Background Non-alcoholic fatty liver disease (NAFLD) has been implicated as a possible cause of hepatocellular carcinoma (HCC) in several general review articles. We performed the first systematic review of the epidemiologic literature. Methods We searched PubMed for original reports published between 1/1992–12/2011 evaluating the association between NAFLD, non-alcoholic steatohepatitis (NASH) and cryptogenic cirrhosis (CC) presumptively NASH-related and the risk of HCC. Studies were categorized as offering potential direct evidence (e.g., cohort studies) or indirect evidence (e.g., case-control or cross-sectional studies or case-series) of an association. Results A total of 17 cohort studies [3 population-based, 9 clinic-based (6 limited to cirrhotics), and 5 natural history], 18 case-control and cross-sectional studies, and 26 case-series were study-eligible. NAFLD or NASH cohorts with few or no cirrhosis cases demonstrated a minimal HCC risk (cumulative HCC mortality between 0%–3% for study periods up to two decades). Consistently increased risk was observed in NASH-cirrhosis cohorts (cumulative incidence between 2.4% over 7-years to 12.8% over 3-years). However, HCC risk was substantially lower in NASH-cirrhosis (NASH-C) cohorts than in HCV-related cirrhosis cohorts. The determinants of elevated risk among NASH-C cohorts were unclear as most studies were underpowered to perform multivariate analysis. Conclusions This systematic review shows that despite several limitations, the epidemiologic evidence supports an association between NAFLD or NASH and an increased HCC risk that seems to be predominantly limited to individuals with cirrhosis.

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Primary liver cancer (PLC) represents approximately 4% of all new cancer cases diagnosed worldwide. The purpose of this review is to describe some of the latest international patterns in PLC incidence and mortality, as well as to give an overview of the main etiological factors. We used two databases, GLOBOCAN 2002 and the World Health Organization (WHO) mortality database to analyze the incidence and mortality rates for PLC in several regions around the world. The highest age adjusted incidence rates (>20 per 100,000) were reported from countries in Southeast Asia and sub-Saharan Africa that are endemic for HBV infection. Countries in Southern Europe have medium-high incidence rates, while low-incidence areas (<5 per 100,000) include South and Central America, and the rest of Europe. Cirrhosis is present in about 80–90% of HCC patients and is thereby the largest single risk factor. Main risk factors include HBV, HCV, aflatoxin and possibly obesity and diabetes. Together HBV and HCV account for 80–90% of all HCC worldwide. HBV continues to be the major HCC risk factor worldwide, although its importance will most likely decrease during the coming decades due to the widespread use of the HBV vaccine in the newborns. HCV has been the dominant viral cause in HCC in North America, some Western countries and Japan. Obesity and diabetes are increasing at a fast pace throughout the world, and if they are proven to be HCC risk factors, they would account for more HCC cases in the future.