Daniel M. Keller, PhD

November 29, 2012

BOSTON — Nonalcoholic fatty liver disease (NAFLD) without cirrhosis is an independent risk factor for hepatocellular carcinoma (HCC), and is becoming more of a risk factor than NAFLD with cirrhosis.

Simple steatosis might also be a risk factor for HCC in the absence of nonalcoholic steatohepatitis (NASH) or cirrhosis, said Rubayat Rahman, MD, MPH, a fellow in the division of gastroenterology and hepatology at the University of Missouri in Columbia. She presented study results here at The Liver Meeting 2012: American Association for the Study of Liver Diseases 63rd Annual Meeting.

The incidence of HCC has been increasing in recent years, although the reason for this has not been established. NAFLD, which is strongly associated with obesity, has also been on the rise.

Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare databases of Medicare enrollment and claims, Dr. Rahman and colleagues studied people 65 years and older who were diagnosed with HCC and liver pathology without multiple risk factors. Control subjects were a random sample of Medicare recipients.

NAFLD Without Cirrhosis Accounts for Increase in NAFLD HCC

The investigators identified 17,895 patients with HCC who met their inclusion criteria. Of those, 2863 (16%) had NAFLD without other risk factors for or causes of HCC.

Overall, NAFLD was the third most common risk factor for HCC, after infection (44%) and alcohol use (19%). For Asians and Pacific Islanders in the United States, NAFLD was the second most common risk factor after infection.

Of the patients with NAFLD HCC, the male/female ratio was about a 2:1, 64% had cirrhosis, 44% had early-stage (I/II) HCC, and 56% had disease of a favorable grade (I/II).

The remaining 36% of patients with NAFLD HCC had no cirrhosis. The male/female ratio of these patients was about 3:2. A higher proportion of these patients than patients with cirrhosis had early-stage HCC (62%; P < .01) of a favorable grade (76%; P < .01).

Half of these patients without cirrhosis — 18% — had steatosis only. The proportions of early-stage (64%) and favorable-grade (77%) HCC were similar to those in the overall noncirrhotic population.

When the investigators compared 2 periods — 1993 to 2000 and 2001 to 2007 — they found that the average annual incidence of NAFLD HCC without cirrhosis increased from 51 to 88 cases (P < .01). In addition, the annuaol incidence of steatosis only increased from 4 to 22 cases (P < .01). Conversely, there was no increase in the annual incidence of NAFLD with cirrhosis (123 vs 122 cases). Thus, the overall increase in NAFLD HCC over the 2 periods (174 vs 210 per year; P < .01) appears to be the result of an increasing incidence of NAFLD HCC without cirrhosis.

In a multivariable analysis, body mass index above 30 kg/m², the presence of diabetes mellitus, and dyslipidemia all were more prevalent in the group with NAFLD HCC without cirrhosis than in the group with cirrhosis (P < .01 for all). The prevalence of hypertension did not differ between the groups.

NAFLD without cirrhosis is independently associated with HCC and is becoming more of a risk factor for HCC than NAFLD with cirrhosis, Dr. Rahman explained. She said the data suggest a unique pathophysiology for the development of HCC in noncirrhotic NAFLD.

Our data suggest that there are no cirrhotic changes in 36% of patients with NAFLD, yet they can develop HCC, she told Medscape Medical News. "Most of the time physicians are not concerned or not aware that they can develop HCC, even from steatosis only or NASH only, without any changes in cirrhosis, she noted.

A high proportion of people with NAFLD without cirrhosis were obese (89.7%) or had diabetes (82.7%), dyslipidemia (71%), or hypertension (62.1%) — all components of metabolic syndrome. "NAFLD is considered to be the hepatic manifestation of these interrelated metabolic risk factors," she explained. "If these are present and you have NAFLD, you are at even higher risk of developing HCC without cirrhosis." She made it clear that the study excluded people with other risk factors for HCC, such as infections and alcohol use.

Besides being aware that steatosis and NAFLD without cirrhosis are risk factors for HCC, Dr. Rahman recommended that physicians diagnose and treat diabetes and hyperlipidemia not only for prevention of cardiovascular events, but also to stave off HCC.

Session moderator Rohit Loomba, MD, MHSc, assistant professor of medicine and epidemiology at the University of California at San Diego School of Medicine, who was not involved in the study, told Medscape Medical News that about 80% of the patients in the study were diabetic, "so maybe a stratified analysis" of patients with and without diabetes is in order.

Moreover, he wonders whether all these patients really had NAFLD or whether some were drinking alcohol, because obesity and alcohol interact to increase the risk for HCC. "I am concerned about that especially because [black people] are at very low risk of developing hepatic steatosis, and in this cohort, the risk of HCC due to NAFLD in blacks was very high — 20%. The only explanation would be that there is occult alcohol use that is not being captured by the SEER–Medicare database," he noted.

Nonetheless, Dr. Loomba said he thinks the study is very important. The investigators just need to examine the data further to make sure their conclusions are correct, he noted.

The study did not receive any commercial funding. Dr. Rahman and Dr. Loomba have disclosed no relevant financial relationships.

The Liver Meeting 2012: American Association for the Study of Liver Diseases (AASLD) 63rd Annual Meeting. Abstract 97. Presented November 11, 2012.

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