The etiology of primary hepatocellular liver cancer, commonly known as hepatocellular carcinoma, is unknown to date. According to epidemiological surveys in high-incidence areas, the following factors may be related to the prevalence of hepatocellular cancer
Causes of morbidity
The etiology and pathogenesis of HCC have not been determined and may be related to a combination of factors. It has been equally found in any region of the world that chronic liver disease from any cause may play an important role in the development and progression of hepatocellular carcinoma. Both epidemiological and experimental studies have shown that viral hepatitis has a specific relationship with the occurrence of primary liver cancer.
Among them, hepatitis B is the most closely related to liver cancer, and the increase in the number of HBsAg-negative liver cancer in recent years is related to hepatitis C. In the former Soviet Union, there are more hepatitis D types. About 90% of liver cancer patients in China have a background of hepatitis B virus (HBV) infection. Other risk factors include alcoholic cirrhosis, hepatic adenoma, chronic intake of aflatoxin, other types of chronic active hepatitis, Wilson’s disease, tyrosinemia, and glycogen accumulation disease. Recent studies have focused on hepatitis B and C viruses, aflatoxin B1 and other chemical carcinogens.
1.Cirrhosis Any cause of cirrhosis can be accompanied by HCC. HCC often occurs on the basis of cirrhosis, and worldwide, about 70% of primary liver cancer occurs on the basis of cirrhosis. The incidence of combined cirrhosis in patients with liver cancer is 68%-74% in the UK and about 70% in Japan. For patients who died of cirrhosis, the detection rate of primary liver cancer at autopsy was 12% to more than 25%. The combined rate of cirrhosis in 500 autopsied liver cancer cases from 1949 to 1979 in China was 84.6%. The Second Military Medical University reported that among 1102 surgically resected liver cancers, 85.2% were combined with cirrhosis, and all of them were hepatocellular carcinoma, and none of the bile duct cell carcinomas had cirrhosis. Not all patients with all types of cirrhosis have the same incidence of hepatocellular carcinoma. Liver cancer mostly occurs in nodular cirrhosis of hepatitis B and C, while biliary, schistosomal, alcoholic, and bruising cirrhosis are less often combined with liver cancer. Overseas reported that 3% of patients who died of primary biliary cirrhosis had liver cancer at autopsy, while more than 40% of patients who died of HBsAg-positive chronic active hepatitis and cirrhosis had liver cancer at autopsy. In 334 cases of nodular cirrhosis autopsy material in China, the detection rate of liver cancer was 55.9%. In early reports, liver cancer combined with cirrhosis was mainly large nodular type, accounting for 73.6%, while a study of 1000 specimens of liver cancer surgically resected since 1980s by the Second Military Medical University showed that the combined rate of cirrhosis was 68%, and small nodular cirrhosis was the main type, accounting for 54.4%, mixed cirrhosis accounted for 29.3%, and large nodular cirrhosis accounted for only 16.3%. It is suggested that with the improvement of the diagnosis and treatment of hepatitis, light hepatitis is more common than heavy hepatitis, and the former is dominated by the formation of small nodular cirrhosis.
Animal studies of chemical carcinogens have shown that regenerative nodules are a promoter of the transformation of hepatocytes into carcinomas. Alcoholic cirrhosis is mostly small nodular in nature, and the rate of carcinogenesis increases with the gradual transformation of small nodules into large nodules after abstinence from alcohol, which supports the above argument. Other causes of cirrhosis, such as primary biliary cirrhosis, α1 antitrypsin deficiency, hepatomegaly, hemochromatosis and Budd-Chiari syndrome, and autoimmune chronic active hepatitis, can complicate HCC. there are two explanations for the mechanism of cirrhosis carcinogenesis: the first explanation is that cirrhosis itself is a precancerous disease, and in the absence of other factors, from proliferation and interstitial transformation leading to the formation of cancer; the second explanation is that the rapid conversion rate of hepatocytes in cirrhosis makes these cells more sensitive to environmental carcinogenic factors, i.e., carcinogenic factors can cause damage to hepatocytes and DNA replication occurs before the damage is repaired, resulting in permanently altered abnormal cells.
Data show that about 32% of liver cancers are not combined with cirrhosis, but even among liver cancers without cirrhosis, the HBsAg positivity rate is as high as 75.3%, suggesting that chronic hepatitis can lead directly to liver cancer without going through the cirrhotic stage. hepatocyte damage and regenerative nodule formation due to HBV or HCV infection underlie the development of cirrhotic liver cancer. When HBV infection of host hepatocytes in the form of gene integration is predominant and does not cause necrosis and proliferation of hepatocytes, it may lead directly to liver cancer without cirrhosis in a relatively short period of time.
2.About 1/3 of patients with primary liver cancer of hepatitis B virus had a history of chronic hepatitis. The epidemiological survey found that the rate of HBsAg positivity in the population in the high prevalence area of HCC is higher than that in the low prevalence area, and the positivity rate of serum HBsAg and other hepatitis B virus markers in HCC patients is as high as 90%, which is significantly higher than that of the healthy population. there is a positive correlation between the incidence of HCC and the prevalence of HBV carriage status, and there is also a close geographical relationship.
(1) The correlation between HBV and HCC can be elucidated by the following points.
(1) The incidence of HCC parallels that of HBsAg carriage: areas with a high prevalence of primary liver cancer are also areas with a high rate of HBsAg carriage, while the natural population in areas with a low prevalence of liver cancer has a lower rate of HBsAg carriage. The carrier rate of HBsAg in our population is about 10%, and there are 120 million HBV carriers nationwide, and about 1 million newborns are infected with HBV every year because their mothers are carriers, while in Europe, America and Oceania where liver cancer is low, the carrier rate of HBsAg is only 1%.
The incidence of chronic HBV infection in liver cancer patients is significantly higher than that in the control population: among 1000 liver cancer patients at the Eastern Hepatobiliary Surgery Institute of the Second Military Medical University, the HBsAg positivity rate was 68.6%; among 992 hospitalized liver cancer patients at Zhongshan Hospital in Shanghai, the HBsAg carriage rate was 69.1% and the anti-HBc positivity rate was 72.1%; both significantly higher than the 10% HBsAg carriage rate in the natural population in China. of HBsAg carriage rate in our natural population. In Taiwan, the HBsAg carriage rate was reported to be 15%, while in liver cancer patients it was 80% and the anti-HBc positivity rate was up to 95%. Even in areas with low incidence of primary liver cancer, the incidence of HBV infection in patients with liver cancer is significantly higher than in the natural population. For example, in the United States, the rate of anti-HBc positivity in liver cancer patients is 24%, which is 6 times higher than that in the control group. The rate of HBsAg positivity in patients with liver cancer in the UK was 25%, also significantly higher than the 1% in the natural population. Detected by immunofluorescence and immunoperoxidase techniques, about 80% of liver cancer specimens had HBsAg in the cytoplasm of paracancerous tissue or hepatocytes, and 20% had HBcAg in the nucleus; lichen red staining showed that the rate of HBsAg positivity in liver cancer specimens was 70.4% to 90%, significantly higher than that of 4.7% in the control group.
HCC patients often have positive s antigen, s antibody, c antigen, c antibody, e antigen and e antibody in the serum, among which double positive s antigen and c antibody is more common. In recent years, it has been found that e antibody positivity is also common.
(③Family aggregation of HCC is seen in families with HBsAg positive, chronic hepatitis and cirrhosis. This indicates that HBV infection is still the main carcinogenic factor in addition to possible genetic factors.
④Hepatocellular carcinoma that is s-antigen positive can also have s-antigen in the cytoplasm of its non-cancerous cells.
⑤Human hepatocellular carcinoma cell lines can secrete HBsAg and AFP.
⑥Cancer cells from HCC patients have HBV-DNA integration. Molecular biology studies have found HBV-DNA base sequences integrated in the DNA of hepatocellular carcinoma cells. Some human hepatocellular carcinoma cell lines can continuously secrete HBsAg and AFP. Since Alexander discovered that the human hepatocellular carcinoma cell line PLC/PRE/5 can secrete HBsAg at a constant rate, successive cell lines such as Hep-3B, Hah-1, Huk-4 and C2HC/8571 have been found to produce HBsAg.
(7) Duck liver cancer and groundhog liver cancer also have hepatitis viruses similar to human hepatitis B virus: the prevalence of animal liver cancer provides important clues for the study of the relationship between hepatitis and liver cancer and serves as a model for etiological studies. The occurrence of liver cancer in groundhogs was found to be associated with hepatitis abroad, and liver cancer in Qidong ducks was also found to be associated with infection with a virus similar to human hepatitis B virus in China. Groundhogs cause liver cancer directly from acute hepatitis, while Qidong ducks have the process of chronic hepatitis → cirrhosis → liver cancer. In summary, HBV infection is an important factor in the development of hepatocellular carcinoma. Although there are a lot of clues suggesting a close relationship between HBV and liver cancer, the exact mechanism and process by which HBV causes liver cancer is still not very clear. Recent studies on the molecular biology of liver cancer have provided new evidence for the oncogenic mechanism of HBV.
⑧ In the same population, the incidence of HCC is much higher in s-antigen carriers than in non-s-antigen carriers. In a prospective study of 3500 HBsAg carriers with 3.5 years of follow-up, 49 cases of liver cancer were found, and the risk of developing liver cancer was 250 times higher than that of the control group.
(2) HBV is almost certainly an initiating factor in the pathogenesis of HCC, and both animal experiments and human studies support a direct oncogenic role for HBV. The major ones include.
(i) HBV integration causing chromosomal deletions and translocations.
(ii) Groundhog hepatovirus integration often activates the cellular proto-oncogene (N, C-myc).
③ HBV integration can alter the genes of human retinoic acid receptor and cyclin A protein, affecting cell differentiation and cell cycle operation.
④Hepatophilic DNA virus genes (HBV, WHV, GSH) act as a transcript to activate viral and cell-promoting factors in trans.
(5) The X-gene protein of HBV has transforming oncogene activity in transgenic mice.
(3) *HBV-DNA and liver cancer oncogenes: The molecular pathogenesis of HBV-DNA and the interaction between HBV-DNA and liver cancer oncogenes are related. HBV-DNA integrated into the DNA of hepatocytes may cause cancer by interacting with oncogenes and/or oncogenes, thereby activating oncogenes and/or causing inactivation of oncogenes. The X protein, the product of the HBV X gene integrated in hepatocytes, functions as a trans-activator and may cause hepatocellular carcinoma by activating the transcription of certain cellular regulatory genes.
(4) Hepatitis C virus (HCV) Since 1989, the relationship between HCV and HCC has begun to gain attention. With the increase in the number of non-HBV-associated HCC cases, the oncogenic role of chronic non-A non-B hepatitis (NANB) has been confirmed. It is believed that more than 90% of patients with NANB are HCV infected. There have been many reports of HCV infection being a major risk factor for the development of HCC. In Japan and Italy, where HBV infection is relatively rare and other environmental factors such as aflatoxin are even less present, the incidence of HCC associated with HBV has decreased, but the overall incidence of HCC has changed little or even increased, suggesting an increased role for other factors, including HCV. in Ksbayashi’s exploration of the etiology of HCC in Japan, it was found that 77% or even up to 80% of HCC patients HCV was detectable in the serum and also found to be present in the HCV series in HCC tissues. In a 15-year observation, Ikeda et al. found that the risk of HCC in chronic HCV cirrhosis was about 3 times greater than that in HBV cirrhosis. In China, Wang Chunjie applied immunohistochemical methods to localize HCV and HBV antigens in 102 HCC tissues and found that the positive detection rates of HCV C33 antigen and HBxAg in HCC were 81.4% and 74.5%, respectively. In HCC, the highest anti-HCV positivity rates were found in southern Europe and Japan, followed by Greece, Australia, Switzerland, Saudi Arabia, and Taiwan, and the lowest in the United States, Africa, India, and other countries in the Far East. The high replication rate of HCV genes and the very low or lack of correction ability make HCV escape the host’s immune defenses and easily turn into chronic persistent infection, which is rarely self-limiting. This carcinogenesis is not a direct transformation of hepatocytes, but may play an indirect role in cell growth and differentiation, such as activation of growth factors, oncogenes or DNA binding proteins. The hypothesis that HCV infection is involved in the mechanism of hepatocarcinogenesis is supported by the fact that HCV sequences were detected in most of the liver tissues of patients with anti-HCV positive hepatocellular carcinoma.
The Second Military Medical University examined 96 patients with hepatocellular carcinoma, 43 patients with chronic hepatitis and 40 patients with cirrhosis, with HCV-Ab positive rates of 11.5%, 9.3% and 10% in serum, respectively. The results showed that the rate of HCV infection in liver cancer patients in China is still low, and some of them are dual infections, suggesting that HCV infection is not yet the main cause of liver cancer in China. However, in recent years, HCV infection related to blood transfusion and use of biological products has been on the increase and may lead to the occurrence of some HBsAg-negative liver cancers, so the prevention and treatment of HCV should not be neglected.
(5) aflatoxin (AFT) AFT is produced by Aspergillus flauus, a group of toxins, which can be divided into aflatoxin B (AFB) and aflatoxin G (AFG) according to different fluorescence, the former is divided into AFBl and AFB2, and the latter is divided into AFG1 and AFG2. It can cause HCC in marmosets, rats, mice and ducks, but there is no evidence of direct carcinogenesis in humans. There is a relationship between the heavier the AFT pollution and the higher the incidence of HCC in Africa and Southeast Asia. AFT is a carcinogenic factor in these high incidence areas, and it is not clear whether AFT is a primary or a promoter in the development of HCC. In Greenland, where HBsAg carriage is high and AFT levels are low, the incidence of HCC is also low. A correlation study by Van Rensburg et al. in nine regions, including Mozambique and Transkei, observed that HBsAg carriage status was an indicator of carcinogenesis, while AFT played a role in later stages or in promoting cancer. a 1982 investigation found that a positive correlation between estimates of AFT exposure from dietary and cereal samples and the minimum incidence of HCC in men. The joint effect of AFT and HBsAg on the incidence of HCC was evaluated by multivariate analysis revealing that AFT was the factor that played the most important role in the geographical variation of HCC in Swaziland.Some scholars in China also studied the relationship between AFB1, HBsAg and HCC in Guangxi region and concluded that HBsAg may precede AFT exposure and lay some pathological foundation for AFT to cause HCC.AFT interacts with HBsAg infection and plays a role especially in the later formation of HCC. In the Philippines, 90 patients diagnosed with HCC and 90 controls were compared, and their AFT exposure was investigated by recall method, resulting in an average intake of 44% more in the HCC case group than in the control group. in the light and heavy exposure groups, both AFT ingestion and alcohol consumption had a synergistic effect, and it is believed that alcohol consumption enhances the HCC-causing effect of AFT. van Rensburg demonstrated experimentally that AFT and the development of HCC are logarithmically and linearly correlated. Aflatoxin can be quickly converted into active substances in the liver and can bind to macromolecules. Its AFB1 metabolite may be an epoxide that can bind to the guanine residue of DNA molecules in the N7 position in a covalent bond, changing the template properties of DNA and interfering with the transcription of DNA. The codon 249 G to T shift of the repressor gene P53 has been measured from a large number of HCC patients, suggesting that this specific substitution in P53 may be characteristic of the genetic alteration caused by AFT, thus indirectly supporting the carcinogenic role of this fungal toxin.
(6) The relationship between parasitic diseases liver parasitism and HCC has not been confirmed so far. Schistosoma haematobium infection is thought to be one of the causes of cholangiocytic hepatocellular carcinoma. Thailand reported that HCC occurred in 11% of T. bovis-infected patients, indicating that there is a correlation between hepatic schistosomiasis and HCC. In Guangxi Fusui County, 43.3% of patients with liver cancer had a history of eating raw fish, while 94.1% of liver cancers were HCC rather than cholangiocarcinoma, and 85.2% were combined with cirrhosis, which can suggest that there is no direct relationship between schistosomiasis and liver cancer. The relationship between schistosomiasis and HCC has not been established, and most scholars believe that there is no causal relationship between the two because the geographical distribution of liver cancer and schistosomiasis is not the same, and most advanced schistosomiasis complicating HCC is based on mixed nodular and small nodular cirrhosis, not liver fibrosis specific to schistosomiasis, and 1/4 of them are also combined with HBsAg positivity. Therefore, there is no basis for schistosomiasis as a direct cause of HCC.
(7) Oral contraceptives and androgens Oral contraceptives were first reported to cause hepatic adenomas in 1971. In an experimental study, 15 mg of hexestrol pills were implanted subcutaneously in Armenian hamsters, and HCC occurred within a few months, which was completely prevented if the estrogen antagonist tamoxifen (triamcinolone) was administered at the same time, indicating the involvement of estrogen in the development of HCC. In the United States, the estrogen content of oral contraceptives is eight times higher than in China, and it can cause benign hepatic adenomas, which also develop into HCC, and the hepatocellular carcinoma will regress when the drug is discontinued. However, it is also believed that oral contraceptives and HCC are just coincidental. And it was found that liver cancer is androgen-dependent tumor, androgen receptors are more than estrogen receptors in HCC tissues, and there are more men than women with HCC.
(8) Ethanol is the most important factor in the etiology of chronic liver disease in western countries, but retrospective pathological anatomical studies and prospective clinical and epidemiological studies have shown that ethanol and HCC are not yet directly related, but at best a co-carcinogenic quality. Ethanol enhances the effects of HBV, nitrosamines, AFT, and induces HCC, and its pro-carcinogenic mechanism is unknown. Some reports suggest that ethanol can affect the metabolism of vitamin A and influence cytochrome P450 activity, thus accelerating the biotransformation of carcinogens.
(9) Environmental factors The incidence of HCC in ditch and pond water drinkers in Qidong, Jiangsu Province is 60/100,000-101/100,000, while in well water drinkers it is only 0-10/100,000, and the relative risk increases in ditch water drinkers. In recent years, the incidence of HCC in the area has decreased after improving water quality, but the underlying factors are not fully understood. The copper, zinc and preservative content of water sources in the endemic area is high, while the molybdenum content is low. the copper content in HCC patients is consistent with changes in water sources, and these changes in trace elements can shed some light on the etiology of HCC. In recent years, selenium deficiency has been found to be associated with HCC, and selenium deficiency is a condition factor in the development and progression of HCC. In addition, the incidence of HCC in the second or subsequent generations of Chinese immigrants to the United States is lower than that of the first generation, and lower than that of residents of their birthplace before relocation, which also indicates the importance of environmental factors.
The incidence rate of liver cancer in Qidong, Jiangsu Province, was 60-101/100,000 for those who drank loose ditch water and only 0-19/100,000 for those who drank well water. The relative risk of ditch water drinkers was 3.00, and the investigation found that a kind of algae producing algal toxins in ditch water may be a clue to the relationship between drinking water pollution and the occurrence of liver cancer.
(10) Genetic factors sometimes appear in the high incidence of HCC in families, especially in those who live together and are related by blood, which is thought to be related to the vertical transmission of hepatitis virus factor, but has yet to be confirmed. The association between HCC and hemochromatosis is only present in patients who have this disease and survive long enough to develop cirrhosis.
(11) Other carcinogenic substances nitrosamines fed to baboons and monkeys can cause single nodule liver cancer, and the coexistence of HBV and nitrosamines can cause multifocal, multinodular liver cancer. Creamy yellow (dimethyl azobenzene), hexachlorobenzene, benzo(a)pyrene, polychlorinated biphenyls, trichloromethane, and 1,2-dibromoethane have been shown to be carcinogenic.
Aflatoxins in the high incidence of liver cancer, especially in the south to corn-based grain local surveys suggest that the prevalence of liver cancer may be related to aflatoxin contamination of food, the population urine aflatoxin B1 metabolite aflatoxin M1 content is high. Aflatoxin B1 is the most powerful carcinogenic agent for liver cancer in animals, but there is no direct evidence of the relationship with human liver cancer so far.
In conclusion, the occurrence of hepatocellular carcinoma is the result of a combination of factors, the exact etiology and mechanism is subject to further research.
The disease develops rapidly and has a high mortality rate, which is a serious health hazard. Since it is difficult to explain the causes and distribution of liver cancer in China and around the world satisfactorily, the occurrence of liver cancer may be caused by multiple factors through multiple pathways; the cancer-causing and cancer-promoting factors may not be exactly the same in different regions, and what are the main factors and the interrelationships among them are yet to be studied.