Non-alcoholic Fatty Liver Disease Contributes to Hepatocarcinogenesis in Non-cirrhotic Liver

A Clinical and Pathological Study

Jacob Alexander; Michael Torbenson; Tsung-Teh Wu; Matthew M. Yeh


J Gastroenterol Hepatol. 2013;28(5):848-854. 

In This Article

Abstract and Introduction


Background and Aim: Hepatocellular carcinoma (HCC) is a major complication of cirrhosis and has been increasing in incidence in recent years. Fatty liver disease is an increasingly common cause of chronic liver disease, and there have been several case reports of HCC in patients with non-cirrhotic fatty liver disease. However, there is limited data from systematic studies with histological confirmation of the presence of both the HCC and the non-cirrhotic fatty liver disease.

Methods: We studied the occurrence of fatty liver disease and the associated demographic, clinical, and pathological characteristics of a large cohort of patients with HCC in non-cirrhotic livers. Patients with intrahepatic cholangiocarcinoma (CC) occurring in non-cirrhotic livers and diagnosed during the same time period were used as the comparison group.

Results: Significant steatosis in the nontumor liver had a statistically significant association with HCC, being present in 54% (85/157) of HCC compared with 27% (32/120) of CC (P < 0.0001). Steatohepatitis was present in 15% (24/157) of HCC and 1% (2/120) of CC (P = 0.0014). Furthermore, HCC was more prevalent in cases with higher grades of steatosis. In addition, the recently described intratumoral steatohepatitic morphology of HCC (SH-HCC) was also associated with significant steatosis in nontumor liver, with significant steatosis being present in 89% with SH-HCC compared with 50% without SH-HCC (P = 0.0162). Finally, SH-HCC was increasingly more prevalent in patients with higher grades of nontumor steatosis.

Conclusions: Taken together, these findings suggest a strong association between fatty liver disease and HCC in non-cirrhotic livers.


Primary liver cancer is the fifth most common malignancy in the world, accounting for approximately 6% of all human cancer and is the third leading cause of cancer-related death worldwide.[1,2] Hepatocellular carcinoma (HCC) constitutes the majority of primary liver cancers, and more than half a million cases are newly diagnosed each year, with an almost equal annual mortality given its high fatality rates.[1,2] Viral hepatitis and cirrhosis are known to be the most common risk factors for HCC, but the exact mechanisms of hepatocarcinogenesis remain unclear, particularly in patients without these risk factors. In recent years, HCC has declined in incidence in countries such as Taiwan and China because of better control of chronic hepatitis B (HBV) infection, but has steadily increased in countries in North America and Europe, and is currently the cancer with the fastest growing mortality rates in the United States.[1–3] The prevalence of obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD) have also been steadily rising in developed countries during the same period. In addition, diabetes and obesity, two conditions strongly associated with NAFLD, have been found to be risk factors for the development of HCC in several studies.[4–14] The development of HCC in cirrhosis secondary to NAFLD is also well documented.[15,16] Although the overall risk is considered to be lower compared with that in cirrhosis from hepatitis C (HCV),[17,18] HCC has been estimated to occur in 5% of the cases of cirrhosis secondary to NAFLD.[19] Additionally, diabetes has been shown to increase the risk of HCC associated with known risk factors such as HCV, HBV, and alcoholic cirrhosis by 1.5-fold.[7] Similarly, hepatic steatosis is also associated with increased risk for HCC in chronic HCV.[20–22]

Despite the well-documented association between cirrhotic fatty liver disease and HCC, fatty liver without cirrhosis or other coexisting liver diseases is often considered to be a relatively harmless condition without any increased risk for HCC or mortality.[23,24] However, recent evidence from clinical and animal studies have suggested an association between non-cirrhotic fatty liver and HCC.[25] A recent study of the SEER-Medicare database also found metabolic syndrome to increase the risk of primary liver cancer independent of other risk factors.[26]

We sought to investigate the association between non-cirrhotic fatty liver and HCC by studying the prevalence of hepatic steatosis in non-cirrhotic livers with HCC and by comparing the demographic, clinical, and the histopathological characteristics of HCC with intrahepatic cholangiocarcinoma (CC) arising in non-cirrhotic livers in a large cohort of patients.