In 1957, Schwarz found that a small dosage of sodium selenite can be used as a preventive agent against hepatonecrosis of rats and Shambager et al observed the cases with metastatic liver cancer and found a decline in selenium levels in the blood of patients with hepatitis and cirrhosis. Later, some studies manifested that the selenium levels in the blood of hepatitis and cirrhosis patients are significantly lower than that of normal people and that the lowering of selenium level in blood had something to do with the severity of liver diseases. Domestic studies also show that the blood selenium levels of the patients with liver diseases decrease progressively from chronic active hepatitis (0.63mg/L ±0.009mg/L) to cirrhosis (0.56mg/L ±0.011mg/L) to liver cancer (0.044mg/L ±0.009mg/L), and this phenomenon shows the lowering of blood selenium levels might be closely related with the degree, progress and canceration of liver damages.
The viral hepatitis is a kind of liver cell damage caused by the combination of various factors of immunity and non- immunity, especially by free radicals and fat peroxides. The liver, as the central bio-metabolic organ in human body, has sufficient mixed functional oxidizing enzymes that can promote the metabolism of poisonous substance and medicine. However, in the course of the metabolism, some poisonous substances and medicines are converted into free radicals, and the free radicals act on cell membranes and cell macromolecules, leading to the peroxidating reaction of fat, the deposit of glycerol trioleate and the formation of fatty liver, damaging the DNA in the cells and the coenzyme nucleotides and promoting the necrosis and canerization of the cells. The damage caused by alcohol also involves free radical action and fat peroxidating reaction.
The fat peroxidating reaction refers to a series of free radical reaction in the mostly unsaturated fatty acid. In the course of the reaction, fat peroxides (LPO) are continuously formed, causing a series of pathological and physiological changes. Under the action of some factors, much more free radicals and fat peroxides are generated, and the later are mainly dissolved in the liver and make serious damage to the liver. The liver plays an important role in the fat and fat peroxide metabolism with the most plasma fat peroxides coming from the liver. When the liver is damaged, the fat peroxides in the serum also undergo a change. Studies also show that the fat peroxides in the serum of patients with acute, chronic and severe hepatitis are significantly higher than that of the healthy people and that of patients with cirrhosis in the compensatory phase don't defer much with that of the healthy people, but significantly higher in the loss compensatory phase.
Glutathione peroxidase (GSH-Px) is an important free radical scavenger in human body, and selenium is an active factor in the glutathione peroxidase, with a mole of glutathione peroxidase containing 4 moles of selenium and a protein subunit containing a selenium atom on the average, and therefore, the selenium has the function of strengthening activity. Domestic scholars have measured the selenium levels and glutathione peroxidase activities in patients with liver cancer, cirrhosis and chronic hepatopathy and the result shows a progressive decline from chronic active hepatitis to cirrhosis to liver cancer and in these groups, the degree of selenium deficiency is proportional to that of the damage caused by selenium deficiency. The selenium can not only decompose and reduce peroxides through the activity of glutathione peroxidase and play the role of anti-peroxidation relying on the reduction of glutathione, but also strengthen anti-oxidation function of Vitamin E, so as to impede the peroxidating reaction that might damage the fat on the cell membranes, mitochondria membranes, particle mmembranes and lysosomal membranes and protect the integrality and stability of cell membranes and the normal physiological function of the cells. In this sense, selenium can be used as a protective factor in resisting hepatonecrosis. When selenium is in short supply, the selenium storage in the liver will be lowered and the metabolic process disturbed, leading to the damage and dying of the liver. Measurement by electric mirror and histochemical method shows selenium deficiency might cause lowered activity and reduced concentration of the Na+,K+-ATP enzymes and 5- nucleotidases on the cell membranes, which will lead to the degeneration and denaturalization of the liver cell membranes and it is believed that selenium deficiency is the histochemical reason of hepatonecrosis. Influenced by this viewpoint, some people have proposed to apply reduced glutathione (GSH) and superoxide dismutases (SOD) to the treatment of liver diseases and have procured a relatively good curative effect. But it has not been confirmed by contrast test in selenium supplementation.
Selenium also has a close relation with liver diseases. At the beginning of 70s, a number of survey of the blood of patients with epidmic diseases in foreign countries shown that the different levels of selenium in the blood of people living in different regions were inversely proportional to the incidence and mortality rates of tumors, indicating that low selenium concentration might be one of the causative factors of cancers. At the beginning of 80s, Yu Shuyu et al checked at random the selenium levels in blood of residents in 8 provinces and 24 regions in China and found also the selenium levels were inversely proportional to the total standardized mortality rates of cancer ranging progressively from esophageal cancer to gastric cancer and to liver cancer. A large-scale epidmic disease study on frogs in high incidence areas of liver cancer has shown the selenium values in blood of the people in these areas are significantly lower than that of the low incidence areas, and the mortality rates of liver cancer are in inverse proportion to the concentrations of selenium in the diet. The perspective study conducted by Willett and Salonen shows low concentration of selenium, for example lower than 45mg/L, has led to a significant increase of risks of having cancers. A case control study at a cross section conducted by Lin Jing et al shows the total selenium levels are expressively lower than that of the control group, and substituting the selenium in blood into a conditional Logistic regression model as a variable of molecular level, it can be seen that the total selenium in blood has a bearing on dosage reaction. Along with the lowering of the total selenium in blood, the risk of having liver cancer will increase and when the selenium in blood is lower than 0.09mg/L, the risk of suffering from cancer is 4.34 times those higher than 0.15mg/L.All these studies are in support to the hypothesis that selenium might be a protective factor in the outbreak of cancer and that low selenium concentration might lead to the increase of cancer risk. Another cross section study also shows the blood selenium levels of liver cancer patients are expressively lower than that of patients with chronic active hepatitis and cirrhosis and normal persons, while that of patients with digestive canal cancer is lower than that of normal persons but that of the liver cancer group is significantly lower than that of the digestive canal cancer group, indicating that low selenium is not only related with the occurrence but also with the progress of liver cancer. Liang Houjie et al have conducted a dynamic observation on the selenium and GSH-Px activity in the plasma, red cells and liver tissue of experimental rats with liver cancer at different stages and found that the selenium and GSH-Px activities begin to lower at the 7 th week after the cancer is induced by diethyl nitrosamine (DEN), continue lower afterward and reach their lowest in the 21 st week, only standing at 33% of that of the control group; the selenium and GSH-Px activities in the cancer tissue are significantly lower than that in the tissue beside the cancer. This shows the selenium storage in the red cells and liver tissue is in significant proportion to the GSH-Px activity, indicating that low selenium is not only a result appeared at the advanced stage of cancer but also might have participated in the canceration at the early stage because during the pathological changes at the early stage, the low selenium phenomenon has already appeared. The lowering of selenium in blood, therefore, is not a result of deposition of selenium in the tissue beside the cancer, but the shortage of selenium in the whole internal environment.
The anti-cancer role shown itself by selenium has attracted great attention from scholars at home and abroad who have conducted a series of studies and experiments on it. The animal experiment conducted by Shamberger shows the selenium supplement with different methods at different stages can all significantly reduce the incidence rate of liver cancer caused the chemistry. Tanka et al have supplemented selenium (methoxybenzene selenium disulfide) 50µg/g to rats, and reduced the incidence rate of liver cancer of the F male rats induced by azoxymethane from 66% to 19%, frequently occurring liver cancer from 2.24/rat to 0.45/rat, liver cancer focus from 12.08cm to 3.74cm. In Qidong, an high incidence area of liver cancer in China , an experience has been conducted in rats in which cancers are induced by AFB1, and than administered with selenium to reduce the incidence rate to more than 50%. In another preventive experiment in this area, the local residents are administered with selenium-added salt and selenium-containing yeast, and the selenium in the blood has been significantly increased and the mortality rates of liver cancer and the incidence rates of viral hepatitis expressively declined. Prof. Yu Shuyu et al, after studies for more than 10 years, have got such a conclusion that the trace element selenium in human body plays a reverse role in the occurrence and progress of liver cancer cells. In the past, scholars have conducted some studies on the roles of sodium selenite, a selenium compound in resisting cancers, but most of them are limited in the fields of removing peroxides and protecting cells, and have not covered the biological effects of selenium compounds. Through a number of experiments, Prof. Yu Shuyu et al have proposed for the first time at home and abroad that sodium selenite has a bearing on all the gene expression, transcription system, energy metabolism and membrane structure of cells, and can reverse the multiplication, differentiation and vicious phenotype of tumor cells. Animal experiments have proved the cancer cells and their carcinogenesis can be reduced by 60% through treatment by selenium supplement outside the body. These experiments, with selenium as a probe, will help in deeply exploring the forming mechanism of cancer cells, indicating the secret of canceration and proposing a instructive basis for the treatment of liver cancer with selenium. In the high incidence area of liver cancer in Qidong, a preventive measure of selenium supplement has been adopted and the incidence rates of liver cancer tend to lower. If this phenomenon can be further evidenced, the prevention of liver diseases, especially liver cancer will have an optimistic prospect.
As to the mechanism of canceration, there is no definite evidence as yet. In Sabonen's opinion, the mechanism why selenium can inhibit the occurrence of cancer might be that selenium can: first, reduce the mutagenicity of cancerizating factors; second, influence the metabolism of carcinogens; third, through GSH-Px, protect cells from damage by free radicals. Scholars at home have conducted a number of animal experiments and proved that selenium can disturb the exuberant energy metabolism, resist the increase of cGMP in cells and constrain the synthesis of DNA, RNA and proteins. Aaseh et al have reported that because liver diseases have been infiltrated by inflammatory cells for a long time, the hyperplasia of collagenous fibers will lead to the activation of white cells and the generation of superoxidated dismutase and peroxides and thus speed up the worsening of liver diseases. Study shows the peroxidating damage to the structures of cells, chromosomes, DNA, RNA and proteins caused by free radicals and their derviations has a close relation with tumors. In the course of canceration of cells, free radical capturing enzyme system is damaged, the synthesis of GSH-Px decreased and anti-oxidizing capacity lowered, leading to the generation of substantive LPO, which start up the "magnification" effect of reaction chains and further induce the canceration of liver cells. The activity of GSH-Px in hyperplasia nodes is lower than normal before canceration, and these variant cells have a rather low anto-oxidase activity and therefore are more feasible to be damaged by free radicals and cancerated.
It is well known that most liver cancer sufferers in our country have undergone three stages, namely HBV infection, cirrhosis after hepatitis and canceration of liver cells, and hepatitis, cirrhosis and lever cancer have a causal relationship. Most liver cancers are generated from coarse nodular cirrhosis caused by hepatitis B. It can be deduced that on the basis of hepatitis, there might be a primary necrotic inflammation that acts as a starting factor to induce the mitochysis of liver cells and make the consecutive arrangement of integrated viruses and their hosts nearby confused. The deficiency of selenium and the decline of GSH--Px activity might have promoted the further worsening and transforming caceration into liver cancer. As to the roles played by selenium in promoting the liver cell necrosis of viral hepatitis, the progress of cirrhosis and canceration, it needs to be further explored.