| AIM:Diabetes mellitus (DM) has been associated with an increased risk of human hepatocellular carcinoma (HCC) in some studies. However, is it certain to draw the conclusion that DM is a "true" independent risk factor for HCC? Considering that the studies were very limited and conducted in some Western countries, no information was available in our Chinese patients, especially in those with single hepatitis B virus (HBV) infection, our study was designed:(1) To determine the role of DM and other associated factors in Chinese HCC patients with cirrhosis, compared with those HCC patients without cirrhosis, in the single setting of HBV infection, after other known concomitant diseases were excluded; (2) To determine the potential role of DM in the progression of cirrhosis to HCC among Chinese HBV infection patients; and (3) To determine the expression and significance of ISR-1 in HCC samples, compared with the surrounding no-tumor tissues, liver cirrhosis and chronic hepatitis tissues.METHODS:A total of 1028 patients, treated at the China-Japan Friendship Hospital, Ministry of Health, in the period January 2003 to June 2009, and with a hospital discharge diagnosis of HCC and/or cirrhosis, were studied. The demographic, clinical biochemical, virological, metabolic, radiological and pathological features/data were analyzed and the multivariate logistic regression model was used to determine the independent factors associated with HCC. One hundred and thirty-three samples, from the patients who were treated at our hospital in the period January 2003 to March 2010, were examined by immunohistochemistry (IHC), including 63 cases from HCC, 48 cases from paracancerous tissues,13 cases from liver cirrhosis, and 9 cases from chronic hepatitis tissues. The multivariate logistic regression model was used to determine the independent factors associated with the positive-expression of IRS-1.RESULTS:Of the total 482 HCC patients,310 were diagnosed with HBV infection and, following the inclusion and exclusion criteria,224 were analyzed, including 122 patients (54.5%) with cirrhosis (the case group) and 102 patients without cirrhosis (the control group). Twenty-seven patients (12.1%) were diabetic, including 19 in the case group and 8 in the control group (19/122=15.6% vs 8/102=7.8%; P=0.077). Thirty-one possible relevant parameters were compared by univariate analysis, and 10 variables were selected for multivariable analysis, including DM (P=0.077), past history of HBV infection (P=0.005), Child-Pugh score (P＜0.001), total bilirubin (P＜0.001), albumin level (P<0.001), international normalized ratio (INR) (P<0.001), alanine aminotransferase (P=0.050), platelet (P＜0.001), total cholesterol (P=0.047), and LDL cholesterol (P=0.002) levels. Diabetes showed a statistical difference by multivariable analysis (odds ratio (OR) 4.88,95% confidence interval (CI) 1.08-21.99, P=0.039), although no significant difference was found in univariate analysis. In addition, three cirrhosis-related parameters remained statistically different, including INR (OR 117.14,95% CI 4.19-3272.28, P=0.005), albumin (OR 0.89,95% CI 0.80-0.99, P=0.027), and platelet count (OR 0.992,95% CI 0.987-0.999, P=0.002).Of the total 1028 patients,224 HCC patients and 248 cirrhotic patients fulfilling the inclusion criteria were analyzed. One hundred and fifteen patients were diagnosed with DM (115/472= 24.4%), including 39 in the HCC group and 76 in the cirrhosis group (17.4% vs.30.6%, P=0.001). In the multivariate analysis, DM was shown as an independent factor associated with HCC (OR 0.376,95% CI 0.175-0.807, P=0.012) when the HCC patients with clinical/symptomatic cirrhosis (n=122) were compared with the simple cirrhotic patients (n=248). After the study population was restricted to the HCC/cirrhotic patients with decompensated liver function, DM was continued to be shown as a protective factor (OR 0.192,95% CI 0.054-0.679, P=0.010). Even the 50 hepatogenous diabetic patients were excluded, similar results could be observed and the protective strength was increased. In addition, higher a-fetoprotein (AFP) level always remained as risk factors among all the aforementioned groups analysis, providing support for the protective role of DM in HCC. Combined with the reported studies, the reason was deduced to be associated with the different treatments of DM.The expression of IRS-1 protein was observed in 28 cases of HCC (28/63, 44.4%),8 cases of paracancerous tissues (8/48,16.7%),5 cases of liver cirrhosis (5/13, 38.5%), and 8 cases of chronic hepatitis (8/9,88.9%). After exclusion of the 19 samples from liver biopsy, adjustment for age, gender, HBV and HCV, HCC was the sole independent associated factor for the expression of IRS-1 (OR 2.846,95% CI 1.104-7.332, P=0.030). Moreover, its expression was not related to the tumor grade of differentiation and presence of tumor thrombus. In addition, we found that the method of sampling was associated with the expression of IRS-1.CONCLUSIONS:In Chinese patients with single HBV infection, DM was found to be associated with an increased risk of HCC; however, it may be a potential protective factor for hepatocellular carcinoma in the progression of cirrhosis to HCC, especially in those with advanced cirrhosis, at least in our study population. For HCC, DM may play different roles in the progression of chronic hepatitis B to cirrhosis and HCC; combined with the reported studies, the reasons may be deduced to be associated with the early intervention and different treatments of DM. The expression of IRS-1 was higher in HCC than in surrounding no-tumor tissues, which may involve in the onset and development of HCC. Our conclusion needs to be validated in more patients and prospective studies are required. Moreover, studies in human tumor cell lines and in mouse models are required to address the associated issues and involved mechanisms. |
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