Basic Diagram of the Liver
Pathology:
Liver flukes are capable of infecting hepatic ducts, the common bile duct, pancreatic ducts, and the gallbladder. The severity of the infection depends of the quantity of liver flukes present and can vary from less than 100 to up to 21,000 flukes. Most infected individuals have less than 100 flukes and show no symptoms of liver fluke infection. In more severe cases, symptoms may include diarrhea, abdominal pain, and splenomegaly. In extreme cases, fever, acute pain and enlargement of the liver, jaundice, tachycardia, weight loss, and eosinophilia may occur13.
Basic Diagram of the Liver
Carcinogenesis:
Liver flukes alone are not sufficient to cause biliary cancer. While cholangiocarcinomas are more prevalent in regions of high liver fluke infection, the amount of infected people that develop cancer is still relatively low. Liver flukes may act as promoters that lead to maligancy when combined with other factors.
Studies Involving Animals:
Development of cholangiocarcinoma in individuals infected with liver flukes has been documented for cats, dogs, fish, rats, and Syrian hamsters. Numerous studies have been done with hamsters indicating that the certain cholangiocellular lesions tend to lead to cholangiocarcinoma. These include cholangiofibrosis, cholangiolofibromas, bile duct hyperplasia with dysplasia, cholangiofibrosis, mucinous cystadenomas, and cholangiofibromas. Carcinogenesis was produced most effectively in the lab by treatment with a hepatocarcinogen prior to infection with liver flukes. Liver fluke infection and continuous intake of a hepatocarcinogen in drinking water or a basal diet also produced a high incidence of cholangiocarcinoma11.
In human beings, chronic infection by liver flukes often leads to:
-desquamation
-hyperplasia
-formation of adenomatous structures with goblet-cell metaplasia in bile ducts
-dilated thick-walled ducts or periductal fibrosis
-proliferation of second-order duct epithelium with infiltration of neutrophils, eosinophils, lymphocytes, macrophages, and plasma cells.
-obstruction of bile ducts and possibly suppurative cholangitis and abcess formation
Results of Chronic Inflammation:
Acute and chronic inflammatory cells are involved in and respond to these conditions and macrophages and eosinophils have been found around the ducts. These cells produce reactive oxygen species and other toxic compounds, such as nitric oxide, nitrate, nitrite, and oxygen radicals, that lead to death and regeneration of the bile ducts.
Some Reactions Producing Reactive Oxygen and Nitrogen Species11
NO.+ NO2 --> N2O3
N2O3 + H2O --> 2HNO2 --> 2NO2- + 2H+
O2 + NADPH --> O2.- + NADP+
O2.- + H2O2 --> O2 + OH. + OH-
This increased amount of cellular turnover is likely to act as a coinitiator of carcinogenesis by increasing the number of pluripotential cells and causing DNA damage from the toxic products of the immune response. Additionally, diets containing N-nitroso compounds or precursors are common and in Thailand and can combine with aminopyrine in the stomach to form DMN, the hepatocarcinogen used to induce cholangiocarcinoma in the hamster model11.
The development of cholangiocarcinoma, as with most cancers, is multifactorial. Contributers are thought to include chronic inflammatory processes, altered cellular detoxification mechanisms, generation of active oxygen radicals, activation of oncogenes, functional loss of tumor-suppressor genes and dysregulation of cell proliferation and cell apoptotic mechanisms6. Infection with O. viverrini specifically has been linked with mutations in the p53 gene without mutation of the c-Ki-ras oncogene11.
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