Environmental factors and risk for liver cancer (hepatocellular carcinoma)

(Continuation) Dietary Aflatoxins

Aflatoxins are one of the most potent hepatocarcinogens in animals. Humans are exposed to these mycotoxins through ingestion of moldy foods, a consequence of poor storage of susceptible grains. Highly exposed populations are primarily those residing in sub-Sahara Africa and east and Southeast Asia. By using a urinary biomarkers of exposure, a prospective population-based cohort study in Shanghai, China, provided the first set of compelling human data linking dietary aflatoxin exposure to the development of HCC, especially in the presence of HBV infection.

These data suggest a synergism (greater than the multiplicative product of individual exposure effects) between HBV and dietary aflatoxin in the causation of HCC. Confirmatory results were noted in cohort studies conducted among other aflatoxin-exposed populations. There is some evidence that genetically determined individual differences in aflatoxin metabolism are important code-terminants of risk in aflatoxin-exposed individuals. Singapore and Shanghai historically are high-risk areas for HCC, both of which have been experiencing steadily decreasing incidence rates over the past 2 decades. Singapore is an island nation in Southeast Asia that has seen tremendous economic progress since its independence in 1965. The decrease in aflatoxin contamination in the food supply as a result of economic development is a likely contributor, at least in part, to the decreasing burden of liver cancer in this newly affluent country. There is a relatively short time interval between the country’s increase in living standards and its liver cancer rate decrease, suggesting that aflatoxins exert a major effect on late-stage carcinogenesis. In China, economic reform began in the 1980s. Again, liver cancer rates in Shanghai began to decrease shortly after its residents’ increase in standard of living.

There is a little information on whether aflatoxins are related to cases of HCC in the United States. It is intriguing that in a pilot study, tumor tissues from 3 of 19 patients with HCC were positive for aflatoxin B1-DNA adducts and 5 of 5 patients tested for aflatoxin B1-albumin adducts in serum yielded positive results.

Alcohol/Tobacco

Clinical studies strongly suggested that excessive alcohol intake was an important contributor to HCC development in North America and Western Europe long before epidemiologic data confirmed this exposure-cancer relationship. The overall data show a clear excess in risk among heavy, long-term drinkers; there is little support for moderate drinking (1-3 drinks/day; 1 drink contains roughly 12-13 g ethanol) being associated with an increased risk for HCC.

Multiple chemical components of cigarette smoke are hepatic carcinogens in animals. Although results are not totally consistent, a number of case-control and cohort studies in diverse populations have implicated cigarette smoking as a causal risk factor for HCC. However, given the strong positive correlation between the use of tobacco and alcohol in based epidemiologic data are considered by many to be inconclusive in establishing a causal role for tobacco in the pathogenesis of HCC.

Dietary Antioxidants

A number of antioxidants, including retinoids and selenium, have been shown to inhibit chemically induced liver cancer in animals. Several prospective cohort studies and a secondary cancer prevention trial have provided strong evidence that dietary antioxidants, specifically retinoids and selenium, may attenuate the deleterious effects of viral and chemical exposures on HCC development. A cohort study of Chinese men in Taiwan examining serum levels of retinol at baseline (i.e., before cancer diagnosis) showed a strong inverse relationship with risk in chronic HBV carriers.

In a separate cohort study, the same group of investigators showed that plasma level of selenium at baseline inversely predicted risk, especially among subjects exhibiting low levels of serum retinol. The latter cohort study also showed that the positive association between alcohol drinking and risk for HCC was observed only among subjects exhibiting low (i.e., <population median) levels of plasma carotenoids (B-carotene -carotene, and lycopene). In a prospective cohort study of 70 cirrhotic patients in Italy, baseline serum retinol levels were significantly lower in incident cases of HCC compared with cirrhotic patients who remained free of the disease after 7 years of follow-up evaluation. Finally, in a randomized controlled trial involving 89 patients who were disease free after curative treatment, those receiving an oral administration of a synthetic retinoid on a daily basis for 12 months had significantly fewer second primary HCCs and experienced significantly longer survival compared with the placebo group, after a median follow-up time of 62 months.

Diabetes

A number of case-control and cohort studies have implicated diabetes as a risk factor for HCC. Obesity is the most important risk factor for diabetes, and the 2 conditions are highly related events. Although the precise mechanism by which obesity/diabetes leads to HCC is unknown, hepatic inflammation leading to oxidative stress/lipid peroxidation, which can cause hepatic injury, fibrosis, and eventual cirrhosis, is one possible pathway. Obesity/diabetes is likely to be an increasingly important contributor to the HCC burden in the United States, given that more Americans approaching the high-risk age range for this disease are positive for diabetes. Several studies have provided evidence that viral hepatitis, alcohol, and diabetes interact synergistically in affecting the developing of HCC.

Oral Contraceptives

Estrogens and progestogens, including those in oral contraceptive formulations, have been shown to be inducers and promoters of liver tumors in animals. Eight case-control studies conducted in relatively young, most noncirrhotic US white and European women had examined if use of oral contraceptives was associated with the development of HCC in this very low risk population. Results were consistent across the studies, showing a summary OR of 2.5 in ever-vs. never-users of oral contraceptives and a summary OR of 5.8 (95 percent CI: 3:10-11.0) for the longest duration of use.

In contrast, studies conducted in high-risk Asian and African women uniformly yielded null results. These seemingly disparate observations can be explained if the combined effects of viral (i.e., HBV) and hormonal (i.e., estrogen) factors on the pathogenesis of HCC were not synergistic, but simply the sum of their individual effects. Under this assumption, a sample size many times larger than those used in the Asian and African studies would be required to detect the additional risk in oral contraceptive users (-2- to 3-fold) against the very high background relative risk (>20-fold) in HBV carriers. There is sparse information on the use of replacement hormones and risk for HCC. The available epidemiologic evidence does not suggest an association.

Arsenic

In areas of Taiwan and Japan where the drinking water supply contains substantial amounts of inorganic arsenic, residents with high exposures are known to exhibit an increased risk for several forms of cancer, including HCC. Oxidative stress induction may be one possible mechanism for the hepatocarcinogenicity of inorganic arsenic, given that increased levels of lipid peroxides in serum have been observed in subjects exposed to high levels of this metal.

Future Trends

The importance of HBV as a cause of HCC in humans will decrease, although slowly for at least another 50 years, as vaccination of at-risk newborns becomes more widespread in Asia and Africa. HCV is already the dominant viral cause of HCC in Japan. There is evidence that HCV has contributed to the increasing incidence of HCC in North America and Europe during the past 2 decades and likely will become the dominant viral cause of this cancer in these low-risk regions. Exposure to dietary aflatoxins is decreasing steadily among native Asians as the continent continues its increase in economic prosperity. Decreased exposure to this hepatic carcinogen is the likely reason for the steadily declining rates of HCC in newly affluent Asian regions, including Singapore and the southeast coastal regions of China. Rates of consumption of tobacco and alcohol continue to increase throughout most of Asia, and are predicted to account for a growing proportion of HCC cases occurring in the local populations. We are confronting a worldwide epidemic of obesity/diabetes. The 2 rated conditions might be partly responsible for the doubling of HCC incidence in the United States during the past 2 decades, and will have an impact on the future worldwide occurrence of this highly malignant tumor.