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)

Porphyria cutanea tarda (PCT), the commonest of all porphyrias, is usually characterized by blisters and fragility of skin in light-exposed areas. It can be clinically indistinguishable from other disorders including variegate porphyria and the diagnosis can only be made by rigorous biochemical analysis. PCT does not cause acute attacks of porphyria. It is usually an acquired condition caused by inhibition of the uroporphyrinogen decarboxylase enzyme in the liver. Hereditary haemochromatosis, hepatitis C virus infection, alcohol, oestrogens and a family history of PCT are the major risk factors for the condition and should be searched for specifically in all patients. Liver disease, including hepatocellular carcinoma, is common in patients with PCT, and should be investigated for at presentation by means of a liver biopsy where possible. Patients with severe hepatic pathology or longstanding untreated PCT need to be monitored for the development of hepatocellular carcinoma in the long term. Low dose twice weekly chloroquine is the mainstay of treatment, but venesection should be used in patients with severe iron overload or hepatitis C-related liver disease. Subsequently, long-term follow-up is needed in all patients to monitor for relapse.
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PMID:The management of porphyria cutanea tarda. 1142 63

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

Patients with porphyria cutanea tarda (PCT) develop hepatocellular carcinoma as a late consequence. Pre-loading of C57BL/10ScSn mice with iron greatly sensitizes them to the induction of hepatic porphyria caused by hexachlorobenzene (HCB). HCB will also cause liver tumors in experimental animals. Elevated liver iron stores are implicated in the development of some human liver cancers in connection with its known catalytic role in generation of highly reactive activated oxygen species. The aim of this study was to determine the lipid and DNA oxidative damage in iron and HCB-induced porphyric mice. C57BL/10ScSn mice received i.p. injections of dextran sulfate (control), iron (Imferon) or combined iron and HCB. 6 weeks after treatment plasma ALT levels and hepatic free iron, porphyrin, lipid peroxides and 8-hydroxyguanosine (8-OHdG) levels were analyzed. Hepatic porphyrin level was significantly (p < 0.001) increased following combined iron/HCB treatment as compared to control mice. The level of lipid peroxides increased 9-fold (p = 0.001) and 35-fold (p < 0.001) after iron and iron/HCB treatment respectively, whereas the level of 8-OHdG was increased 2.5-fold (p = 0.002) and 7.5-fold (p < 0.001) after iron and iron/HCB treatment respectively as compared to control mice. The authors conclude that iron overload in conjugation with HCB induce lipid and DNA oxidative damage in C57BL/10ScSn mice. DNA oxidative damage may be important in the early events of hepatic carcinogenesis in experimental porphyria.
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PMID:Lipid and DNA oxidative damage in experimentally induced hepatic porphyria in C57BL/10ScSn mice. 1147

The possible role of iron in facilitating the development of liver cancer is still debated. The aims of this study were to define the prevalence of the mutations 845G --> A and 187C --> G (C282Y and H63D) in the HFE gene associated with hereditary hemochromatosis in Italian patients with hepatocellular carcinoma occurring in cirrhosis and to analyze the interaction between these mutations and other established risk factors for hepatocellular carcinoma. The HFE gene mutations, performed by polymerase chain reaction, were analyzed in 81 patients (63 males, 18 females) with hepatocellular carcinoma. None of the patients had a phenotype compatible with homozygous hereditary hemochromatosis. Interaction between HFE mutations and exogenous risk factors was analyzed by collecting information on alcohol consumption, hepatitis B and C virus infections, and iron status at the time of diagnosis of chronic liver disease. This analysis was performed only in males to rule out gender influence on patients' iron status by using the case-only approach specifically designed to estimate departure from multiplicative risk ratios under the assumption of independence between genotype and environmental exposure. The prevalence of the C282Y mutation was significantly higher in patients with hepatocellular carcinoma than in normal controls (8.6% vs 1.6%, P < 0.03). At univariate analysis, iron overload was significantly associated with both HFE mutations (P < 0.0001), whereas ongoing hepatitis B virus infection was associated with the C282Y mutation (P < 0.05). By multivariate analysis, a trend for an increased risk of being positive for hepatitis virus markers (OR 2.9, CI 95% 0.9-9.5) and of having been alcohol abusers (OR 3, CI 95% 0.7-14) was observed in patients heterozygous for the HFE mutations. These data indicate that the prevalence of the main mutation associated with hereditary hemochromatosis is significantly higher in cirrhotic Italian patients with hepatocellular carcinoma compared to a normal population and suggest that heterozygotes for HFE mutations exposed to hepatitis virus infections or who had been alcohol abusers could have an increased risk of developing cirrhosis and later liver cancer than people without the mutations exposed to the same risk factors.
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PMID:Mutations in the HFE gene and their interaction with exogenous risk factors in hepatocellular carcinoma. 1150 61

Accumulation of 8-hydroxy-2'-deoxyguanosine (8-OHdG) in DNA, which may result from the continuous reactive oxygen species (ROS) generation associated with chronic inflammation, has been reported in various human preneoplastic lesions and in cancerous tissues. However, no direct causative relationship between the 8-OHdG formation and carcinogenesis has been thus far demonstrated in humans. Directly proving the causality requires showing that depletion of 8-OHdG levels in tissue by interfering with ROS generation results in a reduction in cancer. Chronic hepatitis C virus (HCV) infection is associated with a high risk of hepatocellular carcinoma (HCC). Several studies on patients with chronic HCV have shown that hepatic iron overload is attributable to liver injury and that iron depletion improved serum aminotransferase levels. Excess iron is known to generate ROS within cells, which causes mutagenic lesions, such as 8-OHdG. In this study, therefore, we have evaluated whether therapeutic iron reduction (phlebotomy and low iron diet) with a long-term follow-up (6 years) would decrease the hepatic 8-OHdG levels and the risk of HCC development in patients with chronic HCV. Patients (34) enrolled were those who had undergone standard IFN therapy but had no sustained response. Quantitative immunohistochemistry using the KS-400 image analyzing system and electrochemical detection was used for 8-OHdG detection. With this treatment, elevated hepatic 8-OHdG levels in patients with chronic hepatitis C (8.3 +/- 4.6/10(5) dG) significantly decreased to almost normal levels (2.2 +/- 0.9/10(5) dG; P < 0.001) with concomitant improvement of hepatitis severity, including fibrosis, whereas HCV titers were unaffected. None of these patients developed HCC. Thus, long-term iron reduction therapy in patients with chronic hepatitis C may potentially lower the risk of progression to HCC.
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PMID:Normalization of elevated hepatic 8-hydroxy-2'-deoxyguanosine levels in chronic hepatitis C patients by phlebotomy and low iron diet. 1175 87

Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver and among the most common cancers worldwide. The distribution pattern of HCC shows geographical variation and its pathogenesis is multifactorial. Environmental, infectious, nutritional, metabolic, and endocrine factors contribute directly or indirectly to hepatocarcinogenesis. The synchronous occurrence of different risk factors, such as chronic viral hepatitis B and C, aflatoxin exposure, alcohol consumption or iron overload, in a single patient or patient population further increases the risk. HCC is commonly associated with chronic hepatitis and liver cirrhosis. Different genes have been implicated in the pathogenesis of HCC, and may be divided into four major groups: genes regulating DNA damage response; genes involved in cell cycle control; genes involved in growth inhibition and apoptosis, and genes responsible for cell-cell interaction and signal transduction. Hepatocarcinogenesis is mediated by loss of heterozygosity, somatic mutation, de novo methylation, and/or functional inactivation. As yet, there is no evidence for an ordered sequence of genomic events leading to hepatocarcinogenesis. The pattern of genomic alterations shows great variability, often between two different HCCs from a single patient. HCC evolves from precancerous lesions, and well-differentiated HCC further progresses to a less differentiated form. However, there is still great need for the definition of objective morphological, phenotypic and genetic markers for the progression of HCC.
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PMID:Pathology and pathogenesis of hepatocellular carcinoma. 1193 86

Hepatitis C virus (HCV) infects about 170 million people worldwide, and has been portrayed in the media as a silent killer, incorrectly implying that cirrhosis and hepatocellular carcinoma are the certain final outcomes of infection. Results of numerous population-based surveys indicate that chronic HCV infection is highly prevalent in elderly people who, in most instances, do not develop end-stage liver disease. In individuals who do progress to cirrhosis and hepatocellular carcinoma alcohol plays a fundamental part, via mechanisms that result in increased viral replication, enhanced HCV quasispecies complexity, increased liver-cell death, suppression of immune responses, and iron overload. Although overlaps are present in the histological appearance of the liver in patients with hepatitis C who do and do not drink alcohol, histology could be of some help in revealing the role of alcohol in HCV disease progression even in people who deny drinking. Interventions and high-impact, continuous public-health campaigns are needed to persuade doctors and patients infected with HCV of the importance of abstaining from alcohol if risk of progression towards cirrhosis and hepatocellular carcinoma is to be reduced.
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PMID:Does hepatitis C virus cause severe liver disease only in people who drink alcohol? 1206 96

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the world with an extremely poor prognosis. The major etiologic risk factors for HCC development include toxins (alcohol, aflatoxin B1), androgens and estrogens, hepatitis B virus (HBV) and hepatitis C virus (HCV) infection as well as various inherited metabolic disorders, such as alpha-1-antitrypsin deficiency and hemochromatosis. The molecular pathogenesis of HCC development is very complex and involves alterations in the structure or expression of several tumor suppressor genes, oncogenes and, possibly, mechanisms leading to a genetic instability due to mismatch repair deficiency or chromosomal instability and aneuploidy due to defective chromosomal segregation. Central to the molecular pathogenesis of HCCs are mutations of various genes and a genetic instability which in most cases result from chronic liver disease and the associated enhanced liver cell regeneration and mitotic activity. The prognosis of HCC patients is generally very poor. Most studies report a five year survival rate of less than 5% in symptomatic HCC patients. Furthermore, these tumors have been shown to be quite resistant to radio- or chemotherapy. Investigations of the natural history and clinical course of HCCs revealed long-term survival of patients only with small asymptomatic HCCs that could be treated surgically or by non-surgical interventions. Apart from exploring and refining new HCC treatment strategies, the implementation of existing and the development of novel measures to prevent HCC development are most important. Primary HCC prevention includes among others universal hepatitis B vaccination, antiviral therapy of patients with chronic hepatitis B or C, reduction of food contamination with aflatoxins, elimination of excessive alcohol etc. Also for some genetic diseases there is the potential for HCC prevention by identifying affected family members at risk, such as patients with precirrhotic hemochromatosis. Reduction of iron overload by phlebotomy has been shown to eliminate the progression hemochromatosis to liver cirrhosis and HCC. Preventive measures, therefore, should have a major impact on the incidence of HCCs in patients with acquired and inherited liver diseases. Further, the prevention of a local recurrence or the development of new HCC lesions in patients after successful surgical or non-surgical HCC treatment (secondary prevention) is of paramount importance and is expected to significantly improve disease-free and overall patient survival. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecular prevention are becoming increasingly part of our patient management and will eventually complement and in part replace existing diagnostic, therapeutic and preventive strategies. Overall, this should result in a reduction of the incidence of HCCs, one of the most devastating malignancies worldwide.
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PMID:Molecular targets for prevention of hepatocellular carcinoma. 1214 24

Originally identified as a gene up-regulated by iron overload in mouse liver, the HEPC gene encodes hepcidin, the first mammalian liver-specific antimicrobial peptide and potential key regulator of iron metabolism. Here we demonstrate that during rat liver development, amounts of HEPC transcripts were very low in fetal liver, strongly and transiently increased shortly after birth, and reappeared in adult liver. To gain insight into mechanisms that regulate hepatic expression of hepcidin, 5'-flanking regions of human and mouse HEPC genes were isolated and analyzed by functional and DNA binding assays. Human and mouse HEPC promoter-luciferase reporter vectors exhibited strong basal activity in hepatoma HuH-7 and mouse hepatocytes, respectively, but not in non-hepatic U-2OS cells. We found that CCAAT/enhancer-binding protein alpha (C/EBPalpha) and C/EBPbeta were respectively very potent and weak activators of both human and mouse promoters. In contrast, co-expression of hepatocyte nuclear factor 4alpha (HNF4alpha) failed to induce HEPC promoter activity. By electrophoretic mobility shift assay we demonstrated that one putative C/EBP element found in the human HEPC promoter (-250/-230) predominantly bound C/EBPalpha from rat liver nuclear extracts. Hepatic deletion of the C/EBPalpha gene resulted in reduced expression of HEPC transcripts in mouse liver. In contrast, amounts of HEPC transcripts increased in liver-specific HNF4alpha-null mice. Decrease of hepcidin mRNA in mice lacking hepatic C/EBPalpha was accompanied by iron accumulation in periportal hepatocytes. Finally, iron overload led to a significant increase of C/EBPalpha protein and HEPC transcripts in mouse liver. Taken together, these data demonstrate that C/EBPalpha is likely to be a key regulator of HEPC gene transcription and provide a novel mechanism for cross-talk between the C/EBP pathway and iron metabolism.
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PMID:C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism. Cross-talk between C/EBP pathway and iron metabolism. 1218 49

The present study was aimed at determining whether hepcidin, a recently identified peptide involved in iron metabolism, plays a role in conditions associated with both iron overload and iron deficiency. Hepcidin mRNA levels were assessed in two models of anemia, acute hemolysis provoked by phenylhydrazine and bleeding provoked by repeated phlebotomies. Hepcidin response to hypoxia was also studied, both ex vivo, in human hepatoma cells, and in vivo. Anemia and hypoxia were associated with a dramatic decrease in liver hepcidin gene expression, which may account for the increase in iron release from reticuloendothelial cells and increase in iron absorption frequently observed in these situations. A single injection of turpentine for 16 hours induced a sixfold increase in liver hepcidin mRNA levels and a twofold decrease in serum iron. The hyposideremic effect of turpentine was completely blunted in hepcidin-deficient mice, revealing hepcidin participation in anemia of inflammatory states. These modifications of hepcidin gene expression further suggest a key role for hepcidin in iron homeostasis under various pathophysiological conditions, which may support the pharmaceutical use of hepcidin agonists and antagonists in various iron homeostasis disorders.
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PMID:The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. 1237 Feb 82


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