Epidemiology of Hepatocellular Carcinoma

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Incidence of liver cancer

For the year 2000 it has been estimated that some 564,000 new cases of PLC occurred worldwide, corresponding to 398,364 in men and 165,972 in women.

Table 1 presents the estimated number of cases per year and age-adjusted incidence and mortality rates of PLC worldwide by sex and geographic area. The table presents a combined analysis of the reports of the population-based cancer registries [1] and the World Health Organization mortality databank [2]. PLC accounts for 5.6% of all human cancers

Age-specific incidence rates

In most high-risk areas, such as South-East Asia (Qidong in China) or the West Coast of Africa (Bamako in Mali), PLC rates increase after 20 years of age and peak or stabilize at the age intervals 50 and above (Fig. 3). In these countries PLC is not a rare event at ages 20 to 35. Still, the incidence in Qidong is substantially higher at each age group than the corresponding incidence in Mali, a high-risk country in Africa, and the mean age of occurrence is significantly shifted toward the young

Sex ratios

The correlation between AAIRs PLC in men and women is extremely high in 157 registries worldwide: correlation coefficient [CC] = 0.953, P< 0.001) [6]. An excess of PLC incidence among men compared with women has been well documented. Worldwide, the range of the ratios in the sex-specific AAIRs is 1.3 to 3.6 (Fig. 5) [1]. In high-risk countries, sex ratios tend to be higher, and the male excess is more pronounced below 50 years of age. Migrant populations also show a shift in the sex ratio

Mortality from liver cancer

Coding recommendations of PLC and liver metastasis changed slightly from the eighth to the ninth revisions of the International Classification of Diseases (ICD) implemented after 1965 and 1975, respectively [10], [11]. The 10th revision was introduced as from 1992 [12].

The description of the codes for PLC (155.0 in the eighth and ninth ICD versions) as well as for liver cirrhosis (571 in the eighth and ninth ICD versions) has not changed across these two classifications. The 10th Revision of

Primary liver cancer in ethnic groups and migrant populations

Cancer registries in the United States report on the incidence of PLC by ethnic origin in populations with similar exposures to environmental risk factors. The lowest incidence rates are consistently found among Caucasian Whites (3.8 in men and 1.4 in women). Gradually increasing rates are found in Japanese (5.5 in men and 4.3 in women), Black (7.1 in men and 2.1 in women), Hispanic White (9.8 in men and 3.5 in women), Filipino (10.9 in men and 2.4 in women), Chinese (16.2 in men and 5.0 in

Trends in liver cancer incidence and mortality

International variation in the diagnostic ability as well as in the coding and registration practices for PLC (primary, intrahepatic biliary ducts, metastases, and liver tumors of uncertain nature as if primary or secondary) makes the interpretation of long-term time trends difficult. Of particular concern in some countries is the likely impact of migrants from high-risk countries. These populations are often visible in the health system at the time of diagnosis, and are less likely to be

Risk factors for primary liver cancer

The etiology of PLC has been largely established, and Table 3 shows current estimates of the attributable fractions for the main risk factors by three geographic areas [3].

Hepatitis viruses

Overall, 75% to 80% of the PLC cases can be related to persistent viral infections with either HBV (50–55%) or HCV (25–30%). Worldwide, strong geographic correlations have been found between the incidence of PLC and the prevalences of hepatitis B suface anigen (HBsAg) (CC, 0.67, P< 0.001) or HCV antibody (anti-HCV) (CC, 0.37, P< 0.001) [6].

The role of chronic infection with HBV in the etiology of PLC is well established. Cohort studies conducted worldwide yielded relative risk estimates of 5.6

Aflatoxin

PLC has been related to aflatoxin exposures in human diets in countries where fungal infestation of crops and animal feed are common. Studies that used Aflatoxin/Albumin adducts, Aflatoxin M1 in urine, Aflatoxin-N7-Guanine adducts in urine, or p53-specific mutations (G to T transversions at codon 249), tend to indicate that individuals who are carriers of persistent HBV infection and who are exposed to aflatoxins in their diets have an increased risk of progression to PLC compared with

Alcohol and tobacco

Chronic alcohol abuse and alcoholic cirrhosis have long been recognized as a cause of PLC. However, it is not certain whether alcohol is a true carcinogen or if acts as a cofactor in the presence of coexistent infection with HBV or HCV. Several epidemiologic studies among alcoholics have described a high prevalence of HBV markers (16–70%) and of HCV markers (10–20%) compared with a background prevalence of close to 5% and less than 1%, respectively. These prevalences are even higher in PLC

Hormonal factors

The occurrence of benign liver adenomas and occasional PLC among women who were long-term OC users has been documented. Several case–control studies conducted in developed countries where substantial number of women have used OC for extended periods of time have found risks between 1.6 and 5.5 among ever OC users, and a relationship with duration of use was observed in some of them [76]. In one of the few studies conducted in the Black population in South Africa, a country with high prevalence

Other risk factors and emerging factors

Other factors that may modulate the long-term impact of HBV or HCV persistent infections include dietary factors, some chemicals (such as arsenic), some hereditary conditions (hemochromatosis, Wilson's Disease, and other), and nutritional factors. Growing interest is currently focusing on the associations of PLC with diabetes mellitus [83], [84], [85], [86], obesity, and the syndromes related to insulin resistance. Nonalcoholic fatty liver disease is being proposed as a risk factor for PLC [87]

Prevention for primary liver cancer

By the year 2000, HBV vaccination programs had been implemented in 135 countries, including deprived areas in Africa and Asia. A major input from donor agencies has made it possible in the last decade, and such efforts should be encouraged and supported. HBV vaccination trials initiated in the 1980s have already shown the ability HBV vaccines to prevent the chronic carriage of HBsAg [88], [89] and the development of liver cancer when vaccination takes place at birth in Taiwan [90], or as adults

Summary

PLC remains a major health problem with great geographic variability. Men are consistently more affected than women, and survival is poor worldwide. Increasing trends in incidence in some developed countries including the United States suggest an underlying cohort effect linked to HCV and HBV exposures. Reduction of PLC burden in most developing countries should give priority to HBV vaccination campaigns and to prevention of HBV and HCV contamination. This implies reinforcing control of blood

Acknowledgments

The authors wish to acknowledge with gratitude the support of Cristina Rajo in the preparation of the manuscript.

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    Partial support has been received from the Instituto de Salud Carlos III of the Spanish Government (Grants RTICCC C03/09 and RTICESP C03/10).

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