Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM.
Division of Gastroenterology and Hepatology, University of Virginia Health System, P.O. Box 800708, Charlottesville, Virginia 22908-0708, USA. shc5c@virginia.edu
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 disease 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 steatohepatitis with cirrhosis. Whether therapy aimed at 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.
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