Non-alcoholic fatty liver disease (NAFLD) without cirrhosis appears to be a significant contributor to the increased incidence of hepatocellular carcinoma (HCC), according to a study reported at the annual meeting of the American Association for the Study of Liver Diseases (AASLD). Data from the study suggest that patients with non-cirrhotic NAFLD have a unique underlying pathophysiology for developing HCC, a finding that may help explain the increased incidence of HCC, reported Rubayat Rahman, MD, PhD, of the University of Missouri Division of Gastroenterology and Hepatology. The investigators combined the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database with information on HCC patients from the Medicare Enrollee and Claims File database from 1993 to 2007. Of a total of 17,895 HCC cases, 2,863 (16%) had NAFLD only, without any other HCC risk factors or etiology. The combined database covers 30 percent of the Medicare enrollees, and the SEER database includes 28 percent of the U.S. population enrolled in 18 cancers, with 93 percent of those over 65 years of age, and is matched to Medicare enrollees. According to Dr. Rahman, NAFLD (16%) was the 3rd most common risk factor for HCC after infection (44%) and alcoholic fatty liver (19%) (21% were other factors), and the 2nd most common risk factor after infection in Asian and Pacific Island countries. The analysis showed that 36% of patients with NASH-related HCC were cirrhotic and 18% were only hepatic steatosis and non-NASH or other adverse pathologic changes. A higher proportion of non-cirrhotic patients had early HCC (stage I or II) than cirrhotic patients (62% vs. 44%) and a relatively low cancer grade (grade I or II, 76% vs. 56%). Although the annual percentage of patients with cirrhotic NAFLD-associated HCC has tended to increase since 1993, the annual increase in the number of patients with non-cirrhotic NAFLD-associated HCC has exceeded that of the former since 1999. The average annual number of cases of the latter increased from 51 cases in 1993-2000 to 88 cases in 2001-2007, while no change was observed in the annual number of the former. Patients with non-cirrhotic NAFLD-related HCC had a significantly higher proportion of patients with three metabolic syndromes, including body mass index >30 kg/m2, type 2 diabetes mellitus, and dyslipidemia. Patients with non-cirrhotic NAFLD with each of these conditions were more likely to develop HCC than patients with cirrhotic NAFLD, although the latter had a relatively higher overall odds of developing HCC [odds ratio (OR), 16.5]. In response to a query from participants regarding the lack of a centralized histopathological system assessment at the time of diagnosis of cirrhosis or NASH, Dr. Rahman stated that patients in the Medicare-matched SEER database had CPT procedure codes and ICD-9 diagnosis codes at the time they underwent liver biopsy for diagnosis. Others argued that the high incidence of cancer in the aforementioned patients and the fact that the database did not include patients with a maximum age of 55 years for NASH, suggested that NAFLD should be cautiously included as an independent risk factor for HCC.