Digestive disorders

I./4.1.: Epidemiology and environmental risk factors

Hepatocellular carcinoma (HCC) accounts for 85 to 90% of primary hepatic cancers and about 4% of newly diagnosed cancers worldwide; its incidence is at the 5th and 7th place among malignant neoplasms in men and women respectively. It is the 3rd and 6th most frequent cause of tumor mortality in male and female patients respectively. It is responsible for 1% of the total mortality all over the world. In 2008, 750 000 new cases were diagnosed worldwide, and 695 000 patients died due to primary hepatic carcinoma. In Europe 48 000 new cases of hepatocellular cancer were revealed and 46 000 patients died due to HCC in 2006. Primary hepatocellular cancer is the most frequent cause of tumor mortality of patients with hepatic cirrhosis in Europe.

The incidence of HCC increased worldwide in the recent decades; in the USA the incidence of the disease has increased from 1.4 to 2.4 per 100 000 during the last 10 years; in the UK it doubled between 1975 and 2003, and it increased in France, Canada and Australia as well. The disease occurs 2 to 4 times more frequently in men than in women. Its incidence shows significant geographic differences; it varies between 5.5 and 14.9 per 100 000 inhabitants.

Primary hepatic carcinoma is very frequent in the areas of South-East Asia, Korea, China, Vietnam, Japan, as well as Middle, East and West Africa.

There are significant ethnic differences also within the USA; the incidence is 6.1/100 000 and 12/100 000 among Afro-American and Asian-American men respectively. In Europe the incidence also varies; there are higher values in South-Europe (Southern Italy, Greece) in comparison to other areas of Europe. In areas with a low incidence, HCC occurs more frequently after the 45th year of life, and it is the most prevalent in the 7th decade. In areas with a high incidence the disease presents itself at a younger age, in the 2nd to 3rd decade of life.

The epidemiology of HCC is influenced by factors which are in part genetic, in part etiologic-environmental. Approximately 80% of primary hepatic carcinoma is related to infections with the oncogenic hepatitis-B (HBV) and hepatitis-C (HCV) viruses. In addition to infection with these hepatitis viruses, aflatoxin contamination is also a toxic environmental factor in China and Africa. In Hungary and in the developed countries the increasing incidence of primary hepatic carcinoma is related to alcohol abuse, obesity, diabetes mellitus, and the hepatic manifestation of the metabolic syndrome, non-alcoholic hepatic steatosis. In approximately 80%, primary hepatic carcinoma develops on the ground of hepatic cirrhosis. The yearly incidence of HCC developing in patients with hepatic cirrhosis is 2 to 6% based on international data. In Hungary the development of approximately 900 to 1 000 new cases of HCC per year can be presumed. Hepatic cirrhosis is a precancerous state independently of its etiology.

Risk factors of the development of hepatic carcinoma include hepatitis B, C and D viruses. Alcohol, aflatoxin, organic solvents and smoking are toxic harms. Hormones such as anabolic steroids, estrogens and hormonal contraceptives should also be mentioned. Hereditary metabolic disorders which make susceptible include hemochromatosis, alpha1-antitrypsin deficiency, porphyria cutanea tarda, hereditary tyrosinemia and Wilson’s disease. Of the metabolic disorders associated with insulin resistance non-alcoholic hepatic steatosis, non-alcoholic steatohepatitis, type 2 diabetes mellitus and obesity should be mentioned. Hepatic carcinoma may develop in patients with primary biliary cirrhosis, autoimmune and cryptogenic cirrhosis as well.

The carcinogenic nature of hepatitis B and C viruses has been established; and these have an eminent role among the etiologic factors of hepatic carcinoma. The risk of developing hepatocellular cancer is 50 to 100 fold increased in individuals positive for HBV or HCV. The role of HCV in hepatic carcinogenesis has not been elucidated in detail; HBV however exerts a direct carcinogenic effect: the viral genetic material enters the hepatocyte’s genom. Yearly abdominal ultrasound examination is a part of the care of patients with chronic B or C hepatitis. A sustained virological response can be attained by the current therapies only in a part of patients with chronic viral hepatitis; therefore the prevention of becoming infected is of eminent importance.

Active immunization against hepatitis B infection is available. HCC of HBV origin is the first malignant tumor which can be prevented by vaccination. In order to avoid an infection with hepatitis C virus, adherence to hygienic precautions is essential. In the recent decade several studies demonstrated that the risk of developing hepatic carcinoma has been reduced by interferon or combined interferon-ribavirin treatment, particularly in patients who respond well to therapy.

The cause of hepatic cirrhosis in 80% of the cases is alcohol abuse in Hungary, in West-Europe and in the USA as well. HCC occurs in 3 to 15% of patients with cirrhosis due to alcohol abuse. The most important causes of HCC in patients with hepatic cirrhosis due to alcohol abuse include the accumulation of acetaldehyde and the oxidative stress that leads to lipid peroxidation, damage of the cellular membranes and cellular components, chromosomal alteration and impairment of DNA. Carcinogenic contaminants present in some alcoholic drinks, e.g. nitrosamines, methylcholanthrene, and benzanthracene derivates also play a role in the carcinogenic effect. Deficient nutrition of the potators may be a further carcinogenic factor.

In Africa and in Asia such as in China the significant risk factors of HCC include aflatoxin that belongs to the microtoxins contaminating mostly the cereals. It is produced by Aspergillus species such as A. flavus, and it is one of the most potent natural carcinogenic substances. The active metabolite of aflatoxin causes mutation of the p53 tumor suppressor gene. The concomitant occurrence of HBV infection and aflatoxin contamination increases the risk of HCC sixtyfold. HBV or HCV infection and aflatoxin are responsible for 80% of cases of liver cancer worldwide.

Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. It is present in 20 to 30% of the population in the Western countries. It is often associated with overweight, obesity, type 2 diabetes mellitus, and dyslipidemia. Currently it is the commonest liver disease, and it is associated with inflammation, i.e. non-alcoholic steatohepatitis (NASH) in 20 to 30% of cases, and may lead even to the development of cirrhosis. NASH can be presumed to underlay approximately 70% of hepatic cirrhosis with unknown origin. Insulin resistance plays a central role in its pathophysiology. A correlation between insulin resistance and hepatic carcinogenesis has been revealed by research of the recent years.

Porphyria cutanea tarda is often associated with HCV infection.

The taking of oral contraceptives has been brought in connection with benign hepatic neoplasms, such as adenomas, as well as focal nodular hyperplasia; it is rarely considered as an etiologic factor of HCC. However, the risk of hepatic lesions due to hormonal contraceptives is growing in proportion with the years of use.

When several risk factors are concomitantly present, the possibility for developing primary hepatic carcinoma grows by orders of magnitude.