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)

To examine the clinical significance of serum collagenase activity in chronic liver disease, serum collagenase activity was determined in 50 patients with chronic liver disease and in 24 healthy controls. Collagenase activity was measured after reactivation by denaturing and dissociating the inhibitors with potassium thiocyanate and aminophenylmercuric acetate. In patients with chronic persistent hepatitis, serum collagenase activity was 37% lower than controls, 50% lower in those with chronic active hepatitis, 66% lower in those with cirrhosis and 68% lower in those with hepatocellular carcinoma. Serum collagenase activity was significantly and inversely correlated with serum levels of the aminoterminal propeptide of type III procollagen and type IV collagen 7S domain, indicating that serum collagenase activity decreased as liver active fibrogenesis and/or fibrosis occurred. In contrast, serum levels of the metalloproteinase inhibitor was 30% higher than controls in patients with chronic active hepatitis, 50% higher in those with cirrhosis and 80% higher in those with hepatocellular carcinoma and was inversely correlated with serum collagenase activity. These results suggest that in this assay condition serum collagenase activity is influenced by the metallo-proteinase tissue inhibitor and thus does not reflect the amount of collagenase in the fibrotic liver.
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PMID:Serum collagenase activity in patients with chronic liver disease. 822 26

The treatment of alcoholic liver disease at present consists of abstinence from alcohol, bed rest, and dietary intake or administration of adequate amounts of calories and protein. Besides corticosteroids, which have been shown to improve hospital survival in severely ill patients with alcoholic hepatitis and liver transplantation in advanced cirrhosis, no successful specific therapy is available for alcoholic liver disease. Potential new therapeutic approaches include: (1) Treatment with specific dietary supplements such as polyunsaturated lecithin, which in baboons prevented the progression of the early stages of pericentral and interstitial fibrosis to septal fibrosis and cirrhosis; (2) antagonists to cytokines or antibodies to cytokine receptors for cytokines that have been shown to enhance hepatocellular necrosis or fibrosis; (3) substances that block pathways of oxygen radical formation or increase their metabolism or binding to form nonharmful compounds; (4) inhibition of collagen synthesis by proline analogues that increase intracellular collagen degradation or increase in collagen degradation by stimulation of collagenase or by insertion of exogenous DNA encoding amino or carboxyterminal peptides of procollagen into hepatocytes; and (5) stimulation of hepatic regeneration and recovery from alcohol-inducer liver injury.
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PMID:Treatment of alcoholic liver disease. 833 5

The matrix metalloproteinases (MMPs) gene family includes MMP-1 (interstitial collagenase), MMP-2 (72 kD type IV collagenase/gelatinase), MMP-3 (stromelysin/transin), MMP-7 (putative MMP; pump-1), MMP-8 (granulocyte collagenase) and MMP-9 (92 kD type IV collagenase/gelatinase). This gene family has the common characteristics in the gene structure as follows: All of MMPs have the active site metal ion-binding domain. All six enzymes are activated with the concomitant removal of N-terminal segment of the latent enzyme. The removed segment contains an unpaired cystein residue within the conserved amino acid sequence PRCGVPDV, located immediately adjacent to the proenzyme cleavage site. The authors showed the gene expression of MMP-1 in the process of hepatic fibrosis. The remarkable expression was noted on fibroblasts and macrophages within the newly-formed fibrous bands with lots of infiltrated lymphocytes. Liver cirrhosis did not showed the positive dots of MMP-1 mRNA. On the other hands, the expression of TIMP reported by Takahara et al., revealed the high level of expression in the advanced fibrosis.
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PMID:[Gene expression of MMPs and TIMPs in the process of hepatic fibrosis]. 846 57

Increased acetaldehyde levels have been found in non-alcoholic liver diseases and an acetaldehyde-collagen adduct has been reported in rats with CCl4-induced cirrhosis. In cytosol and microsomes of rats with cirrhosis produced by N-nitrosodimethylamine, a similar acetaldehyde-protein adduct of approximately 200 kD was recognized by rabbit IgG raised against either an in vitro produced hemocyanin-acetaldehyde adduct or an in vivo occurring P4502E1-acetaldehyde adduct isolated from alcohol-fed rats, as well as by anti-rat collagen (I) IgG. Its immune complexes contained 3 proteins that reacted with the anti-collagen IgG and were digested by collagenase: 2 proteins with molecular weights similar to procollagens alpha 1 and alpha 2, and a beta 1,2(I)-like protein which was readily produced by in vitro modification of cytosol with acetaldehyde.
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PMID:Acetaldehyde-collagen adducts in N-nitrosodimethylamine-induced liver cirrhosis in rats. 846 25

Some recent proposals in management of alcoholic liver disease are discussed focusing on early diagnosis and treatment of alcohol abuse itself, alcoholic hepatitis early mortality, clinical meaning of nutritional therapy, serological approach and treatment of hepatic fibrosis, and problems in liver transplantation for end stage alcoholic liver cirrhosis. CAGE or similar systematized brief questionnaires, and desialylated transferrin/total transferrin ratio as serological marker, seems to be interesting contributions to "hidden" alcohol abuse diagnosis and abstinence control while psycho-social support and voluntary incorporation to self-aid groups are the best weapons to reach persistent abstinence. Corticosteroids seems to improve survival in a selected group of patients with severe alcoholic hepatitis, specially in those presenting encephalopathy but free of GI bleeding, decompensated diabetes, active infections, pancreatitis, and other contraindications or adverse effects of these drugs. Relationship between direct toxicity and nutritional deficiencies in pathogenesis of alcoholic liver injury are not clear enough, but malnutrition is generally present in patients requiring hospitalization, and related to clinical severity; oral, enteral or parenteral nutritional supplementation in this order of preference according to patients condition, associated or not with steroid anabolics, are useful in cases with moderate to severe alcoholic hepatitis or decompensated cirrhosis to eliminate the catabolic state, reaching a better nitrogen balance and liver function tests, without special adverse effects. A special role on liver regeneration is discussed. Antioxidants and supernutrients are special "modern" aspects of nutritional therapy in alcoholic liver disease generally related to the MEOS activation in chronic alcoholism, the excessive production of free radicals, and the depletion of glutathione, membrane phospholipids (specially phosphatidycholine), and vitamin A, E, and C. Natural supplements as soybean polyunsaturated lecithin, with high concentration of phosphatidycholine, or oral supplementation with natural metabolic products depleted from the liver of chronic heavy drinkers, such SAMe, have an interesting rationale based on experimental and clinical findings besides availability and costs. Carotenoids and tocopherols supplementation seems to be an useful tool, but are limited in the case of vitamin A because its special toxicity in chronic alcoholism. Serological markers of metabolism of liver connective tissue are clearly involved in fibrogenesis process and other inflammatory connected events; standardization of laboratory methods surely will result in new possibilities of non-invasive valuation of liver injury, evolution and therapeutic response; special histological damage such as sinusoidal "cappilarization" (type i.v. collagen and laminin), endothelial sinusoidal cell function (seric hyaluronate), or collagenase activity (TIMP-1 or tissue inhibitor of metalloproteinases-1) seems to be valuable by these new technologies.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[New suggestions for the management of alcoholic liver diseases]. 852 63

We evaluated the mechanism of increased serum concentrations of the 7S fragment of the N-terminal domain of type IV collagen (7S collagen) in chronic liver disease. We measured the concentrations of hepatic-free and deposited 7S collagens after extraction with Tris-HCl buffer and bacterial collagenase, then compared them with the serum levels in 8 normal controls and 48 patients with chronic liver disease. The hepatic 7S collagen levels extracted with Tris-HCl buffer and collagenase accounted for 7% and 93%, respectively, of the total 7S collagen levels in normal controls. Both hepatic 7S collagen levels as well as serum levels increased in accordance with the progress of liver disease. Serum levels of 7S collagen showed a closer correlation with the hepatic 7S collagen levels extracted with Tris-HCl buffer (r = .822), compared with those extracted with collagenase (r = .382). On the other hand, the histological degrees of liver fibrosis were highly correlated with the hepatic collagenase-extracted 7S collagen levels (r = .822), compared with serum and the hepatic Tris-HCl buffer-extracted levels (r = .478 and r = .537, respectively). Although there was no difference in serum and hepatic 7S collagen levels between B and C viral patients, the serum and hepatic Tris-HCl buffer-extracted 7S collagen levels were higher in patients with alcoholic cirrhosis than patients with viral cirrhosis. However, the hepatic collagenase-extracted levels were similar in both groups. Gel filtration demonstrated that the serum and hepatic Tris-HCl buffer-extracted 7S collagens were mainly eluted in the macromolecular 7S collagen-reactive fraction in cirrhosis, whereas the hepatic collagenase-extracted 7S collagen was eluted in the authentic 7S collagen-reactive fraction. The results suggest that serum 7S collagen levels are not a particularly reliable measure of hepatic fibrosis but reflect the enhanced metabolism, especially synthesis of type IV collagen in the liver.
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PMID:Relationship between serum and hepatic 7S fragments of type IV collagen in chronic liver disease. 862 Nov 48

Heptic fibrosis/cirrhosis is a common hepatic disease characterized by the hyper-accumulation of connective tissue components, and hepatic necrosis. Chronic alcohol ingestion, viral infection, and metabolic disorders are contributing factors and there has been no effective treatment. Hepatocyte growth factor (HGF), originally identified as a potent mitogen for mature hepatocytes, is a long-sought hepatotrophic factor for liver regeneration. Administration of human recombinant HGF into rats with hepatic fibrosis/cirrhosis caused by dimethylnitrosamine (DMN) elicited mitogenic action for hepatocytes, stimulated hepatic collagenase activity, and prevented the onset and progression of hepatic fibrosis/cirrhosis. Accumulation of fibrous tissue components in the liver due to DMN-treatment were markedly decreased in HGF-injected rats. Moreover, HGF completely abrogated death caused by severe hepatic cirrhosis and dysfunction. We postulate that HGF may prove to be an effective treatment for human liver fibrosis/cirrhosis and for chronic hepatic failure.
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PMID:Hepatocyte growth factor suppresses the onset of liver cirrhosis and abrogates lethal hepatic dysfunction in rats. 869 Jul 30

In order to elucidate collagen metabolism in hepatocellular carcinoma (HCC) tissue, we compared levels of different potential markers of collagen metabolism and plasma transforming growth factor-beta 1 in patients with HCC and in patients with liver cirrhosis. Serum levels of prolyl hydroxylase and the tissue inhibitor of metalloproteinase-1 in patients with HCC were significantly higher than those in patients with liver cirrhosis and increased with the size of the HCC tumour, whereas the serum levels of procollagen type III propeptide and type IV collagen 7S domain were similar in the two groups. In HCC, the increased plasma transforming growth factor-beta 1 levels were closely correlated with serum levels of prolyl hydroxylase and the tissue inhibitor of metalloproteinase-1. These findings suggest that, in HCC tissue, the intracellular biosynthesis of collagen is enhanced, whereas the secretion of procollagen is disturbed and the degradation of collagen is suppressed by the excess production of the tissue inhibitor of metalloproteinase-1. The results also suggest that plasma transforming growth factor-beta 1 plays an important role in the altered metabolism of collagen in HCC.
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PMID:Serum markers for fibrosis and plasma transforming growth factor-beta 1 in patients with hepatocellular carcinoma in comparison with patients with liver cirrhosis. 874 16

Alcohol affects the liver through metabolic disturbances associated with its oxidation. Redox changes produced by the hepatic alcohol dehydrogenase pathway affect lipid, carbohydrate and protein metabolism. Ethanol is also oxidized in liver microsomes by the ethanol-inducible cytochrome P4502E1, resulting in ethanol tolerance and selective hepatic perivenular damage. Furthermore, P4502E1 activates various xenobiotics, explaining the increased susceptibility of the heavy drinker to the toxicity of anesthetics, commonly used medications (i.e. isoniazid), analgesics (i.e. acetaminophen), and chemical carcinogens. Induction of microsomal enzymes also contributes to vitamin A depletion, enhances its hepatotoxicity and results in increased acetaldehyde generation from ethanol, with formation of protein adducts, glutathione depletion, free-radical-mediated toxicity, and lipid peroxidation. Chronic ethanol consumption strikingly enhances the number of hepatic collagen-producing activated lipocytes. Both in vivo (in our baboon model of alcoholic cirrhosis) and in vitro (in cultured myofibroblasts and activated lipocytes) ethanol and/or its metabolite acetaldehyde increase collagen accumulation and mRNA for collagen. Gender differences are related, in part, to lower gastric ADH activity (with consequent reduction of first pass ethanol metabolism) in young women, decreased hepatic fatty acid binding protein and increased free-fatty acid levels as well as lesser omega-hydroxylation, all of which result in increased vulnerability to ethanol. Elucidation of the biochemical effects of ethanol are now resulting in improved therapy: in baboons, S-adenosyl-L-methionine attenuates the ethanol-induced glutathione depletion and associated mitochondrial lesions, and polyenylphosphatidylcholine opposes the ethanol-induced hepatic phospholipid depletion, the decrease in phosphatidylethanolamine methyltransferase activity and the activation of hepatic lipocytes, with full prevention of ethanol-induced septal fibrosis and cirrhosis; its dilinoleoyl species also increases collagenase activity in lipocytes. The efficacy of this compound in man is now being studied in randomized multicenter clinical trials.
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PMID:Susceptibility to alcohol-related liver injury. 897 51

Alcohol-induced tissue damage results from associated nutritional deficiencies as well as some direct toxic effects, which have now been linked to the metabolism of ethanol. The main pathway involves liver alcohol dehydrogenase which catalyzes the oxidation of ethanol to acetaldehyde, with a shift to a more reduced state, and results in metabolic disturbances, such as hyperlactacidemia, acidosis, hyperglycemia, hyperuricemia and fatty liver. More severe toxic manifestations are produced by an accessory pathway, the microsomal ethanol oxidizing system involving an ethanol-inducible cytochrome P450 (2E1). After chronic ethanol consumption, there is a 4- to 10-fold induction of 2E1, associated not only with increased acetaldehyde generation but also with production of oxygen radicals that promote lipid peroxidation. Most importantly, 2E1 activates many xenobiotics to toxic metabolites. These include solvents commonly used in industry, anaesthetic agents, medications such as isoniazid, over the counter analgesics (acetaminophen), illicit drugs (cocaine), chemical carcinogens, and even vitamin A and its precursor beta-carotene. Furthermore, enhanced microsomal degradation of retinoids (together with increased hepatic mobilization) promotes their depletion and associated pathology. Induction of 2E1 also yields increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, free radical-mediated toxicity, lipid peroxidation, and increased collagen synthesis. New therapies include adenosyl-L-methionine which, in baboons, replenishes glutathione, and attenuates mitochondrial lesions. In addition, polyenylphosphatidylcholine (PPC) fully prevents ethanol-induced septal fibrosis and cirrhosis, opposes ethanol-induced hepatic phospholipid depletion, decreased phosphatidylethanolamine methyltransferase activity and activation of hepatic lipocytes, whereas its dilinoleoyl species increases collagenase activity. Current clinical trials with PPC are targeted on susceptible populations, namely heavy drinkers at precirrhotic stages.
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PMID:Ethanol metabolism, cirrhosis and alcoholism. 902 26


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