Hepatocellular Carcinoma
The Association between Fatty Liver Disease and Hepatocellular Carcinoma Donna L White, PhD1,2
and Hashem B El-Serag, MD, MPH1,2
1. Clinical Epidemiology and Outcomes Program, Houston Veterans Affairs Health Services Research and Development Center of Excellence, Michael E DeBakey Veterans Affairs Medical Center; 2. Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E DeBakey Veterans Affairs Medical Center
Abstract
Hepatocellular carcinoma (HCC) that has no known etiology (cryptogenic) accounts for almost one-third of HCC in some regions in North America and Europe. Fatty liver disease has been implicated as a possible cause of some cases of cryptogenic cirrhosis. There is epidemiologic evidence in support of a potential association between non-alcoholic fatty liver disease (NAFLD), or its most severe form, non-alcoholic steatohepatitis (NASH), and a modest increase in the risk for HCC. The few available population-based cohort studies of patients with NAFLD/NASH provide modest support for this association; however, given the few HCC cases, there are limited data to identify subgroups at particularly increased HCC risk. Indirect evidence for the NAFLD–HCC association is provided by multiple studies showing significantly higher prevalence of obesity and diabetes among patients with cryptogenic cirrhosis compared with controls with other causes of liver disease.
Keywords Epidemiology, obesity, diabetes, cohort, case-control, risk factors, natural history, fatty liver
Disclosure: Donna L White, PhD, is funded by a National Institutes of Health K01 grant. Hashem B El-Serag, MD, MPH, has no conflicts of interest to declare. Acknowledgment: This material is based upon work supported in part by the Houston Veterans Affairs Health Services Research and Development Center of Excellence (HFP90-020) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK081736-01 and DK078154-03 to Donna L White and Hashem El-Serag, respectively). Received: February 22, 2011 Accepted: April 21, 2011 Citation: US Gastroenterology & Hepatology Review, 2011;7(1):54–8 Correspondence: Hashem B El-Serag, MD, MPH, Michael E DeBakey Veterans Affairs Medical Center, 2002 Holcombe Blvd (MS 152), Houston, TX 77030. E:
hasheme@bcm.edu
Substantial increases in hepatocellular carcinoma (HCC) incidence and mortality rates have been observed in several Western developed countries. For example, in the US, incidence of HCC has rapidly increased during the last two decades1 rapidly increasing cause of cancer-related deaths.2
and is the most In these regions,
hepatitis C virus (HCV) is the most frequent etiologic risk factor, accounting for 30–50% of HCC cases, followed by hepatitis B virus (HBV) (10–15%) and alcoholic liver disease (10–20%). Mendelian disorders, e.g., Wilson’s disease, alpha-1 antitrypsin deficiency, and hemochromatosis, account for a very small proportion of HCC. Cryptogenic or unknown etiology HCC accounts for 15–30% of cases, and as high as 50% in some studies.3
Non-alcoholic fatty liver disease (NAFLD), including its more advanced form non-alcoholic steatohepatitis (NASH), has been proposed as the etiologic factor for many, if not most, cases of cryptogenic HCC. NAFLD has become the leading cause of chronic liver disease in several regions worldwide. Insulin resistance has been reported to be present in virtually all individuals with NAFLD, and has been proposed as the major pathogenic mechanism for this disorder as well as its progression to NASH. Obesity and diabetes are the major clinical manifestations of the insulin resistance syndrome. Over the last few decades there have been coincident large secular increases in obesity,4 HCC-related incidence and mortality.1,6
diabetes,5 and 54
There has been considerable growth in the peer-reviewed literature evaluating the association between NAFLD/NASH and liver-disease related mortality including HCC.7–49
Cohort studies, particularly those
that are population-based, prospective, have a priori and well-defined exposure and outcome groups, and a substantial longitudinal follow-up period, are typically considered the strongest observational epidemiologic design in support of a potential causal association between an etiologic risk factor (i.e. NAFLD) and a clinical outcome (i.e. HCC). Cross-sectional and case-control studies are limited in this regard due to the requisite histopathologic features for confirmed NAFLD/NASH diagnosis being less evident or even absent once cirrhosis is established. However, cross-sectional and case-control studies have evaluated this association indirectly by concomitantly examining diabetes and obesity.
In this review, we have critically evaluated the epidemiologic literature obtained from:
• longitudinal studies that reported on HCC in adults with NAFLD/NASH or cryptogenic cirrhosis that was suspected to be NAFLD/NASH-related;
• •
case-control and cross-sectional studies that examined the association between diabetes or obesity and HCC ascribed to NAFLD/NASH or cryptogenic cirrhosis; and
case reports and case series that described an HCC case group with biopsy-confirmed NASH/NAFLD.
© TOUCH BRIEFINGS 2011
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