Cancer Letters

Cancer Letters

Volume 286, Issue 1, 1 December 2009, Pages 9-14
Cancer Letters

Mini-review
Liver cancer: Descriptive epidemiology and risk factors other than HBV and HCV infection

https://doi.org/10.1016/j.canlet.2008.10.040Get rights and content

Abstract

The incidence of liver cancer is high in all low-resource regions of the world, with the exception of Northern Africa and Western Asia. The estimated worldwide number of new cases of liver cancer in 2002 is 600,000, of which 82% are from developing countries. Given the poor survival from this disease, the estimated number of deaths is similar to that of new cases.

Hepatocellular carcinoma (HCC) is the main form of liver cancer. A part from chronic infections with Hepatitis B and Hepatitis C viruses, which are the main causes of HCC, contamination of foodstuff with aflatoxins, a group of mycotoxins produced by the fungi Aspergillus flavus and Aspergillus parasiticus, is an important contributor to HCC burden in many low-income country. Alcoholic cirrhosis is an important risk factor for HCC in populations with low prevalence of HBV and HCV infection, and the association between tobacco smoking and HCC is now established. Diabetes is also related to an excess risk of HCC and the increased prevalence of overweight and obesity likely contributes to it.

The second most important type of liver cancer is cholangiocarcinoma, whose main known cause is infestation with the liver flukes, Opistorchis viverrini and Clonorchis sinensis, which is frequent in some areas in South-East Asia. Angiosarcoma is a rare form of liver cancer whose occurence is linked to occupational exposure to vinyl chloride.

Section snippets

Descriptive epidemiology

The epidemiology of liver cancer is made complex by the large number of secondary tumours, which are difficult to separate from primary liver cancers without histological verification. The most common histological type of liver malignant neoplasm is hepatocellular carcinoma (HCC). Other forms include: (i) childhood hepatoblastoma, and (ii) adult cholangiocarcinoma (originating from the intrahepatic biliary ducts) and (iii) angiosarcoma (from the intrahepatic blood vessels). Primary liver cancer

Aflatoxin

Ecological studies have shown that the incidence of HCC correlates not only with HBV and HCV infection, but also with contamination of foodstuff with aflatoxins, a group of mycotoxins produced by the fungi Aspergillus flavus and Aspergillus parasiticus, which cause liver cancer in many species of experimental animals [8]. Contamination originates mainly from improper storage of cereals, peanuts and other vegetables and is prevalent in particular in Africa, South-East Asia and China. The

Alcohol drinking

Alcohol drinking is associated with an increased risk of liver cancer [10]. A meta-analysis has shown a dose response relationship between alcohol intake and liver cancer with relative risks (RRs) of 1.19 (95% CI = 1.12–1.27), 1.40 (95% CI = 1.25–1.56), and 1.81 (95% CI = 1.50–2.19) for 25, 50, and 100 g of alcohol intake per day, respectively [11]. It is believed that there is no “safety threshold” for the effects of alcohol on liver [12].

The most probable mechanism of alcohol-related liver cancer is

Tobacco smoking

Tobacco smoking is causally associated with liver cancer [18]. A meta-analysis on smoking and liver cancer [19] concluded an overall OR of 1.56 (95% CI = 1.29–1.87) comparing current-smokers to never-smokers and of 1.49 (95% CI = 1.06–2.10) comparing former smokers to never-smokers. The associations among current smokers appeared to be consistent with the overall RR regardless of region, study design, study sample size, and publication period.

The synergistic interaction between tobacco smoking and

Dietary factors

Several data have been reported on a potentially favorable effect of coffee on liver function and liver diseases, including liver cancer [23]. Data on coffee and liver cancer are based on at least 10 studies, 6 case–control (from Greece, Italy and Japan) and 4 cohort investigations (all of these from Japan). Overall, the pooled relative risk (RR) was 0.54 (95% confidence interval, CI, 0.39–0.76) for case–control studies, and 0.64 (95% CI 0.56–0.74) for cohort studies [14]. Such an inverse

Obesity and diabetes

Obesity is now widely recognized as a significant risk for the development of many types of cancers. A meta-analysis [28] found that the relative risks (RR) for liver cancer were 1.17 (95% CI = 1.02–1.34) for those who were overweight (BMI = 25–30) and 1.89 (95% CI = 1.51–2.36) for those who were obese (BMI  30).

Diabetes, a condition closely associated with obesity, has been proposed as a risk factor for both chronic liver disease and HCC. A case–control study [29] conducted in Italy found an odds

Oral contraceptives

Use of combined estrogen–progestogen oral contraceptives (OC) greatly increases the risk of liver adenomas, and is associated with the risk of HCC, although the absolute risk is likely to be small and has been shown in populations at low HBV risk [35]. Case reports have associated use of anabolic steroids with development of liver cancer, but the evidence is not conclusive at present. A recent meta-analysis was failed to link the use of oral contraception and the risk of HCC due to the huge

Iron overload

An increase in iron storage in the body is a likely cause of HCC: the evidence comes from studies of patients with hemochromatosis (HH) or other disorders of iron metabolism. Iron was observed to be associated with HCC in a group of patients in their end stage of liver diseases other than HH as well (none: reference; mild: OR = 1.59, 95% CI = 1.07–2.38; excess: OR = 2.10, 95% CI = 1.25–3.52) [37]. The effect of iron overload seems to be independent from development of cirrhosis and may interact with

Hepatoblastoma

Hepatoblastoma is the most common childhood hepatic tumor [7]. It represented 1% of malignancies for children younger than 20 years old with a peak incidence of 11.2/1,000,000 during infancy [46]. The etiology of hepatoblastoma is still unknown. Current knowledge on the cause include Beckwith–Wiedemann syndrome, hemohypertrophy, familial adenomatous polyposis, and Gardner’s syndrome. Evidences for parental occupational exposures are not consistent and limited [43].

Cholangiocarcinoma

Intrahepatic

Prevention

The more important way to prevent liver cancer is control of HBV and HCV infection, as discussed in a companion paper. Control of aflatoxin contamination of foodstuffs represents another important preventive measure. While this is easily achieved in high-income countries, its implementation is limited by economic and logistic factors in many high-prevalence regions. Control of alcohol drinking and tobacco smoking represents additional primary preventive measures.

Since about half of HCC, but not

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