Original article
Systematic reviews and meta-analyses
Association Between Nonalcoholic Fatty Liver Disease and Risk for Hepatocellular Cancer, Based on Systematic Review

https://doi.org/10.1016/j.cgh.2012.10.001Get rights and content

Background & Aims

Nonalcoholic fatty liver disease (NAFLD) has been implicated as a cause of hepatocellular carcinoma (HCC). We performed a systematic review of epidemiology studies to confirm the association between these disorders.

Methods

We searched PubMed for original reports published from January 1992 to December 2011 that evaluated the association between NAFLD, nonalcoholic steatohepatitis (NASH), cryptogenic cirrhosis presumed to be NASH-related, and the risk of HCC. Studies were categorized as offering potential direct evidence (eg, cohort studies) or indirect evidence (eg, case-control, cross-sectional, or case-series studies) for an association. We analyzed data from a total of 17 cohort studies (3 population based, 9 clinic based [6 limited to patients with cirrhosis], and 5 natural history), 18 case-control and cross-sectional studies, and 26 case series.

Results

NAFLD or NASH cohorts with few or no cases of cirrhosis cases had a minimal risk for HCC (cumulative HCC mortality of 0%–3% for study periods up to 20 y). Cohorts with NASH and cirrhosis had a consistently higher risk (cumulative incidence ranging from 2.4% over 7 y to 12.8% over 3 y). However, the risk for HCC was substantially lower in these cohorts than for cohorts with hepatitis C–related cirrhosis. Factors that increased risk among cohorts with NASH and cirrhosis could not be determined, because most studies were not sufficiently powered for multivariate analysis.

Conclusions

This systematic review shows that despite several limitations, there is epidemiologic evidence to support an association between NAFLD or NASH and an increased risk of HCC; risk seems to be limited to individuals with cirrhosis.

Section snippets

Methods

We followed published guidelines for the conduct and reporting of systematic reviews.6 We performed a structured keyword search in PubMed to identify original research reports published in print or online in English in peer-reviewed journals between January 1, 1992 and December 31, 2011 that evaluated the association between NAFLD/NASH or CC and HCC either directly (eg, population- and clinic-based cohort studies) or indirectly (eg, cross-sectional and case-control studies and case

Results

Our combined PubMed keyword and review article ancestry searches identified >14,000 citations (study flow diagram, Figure 1). Among the 265 full citations reviewed, the most common reason for exclusion was report did not contain specific results for HCC or did not adequately distinguish HCC attributed to NAFLD/NASH or CC from HCC attributed to other causes (eg, alcohol-related HCC) or other health outcomes (eg, overall liver-related mortality or total mortality). A total of 17 cohort studies,

Discussion

This systematic review shows that despite several limitations, the epidemiologic evidence supports an association between NAFLD/NASH and an increased HCC risk that seems to be predominantly limited to those with cirrhosis. The studies that followed NAFLD or NASH cohorts with either few or no cirrhosis cases at baseline were consistent in showing that NAFLD/NASH was associated with a minimal HCC risk; cumulative HCC mortality rates ranged between 0% and 3% in NAFLD/NASH cohorts, with 5 of 7

Acknowledgments

The authors thank Adrian Rideau, BA, for her administrative assistance.

References (69)

  • H.P. Cotrim et al.

    Nonalcoholic fatty liver disease in Brazil: clinical and histological profile

    Ann Hepatol

    (2011)
  • M. Shimada et al.

    Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis

    J Hepatol

    (2002)
  • B.M. Smith et al.

    Ruptured hepatocellular carcinoma in a patient with nonalcoholic steatohepatitis

    Surg Obes Relat Dis

    (2009)
  • K. Yasui et al.

    Characteristics of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma

    Clin Gastroenterol Hepatol

    (2011)
  • R.E. Bullock et al.

    Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma

    J Hepatol

    (2004)
  • C.D. Williams et al.

    Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study

    Gastroenterology

    (2011)
  • H.B. El-Serag et al.

    The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update

    Ann Intern Med

    (2003)
  • H.B. El-Serag

    Epidemiology of hepatocellular carcinoma in USA

    Hepatol Res

    (2007)
  • G. Musso et al.

    Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity

    Ann Med

    (2011)
  • M. Lazo et al.

    Non-alcoholic fatty liver disease and mortality among US adults: prospective cohort study

    BMJ

    (2011)
  • D. Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    Ann Intern Med

    (2009)
  • H.T. Sorensen et al.

    Risk of liver and other types of cancer in patients with cirrhosis: a nationwide cohort study in Denmark

    Hepatology

    (1998)
  • A. Sanyal et al.

    Population-based risk factors and resource utilization for HCC: US perspective

    Curr Med Res Opin

    (2010)
  • A.J. Sanyal et al.

    Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C

    Hepatology

    (2006)
  • H. Kojima et al.

    Cryptogenic cirrhosis in the region where obesity is not prevalent

    World J Gastroenterol

    (2006)
  • S. Yatsuji et al.

    Clinical features and outcomes of cirrhosis due to non-alcoholic steatohepatitis compared with cirrhosis caused by chronic hepatitis C

    J Gastroenterol Hepatol

    (2009)
  • M.S. Ascha et al.

    The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis

    Hepatology

    (2010)
  • N. Bhala et al.

    The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study

    Hepatology

    (2011)
  • C. Söderberg et al.

    Decreased survival of subjects with elevated liver function tests during a 28-year follow-up

    Hepatology

    (2010)
  • S. Dam-Larsen et al.

    Final results of a long-term, clinical follow-up in fatty liver patients

    Scand J Gastroenterol

    (2009)
  • Y. Arase et al.

    Difference in malignancies of chronic liver disease due to non-alcoholic fatty liver disease or hepatitis C in Japanese elderly patients

    Hepatol Res

    (2012)
  • M. Ekstedt et al.

    Long-term follow-up of patients with NAFLD and elevated liver enzymes

    Hepatology

    (2006)
  • E. Hashimoto et al.

    Hepatocellular carcinoma in patients with nonalcoholic steatohepatitis

    J Gastroenterol

    (2009)
  • Y. Kawamura et al.

    Large-scale long-term follow-up study of Japanese patients with non-alcoholic fatty liver disease for the onset of hepatocellular carcinoma

    Am J Gastroenterol

    (2012)
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    Conflicts of interest The authors disclose no conflicts of interest.

    Funding This material is based on work supported in part by a VA Clinical Research and Development Merit Review Award (H-22934, principal investigator: H. El-Serag, MD, MPH), the National Institute of Diabetes Digestive and Kidney Diseases (K01 DK078154-03 and K24 DK081736-01, principal investigators, D. White and H. El-Serag, respectively), the Texas Medical Center Digestive Disease Center (P30 Center grant DK56338), and the Houston VA HSR&D Center of Excellence (HFP90-020). The U.S. Department of Veteran Affairs, the National Institutes of Health, and the National Institute of Diabetes and Digestive and Kidney Disease played no role in design, implementation, analysis, interpretation or decision to report these results.

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