BACKGROUND:Previous studies have reported the association between type 2 diabetes mellitus (DM2) and hepatocellular carcinoma (HCC).AIMS:To explore the relationships among DM2, antidiabetic therapy and HCC risk.METHODS:We recruited 610 HCC patients compared with 618 matched cirrhotic patients and 1696 Controls. The odds ratio (OR) for HCC in diabetic subjects treated with insulin, sulphonylureas and metformin was calculated.RESULTS:DM2 prevalence was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in Controls (P<0.0001). The OR for HCC in diabetic HCC patients vs Controls was 3.12 [confidence interval (CI) 2.40-3.90; P<0.001] in univariate analysis and 2.50 (CI 1.70-3.69; P<0.0001) in multivariate analysis. Comparing diabetic HCC patients vs liver cirrhosis (LC) cases, univariate analysis showed an OR for HCC of 2.09 (CI 1.50-2.90; P<0.001), whereas on multivariate analysis we found an OR of 1.46 (CI 1.07-1.98; P=0.02). In 84% of the cases, type 2 diabetes mellitus has been present before the HCC diagnosis. Multivariate analysis showed that metformin treatment was associated with a strong and statistically significant reduction of the risk of HCC, as compared with the use of sulphonylureas or insulin, in diabetic HCC patients vs Controls and vs LC cases (OR of 0.15; CI 0.04-0.50; P=0.005 and OR=0.16; CI 0.06-0.46; P=0.0006 respectively).CONCLUSIONS:Our study shows that DM2 is an independent risk factor for HCC and pre-exists to HCC occurrence. In DM2 patients with HCC, metformin therapy is associated with a reduced HCC risk and seems to have a protective effect on HCC development.

Type 2 diabetes mellitus (DM2) has been associated with hepatocellular carcinoma (HCC) development. To study this relationship, we enrolled 465 HCC patients compared with 618 Cirrhotic cases and 490 Controls. The prevalence of DM2 is significantly higher in HCC patients with an Odds Ratio of 3.12 versus Controls. In HCC cases with alcohol abuse, the frequency of DM2 is the highest. In our HCC patients, when HCV infection is associated with alcohol abuse, the liver cancer develops earlier. In addition, multivariate analysis shows that alcohol consumption is an independent risk factor for HCC more relevant than HCV infection.

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 patients and controls as comparison groups. RESULTS DM2 prevalence was 31.2% in patients with HCC, 23.2% in cirrhotic patients and 12.6% in controls (P < 0.0001). In 86% of study subjects, DM2 had been diagnosed for more than 1 year before the HCC diagnosis. HCC patients with DM2 had a 1.5-2.5-fold increased risk of liver cancer. The HbA1c mean levels were significantly higher in DM2 patients with HCC than in cirrhotic and control DM2 patients. Antidiabetic treatment with metformin was more common among cirrhotic and control DM2 subjects than among cases with HCC. In both series of multivariate analyses, treatment with metformin significantly reduced the risk of HCC by more than 80% compared with sulphonylureas and insulin therapy. No significant differences were seen between sulphonylureas and insulin treatment. Elevated HbA1c levels were positively related to the risk for HCC in diabetic patients, with a 26%-50% increase in risk for each 1% increase in HbA1c values. CONCLUSION In patients with preexisting DM2, the risk of HCC is positively associated with poor chronic glycemic control and significantly decreased by metformin therapy.

Hepatocellular carcinoma (HCC) ranks as the fifth most common malignancy worldwide, and its incidence is especially increasing in male populations of Western countries [1]. Recognized risk factors ...

AIM:To explore the association between hepatocellular carcinoma (HCC) and type 2 diabetes mellitus, describe the temporal relations between the onset of diabetes and the development of HCC and evaluate the possible effects of antidiabetic therapy on HCC risk.METHODS:We recruited 465 HCC patients, 618 with cirrhosis and 490 control subjects. We evaluated the odds ratio (OR) for HCC by univariate and multivariate analysis. Moreover, OR for HCC in diabetic subjects treated with insulin or sulphanylureas and with metformin were calculated.RESULTS:The prevalence of diabetes mellitus was 31.2% in HCC, 23.3% in cirrhotic patients and 12.7% in the Control group. By univariate and multivariate analysis, the OR for HCC in diabetic patients were respectively 3.12 (CI 2.2-4.4, P < 0.001) and 2.2 (CI 1.2-4.4, P = 0.01). In 84.9% of cases, type 2 diabetes mellitus was present before the diagnosis of HCC. Moreover, we report an OR for HCC of 2.99 (CI 1.34-6.65, P = 0.007) in diabetic patients treated with insulin or sulphanylureas, and an OR of 0.33 (CI 0.1-0.7, P = 0.006) in diabetic patients treated with metformin.CONCLUSION:Our study confirms that type 2 diabetes mellitus is an independent risk factor for HCC and pre-exists in the majority of HCC patients. Moreover, in male patients with type 2 diabetes mellitus, our data shows a direct association of HCC with insulin and sulphanylureas treatment and an inverse relationship with metformin therapy.

Objectives To investigate the role of insulin resistance (IR) and insulin plasma levels (IRI) in patients with chronic liver disease (CLD) and hepatocellular carcinoma (HCC). Methods We recruited the following patients: 125 with HCC, 128 with liver cirrhosis (LC) and 133 with chronic hepatitis C (CHC). IR was assessed by the HOMA-IR method. To define IR and hyperinsulinemia we selected as a cut-off level, the value of the 80th percentile for HOMA-IR (2.72) and IRI (11.18) in 113 healthy subjects. Results The mean levels of HOMA-IR and IRI increase progressively among CHC (2.7 ± 2.9 and 11.5 ± 10.5, respectively), LC (5.4 ± 4.5 and 17.6 ± 11.2) and HCC (6.4 ± 9.8 and 18.2 ± 18.8). In the upper quintiles for HOMA-IR and IRI, the frequency of patients in the LC and HCC groups was twice as much in CHC cases. HCC with DM2 have the greatest percentage above the 80th percentile of HOMA-IR, their quintiles distribution is inverted and HOMA-IR mean values are significantly higher in comparison with HCC without DM2 cases. Discussion Our study shows that the association between IR and CLD begins in the early stages of liver fibrosis. DM2 increases HOMA-IR and IRI mean levels in HCC patients and these metabolic factors could play a major role in the link between diabetes mellitus and hepatocarcinoma.

AIMTo investigate the relationships between Type 2 diabetes mellitus (DM2) and the risk of hepatocellular carcinoma (HCC).METHODSWe studied the association between DM2 and HCC in a large case-control study that enrolled 465 consecutive Caucasian patients with HCC (78.3% males, mean age 68.5 +/- 8.9 years) compared with an age and sex matched control group of 490 subjects.RESULTSPrevalence of DM2 was significantly higher in HCC patients (31.2% vs 12.7%; OR = 3.12, 95% CI: 2.22-4.43) and in HCC cases with alcohol abuse. DM2 has been diagnosed before the appearance of HCC in 84.1% of diabetic HCC subjects with mean duration of 141.5 mo, higher in cases treated with insulin than in those with oral antidiabetic agents (171.5 vs 118.7 mo). Compared to controls, males DM2 with HCC were more frequently treated with insulin (38.1% vs 17.6%, P = 0.009) and with sulfonylurea with or without metformin than with diet with or without metformin (84% vs 68.3%, P = 0.049).CONCLUSIONDM2 in our patients is associated with a 3-fold increase risk of HCC. In most of our cases DM2 pre-existed to HCC. Patients with DM2 and chronic liver disease, particularly insulin treated males, should be considered for HCC close surveillance programs.

To the Editor: We read with interest the article by Lewden et al1 on the changes in causes of death among adult infected by HIV in the last years. The investigators have observed an increase in the proportion of cancers not related to HIV, liver-related diseases, and cardiovascular diseases. Particularly, they have reported that 24% of liver-related deaths are due to hepatocarcinoma. Several factors may explain these changes, such as an increase of the mean age of general western populations and of the cohort of hepatitis C virus-infected patients before the discovery of the hepatitis C virus and subsequent possibility to prevent this infection. Moreover, we suggest type 2 diabetes mellitus as a possible underlying cause of the increased mortality for solid tumor, particularly hepatocarcinoma.2 In the last years, it has been observed a dramatical increase in incidence and prevalence of type 2 diabetes mellitus related with the changes in the lifestyle in most developed countries. Similarly, an increasing incidence of type 13 and type 2 diabetes mellitus4-8 has been reported also in HIV-infected population. Several studies4-8 have reported that, in addition to traditional risk factors, treatment with protease inhibitor-containing regimens and nucleoside reverse transcriptase inhibitor-containing regimens were associated with increased risk of developing type 2 diabetes mellitus, metabolic syndrome, and cardiovascular diseases in HIV-infected subjects. Moreover, several epidemiological studies have shown an association between type 2 diabetes mellitus and risk of developing solid tumor,9 particularly hepatocarcinoma.2,10-12 This association may be due to growth promoting and inhibiting of apoptosis effects of insulin and insulin-like growth factor-I. Indeed, in vitro studies have shown a carcinogenic effect of insulin and insulin-like growth factor-I on liver and other tissues.13-16 Because HIV-infected subjects are characterized by a higher risk and a higher prevalence of type 2 diabetes mellitus, related also to antiretroviral therapy, and type 2 diabetes has been associated with increased risk of hepatocarcinoma, we hypothesize that type 2 diabetes mellitus may play a role to explain the changes in causes of death among HIV-infected adults, particularly the increased prevalence of hepatocarcinoma. Antonio Perciaccante, MD Giorgio Zanette, MD Valter Donadon, MD Pordenone Hospital, 3rd Internal Medicine and Diabetic Clinic Pordenone, Italy

Our aim was to evaluate the role of N‐acetyltransferase (NAT2) and glutathione S‐transferase M1 and T1 (GSTM1 and GSTT1) polymorphisms in hepatocellular carcinoma (HCC) according to cigarette smoking, taking into account hepatitis B (HBV) and C (HCV) viral infection as well as alcohol consumption. A hospital‐based case‐control study was conducted in 2 areas of north Italy. Cases (n = 200) were patients hospitalized for HCC, and controls (n = 400) were patients admitted for reasons other than liver disease, neoplasms and tobacco‐ and alcohol‐related diseases. Genotypes were determined using PCR and the PCR/restriction fragment length polymorphism–based method. The putative risk genotypes NAT2 slow acetylator, GSTM1 null and GSTT1 null were not associated with HCC (OR = 1.3, 95% CI 0.8–2.0; OR = 1.0, 95% CI 0.6–1.5; OR = 0.8, 95% CI 0.4–1.4, respectively). Although not statistically significant, an increase in HCC risk was observed among light smokers (1–20 pack‐years) carrying GSTT1 null (OR = 1.7, 95% CI 0.6–4.7) and NAT2 slow acetylator (OR = 1.3, 95% CI 0.6–3.0) genotypes. In conclusion, there was no evidence for a gene–environment interaction in HCC risk for GSTM1, GSTT1 and NAT2 genotypes. © 2005 Wiley‐Liss, Inc.

OBJECTIVE:The aim of this study was to investigate the role of alcohol dehydrogenase type 3 (ADH3), glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) polymorphisms in modifying hepatocellular carcinoma (HCC) risk according to alcohol intake.METHODS:A hospital-based case-control study was conducted in two areas of North Italy. Two-hundred cases hospitalized for HCC and 400 controls were recruited. Genotypes were determined using PCR and the PCR/restriction fragment length polymorphism-based method.RESULTS:There was no association of the putative risk genotypes ADH3(1-1), GSTM1 null and GSTT1 null with HCC (odds ratio [OR], 0.8; 95% confidence interval [CI], 0.5-1.3; OR, 1.0; 95% CI, 0.6-1.5; OR, 0.8; 95% CI, 0.4-1.4, respectively). A steady increase in HCC risk with increasing alcohol intake, which did not vary according to ADH3 and GSTT1 genotypes, was observed. Nevertheless, the OR for HCC due to an alcohol intake of >100 g of ethanol per day increased in subjects with GSTM1 null genotype (OR, 8.5; 95% CI, 3.9-18.6) compared to GSTM1 non-null genotype (OR, 4.5; 95% CI, 2.0-10.0).CONCLUSIONS:ADH3(1-1) and GSTT1 null genotypes did not modify the risk of HCC due to alcohol intake whereas an influence of GSTM1 null genotype for high ethanol consumption was suggested.

An increase in total and low density lipoprotein (LDL) cholesterol concentrations is related to the incidence of cardiovascular heart disease. The purpose of this study was to compare the efficacy and safety of pravastatin, an HMG-CoA reductase inhibitor, versus gemfibrozil, a fibrate, in the treatment of primary hypercholesterolaemia. 855 subjects (males and females, aged between 18 and 70 years) with total cholesterol (TC) concentrations > 240 mg/dl and triglyceride (TG) concentrations < 250 mg/dl were enrolled. After a pretreatment diet period, patients received either pravastatin 20 mg/day (659 patients) or gemfibrozil 1200 mg/day (196 patients). At the end of the 12-week treatment period, reductions in TC (−23%) and LDL-C (−31%) were noted in the pravastatin group. Gemfibrozil reduced TC by 16% and LDL by 20%. High density lipoprotein (HDL) cholesterol concentrations increased in a similar way in the two groups: pravastatin +10%, gemfibrozil+11%. Triglycerides decreased by 14% with pravastatin and by 22% with gemfibrozil. Pravastatin and gemfibrozil were both well tolerated. No significant adverse events or variations in laboratory parameters occurred during this study.

The relationship between urinary albumin excretion rate (UAE) and some metabolic and haemodynamic characteristics was studied in 62 (50 male, 12 female) type 2 (non-insulin-dependent) diabetic patients, with (26 male, 5 female) and without (24 male, 7 female) ischaemic heart disease (IHD), free from overt diabetic nephropathy. The overall population was subdivided into quartiles on the basis of UAE values (mg/24h): group 1 (16 subjects), 3.3–7 (range); group 2 (15 subjects), 7.22–11.8; group 3 (15 subjects), 11.9–30; group 4 (16 microalbuminuric subjects), 31.7–226. The groups were comparable with regard to age, duration of diabetes and prevalence of smokers. From group 1 to group 4 we found increasing levels of body mass index (BMI) (24.2±0.6, 26.6±0.7, 27.6±0.7, 27.6±0.9 kg/m2;P=0.007), HbA1c (5.99±0.2, 6.45±0.35, 7.02±0.41, 7.4±0.39%;P=0.017), total cholesterol (5.30±0.26, 5.51±0.34, 6.14±0.21, 6.32±0.26 mmol/l;P=0.026), triglycerides (1.37±0.20, 1.67±0.21, 2.07±0.29, 2.55±0.45 mmol/l;P=0.034) and prevalence of hypertension (50%, 67%, 67%, 81%;P=0.088). No significant differences were found between C-peptide, insulin resistance (K index of insulin tolerance test) and high-density lipoprotein (HDL)-cholesterol levels. Groups 1+2 had a lower prevalence of IHD in comparison with groups 3+4 (42% vs 58%,P=0.069). Using multiple regression analysis, only HbA1c was independently associated with log10 UAE in the overall population (P=0.002), including as independent variables age, duration of diabetes, BMI, total cholesterol, triglycerides and mean arterial pressure. In conclusion: (1) type 2 diabetic patients show higher BMI, HbA1c, total cholesterol, triglyceride levels and prevalence of hypertension with increasing UAE, even in the normoalbuminuric range; (2) the prevalence of IHD is higher in the groups with elevated UAE; (3) glycaemic control is the only metabolic characteristic independently associated with UAE.