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)

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

In hepatocellular carcinoma (HCC) iron has been implicated as a risk factor primarily in patients with hereditary haemochromatosis (HH) and cirrhosis. The wild-type HH (HFE) protein complexes with the transferrin receptor (TFR), and two HFE mutations (Cys282Tyr and His63Asp) have been found to increase the affinity of the TFR for transferrin resulting in an increased cellular uptake of iron. In previous studies we found an interaction between HFE and TFR genotypes in multiple myeloma and breast and colorectal carcinomas. In the present investigation we have studied HFE and TFR genotypes in 54 Swedish patients with HCC, using DNA from archival samples of paraffin wax blocks. The same HFE-TFR interaction as in the previously studied neoplastic disorders was found. Individuals carrying the HFE282Tyr allele (homo- and heterozygotes) in combination with homozygosity for the TFR Ser allele showed an increased risk for HCC (OR = 3.5; 95% confidence interval, CI = 1.3-9.3), which was further increased in HFE Tyr homozygotes and compound (Tyr/Asp) heterozygotes in combination with TFR 142Ser homozygosity (OR = 17.2; 95% CI = 1.8-168.9). The presence of liver cirrhosis could only be assessed in part of the patient material. In patients with verified liver cirrhosis the risk figures were substantially increased: for HFE 282 Tyr carriers in combination with TFR 142 Ser/Ser OR = 7.2; 95% CI = 2.0-25.5 and for HFE 282Tyr homozygotes and compound heterozygotes in combination with TFR 142Ser homozygosity, OR = 62.8; 95% CI = 6.1-642.5.
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PMID:Interaction between haemochromatosis and transferrin receptor genes in hepatocellular carcinoma. 1109 44

Hereditary hemochromatosis (hh, type 1 hemochromatosis) is an autosomal recessive trait characterized by hyperabsorption of dietary iron. The disease trait occurs in approximately five per thousand Caucasians of northern European descent. The causative gene, designated HFE, was isolated and characterized in 1996; most individuals with hh are homozygous for a mutation resulting in a change from cysteine to tyrosine at residue 282 of the HFE protein (C282Y). Wild-type HFE protein binds to the transferrin receptor, and by an undefined mechanism the enterocyte is "programmed" to absorb an amount of dietary iron precisely matched to the body's needs. The C282Y mutant protein is not expressed on the cell surface and does not bind to the transferrin receptor; the result is an enterocyte programmed to absorb slightly more iron than required. Most individuals with hh display a common laboratory phenotype, an elevated transferrin saturation. Iron stores in excess of normal eventually occur in most men and some women. The prevalence of organ damage due to iron overload, however, remains a controversial issue. Published estimates range from less than 1% to "nearly all." The main reason for this discrepancy has been ascertainment bias. Retrospective studies have been biased in favor of individuals with morbid complications of hh, whereas screening studies of groups such as blood donors generally include only healthy subjects. We focus here on a review of studies that have attempted to avoid ascertainment bias. If biopsy-proven hepatic fibrosis and/or cirrhosis is employed as the single criterion for disease-related morbidity, clinical penetrance of hh occurs in 4% to 25% of homozygotes. This range, although narrower than in biased studies, is still wide and requires clarification. A large-scale population-based study has been sponsored by the National Institutes of Health to address this issue. Until results become available, the pragmatic approach is to continue to screen for hemochromatosis in the primary care setting and to maintain serum ferritin values at approximately 100 micro g/L or lower with phlebotomy therapy.
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PMID:Hereditary hemochromatosis. 1238 98

Mild iron overload in chronic hepatitis C is associated with liver fibrosis, hepatitis C virus (HCV) genotype 1b infection, and an impaired response to interferon therapy. In this study we evaluated whether polymorphisms in the hemochromatosis gene HFE and the transferrin receptor gene TFR1 are associated with these typical findings. The study considered 246 HCV-infected patients and 200 blood donors as controls, in which C282Y, H63D, and S65C mutations ( HFE) and the S142G polymorphism ( TFR1) were detected. HCV genotype, serum ferritin levels, stainable intrahepatic iron, and grade of fibrosis according to the METAVIR score (F0-F4) were determined. In HCV-infected patients, heterozygosity for the C282Y mutation in HFE was significantly associated with elevated serum ferritin levels, stainable liver iron, and advanced fibrosis or cirrhosis (F2-F4). By multivariate logistic regression analysis the odds ratio for the development of advanced fibrosis or cirrhosis (F2-F4) was 2.5 for HCV-infected patients carrying a heterozygous C282Y mutation and 4.8 for HCV-infected patients with C282Y/H63D and C282Y/S65C compound heterozygosity. Heterozygosity for the C282Y mutation in HFE contributes to iron accumulation and fibrosis progression in chronic hepatitis C.
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PMID:Hemochromatosis and transferrin receptor gene polymorphisms in chronic hepatitis C: impact on iron status, liver injury and HCV genotype. 1476 Aug 28

Hereditary hemocromatosis (HH) is a genetic disease with a recessive autosomic pattern, in which inadequate iron (Fe) absorption is made by the intestinal cell. As consequence of that process, takes place a progressive accumulation of metal in different organs, predominantly in the liver. This leads to an alteration of liver structure and function: cirrhosis and hepatocarcinoma (1). The gene implied in this pathology was identified (HFE) in 1996. This codes a similar molecule to the mayor histocompatibility complex type 1(MHC-T1 like) that can modulate the transport of PE binding the transferrin receptor. This progress allows a deep understanding of the molecular and cellular biology of the homeostasis of the Fe and its alterations in the NH. The diagnosis of disease by means of a genetic test let to carry out a familiar screening and to detect asymptomatic carriers. This makes possible to begin the appropriate treatment at early stages of the disease in order to avoid its consequences and offering a better quality of life to these patients.
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PMID:[Advances in hereditary hemochromatosis]. 1470 3

Transferrin receptor 2 (TfR2) is a type 2 transmembrane protein expressed in hepatocytes that binds iron-bound transferrin (Tf). Mutations in TfR2 cause one form of hereditary hemochromatosis, a disease in which excessive absorption of dietary iron can lead to liver cirrhosis, diabetes, arthritis, and heart failure. The function of TfR2 in iron homeostasis is unknown. We have studied the regulation of TfR2 in HepG2 cells. Western blot analysis shows that TfR2 increases in a time- and dose-dependent manner after diferric Tf is added to the culture medium. In cells exposed to diferric Tf, the amount of TfR2 returns to control levels within 8 hours after the removal of diferric Tf from the medium. However, TfR2 does not increase when non-Tf-bound iron (FeNTA) or apo Tf is added to the medium. The response to diferric Tf appears to be hepatocyte specific. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis shows that TfR2 mRNA levels do not change in cells exposed to diferric Tf. Rather, the increase in TfR2 is attributed to an increase in the half-life of TfR2 protein in cells exposed to diferric Tf. Our results support a role for TfR2 in monitoring iron levels by sensing changes in the concentration of diferric Tf.
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PMID:Diferric transferrin regulates transferrin receptor 2 protein stability. 1531 90

Hepatitis C virus (HCV) is the main cause of hepatocellular carcinoma in industrialized countries. HCV-HIV-1 co-infection occurs frequently among users of illicit intravenous drugs, thereby increasing the severity of HIV disease and the evolution of chronic active hepatitis towards cirrhosis and hepatocellular carcinoma. The present work shows that THP-1 monocytoid cells are susceptible to HCV infection, of strain 1b, and that this strain can induce cellular modifications in this cell line. Infection of HCV was demonstrated by positivity for the E2 antigen within THP-1 cells and by indirect immunofluorescence; moreover, HCV-RNA was detected in supernatants of THP-1 cells from day 7 post-inoculation. Cell shape and membrane surface antigens varied upon viral infection, which is also capable of inducing oxygen radicals. In particular we underline the relevant intracellular accumulation of ferritin that paralleled an increase of cell surface expression of the transferrin receptor. Evaluation of cellular events upon HCV infection in THP-1 cells may represent a useful tool with which to identify alteration in monocytes metabolism and to study therapeutic approaches for such alterations.
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PMID:Effect of HCV infection on THP-1 monocytoid cells. 1551 25

Iron can accumulate in the liver in a variety of conditions, including congenital, systemic iron-loading conditions (hereditary hemochromatosis), conditions associated with systemic macrophage iron accumulation (transfusions, hemolytic conditions, anemia of chronic disease, etc), in some hepatitidies (hepatitis C, alcoholic liver disease, porphyria cutanea tarda), and liver-specific iron accumulation of uncertain pathogenesis in cirrhosis. The anatomic pathologist will be faced with the task of determining whether iron accumulation in the liver is significant and, if so, the nature of the disease that lead to the accumulation (ie diagnosis). The tools available to the pathologist include (most importantly) histologic examination with iron stain, quantitative iron analysis, clinical history, laboratory iron tests (serum iron and iron-binding capacity, serum ferritin) and germline genetic analysis for mutations in genes known to be associated with hemochromatosis (HFE, ferroportin, hepcidin, hemojuvelin, transferrin receptor-2). This article provides an overview of the above.
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PMID:Iron overload syndromes and the liver. 1748 50

In thalassemia, deficient globin-chain production during erythropoiesis results in anemia. Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death. Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism. To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression.
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PMID:High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. 1782 18

The incidence of acute rejection is significantly higher in hepatitis C virus (HCV) liver-transplant patients than in patients who have received a graft for other liver diseases, i.e., mainly alcoholic cirrhosis. The aim of this study was to assess T-cell function, i.e., intralymphocyte cytokine expression (IL-2 and TNF-alpha), T-cell activation [i.e., transferrin receptor (CD71) and interleukin (IL)-2 alpha-chain (CD25) expression], and T-cell proliferation using a flow-cytometry whole-blood assay in patients waiting for a liver transplantation (n=49). Our data suggest that, in mitogen-stimulated T-cells, (i) intra-lymphocyte cytokine expression is significantly higher in patients with liver disease than in healthy volunteers (n=25); (ii) the expression of T-cell activation markers is decreased in patients with liver cirrhosis compared to healthy volunteers, and (iii) the expression of T-cell activation markers and T-cell proliferation are increased in patients with HCV infection (n=15) compared to those without HCV infection (n=34), particularly compared to patients with alcoholic liver disease (n=19). Circulating CD19-positive cells count was also significantly higher in HCV-positive patients. In conclusion, in vitro, mitogen-stimulated T-cell seem to induce a higher immune response in the blood from patients waiting for a liver transplant for HCV-related liver disease than those without HCV infection, and particularly those with alcoholic liver disease.
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PMID:In vitro mitogen-stimulated T-cell from hepatitis C virus-positive liver transplantation candidates, increases T-cell activation markers and T-cell proliferation. 1850 86


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