| Background & Aims:Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most important risk factors for the development of HCC. HCC and the main causal factors of HCC do not have a uniform geographic distribution. Rather,80% of all cases throughout the world occur in developing countries, with 55% occurring in China alone. In developing regions, such as Asia and Africa, chronic HBV infection is the main risk factor, whereas in developed countries, chronic HCV infection is the main risk factor and other causes of cirrhosis are also relevant. In China, nearly 80% of HCC cases have been linked to HBV infection, and approximately 60%-90% of these develop in patients with cirrhosis. Older age, male sex, cirrhosis and sustained activity of liver disease are important predicators for HCC. In patients with chronic HBV infection, HBV DNA level, viral genotype, and HBeAg status have been identified as risk factors for HCC. Other potential risk factors, such as diabetes mellitus, alcohol abuse, obesity, and family history of liver cancer may also play a role in the development of HCC.A number of cohort and case-control studies have investigated the relationships between diabetes mellitus and HCC risk. Type 2 diabetes has been suggested as an independent risk factor for the development of HCC. However, the role of type 2 diabetes in the development of HCC in the presence of chronic hepatitis B (CHB) has not been well documented.First, only a few cohort studies have followed a population with chronic HBV infection. In addition, most of the case-control studies used a normal population or cancers other than HCC as controls, and chronic HBV infection status was not well matched between cases and controls. Chronic HBV carriers have a 100-fold increased relative risk of developing HCC compared with non-carriers. The presence of chronic HBV infection might confound other risk factors for HCC.Second, none of these studies followed a cohort of patients with CHB or matched cirrhosis status between cases and controls with CHB. These studies may also inappropriately estimate the role of type 2 diabetes in HCC development in the presence of CHB. The majority of HBV-related HCC develops in patients with cirrhosis, in which the prevalence of type 2 diabetes is higher than in the general population, and in CHB patients without cirrhosis.Third, whether type 2 diabetes plays the same role in HCC development between men and women in the presence of CHB is not clear. It has been speculated that in the presence of other strong etiological risk factors for HCC, such as chronic HBV infection, cirrhosis, and male gender, type 2 diabetes plays a minor role in its development.Besides, in the presence of CHB, the relationship between type 2 diabetes duration and HCC risk was not clear.Thus, the aims of this hospital-based case-control study was to more precisely evaluate the role of type 2 diabetes in the development of HCC in the presence of CHB, to explore whether type 2 diabetes plays the same role in HCC development in males and females and in cirrhotic and noncirrhotic patients with CHB, and to evaluate the association of diabetes during with HCC risk.Methods:This case-control study was part of an ongoing hospital-based prospective investigation that was conducted in Jinan Infectious Disease Hospital, Shandong University, a tertiary hospital in Shandong, China. The study was approved by the ethics committee of Jinan Infectious Disease Hospital, Shandong University, and written informed consent for participation was obtained from each study participant.Subjects who fulfilled the following criteria were recruited into the study: hospitalized for HCC or CHB, age≥30 years, positive for hepatitis B surface antigen (HBsAg), negative for anti-HCV, without a history or other evidence of cancer other than HCC, without a history or other evidence of hepatitis other than hepatitis B, no cancer treatment, and no treatment with nucleotide/nucleosides or interferon, Han population, and residence of Shandong Province. Subjects with a history of alcohol consumption were excluded from further analysis.From January 2004 and December 2008, a total of 6,275 eligible consecutive patients (1,105 HBV-related HCC and 5170 CHB without HCC) were enrolled. A total of 1105 HBV-related HCC patients were used as the case in this study. The 5170 hospital cross-sectional CHB patients without HCC were used as the control.Upon entry to the hospital, all subjects were interviewed by trained physicians. Demographic data, family histories, and medical histories were collected. Physical examinations, blood counts, ABO blood type, Rh factor, serum biochemical parameters, prothrombin time, serum alpha-fetoprotein (AFP), anti-HCV, hepatitis B surface antigen (HBsAg), anti-HBs, HBeAg, anti-HBe, and anti-HBc were all measured. HBV DNA quantification, ultrasound examinations, and gastrointestinal barium meal X-ray examinations were also performed.The variables analyzed in this study included age, sex, city of residence, family history of liver cancer, type 2 diabetes, hepatitis B e antigen (HBeAg), HBVDNA, cirrhosis, Child-pugh grade. All data analyses were performed using SPSS v.13.0.Demographic and clinical parameters were evaluated using the chi-squared test for categorical variables, independent-Samples t-test for continuous variables with normal curve distribution, and the Mann-Whitney U test or Kruskal-Wallis test for continuous variables with skewed distribution. Possible confounding effects among the variables were adjusted using a multivariate logistic regression model, and adjusted odds ratios (AORs) and 95 % confidence intervals (CI) were calculated. Effect modifications were evaluated by stratification, statistical interaction was assessed by including main effect variables and their product terms in the logistic regression model. For all tests, P values were 2 sided. A P value of less than 0.05 was considered significant.Results:1. Patient Characteristics Most HCC patients were male (84.7%), HBeAg negative (76.8%), and cirrhotic (68.7%). Cases and controls had a similar distribution of family history of liver cancer and city of residence (Jinan and other cities of Shandong Province). The prevalence of HBVDNA>105copies/mL were lower among cases than among controls. HCC patients were older than controls; the mean age±standard error was 53.8±9.3 for patients with HCC and 44.9±10.7 for controls. The mean age±standard error of male and female subjects with HCC was 53.4±9.1 years and 56.0±10.0 years (p=0.001), respectively. The mean age of HCC patients with cirrhosis and without cirrhosis was similar (53.9±9.0 vs 53.6±9.8, P=0.54).After adjusting age, sex, city of residence, family history of liver cancer, HBeAg status and cirrhosis, multiple logistic regression analyses indicate the AOR (95%CI) of HCC risk for male sex, old age (10-year increment), and cirrhosis are 2.6 (2.2-3.2),2.0 (1.8-2.1),2.8 (2.4-3.3) respectively.2. Prevalence of Type 2 Diabetes The overall prevalence of type 2 diabetes in HCC patients and the cross-sectional controls was 8.4% and 6.3 %, respectively (P=0.01). However, in every age group the prevalence of type 2 diabetes among HCC patients is not higher than among controls. On the contrary, in the 50- to 59-year-old age group, the prevalence of type 2 diabetes is higher among CHB controls than among HCC patients. In male patients, the prevalence of type 2 diabetes was similar between HCC cases and controls. However, in female patients and in patients without cirrhosis, type 2 diabetes was more frequent among HCC patients than among controls. Unexpectedly, the prevalence of type 2 diabetes is higher among HCC patients without cirrhosis than among those with cirrhosis (12.1% vs 6.7%, P=0.003).3. Type 2 diabetes and HCC risk In multivariate logistic regression comparing all HCC cases with the hospital cross-sectional controls, no association between type 2 diabetes and HCC risk was observed. However, in subgroup analysis in female subjects, a significant association between type 2 diabetes and HCC risk was observed with adjusted ORs (AORs) of 1.9 (95% CI,1.1-3.4). In contrast, subgroup analysis in male subjects, no association between type 2 diabetes and HCC risk was observed. These indicate effect modification (heterogeneity) of gender. The estimated X2 for homogeneity between AORs in men and women was 5.7. In addition, including an interaction term of gender and type 2 diabetes in the logistic regression model along with the main effects of gender and type 2 diabetes revealed a significant interaction between gender and type 2 diabetes on HCC development (P=0.008). Besides, including an interaction term of cirrhosis and type 2 diabetes in the logistic regression model along with the main effects of cirrhosis status and type 2 diabetes revealed a significant interaction between cirrhosis status and type 2 diabetes on HCC development (P=0.004). Restricted multivariate logistic regression analyses among female patients without cirrhosis indicated a strong association between type 2 diabetes and HCC risk, with an AOR of 5.6 (95% CI,2.2-14.1). In female patients with cirrhosis, no association between type 2 diabetes and HCC risk was observed.The proportion of patients with a duration of type 2 diabetes>5years is significantly higher among HCC cases than among controls (36.6% vs.19.2%, P<0.001). Restricted analyses among diabetic cases and controls showed the AOR of developing HCC were 2.2 (95%CI,2.2-4.2) for patients diagnosed with a duration of diabetes>5 years after adjusting age, sex, family history of liver cancer, HBeAg, and cirrhosis. Conclusions:In conclusion, type 2 diabetes is independently associated with the increased risk of HCC in female patients with CHB. Longer duration of diabetes is associated with increased HCC risk. Female CHB patients with type 2 diabetes are of a high HCC risk population and should be considered for HCC close surveillance program. Gender differences in HCC risk and known risk factors are substantial and warrant further study. |
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