Population attributable risk of aflatoxin-related liver cancer: Systematic review and meta-analysis☆
Introduction
Aflatoxins are toxic and carcinogenic chemicals produced primarily by the fungi Aspergillus flavus and A. parasiticus, which infect food crops such as maize, peanuts, and tree nuts. About 4.5 billion people worldwide are exposed to dietary aflatoxins.1 Exposures are highest in tropical and subtropical regions of the world, where maize and peanuts are dietary staples and food storage conditions are suboptimal.1, 2
Aflatoxins are amongst the most potent naturally occurring human hepatocarcinogens known. The International Agency for Research on Cancer (IARC) has classified “naturally occurring mixes of aflatoxins” as a Group 1 human carcinogen.3 Abundant epidemiological evidence suggests that aflatoxin exposure synergises with chronic hepatitis B virus (HBV) infection to increase liver cancer (hepatocellular carcinoma, HCC) risk in populations with both risk factors.4, 5, 6, 7, 8 More recently, toxicological models for the mechanism of the synergism of these two risk factors have emerged,9, 10, 11 and are summarised in Wild and Gong.12 Unfortunately, both high aflatoxin exposure and HBV are prevalent in many parts of the developing world, particularly Asia and Africa.
Previously, by compiling food consumption and aflatoxin contamination data in multiple countries and conducting a quantitative cancer risk assessment, we estimated that 25,200–155,000 (5–28%) annual HCC cases worldwide could be attributed to aflatoxin exposure.13 This large range highlights the limitations in obtaining exposures solely from food surveys, uncertainties in the nature of the dose–response relationship, and uncertainties in HBV prevalence data in different nations.
In this context, systematically analysing human studies that relate biomarkers of aflatoxin exposure and HBV infection to HCC may provide a more precise and accurate measurement of burden of HCC caused by aflatoxin. Therefore, in this study, we systematically reviewed epidemiological studies on these associations in different world regions. By combining the relevant odds ratios (ORs) and relative risks (RRs) from these studies, we conducted meta-analyses to calculate population-attributable risk (PAR) of aflatoxin-related HCC in the population overall, as well as in HBV+ and HBV− populations. PAR is the proportion of disease cases that could be avoided if a particular risk factor was eliminated in a population. In the context of our study, PAR of aflatoxin-related HCC is the proportion of HCC cases that could be avoided in a chosen population by reducing aflatoxin exposures (as measured by biomarkers) from detectable to undetectable levels.
Section snippets
Search strategy
We performed a literature search until May 13th, 2011, using the following search terms on Medline/PubMed: (aflatoxin) and (hepatitis B) and (liver cancer); (aflatoxin) and (hepatitis B) and (hepatocellular carcinoma). Additionally, we searched reference lists from retrieved articles to identify further relevant studies. Our systematic review and meta-analyses were conducted in adherence to PRISMA standards for reporting meta-analyses.14
Eligibility criteria
Studies were included in the systematic review if they met
Literature search
The step-by-step process of our literature search is presented in Fig. 1. From 479 results, we excluded human cell line studies, animal studies, and review articles. Using the eligibility criteria described above, 27 studies were selected. Three more relevant studies were identified from the reference lists of the 27 selected studies. We then read the full texts of these 30 studies. Six studies were excluded because they were duplicated reports from the same population in the same time period,
Discussion
Aflatoxin exposure is significantly associated with HCC risk regardless of HBV status. Our meta-analyses show that in areas of high aflatoxin exposure and chronic HBV infection, aflatoxin exposure and HBV have a nearly perfectly multiplicative relationship in increasing HCC risk. In populations including both HBV+ and HBV− individuals in the geographic regions studied, the PAR of aflatoxin-related HCC was estimated at 17% (14–19%). This implies that if it were possible to reduce aflatoxin to
Conflict of interest statement
The authors declare that they have no competing financial interests.
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This work was funded by the National Cancer Institute (5R01CA153073-02) of the United States National Institutes of Health.