Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hereditary hemochromatosis (HFE) is an inherited recessive disorder which causes progressive iron overload. Homozygotes for the affected gene develop symptoms of parenchymal organ damage and especially liver cirrhosis in midlife. Early diagnosis is important in order to prevent symptoms. The protein responsible for the increased iron absorption is unknown. The tight association of the disease gene with HLA-A has been known for nearly 20 years, but its precise localization remains uncertain. Linkage and linkage disequilibrium analyses in different populations have focussed on two possible locations of the gene either very close to HLA-A, or at the telomeric site of 6p in the vicinity of the D6S105 marker.
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PMID:Hunting the hemochromatosis gene: progress and problems. 783 73

HHC is the most common inherited metabolic disease among the white population worldwide, with a gene frequency of about 10% and a frequency of homozygosity of about 1 of 250. Many patients harbor a common haplotype of informative markers on chromosome 6p2l.23, suggesting a strong founder effect exerted by a common Celtic ancestor. With the advent of screening tests (serum Tf saturation, fe), many subjects with HHC are being identified before development of cirrhosis or diabetes mellitus, and early detection is important because prompt and vigorous iron reduction prevents development of such complications and assures normal life expectancy. The HIC can be estimated as accurately by specialized magnetic resonance imaging or susceptometric measurements as by chemical measurements on liver biopsy specimens. However, biopsy specimens retain value for showing fibrosis/cirrhosis and dysplastic hepatocytes, both of which increase risks of HCC development. There is growing evidence that iron in the liver plays an important role in non-HHC diseases, such as alcoholic liver disease, chronic viral hepatitis, and porphyria cutanea tarda. The complicated, manifold roles of iron in pathogenesis of the latter disorder include enhancement of production and irreversible oxidation of uroporphyrinogen, as well as formation of an inhibitor targeted specifically at hepatic uroporphyrinogen decarboxylase. The nature of the gene and gene product that are abnormal in HHC remain elusive, despite the intense efforts of several investigative groups. The search has been hampered by a dearth of informative markers in HHC patients in the relevant region of chromosome 6p. Note added in proof: The cloning of a candidate gene, the mutation of which may perhaps cause HLA-linked hemochromatosis, has just been reported (Feder et al: A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nature (Genetics) 1996;399-408). These workers identified a 250-kb region move than three megabases telomeric of the MHC that was identical in 85% of chromosomes of HHC patients. Within this region, they identified a gene related to the MHC class I family, termed HLA-H, containing two missense alterations one of which is predicted to inactivate this class of proteins. 83% of 178 patients were homozygous for this mutation (Cys 282Tyr). This variant was also found on 3.2% of control chromosomes, as would be expected for such a common disorder. Functional studies are awaited with great interest.
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PMID:An update on iron metabolism: summary of the Fifth International Conference on Disorders of Iron Metabolism. 878 49

Precise diagnosis of well-differentiated hepatocellular carcinoma (HCC) is sometimes difficult to establish. Telomerase activity was examined by telomeric-repeat-amplification protocol (TRAP) in 37 HCC nodules smaller than 3 cm in diameter, including 24 fine-needle-aspiration biopsy specimens, 22 non-tumor chronic-liver-disease tissues (9 chronic hepatitis and 13 liver cirrhosis) and 3 normal liver tissues. Telomerase activity was assayed by serially diluted samples and quantitated by using an internal telomerase assay standard (ITAS). Telomerase activity was detected in all HCC and in 11 of 22 non-tumor chronic-liver-disease tissues. Normal liver samples had undetectable telomerase activity. Cut-off level of telomerase activity for its practical usage in HCC diagnosis was tentatively set for 0.6 microg liver protein/assay at 10-cell equivalent activity of a gastric-cancer cell line, MKN-1. This level was twice the highest activity in non-tumor chronic liver disease therefore, telomerase activity in all non-tumor liver samples was below this level. The telomerase-positive incidence exceeding this cut-off level was 73% (11/15) in well-differentiated HCC, 94% (16/17) in moderately differentiated HCC and 100% (5/5) in poorly differentiated HCC. Well-differentiated HCC showed low positivity by other diagnostic markers. 21% by AFP, 0% by PIVKA-II and 13% by angiography. The detection of telomerase activity may thus be a useful additional tool for precise and early diagnosis of small differentiated HCC, even when diagnosis is inconclusive by conventional techniques.
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PMID:Significance of telomerase activity in the diagnosis of small differentiated hepatocellular carcinoma. 913 46

Telomerase is highly activated in human immortal cell lines and tumor tissues, whereas it is not activated in primary cell strains and many tumor-adjacent tissues. It is suggested that telomerase activation is one of the critical steps in malignant transformation. In the present study, the telomerase activity was investigated in hepatocellular carcinoma tissues and non-tumor liver tissues from Korean patients with chronic hepatitis and cirrhosis. Eighty two liver tissues (24 chronic hepatitis specimens, 34 cirrhosis specimens, and 24 hepatocellular carcinomas) were obtained from 23 chronic viral hepatitis patients, 19 cirrhosis patients (including 7 liver transplants), and 24 patients with hepatocellular carcinoma, of which the surrounding non-tumor liver tissues were available in 16 patients (1 chronic hepatitis and 15 cirrhosis). As negative controls, 3 normal liver tissues were included. Protein from liver specimens was purified by a detergent lysis method as described elsewhere, and telomerase activity was measured in 2 diluents of each sample (1:1 and 1:100) by a telomeric repeat amplification protocol (TRAP). Telomerase was strongly activated in 79% (19/24) of the hepatocellular carcinomas, while weakly in 8% (2/24) of the chronic hepatitis tissues and in 24% (8/34) of the cirrhosis tissues. All of 3 normal control livers showed no telomerase activation. No relationship could be observed between the enhancement of telomerase activity and tumor nature. None of the chronic heaptitis or cirrhosis patients with mild telomerase activation in the liver have developed hepatocellular carcinoma for at least 2 years of follow-up period. These results suggest that the strong enhancement of telomerase activity may be a critical part of hepatocarcinogenesis, although the exact mechanism of such high activation in hepatocellular carcinoma is not clear. In addition, further study will be necessary to clarify the reason why no telomerase activity detectable by a conventional TRAP can be seen in some hepatocellular carcinoma.
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PMID:Telomerase is strongly activated in hepatocellular carcinoma but not in chronic hepatitis and cirrhosis. 987 20

Telomerase is a specialized type of reverse transcriptase that catalyzes the synthesis and extension of telomeric DNA. High levels of telomerase activity have been detected in most hepatocellular carcinoma (HCC) tissues; very weak telomerase activity is, however, detected in approximately half of nontumorous chronic liver disease tissues. The purpose of this study was to investigate the possible source of this weak telomerase activity in these tissues using quantitative competitive reverse transcription (RT)-polymerase chain reaction (PCR) and in situ RT-PCR. Competitive RT-PCR indicated that the relative amount of human telomerase RNA (hTR) was significantly higher in chronic hepatitis or liver cirrhosis compared with the normal liver (p < 0.005), and in HCC compared with the normal liver (p < 0.001) and with chronic hepatitis or liver cirrhosis (p < 0.0001). In the normal liver tissue, hTR was detected by in situ RT-PCR in occasional sinusoidal cells and nuclei of occasional hepatocytes. In tumor-free liver or tumor-bearing liver, hTR was detected in sinusoidal cells, infiltrating lymphocytes, occasional proliferative bile ductal epithelial cells, and the nuclei of occasional hepatocytes. In HCC, hTR was detected in nuclei of all HCC cells as an intense signal and in sinusoidal cells. These results indicate that the amount of hTR increases in the nuclei of hepatocytes during hepatocarcinogenesis, and that the cells associated with the weak telomerase activity in approximately half of the nontumorous chronic liver lesions are mainly migrating lymphocytes and sinusoidal cells.
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PMID:Quantitative analysis and in situ localization of human telomerase RNA in chronic liver disease and hepatocellular carcinoma. 995 7

Hepatocellular carcinoma (HCC) is a common malignancy worldwide and highly associated with chronic virus-B or -C infection and cirrhosis. Molecular studies have shown high frequency of loss of heterozygosity (LOH) in some specific chromosome regions, but LOH on chromosome 9 in HCC has not been thoroughly investigated. In our investigation of chromosome 9 with 19 polymerase-chain-reaction (PCR)-based polymorphic microsatellite markers, 30 of 48 HCC tissue samples (63%) had LOH, and a distinct common deletion region and a region of loss were identified. The first region was located at the 9p21 region and the minimal deletion region was located between loci D9S1747 and D9S1748. This is a region of approximately 200 kb which includes the p16 tumor-suppressor gene. A region of loss was located on 9p13 to 9q33. The putative tumor-suppressor gene for nevoid-basal-cell-carcinoma syndrome (NBCCS) at 9q22.3 resides within this region. In addition to LOH, 4 HCC cases showed possible homozygous deletions at 9p21 with markers D9S1748, D9S1752 and D9S171 by multiplex PCR analysis. In 3 cases, the minimal region of possible homozygous deletion was approximately 300 kb and was defined between markers D9S1747 and D9S1752. Since this deletion region includes both the p15 and the p16 tumor-suppressor genes, these genes were possibly inactivated by homozygous deletion in HCC. In addition, a second region of possible homozygous deletion was present on the centromeric side of 9p21. However, these changes are not associated with age, gender, size or tumor-cell differentiation. Our data also suggest that inactivation of the p16 and the p15 genes and the possibility of other unknown tumor-suppressor genes located on these defined deleted regions of chromosome 9 may be involved in the pathogenesis of HCC.
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PMID:Frequent allelic loss on chromosome 9 in hepatocellular carcinoma. 1020 42

Hemochromatosis is a recessive disorder of iron metabolism characterized by progressive iron loading of parenchymal organs, which accounts for clinical complications such as cirrhosis, diabetes mellitus, cardiopathy, endocrine dysfunctions and arthropathy. Clinical complications, which usually develop after the third or fourth decade of life, can be fatal but may be prevented by phlebotomy if iron excess is detected at a very early stage. The hemochromatosis gene (HFE), located 4.5 megabases telomeric to the HLA-A locus, encodes an HLA class I like protein and two missense mutations, C282Y and H63D in complete disequilibrium have been identified within this gene. Due to its high frequency in the general population, the involvement of H63D in the pathogenesis of the disease remains controversial, and it might correspond to a minor mutation. Conversely, the C282Y mutation is tightly linked to the disease, as it accounts for 80 to 100% of the hemochromatosis cases in Northern Europe. The lower frequency observed, in the patients, in Italy and South of France led to imagine either the implication of other mutations or of other genes. The C282Y mutation is absent in Asia and Africa and is present in the general population with a decreasing gradient of frequency from Northern to Southern Europe. The prevalence of the disease was usually estimated to be 3% but the observed frequency of the C282Y homozygotes is 5% in our breton population raising the question of the penetrance of the disease, and consequently the use of the genotypic test for its systematic screening. As HFE encodes a membrane protein similar to HLA class I protein, its contribution to iron overload is not obvious. The normal protein is predicted to to be expressed at the cell surface in association with beta 2-microglobulin, a localization for which C282Y is critical as it disrupts this association. This protein has also been shown to form a stable complex with the transferrin receptor leading to a decreased affinity for transferrin. A better knowledge of its function will help to decipher iron and different metal-ions metabolism. Although the exact role of the HFE protein is unknown, the genotypic test allows the clinicians to ascertain their diagnosis and genetic counselling.
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PMID:[Molecular genetics of hemochromatosis]. 1052 Apr 11

Telomerase enzymatic activity has been detected in most human malignant tumours including hepatocellular carcinoma. In order to assess the cellular source, the topographic distribution, and the chronology of telomerase re-expression during human liver carcinogenesis, an in situ technique derived from the standard TRAP (telomeric repeat amplification protocol) assay was set up that allowed the detection of telomerase enzyme activity at the cellular level on frozen liver tissue sections. In situ TRAP (ISTRAP) was performed on 27 hepatocellular carcinomas (HCCs) and 57 non-tumour livers, including normal liver without HCC, liver samples adjacent to tumour with and without hepatic cirrhosis, and biopsies of chronic hepatitis. In HCC, telomerase was detected in the nuclei of liver tumour cells in 23/27 cases (85%), with a heterogeneous distribution within the tumour. This signal was also detected in clusters of hepatocytes in 16/26 (61%) samples of liver adjacent to HCC, in 10/23 (43%) cases of chronic viral hepatitis without adjacent HCC, and in scattered nuclei of 2/8 histologically normal livers. Comparison of the results obtained with ISTRAP and standard TRAP assays on tissue extracts suggests a gain in sensitivity with the in situ technique. This study confirms that telomerase is expressed in most HCCs and suggests that focal telomerase reactivation is an early event during human liver carcinogenesis. ISTRAP is a sensitive technique that allows the study of telomerase expression in the morphological context.
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PMID:In situ detection of telomerase enzymatic activity in human hepatocellular carcinogenesis. 1152 54

Differentiation between well-differentiated hepatocellular carcinoma (HCC) and nonmalignant lesions with increased cellular proliferation may be difficult in needle biopsies. Based on recurrent chromosome aberrations known for HCC, we developed a nonfluorescent in situ hybridization technique that allows combination with morphological analysis in bright-field microscopy. Fourteen biopsies of HCC and 31 samples of regenerative nodules (n = 10), chronic hepatitis (n = 10), fibrosis or cirrhosis of unknown origin (n = 5), focal nodular hyperplasia (n = 2), primary biliary cirrhosis (n = 2), steatosis (n = 1), and adenomatous hyperplasia (n = 1) were analyzed with probes specific for the centromeric regions of chromosomes 1, 6, 7, and 8. After microwave pretreatment and in situ hybridization, signals were detected using a tyramine-based system and AEC as substrate. Evaluation of signals was done by conventional bright-field microscopy. Using this approach, aberrant counts were seen for at least one chromosome in 12/14 cases of HCC. In contrast, none of the nonmalignant lesions revealed aberrant counts for any of the chromosomes analyzed. In conclusion, this new combination of in situ hybridization and tyramine amplification allows fast and reliable evaluation of chromosome aberrations in a histomorphological context similar to paraffin immunohistochemistry. Registration of imbalances contributes to a reliable differentiation between malignant and nonmalignant lesions of the liver.
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PMID:Detection of chromosomal aberrations in well-differentiated hepatocellular carcinoma by bright-field in situ hybridization. 1195 Sep 23

We previously described frequent 6q14 deletion and polysomy 6 in 25 hepatocellular carcinomas (HCC) by fluorescence in situ hybridization (FISH). A more favorable prognosis was noted in patients with 6q14 deletions. To confirm this clinical association, a two-colored FISH study was carried out on 77 HCC using a combination of a yeast artificial chromosome probe (813_E_12) of the 6q14 region and a chromosome 6 centromeric probe (D6Z1) for simultaneous evaluation of the copy number change and chromosome arm deletion. The 77 HCC were divided into four groups according to the copy number of the centromeric signal: 26 with HCC (33.7%) were disomy for chromosome 6, 9 with HCC (11.7%) were trisomy, 29 with HCC (37.6%) were tetrasomy, and 13 with HCC (17%) were classified as hypersomy with presence of one major clone (>7%) of pentasomy or hexasomy of chromosome 6. Allelic loss at 6q14 was found in 40 with HCC (52%). The distribution of sex, age, stage, tumor size, tumor grade, and viral markers in each group showed no significant differences. An association with cirrhosis, however, was significantly lower in the hypersomy group (P = 0.001). The tetrasomy group had the best survival. An interaction between 6q14 deletion and numerical change of chromosome 6 on patients' survival were also noted. For patients with 6q14 deletion, both disomy and tetrasomy groups had significantly better survival rates than trisomy and hypersomy groups. In contrast, no differences in survival rates could be observed among these four groups for patients without the 6q14 deletion. The association with more favorable prognosis shown in this study indicates that tetrasomy 6 and 6q14 deletion may play an important role in the tumorigenesis of hepatocellular carcinoma and is worthy of further investigation.
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PMID:Tetrasomy 6 and 6q14 deletion are associated with better survival in hepatocellular carcinomas. a fluorescence in situ hybridization study of 77 cases. 1281 Feb 52


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