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)

During experimental CCl4 cirrhosis, an increase of membrane-associated factor stimulating 3T3 cell proliferation in vitro was observed. This stimulator is a 150-kD protein similar to one previously described. In situ perfusion released growth stimulatory activity, suggesting a peripheral plasma membrane protein localizing on basolateral surfaces. The activity increased with increasing number of CCl4 treatments, reaching a maximum at the 14th intoxication. It was faster than the proliferation of connective tissues determined histologically. Cessation of treatment caused a decrease in activity to that of the level of untreated liver, although the number of fibroblastlike cells remained large. This data, taken with the results of experiments with enriched hepatocyte fraction, may serve as an evidence in favor of hepatocyte origin of the factor. A factor inhibiting fibroblast proliferation was measured in detergent extracts from membranes, suggesting an integral membrane protein. The activity of the inhibitory factor increased in acute liver lesions, but at the stage of maximal fibrogenesis this factor is reduced to levels comparable to those of the intact liver. Therefore it is unlikely that this factor is involved in CCl4-induced fibrogenesis at the final stages. These factors may be common controls for various hepatic lesions causing fibrosis, both in clinical and experimental modeling.
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PMID:Liver plasma membrane-associated fibroblast growth: stimulatory and inhibitory activities during experimental cirrhosis. 154 35

In the course of experimental CCl4-induced cirrhosis, an increase of the membrane-associated factor stimulating 3T3 cells' proliferation in vitro was observed. Gel filtration showed an approximate molecular mass of 150 kDa. Extraction of growth stimulatory activity by liver perfusion in situ demonstrated a peripheral plasma membrane protein localization. The activity increased with an increasing number of CCl4 treatments, reaching a maximum at the tenth intoxication, faster than the proliferation of connective tissues. Cessation of treatment caused a decrease in activity to the level of untreated liver, although the amount of fibroblast-like cells remained large, which is evidence in favour of an hepatocyte origin of the factor.
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PMID:A correlation between liver plasma membrane-associated stimulatory activity (PMASA) and experimental cirrhosis formation. 199 78

Adverse drug reactions may mimic almost any kind of liver disease. Acute hepatitis is often due to the formation of reactive metabolites in the liver. Despite several protective mechanisms (epoxide hydrolases, conjugation with glutathione), this formation may lead to predictable toxic hepatitis after hugh overdoses (e.g. paracetamol), or to idiosyncratic toxic hepatitis after therapeutic doses (e.g. isoniazid). Both genetic factors (e.g. constitutive levels of cytochrome P-450 isoenzymes, or defects in protective mechanisms) and acquired factors (e.g. malnutrition, or chronic intake of alcohol or other microsomal enzyme inducers) may explain the unique susceptibility of some patients. Formation of chemically reactive metabolites may also lead to allergic hepatitis, probably through immunization against plasma membrane protein epitopes modified by the covalent binding of the reactive metabolites. This may be the mechanism for acute hepatitis produced by many drugs (e.g. amineptine, erythromycin derivatives, halothane, imipramine, isaxonine, alpha-methyldopa, tienilic acid, etc.). Genetic defects in several protective mechanisms (e.g. epoxide hydrolase, acetylation) may explain the unique susceptibility of some patients, possibly by increasing exposure to allergenic, metabolite-altered plasma membrane protein epitopes. Like toxic idiosyncratic hepatitis, allergic hepatitis occurs in a few patients only. Unlike toxic hepatitis, allergic hepatitis is frequently associated with fever, rash or other hypersensitivity manifestations; it may be hepatocellular, mixed or cholestatic; it promptly recurs after inadvertent drug rechallenge. Lysosomal phospholipidosis occurs frequently with three antianginal drugs (diethylaminoethoxyhexestrol, amiodarone and perhexiline). These cationic, amphiphilic drugs may form phospholipid-drug complexes within lysosomes. Such complexes resist phospholipases and accumulate within enlarged lysosomes, forming myeloid figures. This phospholipidosis has little clinical importance. In a few patients, however, it is associated with alcoholic-like liver lesions leading to overt liver disease and, at times, cirrhosis. Subjects with a deficiency in a particular isoenzyme of cytochrome P-450 poorly metabolize perhexiline and are at higher risk of developing liver lesions. Prolonged, drug-induced liver-cell necrosis may also lead to subacute hepatitis, chronic hepatitis or even cirrhosis. This usually occurs when the drug administration is continued, either because the liver disease remains undetected or because its drug aetiology is overlooked. Several autoantibodies may be present.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Acute and chronic drug-induced hepatitis. 304 68

In sera of patients with fibrotic liver diseases (n = 33) classified histologically into various degrees of liver fibrosis (n = 21) and cirrhosis (n = 12) the concentrations of the basement membrane protein laminin and of its pepsinresistant fragment P1 and of the N-terminal propeptide of type III procollagen were determined. The concentrations of both proteins were related to the portal venous pressure measured in these patients. Compared with the reference population (n = 146) the concentration of laminin increases from 1.04 U/ml (normal persons) to 1.69 +/- 0.46 U/ml in liver fibrotic and 2.58 +/- 0.87 U/ml in liver cirrhotic patients. Although the concentrations of the propeptide of type III procollagen increase also there exist only weak correlations between both connective tissue proteins in serum. Laminin is correlated highly positive with the portal venous pressure in cirrhotic subjects (r = 0.9206), the extent of laminin elevation reflects closely the degree of portal hypertension. Virtually all of the fibrotic patients having a laminin concentration within the reference range had a normal portal venous pressure. The data suggest laminin as a potentially useful parameter for monitoring the portal venous pressure in cirrhotic and severe fibrotic patients.
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PMID:Serum concentrations of laminin and aminoterminal propeptide of type III procollagen in relation to the portal venous pressure of fibrotic liver diseases. 380 32

The two major constituents of basement membranes are type IV collagen and laminin. Specific radioimmunoassays are described here for two structural domains of these proteins (7-S collagen and the fragment P1, respectively) that allow the related antigens to be quantified in human serum. The serum 7-S collagen antigen was uniform in size, whereas the laminin P1 antigenicity was heterogeneous. These proteins were measured in sera from sixty-three alcoholics, divided on the basis of liver histology into four groups: normal light microscopy, fatty liver, alcoholic cirrhosis with hepatitis and inactive cirrhosis. The group with cirrhosis and hepatitis had clearly elevated values in both assays, differing significantly from the others. A few pathological results were also seen in the other groups. The increases noted in 7-S collagen concentration were larger than those in laminin P1. During follow-up of a patient with cirrhosis and hepatitis the 7-S collagen level in particular seemed to reflect the course of the disease. The elevated basement membrane protein concentrations in serum may be associated with the formation of real basement membranes in the perisinusoidal space, a process known as capillarization of the sinusoids which is found during the development of liver cirrhosis.
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PMID:Type IV collagen and laminin-related antigens in human serum in alcoholic liver disease. 392 6

Rabbits given weekly injections of two human liver-specific proteins, one a cell membrane antigen known as LSP, the other a cytoplasmic protein known as LP2, in combination with complete Freund's adjuvant (CFA) developed chronic active hepatitis. Although this lesion persisted for at least 1 year in some animals, cirrhosis did not supervene. Chronic active hepatitis was also produced by injection of the membrane protein LSP in CFA, without LP2. Unexpectedly, injection of a human skeletal muscle extract in CFA also caused chronic active hepatitis. It is possible therefore that sensitization to antigens other than liver-specific proteins may play a part in the pathogenesis of chronic active hepatitis.
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PMID:Studies on experimental chronic active hepatitis in the rabbit. I. Induction of the disease by immunization with muscle as well as liver proteins. 646 55

Sera from 14 normal control subjects, 30 patients with alcoholic liver diseases (fatty liver, n = 8; hepatitis, n = 13; liver cirrhosis, n = 9), 7 controls with chronic hepatitis B, and 8 controls with chronic hepatitis C were masured for their concentrations of antibodies against HepG2 membrane protein by a binding assay utilizing 125I-labeled protein A. When the cut-off level was set as the mean value plus 2 SD of normal control subjects, the incidence of positivity was 75%, 69.2%, and 77.8% in patients with alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis, respectively. Both the mean serum antibody values and the positive incidence were significantly higher in patients with alcoholic liver diseases than in either the normal controls or in the control patients with chronic hepatitis. Sodium dodecylsulfate polyacrylamide gel electrophoresis of 125I-labeled HepG2 membrane protein precipitated with IgG from patients with alcoholic liver diseases revealed an immunoreactive band at a molecular weight of 78,000 daltons (gp78). The antibody activity remained after immunoabsorption by human liver-specific lipoprotein (LSP) but decreased when HepG2 cells were pre-treated with trypsin or neuraminidase. Consequently, gp78 appears to be a glycoprotein distinct from LSP, and is specifically recognized by IgG from patients with alcoholic liver diseases. This assay may provide a new system to measure autoantibody to hepatocytes in alcoholic liver diseases.
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PMID:Autoantibody against a 78 kDa membrane protein of HepG2 cell in the sera of patients with alcoholic liver diseases. 896 93

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

With the global pandemic of hepatitis B and C infections, the incidence of Hepatocellular carcinoma (HCC) is rapidly increasing world wide. We identified glypican-3 (GPC3), a novel oncofetal gene over-expressed specifically in human HCC, as based on data of cDNA microarrays. As GPC3 is a GPI-anchored membrane protein and could be secreted, we attempted to detect secreted GPC3 protein in sera from HCC patients using Western blotting and ELISA. GPC3 protein was positive in sera of 40.0% (16/40) of HCC patients, and negative in sera from subjects with liver cirrhosis (LC) (0/13), chronic hepatitis (CH) (0/34), and healthy donors (0/60). All subjects were Japanese. Although 12 of 40 HCC patients were negative for both alpha-fetoprotein (AFP) and PIVKA-II well known tumor markers of HCC, four of these were GPC3-positive in the sera. We also observed vanishing GPC3 protein in the sera of three patients after the surgical treatment for HCC. On the other hand, immunohistochemical analysis revealed that HCC expressed GPC3 protein in all 14 HCC patients tested. In conclusion, GPC3, as defined in this study was shown to be a useful tumor marker for cancer-diagnosis for large numbers of patients with HCC.
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PMID:Glypican-3, overexpressed specifically in human hepatocellular carcinoma, is a novel tumor marker. 1530 Jun 2

Glypican-3 (GPC3) mRNA and protein are expressed in >80% of human hepatocellular carcinomas (HCC) but not in normal tissues except for placenta and fetal liver. The oncofetal antigen GPC3 is a glycosylphosphatidyl inositol-anchored membrane protein and may be secreted. It is a novel tumor marker for human HCC: GPC3 protein was present in sera from 40-50% of HCC patients, but was not detected in sera from patients with liver cirrhosis or chronic hepatitis, or in sera from healthy individuals. alpha-Fetoprotein (AFP) and PIVKA-II (protein induced by vitamin K absence or antagonist-II), are well known major tumor markers for HCC. Generally, AFP shows high positivity for HCC but also high false-positivity in detection assays. Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein (AFP-L3) is a recently described marker of HCC. Detection of AFP-L3 shows a much higher specificity than AFP, but a lower sensitivity. On the other hand, detection of PIVKA-II shows a lower false-positivity, but is not always sensitive enough to detect low levels secreted by small HCCs. There was no correlation between the three tumor markers, AFP, PIVKA-II, and GPC3 in terms of their presence in HCC cells. All three tumor markers showed similar positivity in patients with HCC, detecting 80% of patients with the disease. GPC3 is also a novel tumor marker for the diagnosis of human melanoma, especially in the early stages of the disease. Expression of GPC3 mRNA and protein was evident in tumor cells from >80% of patients with melanoma and melanocytic nevus, which is a common benign lesion. GPC3 protein was detected in sera from 40% (36/91) of melanoma patients, but not in sera from those with large congenital melanocytic nevus, or from healthy donors. Surprisingly, we detected serum GPC3 even in patients with stage 0, in situ melanoma. The positive detection rate of serum GPC3 at stage 0, I, and II (44.4%, 40.0%, 47.6%, respectively) was significantly higher than that of 5-S-cysteinyldopa, a well known tumor marker for melanoma (0.0%, 8.0%, and 10.0%, respectively). Interestingly, GPC3 was highly immunogenic in mice and elicited effective anti-tumor immunity with no evidence of autoimmunity. Thus, GPC3 is useful for diagnosis of HCC and melanoma and may also have a role in immunotherapy or tumor prevention. However, studies in humans are warranted.
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PMID:Usefulness of the novel oncofetal antigen glypican-3 for diagnosis of hepatocellular carcinoma and melanoma. 1580 27


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