Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related deaths [1
]. In recent years, a significant increase in hepatocellular carcinoma incidence and mortality rates has been observed in developed countries, but the causes of this growth are only partially understood. Although the main risk factors for HCC are hepatitis C virus, hepatitis B virus (HBV) and chronic alcohol abuse, at least 25% of HCC cases do not have any known etiology, suggesting that further risk factors could be responsible for the increasing incidence of HCC. Diabetes mellitus has recently been proposed as a risk factor for HCC [2
]. During the past two decades, the prevalence of diabetes mellitus, and in particular of type 2 diabetes mellitus, has dramatically increased in many countries, including Italy [4
]. Sedentary lifestyles, excessive food consumption and obesity appear to be the main causes of the current diabetes mellitus epidemic in the western world [5
Previous studies on the association between diabetes mellitus and liver diseases showed that type 2 diabetes mellitus appears to be a cause of non-alcoholic fatty liver disease (NAFLD) and that cirrhosis and hepatitis C virus infection increase the susceptibility to diabetes mellitus [6
Moreover, conflicting results were reported on the association between diabetes mellitus and solid tumors, in particular HCC [3
]. While earlier investigations did not report any association between diabetes mellitus and HCC, recent data clearly indicate that diabetes mellitus is a risk factor for HCC [13
However, the precise relation between diabetes mellitus and chronic liver diseases still needs to be further investigated. Two recent studies have suggested a synergistic interaction in the HCC occurrence among heavy alcohol consumption, chronic viral hepatitis and diabetes mellitus in American blacks and whites [16
]. The aims of our study are to provide a precise assessment on the effect of alcohol consumption and HCV infections, alone and as co-factors of diabetes mellitus, on the risk of HCC in Italian patients.
Each subject with diabetes mellitus in the HCC and LC groups showed the clinical and metabolic characteristics of type 2 diabetes mellitus. Of note, none of our HCC or liver cirrhosis patients had type 1 diabetes mellitus.
As shown in Table 2
, the prevalence of DM2 was 31.2% in the HCC group, 23.3% in the LC group and 12.7% in the Controls. The prevalence of DM2 in the three groups were statistically different (P
< 0.0001), with an OR of 3.12 (CI 2.2−4.4; P
< 0.001) in HCC group versus
Controls and an OR of 2.09 (CI 1.5−2.9; P
< 0.001) in HCC versus
Etiology of the chronic liver disease, mean age at HCC diagnosis and DM2 prevalence in the HCC patients are summarized in Table 3
. Notably, alcohol related HCC had a significantly higher prevalence of DM2 compared to the HCV-positive group of HCC (36.9% versus
3.1. Age at Diagnosis of HCC According to Etiology of Liver Disease
In the subgroup of patients with HCV infection associated to alcohol abuse, the age of HCC diagnosis is similar to the patients with only alcohol abuse as a risk factor for HCC (66.7 ± 8.5 years), but significantly lower than in the subgroup of patients with HCV infection (67.7 ± 9.3 versus
71.5 ± 7.3 years; P
< 0.001) (Table 3
3.2. Multivariate Analysis
Multivariate logistic regression analysis was used to assess the independent role of different variables in HCC patients considering Controls as the comparison group (Table 4
). HCV infection, alcohol abuse and DM2 are independent variables associated with risk of HCC and alcohol abuse shows the highest risk of HCC occurrence (OR = 121.2; CI 61.9–233.7; P
< 0.001).When considering cirrhotic patients as comparison groups the OR for DM2 was 1.4 (CI 1.0–1.9; P
3.3. Time Interval from Type 2 Diabetes Mellitus Onset to HCC Diagnosis
The data collected in the records of our Diabetes Clinic show that in 122 patients (84.9%), DM2 was diagnosed at least six months before the onset of HCC, while in only 23 patients (15.1%) DM2 was recognized after the diagnosis of HCC.
The time interval between DM2 diagnosis and HCC onset was exactly calculated: diabetes was found to be present prior to the HCC diagnosis for a mean time of 141.5 ± 9.4 months.
In the subgroup with pre-existing DM2, the time interval until the diagnosis of HCC was longer in insulin treated patients than in those treated with antidiabetic oral agents (171.5 ± 87.6 versus
118.7 ± 95.2 months; P
< 0.05) (Table 5
3.4. Interactive Effect of the Association among Type 2 Diabetes Mellitus and HCV Infection
As regards to the effect of HCV as cofactor of DM2, we found an OR
for HCC of 2.7 (CI 1.9−4.0; P <
0.0001) in HCC patients versus
Controls with HCV infection alone and of 36.9 (CI 21.6−60.5; P <
0.0001) if HCV infection is associated with DM2, with a Rothman’s Synergy Index of 9.2. (CI 4.7−17.2) (Table 6
3.5. Interactive Effect of the Association among Type 2 Diabetes Mellitus and Alcohol Abuse
Evaluating the association among DM2 and alcohol abuse in HCC versus
Controls group, the alcohol abuse alone shows an OR
for HCC of 3.7 (CI 2.5−5.4; P <
0.0001) and of 49.0 (CI 21.5−111.8; P <
0.0001) when alcohol is associated to DM2, with a Rothman’s Synergy Index of 9.8 (CI 4.9−18.4) (Table 7
Our study shows that HCV infection, alcohol abuse and DM2 are independent risk factors for HCC. Alcohol abuse seems to have a stronger effect on HCC risk, more than HCV infection and DM2 by itself. In fact, the OR for HCC is significantly higher when DM2 is associated with alcohol abuse (49.0) than with chronic HCV infection (36.9). In addition, alcohol consumption significantly lowers the mean age of HCC occurrence in HCV-positive patients of our population and the prevalence of DM2 that is higher in patients with alcohol abuse than in HCV-positive patients.
In this study, every HCC and cirrhotic patient with abnormal glucose tolerance showed clinical and pathophysiological characteristics of DM2. The results of our study are consistent with the theory of the biological mechanisms underlying the epidemiological association between diabetes mellitus and cancer. In fact, this hypothesis postulates that the diabetes-cancer association is likely to be related to insulin resistance and consequent hyperinsulinemia, which are typical features in the majority of type 2 diabetes mellitus patients. Ten years ago, McKeown-Eyssen [27
] and Giovannucci [28
] observed that risk factors for cancer and insulin resistance in developed countries are almost the same. To explain this analogy, they suggested that protracted exposure to hyperinsulinemia increases the levels of IGF-1, which plays a pivotal role in carcinogenesis (insulin-cancer hypothesis) [29
]. In addition, the predictive value of hyperinsulinemia on total cancer mortality [9
] and fatal liver tumor incidence [30
] has been demonstrated in non-diabetic subjects by two recent prospective analysis.
The mechanisms through which alcohol consumption and diabetes mellitus promote the development of HCC are unknown. Although moderate alcohol intake is associated with a reduced risk of DM2, high alcohol consumption seems to have an increased risk of DM2 compared to moderate consumers [31
]. There is a supposed role of oxidative stress, like during the heavy alcohol consumption, in the onset and progression of diabetes mellitus and its complications, related to chronic hyperglycemia. In diabetes mellitus patients, an increased blood glucose level may stimulate glycosylation of proteins, including hemoglobin, leading to an increase in the release of iron from hemoglobin and further production of free radicals causing oxidative stress, in fact the finding of high concentration of serum ferritin in patients with diabetes mellitus may reflects an increased body iron stores [32
]. The fact that iron is a powerful pro-oxidant and that oxidative stress is increased in impaired glucose tolerance states, suggests a possible role for oxidative stress in pathogenesis of diabetes mellitus and its complications on the liver, such as cirrhosis. It is also possible that alcohol-induced oxidative stress may increase the susceptibility of patients with diabetes mellitus to DNA damage and HCC development. Moreover, heavy alcohol consumption could directly induce hepatic cellular injury and toxicity leading to the development of liver fibrosis and cirrhosis [37
]. In addition, oxidation and metabolism of ethanol in the liver by microsomal enzymes may contribute to liver carcinogenesis [38
].Generation of acetaldehyde, and oxygen free radical during ethanol metabolism is also associated with development of alcohol related liver disease through oxidative stress [39
The association between chronic ethanol abuse and the development of cirrhosis, as well between cirrhosis and the development of HCC is well documented. Ethanol and its metabolism affect cell signaling pathways that regulate normal and abnormal hepatocyte function, proliferation and apoptosis, deplete the body’s natural antioxidant supply of glutathione and increase oxygen radical production, leading to release of proinflammatory cytokines [40
]. Oxidative stress is a central factor involved in alcohol-induced liver injury and a critical event in carcinogenesis. [41
]. Moreover intake of alcohol results in decreased hepatic levels of vitamin A, that plays an important role in controlling cell growth, differentiation and apoptosis, as well on carcinogenesis [42
In type 2 diabetes mellitus patients the mortality ratio for liver related events is higher than that for cardiovascular events [43
]. However, patients with DM2 often suffer from liver disease, and diabetes is a recognized cause of NAFLD and cryptogenic cirrhosis. In fact, it is well-known that the natural history of NAFLD might progress, over a period of many years, from steatosis to steatohepatitis, cirrhosis and, sometimes, to HCC [6
]. On the other hand, 20% of patients with cirrhosis have overt diabetes (hepatogenous diabetes) and 60% have impaired glucose tolerance [44
]. Thus, the association between diabetes and cirrhosis is complex and reciprocal.
To evaluate the interactions between DM2, HCV infection, alcohol abuse and HCC, we performed a single centre, retrospective case-control study on HCC patients comparing them, not only to a group of Control subjects without liver diseases and diabetes mellitus, but also to a series of cirrhotic patients.
Our study shows that the prevalence of DM2 in the LC group is intermediate between those of the HCC and Controls, indicating that the underlying liver cirrhosis is not the only cause of diabetes in HCC patients. The evidence that DM2, HCV infections and alcohol abuse are a risk factor for HCC in our patients is demonstrated by multivariate analyses, which show an OR for HCC of 2.2 for DM2, 106.5 for HCV infections and 121.2 for alcohol abuse. The prevalence of DM2 is significantly higher in HCC patients with alcohol abuse and have a synergic effect on HCC occurrence more evident than the association between DM2 and HCV infection.
The precise temporal relation between the onset of type 2 diabetes mellitus and diagnosis of HCC is only partially understood. A previous prospective study [11
], conducted in a large cohort of males with and without diabetes mellitus, investigated for the first time, the temporal relationship between diabetes and HCC, showing a two-fold increase of HCC incidence among patients with diabetes. Our study showed that DM2 is present for a mean of 141 months before the diagnosis of HCC.
A new finding of the current study is the demonstration of synergistic (excess over additivity) effects on HCC between HCV infections, alcohol abuse and diabetes, independent of each other’s effects. Indeed the combined effect of viral hepatitis C and diabetes and alcohol abuse and diabetes were both more than the sum of the individual effects as showed by the Rothman’s Synergy Index that is more relevant for alcohol abuse than for HCV infection as cofactors of diabetes mellitus on HCC development. This suggest that heavy alcohol consumption, in addition to its own direct effects may exacerbate the effect of diabetes mellitus and chronic hepatitis C virus infection on chronic liver diseases and HCC.
The results of our study, therefore, have important implications in the clinical management of diabetes mellitus, particularly in patients with DM2 and chronic liver diseases, because we found that they are at high-risk for HCC. This observation is of primary relevance to the implementation of prevention policies and to encourage the most adequate and cost-effective programs of surveillance in cirrhotic patients.
Thus, our data suggests that patients with DM2 and chronic liver disease should first control their diabetes through diet and changes in lifestyle, to decrease their weight and increase physical activity.
In our study HCV infection, alcohol abuse and DM2 are independent predictors of HCC development. Furthermore our data show that in our population, alcohol consumption, DM2 and HCV-positivity exert synergistic effects on risk of HCC. These factors are likely contributors to the rising incidence of HCC in our and other developed countries. Moreover, public health considerations should prompt the study of HCC prevention strategies among high-risk individuals. In the meantime, it would seem prudent for patients having chronic hepatitis infections or diabetes mellitus consider abstaining from alcohol consumption to reduce the effect of alcohol when combined with these other risk factors.