Relationship between hepatocellular carcinoma and cirrhosis.
No agreement exists on the dose-effect relation between alcohol intake and risk of HCC. Some authors argue that the risk of developing liver disease does not. tween patients with hepatocellular carcinoma with and without cirrhosis. Patients with cirrhosis sur- vived slightly longer, but the difference was not biologically. Liver cirrhosis may limit surgical and interventional approaches to cancer Natural history of hepatocellular carcinoma and prognosis in relation to treatment .
Other aspects of the relation between alcohol drinking and HCC are still unresolved, namely, the effects of type of alcoholic beverage usually consumed, duration of drinking, age at start, and time since quitting.
Synergisms between alcohol and hepatitis B virus infection and between alcohol and hepatitis C virus infection in increasing the risk of HCC have been suggested by epidemiologic and pathologic studies 10 However, we know of no data available on the pattern of this interaction for various levels of alcohol intake.
We investigated the relation between alcohol habits and HCC in men and women separately, also taking account of hepatitis B and hepatitis C virus infections. To this end, the decision to perform the study in the Brescia area seemed particularly appropriate because of the high incidence of liver cancer in the area 12 and because alcohol intake is a major cause of HCC 13 and of cirrhosis 1415 as well as hepatitis B and hepatitis C virus infections in Italy.
Briefly, this hospital-based case-control study was carried out in the province of Brescia population about 1 million inhabitantsnorthern Italy. We prospectively recruited as cases of patients We enrolled as controls of subjects Subjects hospitalized for injuries were also excluded because of the relation between such conditions and alcohol abuse.
Both cases and controls were born in Italy, lived in the province of Brescia, and were less than 76 years of age. Among HCC cases, The project was approved by a local ethics committee.
The Etiology of Hepatocellular Carcinoma and Consequences for Treatment
Written informed consent was obtained from all patients. At the hospital, a standardized questionnaire was used to interview cases and controls about their history of alcohol drinking We assessed total alcohol intake according to the average ethanol content, by volume, of wine 12 percentbeer 5 percentand spirits 40 percent.
Subjects who reported at the time of the interview that they consumed alcohol were considered current drinkers. Subjects who had stopped drinking at least 1 year previously were considered former drinkers, while those who had stopped more recently were included among current drinkers.
The questionnaire used for collecting information on history of alcohol intake has been described in detail by Corrao et al. Briefly, each subject's life was divided into decades, from age 20—29 to 60 years or more, and his or her usual daily or weekly intake during the decade was collected for each type of alcoholic beverage. The dates of beginning and stopping alcohol intake were also recorded to compute duration of drinking, age at start, and time since quitting for former drinkers.
Given the evidence of a latency period of at least 5 years for alcohol-related onset of cirrhosis 18 and of the same interval between onset of cirrhosis and HCC development 19we evaluated two measures of alcohol intake in the past as exposure variables.
The Relationship Between Hepatocellular Carcinoma and Hepatitis B and C Virus
Second, we computed average intake of alcohol during the period of regular consumption. Both measures were computed in grams of ethanol per day. These proinflammatory cytokines are both known to induce IR [ 32 ], and there is evidence to suggest that Kupffer cells [ 7 ] stimulated by oxidative stress [ 33 ] and exposure to the HCV core protein [ 34 ] are a likely source.
Taken together, these data suggest that the process by which HCV infection can contribute to IR is complex and involves multiple mechanisms. Patients with both HCV infection and alcohol abuse have been shown to develop more severe fibrosis and have higher rates of cirrhosis and HCC than nondrinkers [ 35 ].
The risk for developing HCC has also been shown to increase as levels of alcohol intake rise [ 28 ]. The mechanisms by which alcohol worsens HCV-related liver disease are not clear, although several possibilities have been proposed, including: However, the dominant mechanism for synergism between alcohol and HCV infection appears to be increased oxidative stress.
As mentioned above, HCV core protein localizes at the mitochondrial membrane and promotes oxidative stress. Ethanol potentiates this mitochondrial injury by further increasing reactive oxygen species ROS production and enhancing hepatic glutathione oxidation. Autoimmune Hepatitis Autoimmune hepatitis AIH is a condition of unknown etiology that is characterized by a progressive destruction of the liver parenchyma, often leading to fibrosis and liver cirrhosis.
This surprisingly low incidence of HCC in patients with AIH suggests that there may be some pathologic mechanism preventing cancer progression.
One hypothesis has highlighted the common use of immunosuppressants in these patients. If confirmed, this could affect future therapeutic options afforded to patients with HCC. However, further characterization is needed before any definitive conclusions can be drawn.
- MATERIALS AND METHODS
It occurs in the absence of alcohol use, although the hepatic histology appears consistent with alcoholic hepatitis [ 42 ], with changes in histology including hepatic steatosis, inflammation, hepatocyte injury as exemplified by cytologic ballooning and Mallory's hyaline, and fibrosis [ 43 ].
Epidemiologic studies show that NAFLD is closely linked with the metabolic syndrome, particularly type 2 diabetes mellitus and obesity [ 45 ], with NAFLD occurring almost universally among diabetic patients who are morbidly obese [ 46 ].
Moreover, NASH in association with multiple components of the metabolic syndrome is thought to increase the risk for developing chronic liver disease, cirrhosis, and HCC [ 45 ].
Although the pathophysiologic mechanisms driving NAFLD and the associated progressive hepatocellular damage are not fully understood, a number of processes have been described. IR is a complex process that likely involves both insulin secretion and action, and is closely associated with obesity [ 46 ].