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)

Several clinical observations suggest that hepatocellular carcinoma (HCC or "hepatoma") may be a hormone-dependent tumour; the apparent relation to anabolic steroids and oral contraceptive preparations, and the striking male predominance particularly among patients with cirrhosis. In many animal models thyroid hormones, prolactin and testosterone stimulate tumour growth, and the latter may enhance the progression of chemically-induced hyperplastic nodules to frank malignancy. In animals and humans, both oestrogen and androgen receptors have been reported in normal and malignant liver tissue though some of the evidence is conflicting and the amounts detected vary widely. From a therapeutic standpoint, we failed to show any advantage from the addition of tamoxifen to adriamycin, in a controlled trial although other workers have, more recently, reported prolonged survival using tamoxifen alone. About 20% of HCC patients receiving the antiandrogen cyproterone acetate showed a clinical response.
J Steroid Biochem Mol Biol 1990 Dec 20
PMID:Growth factors, endocrine aspects and hormonal treatment in hepatocellular carcinoma--an overview. 217 61

Homozygosity for alpha 1-antitrypsin deficiency, usually of the genotype PIZZ, is one of the more common single gene defects in infants of European origin, occurring in about 1 in 2000 to 1 in 7000 of the newborn population. About 17% of such infants present with neonatal hepatitis and a small number with intracranial haemorrhage thought to be caused by vitamin K deficiency associated with cholestasis. At least 3% of PIZZ infants will die of cirrhosis in later childhood unless successfully treated by liver transplant. The pathogenesis of the liver disease is not understood and this is unsatisfactory both for treatment and for genetic counselling. The locus coding for alpha 1-antitrypsin (alpha 1AT) is designated PI for proteinase inhibitor. Careful study of the genotypes at this locus in neonatal disease shows that the only certain association is with the homozygous PIZZ genotype. The mutation results in a normal rate of synthesis of a polypeptide that becomes entrapped in the endoplasmic reticulum of the hepatocyte. Some other factor (or factors), as yet unidentified, determines whether severe liver damage results. The low level of alpha 1AT in the plasma seems unlikely to be the primary cause of damage but may play a secondary role. There is some evidence that the other factor(s) may be familial since in one study, though not in all, a high correlation for severity of liver disease was found between PIZZ siblings. The heterogeneity of the clinical course does not result from heterogeneity of PIZ alleles and there is no evidence that it is determined by variation in other related genes on chromosome 14. Only two possible clues have emerged so far. There is some evidence of a protective effect of breast-feeding, and a recent study has found the HLA class II DR3 antigen to be more common than expected in children with alpha 1-antitrypsin deficiency and liver disease. Accumulation of alpha 1AT protein in the hepatocytes may predispose them to some unidentified alteration of the immune response. It is possible that lack of antiprotease activity in the plasma might exacerbate the original damage, so the possibility of useful therapy with alpha 1AT cannot be ruled out entirely. At present, there is no valid way of predicting the severity of disease in a PIZZ child; hence, it is common for parents of a severely affected child to wish to terminate any future PIZZ pregnancy. The most direct method to diagnose the PIZZ genotype of a chorion villus sample is by allele-specific hybridization or sequencing of amplified DNA.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Biol Med 1990 Apr
PMID:Genetics of alpha 1-antitrypsin deficiency in relation to neonatal liver disease. 218 61

Hepatic production of type I collagen is markedly increased in liver cirrhosis. Previous studies using primary liver cell cultures have demonstrated that hepatocytes, lipocytes and endothelial cells are all capable of producing collagen. In this study in situ hybridization and hepatic cell sorting have been used to identify which cells are expressing the type I collagen gene, alpha 1(I), in normal rat liver. Northern blotting of mRNAs from purified hepatic cell populations demonstrated that both hepatocytes and several types of non-parenchymal cells express the collagen alpha 1(I) gene. Calculations based on cell numbers, yields of mRNA, and cellular mRNA concentration demonstrated that the majority of collagen alpha 1(I) mRNA originates from the hepatocytes in the normal liver. Localization of a collagen alpha 1(I) mRNA by in situ hybridization confirmed that both hepatocytes and non-parenchymal cells express this gene. Furthermore, collagen alpha 1(I) gene expression in hepatocytes was obtained by transfecting a reporter gene driven by the collagen alpha (I) 5' regulatory segment in primary liver cell cultures. Future experiments will further characterize the regulation of collagen alpha 1(I) gene expression in the liver.
Mol Biol Med 1990 Apr
PMID:Expression of collagen genes in the liver. 234 27

DNA of individual cirrhotic nodules (CN) and hepatocellular carcinoma nodules (HCN) of three hepatitis B surface antigen positive autopsy cases with macronodular cirrhosis were analyzed by Southern blot and slot blot hybridization with a hepatitis B virus (HBV) DNA probe. Evidence of episomal or replicating viral DNA, viral DNA integration at the same cellular DNA site in many cells (clonal integration) and viral integration in different cellular DNA sites in many different cells (non-clonal integration) was found in different cirrhotic nodules of the same liver, indicating heterogeneity in the state of HBV in different cells and in different cirrhotic nodules within each infected liver. Episomal or replicating viral DNA forms were found in all cirrhotic nodules of one liver, in less than 10% of examined nodules of a second liver and in none of the third. Evidence of clonal viral integration was found in CN of all three livers and non-clonal integration in CN of the latter two. Cirrhotic nodules with apparent different integrations in many different cells (non-clonal integration) outnumbered those with the same integration site in many cells (clonal integration), and many cirrhotic nodules in those two livers had no detectable viral DNA. Cirrhotic nodules with a viral integration in the same cellular DNA site in many cells would appear to have been formed by clonal expansion of an original cell containing the viral integration, and cirrhotic nodules with different integrations in many different cells (non-clonal integration) may have been formed by recruitment of many different cells with different viral integrations or by clonal expansion of cells without HBV integrations and subsequent viral integrations occurring integration. In one liver, three different hepatocellular carcinoma nodules appeared to represent metastatic lesions because the clonal pattern of HBV integration was identical in each, and in another liver different HCN appeared to be of different clonal origin, i.e. to have arisen from different cells, because multiple viral integrations (i.e. multiple individual restriction fragments with HBV sequences) were each different in different HCN of that liver.
Mol Biol Med 1989 Oct
PMID:State of hepatitis B viral genomes in cirrhotic and hepatocellular carcinoma nodules. 256 May 24

Hepatic cirrhosis was induced in guinea pigs by ligation of the common bile duct and innervation of the liver was studied by fluorescence histochemistry (glyoxylic acid method), acetylcholinesterase (AChE) neurohistochemistry (modified Karnovsky and Roots method), and transmission electron microscopy. In control animals the adrenergic terminals showed connections with endothelial cells, hepatocytes and fat-storing cells, but no cholinergic terminals were evident. Cirrhosis was present 6 weeks after the bile duct ligation and marked fibrosis, accompanied by bile duct proliferation, was evident in the portal areas. Numerous AChE-positive nerve fibers traversed the collagenous bundles in the fibrotic areas, and cholinergic terminals formed close contacts with fibroblasts. Each axon terminal was found to contain numerous small coreless vesicles and AChE-reaction products were confirmed in the space between a nerve terminal and a fibroblast. In contrast, fluorescence adrenergic nerve fibers and their terminals remained unchanged. This study demonstrates that parasympathetic cholinergic innervation participates in some stages in the development of hepatic cirrhosis.
Virchows Arch B Cell Pathol Incl Mol Pathol 1989
PMID:Ultrastructure of cholinergic innervation in the cirrhotic liver in guinea pigs. Neurohistochemical and ultrastructural study. 256 52

To investigate insulin action in muscle and adipose tissue in hepatic cirrhosis, a recently described animal model was used. Dimethylnitrosamine administration induced histologically proven cirrhosis. Contrary to expectation, muscle strips from cirrhotic rats displayed increased insulin sensitivity both with respect to glycogen synthesis (ED50 0.11 +/- 0.01 vs 0.23 +/- 0.04 nmol/l; p less than 0.03) and glucose oxidation (ED50 0.36 +/- 0.07 vs 0.97 +/- 12 nmol/l; p less than 0.02). As the cirrhotic rats had failed to gain weight normally, it is postulated that a state of relative starvation accounted for the enhanced insulin sensitivity. These data demonstrate that the severe insulin resistance characteristically associated with cirrhosis is reversible. Control of nutritional state in future studies upon DMNA induced cirrhosis should permit detailed examination of the cellular mechanisms controlling insulin sensitivity in hepatic cirrhosis.
Mol Cell Biochem 1989 Aug 15
PMID:Insulin sensitivity in experimental cirrhosis. 267 70

Alpha-1-antitrypsin (AAT) is the predominant protease inhibitor in human sera. The major physiological role of this inhibitor is to protect elastin fibers in the alveolar structure of the lung from excessive degradation by neutrophil elastase. AAT is synthesized predominantly by hepatocytes, although the AAT gene is expressed to a small degree in the epithelial cells of various tissues. Recent studies have shown that the enhanced liver-specific expression of the AAT gene is controlled by the binding of hepatic nuclear proteins to specific DNA sequences upstream from the structural gene. A variety of mutations within the AAT gene have been identified that result in a partial deficiency or total absence of the inhibitor in sera. Inheritance of a particular combination of these alleles can result in a predisposition towards the development of destructive lung disease. Interestingly, the most common AAT deficiency variant, designated PiZ, causes the mutant protein to accumulate as an insoluble aggregate within the lumen of the hepatic rough endoplasmic reticulum, which is an etiological agent for the development of liver disease. Overall, investigation into the genetic control of AAT has led to an increased understanding of the factors that control hepatic gene expression, as well as mechanisms involved in the pathophysiology of emphysema and liver cirrhosis.
Mol Biol Med 1989 Apr
PMID:Genetic control of human alpha-1-antitrypsin. 269 88

The pathogenesis of hepatitis B virus (HBV) infection is variable and can result in the development of acute and chronic hepatitis, cirrhosis and primary hepatocellular carcinoma (PHC). In this review, the relationship between the patterns of virus gene expression, host immunological responses, and liver pathology in chronic infection will be discussed. Available evidence suggests that the virus is not directly cytopathic to liver cells and that the pathologic sequelae to infection are mediated by both humoral and cellular immune responses against one or more virus gene products. In addition, chronic liver disease might also be mediated by autoaggressive immune responses that may be stimulated by the direct action of virus gene products upon host gene expression, by the lysis of infected hepatocytes by virus specific host immune responses, or by both. Given the complex and variable outcome of HBV infection, the lack of adequate treatment for chronic liver disease, and the fact that long-term infection dramatically increases the risk of developing PHC, the future provides challenges for devising new models to study, understand and successfully manipulate the pathogenesis of chronic HBV infection.
Mol Biol Med 1989 Oct
PMID:Hepatitis B virus gene products as immunological targets in chronic infection. 269 58

Ammonia clearance, portal blood ammonia, and amino acid concentrations were studied during induction of cirrhosis by carbon tetrachloride in rats. Exposure to CCl4 vapors twice weekly for 7-16 weeks doubled orotic acid excretion. If exposure was discontinued for 7 days, the orotic acid excretion decreased despite the presence of cirrhosis proven histologically. Replacement of dietary casein with soybean protein eliminated the CCl4-induced orotic aciduria in growing rats but not in adults. Supplementation of casein with 1.5% arginine did not prevent CCl4-induced orotic aciduria. [14C]Orotate uptake into RNA and DNA of liver was not impaired. Perfusion of livers of cirrhotic animals with ammonia concentrations between 0.2 and 3.0 mM revealed no significant decreases in urea synthesis rates due to cirrhosis and no increase in the tendency to make orotic acid at a given ammonia concentration. However, ammonia uptake by cirrhotic livers was significantly reduced, resulting in higher ammonia concentrations in the effluent when there was moderate-to-severe cirrhosis. Portal blood samples taken from rats exposed to CCl4 had higher ammonia concentrations as cirrhosis worsened. The results lend support to the "intact hepatocyte" hypothesis of cirrhosis which attributes metabolic abnormalities to intrahepatic shunts.
Exp Mol Pathol 1989 Jun
PMID:Orotic acid overproduction in experimental cirrhosis of rats. 272 54

Collagenolytic activity has been measured in insoluble sediments of normal and CCl4-induced cirrhotic rat liver. Two techniques were used: in one assay, the insoluble liver sediments were incubated with a radioactively labeled exogenous substrate; in the other assay, the endogenous collagen present in the insoluble liver sediments served as the substrate. Animals in various stages of development of CCl4-induced cirrhosis were used. Results suggest that in rat liver cirrhosis collagenolytic activity assayed with both techniques appears to increase when expressed as weight of collagen degraded in 24 hr. On the other hand, when the data are corrected for the variable amounts of collagen present in the insoluble liver sediments and expressed as weight of collagen degraded in 24 hr per unit weight of total collagen incubated, collagenolytic activity is shown to be significantly decreased below the normal level and to remain so for prolonged periods.
Exp Mol Pathol 1987 Dec
PMID:Collagenolytic activity in experimental cirrhosis of the liver. 282 36


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