Obesity and liver cancer

Epidemiological studies have shown that obesity is a risk factor for hepatocellular carcinoma. Similar studies further indicate that diabetes is also a major risk factor. Both obesity and diabetes are frequently associated with nonalcoholic fatty liver disease, and case reports have shown progression of nonalcoholic fatty liver disease to cirrhosis and hepatocellular carcinoma. Although no study has clearly tied all of these variables together, it is likely that the association of hepatocellular carcinoma with obesity represents the progression of underlying nonalcoholic fatty liver discase to cirrhosis.

The mechanism most likely involves replicative senescence of steatotic mature hepatocytes and compensatory hyperplasia of progenitor (oval) cells as a reaction to chronic injury due to ongoing nonalcoholic steatohepatitis and resultant hepatic fibrosis. Growth factors associated with chronic inflammation, type 2 diabetes, and DNA mutations as a result of lipid peroxidation probably play significant roles in clonal expansion and hepatocellular carcinoma progression. It remains unclear whether cirrhosis is a prerequisite for the development of hepatocellular carcinoma or whether hepatocellular carcinoma can develop in fatty liver in the absence of cirrhosis.

However, well-documented case reports suggest that most cases of hepatocellular carcinoma arise in the setting of nonalcoholic fatty liver disease reduces the risk of hepatocellular carcinoma remains to be shown. Prophylactic measures and the role of cancer surveillance have not been adequately investigated, but current evidence suggests a risk for hepatocellular carcinoma in nonalcoholic steatohepatitis-related cirrhosis that rivals that of hepatocellular carcinoma in hepatitis C virus-related cirrhosis, particularly in older male patients. The increasing incidence of hepatocellular carcinoma (HCC) in the United States has been largely attributed to the past epidemic of hepatitis C virus (HCV) infection and HCV-associated cirrhosis.

However, these changes in the incidence of HCC have also paralleled an epidemic of obesity and type 2 diabetes and an associated high prevalence of nonalcoholic fatty liver disease (NAFLD), which is now recognized as one of the most common of all liver diseases. Although, there is probably substantial ethnic variation, it is estimated that 90 percent of people with obesity (body mass index (BMI) >30KG/M2) have some form of fatty liver, ranging from simple steatosis to more severe forms of nonalcoholic steatohepatitis (NASH), including cirrhosis. An increasing number of publications point toward underlying NAFLD as the key link between obesity and HCC.

In most cases, this probably involves the progression of NASH to cirrhosis and the subsequent development of carcinoma. Although animal models of fatty liver in which HCC develops without cirrhosis leave the question open, most human studies suggest that silent progression of NASH to cirrhosis is a prerequisite to HCC. Thus, the diagnosis of antecedent NASH may go unrecorded when such a patient presents initially with HCC.

Obesity And Hepatocellular Carcinoma

Obesity is now widely recognized as a significant risk for the development of many types of cancer. Primary liver cancer has been associated with obesity in 2 large population prevalence studies. In a study from Denmark, the relative risk of liver cancer in a study cohort of 43,965 obese patients was increased to 1.9 compared with the general population. Although the authors attributed some of this risk to alcohol use, similar results were noted, after adjustment for alcohol use, in a more recent US study. This study included 404,576 men and 495,477 women aged >30 years with a BMI >18.5 kg/m2 at enrollment who were observed for 16 years.

Overall and site-specific cancer-related deaths were stratified according to BMI. Although histological data were not available, the relative risk of dying from liver cancer was 1.68 times higher among women with a baseline BMI>35kg/m2 and was 4.52 times higher for men with a similarly increased BMI compared with the reference groups with baseline BMIs of 18.5 to 24.9 kg/m2. Among the male group, liver cancer had the highest relative-risk increase of all of the cancers studied. Nair et al. examined the role of obesity as an independent risk factor for HCC in 19,271 patients with cirrhosis who underwent transplantation in the United States between 1991 and 2000.

The patients were stratified into 3 groups according to BMI at the time of listing: <25 kg/m2, 25.1-30 kg/m2 (overweight), and >30 kg/m2 (obese). The overall incidence of HCC was 3.5 percent (n=659). Multivariate analysis showed obesity to be a statistically significant independent risk factor for HCC in patients with alcoholic (odds ration =3.2) crytogenic (odds ration=11.1) cirrhosis, but not in patients with HCV infection, chronic hepatitis B virus (HBV) infection, primary biliary cirrhosis, and autoimmune hepatitis. The authors hypothesized that the role of antecedent steatosis in both alcoholic liver disease and cryptogenic cirrhosis provided a common tread that explained the apparent disease-specific risk associated with obesity.

Therapeutic Implications

On the basis of the suspected pathogenesis of HCC in obesity (NAFLD, NASH, fibrosis, cirrhosis, and HCC, treating NAFLD may also alter the risk of HCC. Thiazolidinediones seem to decrease hepatic fat, probably through changes in adipocyte insulin sensitivity and possibly through alterations of fatty acid metabolism in mitochondria and peroxisomes. Such an effect is likely to reduce the risk of cancer by decreasing inflammation and lipid peroxidation. However, much has yet to be learned about the effects of these agents and other forms of therapy, such as metformin and dietary manipulations.

Other preventive measures also deserve consideration. Given the expression of cyclooxygenase-2 in human HCC, the use of prophylactic cyclooxygenase inhibitors may be of benefit, although the potential adverse effects of these agents, such as fluid retention and bleeding risk in cirrhosis, warrant caution. On a more practical level, it is also important to note that the risk of HCC seems to be substantial in patients with NAFLD with cirrhosis. This raises the issue of whether there is any benefit to screening and surveillance for HCC in patients with NASH who have significant fibrosis or cirrhosis. There are insufficient data to formally recommend routine surveillance for HCC in such patients, but discussion of the risks of HCC and of means to modify these risks is appropriate.