hepatectomy in patients with hepatocellular carcinoma

BACKGROUND/AIMS: Hepatic resection is still associated with a higher morbidity than other major abdominal surgery. The aim of this study was to define risk factors for postoperative morbidity, and to evaluate the plasma cytokine pattern to detect early postoperative infection in patients with hepatocellular carcinoma. METHODOLOGY: One hundred and thirty-nine hepatic resections for hepatocellular carcinoma over a 10-year period from 1987 to 1997 were performed. Preoperative and intraoperative predictors of morbid outcomes were analyzed using multiple regression in a stepwise, logistic model. The postoperative concentrations of interleukin-6, interleukin-8, granulocytecolony stimulating factor, endotoxin and hepatocyte growth factor were measured in 32 patients following hepatic resection. RESULTS: Mortality rate within 30 postoperative days was 2.2%, with morbidity occurring in 40.2%. Significant pre- and intraoperative predictors for morbidity were ICGR15 and the presence of liver cirrhosis. Changes of interleukin-6, interleukin-8, granulocytecolony stimulating factor and endotoxin levels were not consistent with the occurrence of postoperative complications. However, the postoperative peak hepatocyte growth factor levels were positively correlated with morbidity. CONCLUSIONS: ICGR15 and presence of liver cirrhosis had a marked effect on the incidence of postoperative complications after hepatectomy for hepatocellular carcinoma. An increase of serum hepatocyte growth factor level could be used to detect complications in the early postoperative period, but the inflammatory cytokine response after hepatectomy did not relate to an increased complication rate.     

Extrahepatic metastasis of hepatocellular carcinoma: incidence and risk factors

Background: Extrahepatic metastasis of hepatocellular carcinoma (HCC) is of growing importance as the survival of patients has been improved owing to advances in treatments to intrahepatic lesions. Methods: To elucidate the incidence and risk factors of extrahepatic metastasis of HCC, we enrolled 1573 (1131 treatment‐naïve and 442 previously treated on referral) patients with HCC without extrahepatic tumour spread treated at the authors' department between 1990 and 2003. Patients received medical treatment including percutaneous ablation and transcatheter arterial chemoembolization, and followed by dynamic computed tomography (CT) or magnetic resonance imaging (MRI) and tumour markers every 3–4 months. Extrahepatic metastasis was diagnosed by plain X‐ray, CT, MRI and scintigraphy. Clinical parameters at the time of treatment to intrahepatic lesions were evaluated as a predictor of subsequent extrahepatic metastasis among the 1131 treatment‐naïve patients by Cox's proportional hazard model. Results: During the average observation period of 3.9 years, extrahepatic metastasis was diagnosed in 123 in the treatment‐naïve and 53 in the patients treated previously. The incidence rate of extrahepatic metastasis, as detected during the lifetime after medical treatment of HCC, was approximately 13% at 5 years. Multivariate analysis with Cox proportional hazard model revealed that positivity for viral markers, lager tumour diameter, multiple tumour nodules, presence of vascular tumour invasion and elevated tumour markers were associated with the development of extrahepatic metastasis. Conclusion: The incidence of extrahepatic metastasis of HCC diagnosed during clinical course was not frequent. Advanced intrahepatic lesions, presence of vascular tumour invasion, elevated tumour markers and presence of viral hepatitis were risk factors for extrahepatic metastasis.     

Alcohol,postprandial plasma glucose,and prognosis of hepatocellular carcinoma

AIM:To identify factors associated with prognosis of hepatocellular carcinoma(HCC) after initial therapy.METHODS:A total of 377 HCC patients who were newly treated at Katsushika Medical Center,Japan from January 2000 to December 2009 and followed up for > 2 years,or died during follow-up,were enrolled.The factors related to survival were first analyzed in 377 patients with HCC tumor stage T1-T4 using multivariate Cox proportional hazards regression analysis.A similar analysis was performed in 282 patients with tumor stage T1-T3.Additionally,factors associated with the period between initial and subsequent therapy were examined in 144 patients who did not show local recurrence.Finally,214 HCC stage T1-T3 patients who died during the observation period were classified into four groups according to their alcohol consumption and postprandial glucose levels,and differences in their causes of death were examined.RESULTS:On multivariate Cox proportional hazards regression analysis,the following were significantly associated with survival:underlying liver disease stage [non-cirrhosis/Child-Pugh A vs B/C,hazard ratio(HR):0.603,95% CI:0.417-0.874,P = 0.0079],HCC stage(T1/T2 vs T3/T4,HR:0.447,95% CI:0.347-0.576,P < 0.0001),and mean postprandial plasma glucose after initial therapy(< 200 vs ≥ 200 mg/dL,HR:0.181,95% CI:0.067-0.488,P = 0.0008).In T1-T3 patients,uninterrupted alcohol consumption after initial therapy(no vs yes,HR:0.641,95% CI:0.469-0.877,P = 0.0055) was significant in addition to underlying liver disease stage(non-cirrhosis/Child-Pugh A vs B/C,HR:0649,95% CI:0.476-0.885,P = 0.0068),HCC stage(T1 vs T2/T3,HR:0.788,95% CI:0.653-0.945,P = 0.0108),and mean postprandial plasma glucose after initial therapy(< 200 mg/dL vs ≥ 200 mg/dL,HR:0.502,95% CI:0.337-0.747,P = 0.0005).In patients without local recurrence,time from initial to subsequent therapy for newly emerging HCC was significantly longer in the "postprandial glucose within 200 mg/dL group" than the "postprandial glucose > 200 mg/dL group"(l     

Histopathology of type C liver disease for determining hepatocellular carcinoma risk factors

AIM:To evaluate the histopathological findings of type C liver disease to determine risk factors for development of hepatocellular carcinoma(HCC).METHODS:We studied 232 patients,who underwent liver biopsy for type C chronic liver disease between 1992 and 2009,with sustained virological response(SVR)after interferon therapy.The patients were divided into two groups according to the F stage 0+1+2 group(n = 182)and F3+4 group(n = 50).We prospectively observed and compared the incidence of HCC of the patients with SVR in the F0+1+2 and F3+4 groups.Then,the background factors and liver histopathological findings,including the degree of fibrosis,F stage,inflammation,necrosis,bile duct obstruction,fat deposition,and degree of irregular regeneration(IR)of hepatocytes,were correlated with the risk of developing HCC.RESULTS:HCC developed in three of 182(1.6%)patients in the F0+1+2 group,and four of 50(8.0%)in the F3+4 group.The cumulative incidence of HCC in the former group was found to be significantly lower than in the F3+4 group(log rank test P = 0.0224).The presence of atypical hepatocytes among IR of hepatocytes in the F3+4 group resulted in a higher cumulative incidence of HCC,and was significantly correlated with risk of HCC development(RR = 20.748,95%CI:1.335-322.5,P = 0.0303).CONCLUSION:Atypical hepatocytes among the histopathological findings of type C liver disease may be an important risk factor for HCC development along with progression of liver fibrosis.