The incidence of hepatocellular carcinoma has gradually increased in recent years, but the cause of its occurrence has not yet been determined. Nonalcoholic fatty liver disease, which has a strong correlation with obesity, is also on the rise. By analyzing surveillance information, epidemiology and end results (SEER) from Medicare enrollment and claims databases, Dr. Rahman and colleagues studied older patients 65 years of age and older with a diagnosis of hepatocellular carcinoma or liver lesions not associated with multiple risk factors. The control sample was a randomized population of Medicare enrollees. Nonalcoholic fatty liver disease without cirrhosis led to an increase in nonalcoholic fatty liver disease hepatocellular carcinoma. A total of 17895 patients with hepatocellular carcinoma met the inclusion criteria, as confirmed by the investigators. Of these, 2863 (16%) patients with NAFLD had no other risk factors for hepatocellular carcinoma or causes of hepatocellular carcinoma. Overall, NAFLD was the third leading risk factor for hepatocellular carcinoma, with infection (44%) and alcohol consumption (19%) ranking in the top two categories. For Asian Americans and Pacific Islanders, NAFLD is the second leading risk factor after infection. The ratio of men to women with NAFLD hepatocellular carcinoma was approximately 2:1, with 64% having cirrhosis, 44% having early stage (I/II) hepatocellular carcinoma, and 56% having well-staged (I/II) tumors. The remaining 36% of patients with NAFLD hepatocellular carcinoma did not have cirrhosis. The male to female ratio was approximately 3:2, and a higher proportion of these patients had early-stage (62%; P<.01) hepatocellular carcinoma and good tumor grade (76%; P<.01) compared with those with cirrhosis. Half (18%) of patients without cirrhotic NAFLD had only steatosis in hepatocellular carcinoma. The proportion of patients whose stage was early (64%) and whose grade was good (77%) was similar to the overall cirrhosis-free population. When the investigators compared data from 2 periods (1993-2000 and 2001-2007), they found that the mean annual incidence of nonalcoholic fatty liver hepatocellular carcinoma without cirrhosis increased from 51 to 88 cases ( P< .01). In addition, the annual number of cases of steatosis increased from only 4 to 22 ( P<.01). In contrast, there was no increase in the annual number of cases of nonalcoholic fatty liver disease in cirrhosis (123 cases versus 122 cases). Thus, the overall increase in nonalcoholic fatty liver hepatocellular carcinoma over the 2 periods (174 versus 210 cases per year; P < .01) appears to be the result of an increase in nonalcoholic fatty liver hepatocellular carcinoma without cirrhosis. Multivariate analysis revealed that body mass index over 30 kg/m, diabetes mellitus, and dyslipidemia were more common within the group of patients with nonalcoholic fatty liver hepatocellular carcinoma without cirrhosis compared with the group of patients with cirrhosis (P < 0.01). Dr. Rahman explained that cirrhosis-free NAFLD was independently associated with hepatocellular carcinoma and was a more strongly associated risk factor than cirrhosis-free NAFLD. She said the data suggest a unique pathophysiological mechanism for hepatocellular carcinogenesis in non-cirrhotic NAFLD. Our data suggest that 36% of patients with NAFLD do not develop cirrhosis, but they develop hepatocellular carcinoma, she told Medscape Medical News. She told Medscape Medical News. she emphasized, "Often physicians are not paying attention or are simply unaware that they develop hepatocellular carcinoma, even in cases where there is only steatosis or only NASH pathology without any signs of cirrhosis." A fairly high percentage of patients without cirrhotic NAFLD have obesity (89.7 percent) or diabetes (82.7 percent), dyslipidemia (71 percent) or hypertension (62.1 percent) -- all manifestations of the metabolic syndrome. "NAFLD is considered to be the hepatic manifestation of these interrelated metabolic risk factors." She explained, "If these conditions are present and you have NAFLD, you will have a higher risk of developing cirrhosis-free hepatocellular carcinoma." She specified that the study excluded patients with other risk factors for hepatocellular carcinoma, such as infection and alcohol consumption. In addition to understanding that cirrhosis-free steatosis and NAFLD are risk factors for hepatocellular carcinoma, Rahman recommends that physicians should diagnose and treat diabetes and hyperlipidemia, which can help prevent not only cardiovascular events but also hepatocellular carcinoma.