Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Wilson's disease can result in fulminant liver failure due to hepatic copper overload. The CD95 system mediates apoptosis and has been demonstrated to be involved in liver disease. In this study CD95 mediated apoptosis was investigated in patients with fulminant hepatic failure in the course of Wilson's disease and in an in vitro model of copper treated human hepatoma cells. In patients, hepatic expression of CD95 and CD95L mRNA and apoptosis were detected. Copper overload in vitro resulted in hepatocytic apoptosis which could be reduced with a neutralizing anti-CD95L antibody. Copper treatment of hepatocytes results in activation of the CD95 system and induction of apoptosis which is operative during the course of hepatic failure in acute Wilson's disease.
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PMID:Hepatic failure and liver cell damage in acute Wilson's disease involve CD95 (APO-1/Fas) mediated apoptosis. 958 33

Hepatocellular carcinoma (HCC) is the most frequent primary cancer of the liver and the most frequent tumour in males, worldwide. The annual incidence of HCC is maximum in Asian and African countries, lower in western countries where it is close to 4/100,000 inhabitants. In 90% of the cases, HCC complicates course of liver cirrhosis, with an annual incidence in cirrhoties of 2 to 6%. Risk factors for HCC in cirrhotics are male gender (sex-ratio: 4/1), age (above 50 years old), macronodular cirrhosis and large cell dysplasia. HCC can complicate the course of cirrhosis of any cause, but might be less frequent in primary biliary cirrhosis, Wilson's disease and auto-immune hepatitis. Currently, the diagnosis of HCC is usually considered in the presence of a focal nodular lesion, during systematic ultrasonographic examination of the liver. In high incidence areas, HCC can still be diagnosed because of HCC-related symptoms. In the case of a focal lesion discovered on a cirrhotic liver, the diagnosis of HCC can be confirmed by studying the behaviour of the lesion of helical CT scan of the liver (enhancement of the tumour during the arterial phase) or MRI (hyperintensity of the tumour on T2 relaxation time); study of peritumour vessels can also be helpful. Serum alpha-foeto-protein level, when higher than 300 to 500 micrograms/L is very specific of HCC. When aggressive treatment of HCC is considered and when the diagnosis of HCC remains uncertain, HCC can be assessed by means of cytological or histological study of the tumour on samples taken by fineneedle aspiration (80% sensitivity) or liver biopsy during laparoscopic laparotomy. Forthcoming improvements in imaging technology might eliminate the need for such invasive diagnostic techniques in the future.
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PMID:[Epidemiology and diagnosis of hepatocellular carcinomas in cirrhosis]. 975

Liver transplantation in pediatric patients represents about 10% of a total of 23,000 transplantations registered in the European Liver Transplantation Register (ELTR)since 1968. The pediatric patients show a specific spectrum of indications with cholestatic liver disorders ranking first, followed by hepatic based metabolic disorders. There has been a significant improvement of survival in transplantation since the early 80ies. The overall survival standard is nowadays in the range of 80%. There is a trend towards even better results in metabolic disorders. The clinical presentation of liver disease caused by metabolic disorders shows a wide range from acute liver, cerebral, cardiac and renal failure to chronic end stage liver, kidney and heart disease potentially complicated by hepatocellular carcinoma. In many cases, the diagnosis of a underlying metabolic disorder is very difficult and time consuming so the decision to do a liver transplantation may be necessary before a final diagnosis is established. Having these problems in mind, the consideration of absolute and relative contraindications for liver transplantation in metabolic disorders is even more difficult than it is already in cholestatic or inflammatory liver disorders. The individual evaluation of a patient suffering from a hepatic metabolic disorder must consider in addition the often dramatic restriction of quality of life due to rigorous dietary restrictions or other therapies. This makes clear that suitable methods to measure quality of life must be developed and applied in order to fulfill this goal. The extension of indications for liver transplantation even to disorders with only partial defects in otherwise healthy livers was possible by using innovative surgical techniques such as partial, living related, split, in situ split and auxiliary orthotopic transplantation. These techniques allowed to reduce the mortality on pediatric waiting lists significantly without restricting the general donor pool. However, living related liver transplantation is handicaped by the heterozygous status of the parent donor. This plays a role especially in patients with progressive familial intrahepatic cholestasis (PFIC) and Wilson's disease.
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PMID:Liver transplantation in metabolic disorders. 1054 96

An inbred rat strain, LEC (long evans cinnamon) has been used as a model of human Wilson's disease. This animal suffers from a severe type of hepatitis, the clinical manifestations of which are similar to human fulminant hepatitis for 4-5 months which is caused by accumulation of copper in the liver. The surviving rats develop chronic hepatitis, followed by the development of spontaneous hepatoma. In contrast to studies with hepatocellular carcinomas (HCCs), the studies have great advantages in that the animals have identical genetic background, can be raised under a fixed condition, and the development of HCC is reproducible. We took two HCC samples and analysed their genomic DNA using RLGS (restriction landmark genomic scanning), which involves two-dimensional electrophoresis of genomic DNA allowing the survey of some 1,000 NotI sites throughout the genome. Using this technique, we discovered landmark spots that were either decreased or increased in intensity in HCC and compared them with the RLGS profile obtained from the DNA of control normal LEC rat liver. Approximately 1,300 spots were compared, and the intensity of two spots was found to be decreased about half and one was increased 1.3-1.7 folds. Although the mechanism of these changes and the properties of the changed DNA are yet to be studied, recurrent genomic changes in the LEC rat HCC could prove to be a good model system for elucidating the essential genetic events in association with hepatocarcinogenesis.
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PMID:Genomic DNA analyses of spontaneous hepatocellular carcinomas in LEC rat liver using a new technique. 1067 78

Wilson's disease is a genetic disorder characterized by the accumulation of copper in the body due to a defect of biliary copper excretion. However, the mechanism of biliary copper excretion has not been fully clarified. We examined the effect of copper on the intracellular localization of the Wilson disease gene product (ATP7B) and green fluorescent protein (GFP)-tagged ATP7B in a human hepatoma cell line (Huh7). The intracellular organelles were visualized by fluorescence microscopy. GFP-ATP7B colocalized with late endosome markers, but not with endoplasmic reticulum, Golgi, or lysosome markers in both the steady and copper-loaded states. ATP7B mainly localized at the perinuclear regions in both states. These results suggest that the main localization of ATP7B is in the late endosomes in both the steady and copper-loaded states. ATP7B seems to translocate copper from the cytosol to the late endosomal lumen, thus participating in biliary copper excretion via lysosomes.
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PMID:Copper does not alter the intracellular distribution of ATP7B, a copper-transporting ATPase. 1097 14

The mutant strain Long-Evans Cinnamon (LEC) rat, which accumulates copper in the liver because of a mutation in the Atp7b gene, encoding a copper-ATPase, is a model of Wilson disease. It spontaneously develops hepatitis, and subsequently hepatocellular carcinoma and cholangiofibrosis. Excess intracellular copper has been thought to induce DNA damage through reactive oxygen species produced by Cu (II)/Cu (I) redox cycling, and also by direct interaction with DNA. We have developed lacI transgenic Wilson disease (WND-B) rats by mating LEC with Big Blue F344 rats carrying a lambda shuttle vector harboring the lacI gene. lacI mutations of the livers of C-B heterozygous (Atp7b w/m, lacI) and WND-B homozygous (Atp7b m/m, lacI) rats at 6, 24, and 40 weeks of ages were analyzed. Mutant frequencies in the WND-B rats were 2.0 +/- 0.7 x 10(-5), 5.3 +/- 0.9 x 10(-5), and 5.3 +/- 1.0 x 10(-5), respectively, significantly higher than those of C-B rats. Nucleotide sequence analysis revealed that the frequency of deletion mutations of more than two nucleotides were much higher, 15% in WND-B rats, but only 2% in C-B rats. In addition, the average size of deletion was larger in the former. Loss of oligonucleotide-repeat units was specific and relatively frequent in WND-B rats. This type of mutation might be implicated in the induction of DNA strand scissions by reactive oxygen species. These findings suggest that the increase in mutant frequencies and/or the specific type of mutation according to copper accumulation play a crucial role in hepatocarcinogenesis in LEC rats.
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PMID:Increased mutant frequency and altered mutation spectrum of the lacI transgene in Wilson disease rats with hepatitis. 1101 32

Copper toxicity causes hepatic damage that can lead to the development of hepatocarcinoma. Similarly, copper deficiency has been reported to increase hepatocyte tumorigenesis. Thus, the objective of this work was to explore the role of copper toxicity and deficiency in the regulation of the tumor suppressor protein p53. Using Northern analysis, Western analysis, immunocytochemistry and the human hepatoma cell line Hep G2, this work showed that elevations in hepatocyte copper consistent with Wilson's disease (5.7-fold increase) induced p53 mRNA and confirmed that copper toxicity is correlated with apoptotic cell death. However, Western analysis and immunocytochemistry showed that post-transcriptional mechanisms are a significant part of the process, with p53 translocation from the cytosol into the nucleus of copper-treated cells. Treatment of Hep G2 cells with increasing concentrations of the copper chelator tetraethylenepentamine (TEPA, 0-50 micromol/L, 48 h) reduced cellular copper and increased mean p53 mRNA abundance by over fourfold with nuclear translocation of the wild-type protein. However, TEPA treatment did not result in a loss of cell viability or appear to induce apoptosis.
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PMID:Tumor suppressor protein p53 mRNA and subcellular localization are altered by changes in cellular copper in human Hep G2 cells. 1134 94

Advances in imaging technology and development of liver-specific contrast agents have significantly increased the role of radiology in the detection and characterization of processes diffusely involving the liver. Tailored magnetic resonance imaging (MRI) sequences allow an accurate detection of many storage and metabolic diseases, such as iron overload disorders and steatosis (fatty liver). Faster scanning techniques available with both computed tomography (CT) and MRI provide, by assessing contrast dynamics, sufficient information for the characterization of diffuse neoplastic and vascular disorders. Characteristic changes in attenuation on CT, signal intensity on MRI, and enhancing features can be used to diagnose specific diffuse diseases such as candidiasis, diffuse/multifocal hepatocellular carcinoma, and schistosomiasis. Although an overlap in imaging findings still exists, familiarity with the imaging features of uncommon disorders such as Wilson's disease, amyloidosis, and sarcoidosis may be diagnostic in the proper clinical setting. This review focuses on the current role of imaging in the detection and characterization of diffuse liver disorders. Recent developments that have amplified the role of noninvasive diagnostic evaluation of these conditions are especially highlighted.
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PMID:Imaging of diffuse liver disease. 1143 72

Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, anti-angiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cu-chelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.
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PMID:The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells. 1174 76

Genetic factors play a privotal role in the pathogenesis of several liver diseases. A review is devoted to discussing the genetics of autoimmune hepatitis, chronic viral hepatitis B and C, cholestatic and alcoholic liver diseases, UDP-glucuronyl transferase deficiency, alpha, antitripsin deficiency, hereditary haemochromatosis, Wilson's disease and hepatocellular carcinoma.
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PMID:[Genetic aspects of liver diseases]. 1181 76


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