| Can Dietary Fish Intake Prevent Liver Cancer? Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland Multidisciplinary Liver Tumor Clinic, Ann Arbor VA Medical Center, University of Michigan Health Systems, Ann Arbor, Michigan published online 27 April 2012.
See “Consumption of n-3 fatty acids and fish reduces risk of hepatocellular carcinoma,” by Sawada N, Inoue M, Iwasaki M, et al, on page 1468.
Hepatocellular carcinoma (HCC) is a common cancer worldwide, with poor 5-year survival. An estimated 748,300 new cases and 695,900 cancer deaths occur per year, ranking it fifth among cancers for incidence and third among cancers for mortality.1 There is considerable geographic variation in the incidence of HCC. The largest concentration of HCC cases in the world is in Asia, followed by Africa, Europe, and North and South America.2 Chronic hepatitis B (HBV) infection is the most important risk factor for HCC worldwide, especially in Asia. In Asian and African countries, >80% of patients with HCC have underlying chronic HBV infection.3 The 1 exception in Asia is Japan, where the prevalence of HCC has been related to chronic hepatitis C (HCV) infection.4 In Western countries, however, chronic HCV infection has been determined to be present in about 60% of patients with HCC, and is the main etiologic agent leading to HCC,5, 6 with obesity and insulin resistance also thought to be important risk factors. The incidence of HCC is expected to continue to rise in Western countries as the cohort of patients infected with HCV ages, concurrent with the increasing prevalence of obesity and diabetes.
Within the context of chronic HCV and HBV infection, the presence of cirrhosis is the most important risk factor in the development of HCC.7 Nonmodifiable risk factors include older age, male gender, and family history of HCC (Figure 1). There are several modifiable risk factors in HCC, of which the most important are alcohol and tobacco. There is evidence of a dose-dependent effect of alcohol and tobacco and HCC,8, 9 including a synergistic effect with viral hepatitis.10
However, identifying additional modifiable risk factors, including diet, is important. A number of hypotheses link different aspects of diet with HCC, including coffee and tea, fructose, iron, red and white meats, types of fat, selenium, vitamin D, and vitamin E. Of these exposures, the most data is available for coffee, where associations have been observed for HCC,11 progression from fibrosis to cirrhosis and clinical outcomes,12 and, in the context of HCV, response to peginterferon and ribavirin therapy.13 However, associations with other dietary components remain unclear.
Studies of diet are challenging for several methodologic reasons. First, diet is complex and interrelated with other aspects of lifestyle. Individuals who eat a lot of fish, for example, likely also have many other behaviors that are associated with cancer. Also, assessing diet is difficult. Most studies use food frequency questionnaires, requiring study participants to answer questions about their typical diet over the past year. As might be expected, such instruments assess diet with error.14 Cross-sectional, case-control studies suffer from an additional potential methodologic limitation, because cases may overestimate behaviors they consider harmful and underestimate those they consider helpful. A stronger methodologic design is the prospective cohort, in which participants' diet and other behaviors are assessed before disease diagnosis. Although diet and other behaviors are still measured with error, such assessments are thought to be less biased, because participants complete their questionnaires without knowledge of their future disease diagnosis. However, even in prospective cohorts, challenges remain. Most such studies have been conducted in populations with low rates of liver cancer, limiting statistical power. Studies also tend to lack information on important HCC risk factors, including HBV and HCV infection status, and underlying liver disease.
Within this context, the manuscript by Sawada et al15 detailing inverse associations between fish and n-3 fatty acid consumption with HCC risk in 90,296 participants of the Japan Public Health Center-based Prospective Study, published in this issue of Gastroenterology, is of particular interest. Fish is a rich source of n-3 fatty acids and micronutrients including selenium and vitamin D. A large literature supports a protective effect for fish and n-3 fatty acid intake on cardiovascular disease,16, 17 and suggested mechanisms, including lower plasma triglycerides and reduced inflammation, could also apply to the liver. Relative to previous studies, the current analysis has a number of important advantages, including that it was conducted in a population that eats a lot of fish. The authors assessed important HCC risk factors, including alcohol, body mass index, diabetes, tobacco smoking, and, in a subset of the cohort, HBV, HCV, and the liver enzyme alanine aminotransferase.
In this cohort, the authors observe an inverse association between fish and incident HCC, with participants in the highest quintile of fish intake having 0.64 times the risk (95% confidence interval, 0.41–1.02) of participants in the lowest quintile; similar results were observed in those in the highest quintile of eating n-3 fatty acid rich fish (0.64; 95% confidence interval, 0.42–0.96), with evidence of a dose-response (P for trend across categories = .04). Associations were also observed for specific fatty acids, including eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid. Although previous studies have not specifically investigated n-3 fatty acids and HCC, the current results are consistent with 2 previous cohort studies.18, 19, 20 One recent US cohort observed an inverse association with incident HCC, but was conducted in a population with limited fish consumption and lacked information on HBV and HCV status.18, 19 A second cohort from Japan also observed an inverse association, but presented only univariate, unadjusted, analyses.20 A number of laboratory studies have also linked n-3 fatty acids with liver health21; for example, a 2007 study observed a prevention effect of n-3 fatty acid intake on acute hepatitis in a transgenic mouse model,22 whereas a 2004 study observed decreased hepatic triglycerides in rats fed fish oil relative to control animals.23
Although the current results are tantalizing, care must be taken before fish and n-3 fatty acids should be recommended as HCC preventive agents. Existing results from 3 prospective cohorts are consistent and each suggests an inverse association. However, the current studies have limitations and further replication is needed. As observational studies, despite careful adjustment for liver cancer risk factors, associations with fish and n-3 fatty acid intake may simply reflect other lifestyle or environmental exposures. Also, in each study, diet (and other important risk factors such as alcohol, tobacco, and coffee) was assessed by questionnaire at a single time point and thus may not reflect use over the entire lifetime. Preexisting liver disease is a concern, because it typically occurs well before liver cancer diagnosis and may affect dietary intake. The authors adjust for self-reported liver disease and in a subset of their cohort, ALT levels, which correlated with chronic liver disease, are not a sensitive marker. These analyses are important given that patients with chronic liver disease, especially those with cirrhosis, are at high risk for developing HCC. Because ALT levels and self-report are imperfect proxies for underlying liver disease, the observed attenuation of the authors' results after excluding those with self-reported liver disease is of concern. In addition, the measurement of chronic HCV infection in only 19% of the entire cohort is problematic, given the high prevalence of this infection among patients with HCC in Japan, although among this subset of participants, results were similar to those overall after adjustment for HCV infection.
Diet was also assessed with error; for example, correlations for fish and n-3 fatty acid intake within a subset of participants completing a food frequency questionnaire and recording their diet over a 14- or 28-day period only ranged from 0.21 to 0.45. However, because error on the questionnaire is unlikely to be correlated with future disease risk, such errors would likely attenuate any observed risk estimates. The current study also examined associations for fish and n-3 fatty acids in Japan, where the major risk factor is chronic HCV infection.4 Yet, most mechanistic and laboratory studies of n-3 fatty acids in liver disease have occurred within the context of nonalcoholic fatty liver disease.24 Future studies are needed, therefore, to evaluate and confirm inverse associations between fish and n-3 fatty acids and liver cancer in populations with other spectrums of liver cancer risk factors. Studies with detailed information on preexisting, underlying liver disease are particularly needed. In addition, even if fish were truly associated with protection from HCC, it is not clear from the current analysis whether the protection stems from n-3 fatty acids or from another component, such as vitamin D or selenium. Additional studies, therefore, are needed to define which aspects of dietary fish intake may be inversely associated with liver cancer. Further mechanistic and laboratory studies are also needed to support these epidemiologic findings.
In conclusion, this study shows an inverse relationship between fish intake and incident HCC. Given the multiple risk factors identified in HCC, it highlights the difficulty in performing prospective studies properly adjusting for these risk factors. Although fish and n-3 fatty acid intake cannot be recommended for HCC prevention currently, these provocative results merit future study.
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发表于 2012-6-2 15:36
