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)

Studies were undertaken to evaluate the cytotoxicity of peripheral lymphocytes obtained from patients with alcoholic hepatitis. Lymphocyte cytotoxicity to Chang liver cells was investigated by a microcytotoxicity test, and that to autologous liver cells obtained by percutaneous liver biopsy was studied using a 51Cr release assay. Lymphocytes from patients with alcoholic hepatitis were found to be highly cytotoxic to Chang liver cells and autologous liver cells when compared to those of healthy subjects (P is less than 0.001). Cell-free supernatant fluid of lymphocytes from patients with alcoholic hepatitis incubated with purified alcoholic hyalin for 5 days was significantly cytotoxic to Chang liver cells (P is less than 0.01), indicating that a cytotoxic factor is elaborated by sensitized lymphocytes. A significant reduction in cytotoxicity was noted with disappearance of clinical features or direct addition of a purified isolate of alcoholic hyalin or its preincubation with lymphocytes. Preincubation of sensitized lymphocytes with acetaldehyde increased cytotoxicity for autologous liver beyond that obtained by the combined effects of lymphocytes alone and acetaldehyde alone (P is less than 0.001), interpreted as evidence that ethanol toxicity and hyperactivity of lymphocytes independently and collectively contribute to development of cirrhosis in patients with alcoholic hepatitis who continue to imbibe alcohol.
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PMID:Lymphocyte cytotoxicity in alcoholic hepatitis. 6 6

The effects of ethanol on hepatic cellular metabolism and structure depend mainly on the dose and duration of intake. Following the ingestion of a substantial amount of ethanol, its presence alters a number of hepatic functions in part because of the change in the hepatic redox state (NADH/NAD ratio), resulting for instance in reduction of lipid oxidation. Furthermore, chronic ethanol consumption, at least in its early stages, produces adaptive metabolic changes in the endoplasmic reticulum which result not only in increased metabolism of drugs and accelerated lipoprotein production but also in activation of hepatotoxic compounds. Even more extended periods of ethanol intake result in damage to cell organelles in what can be considered a third stage of the alcohol effect namely that of injury. The injury involves primarily mitochondria, possibly as a consequence of effects of acetaldehyde, the first product of ethanol metabolism. Metabolites of ethanol also alter microtubular function. A defect in protein secretion may be the basis for protein retention and "ballooning" of the hepatocyte. Prolongation of ethanol induced injury eventually culminates in hepatic lesions such as alcoholic hepatitis and cirrhosis. Ethanol can be incriminated as a direct etiologic agent of the liver injury, since liver cirrhosis has been reproduced experimentally in baboons fed alcohol, despite an adequate diet.
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PMID:[Pathogenesis of alcoholic liver injury (author's transl)]. 11 23

Significant liver disease including fatty metamorphosis, alcoholic hepatitis, cirrhosis, and hepatoma occur in two thirds of subjects who consume alcoholic beverages in sufficient quantities to interfere with work and social responsibilities; this is of major importance in the rapidly escalating morbidity and mortality from alcoholism. Chronic alcoholics should be routinely evaluated for the presence of altered liver function and structure. Clearance of indocyanine green using dichromatic ear densitometry and computer and analysis provides a simple and sensitive method for mass screening of such patients. Clinical studies of lymphocyte reactivity to purified alcoholic hyaline may be valuable in recognizing alcoholic hepatitis, the precursor of cirrhosis. Ethanol toxicity, malnutrition and constitutional factors contribute to the development of hepatic fibrosis and cirrhosis in alcoholics. Ethanol and/or acetaldehyde and the supernatant from lymphocytes stimulated by alcoholic hyaline cause a significant increase in the incorporation of proline into collagen of the damaged liver. Abstinence and correction of nutrient deficits are the cornerstones of treatment for alcoholic liver disease; a daily meal and dietary supplements should be provided for those with liver injury who continue to imbibe. Alcoholics with progressive liver disease despite supportive therapy may be aided by pharmacologic agents which suppress immunologic response and reduce fibrogenesis.
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PMID:Liver disease of the alcoholic. 16 41

Hepatic metabolism of ethanol to acetaldehyde by the alcohol dehydrogenase pathway is associated with the generation of reducing equivalents as NADH. Conversely, reducing equivalents are consumed when ethanol oxidation is catalyzed by the NADPH dependent microsomal ethanol oxidizing system. Since the major fraction of ethanol metabolism proceeds via alcohol dehydrogenase and since the oxidation of acetaldehyde also generates NADH, an excess of reducing equivalents is produced. This explains a variety of effects following acute ethanol administration, including hyperlactacidemia, hyperuricemia, enhanced lipogenesis and depressed lipid oxidation. To the extent that ethanol is oxidized by the alternate microsomal ethanol oxidizing system pathway, it slows the metabolism of other microsomal substrates. Following chronic ethanol consumption, adaptive microsomal changes prevail, which include enhanced ethanol and drug metabolism, and increased lipoprotein production. Severe hepatic lesions (alcoholic hepatitis and cirrhosis) develop after prolonged ethanol consumption in baboons. These injurious alterations are not prevented by nutritionally adequate diets and can therefore be ascribed to ethanol rather than to dietary inadequacy.
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PMID:Differences in hepatic and metabolic changes after acute and chronic alcohol consumption. 24 Jul 42

The present paper is devoted to overview the basic concepts of ethanol-induced hepatic injury and therapeutic modalities by which alcoholic liver disease can be alleviated. The role of alcohol dehydrogenase of both hepatic and gastric origin as well as the importance of the number one metabolite acetaldehyde are discussed, furthermore the effects of microsomal ethanol oxidizing system are also described. The features of the major clinicopathological consequences of alcohol abuse fatty liver, alcoholic hepatitis are briefly outlined, and the basic pathogenetic mechanisms that lead to cirrhosis--cell necrosis, regeneration and fibroplasia--are shown. The understanding of the pathophysiology of alcohol-induced liver injury may improve the therapy with drugs and nutritional factors, and allow successful prevention through the early recognition of heavy drinkers before their social or medical disintegration. In the management of alcoholic liver diseases, among the true hepatoprotective agents a naturally occurring flavonoid silymarin and an active methyl-donor metabolite S-adenosyl-L-methionine seem to be promising. An antifibrotic treatment with colchicine might also be of importance. Further prospective, well-designed, controlled clinical trials are still warranted to evaluate real efficacy of these drugs. The hepatic consequences of alcohol abuse may be treatable, however, prevention would be the true resolution of the major global health problem of alcoholism.
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PMID:Pathogenesis and management of alcoholic liver injury. 134

We recently found that polyunsaturated lecithin prevents ethanol from causing cirrhosis in the baboon. Because transformation of lipocytes to transitional cells plays a key role in hepatic fibrogenesis in vivo, and because this process in alcohol-fed baboons was found to be attenuated by polyunsaturated lecithin, we focused on lipocytes to study the mechanism of the protective effect. Rat lipocytes cultured on plastic undergo spontaneous activation, accompanied by expression of alpha-smooth muscle actin isoform and production of substantial amounts of type I collagen. The latter was further increased on incubation with acetaldehyde. This in vitro model was used here to study how acetaldehyde-mediated collagen production and accumulation can be turned off. Addition of polyunsaturated lecithin (10 mumols/L) was found to prevent the acetaldehyde-induced increase in collagen accumulation by 83% (p less than 0.001). By contrast, a saturated phospholipid (10 mumols/L dilauroyl phosphatidylcholine), a monounsaturated one (10 mumols/L linoleoyl-palmitoyl phosphatidylcholine) or linoleic acid (20 mumols/L bound to albumin) had no such effect. Incorporation of [3H]proline into collagen and the expression of alpha-1 (I) procollagen mRNA were increased by acetaldehyde; the latter was not significantly affected by polyunsaturated lecithin. Polyunsaturated lecithin increased lipocyte collagenase activity by 100% (p less than 0.001), whereas dilauroyl phosphatidylcholine, linoleoyl-palmitoyl phosphatidylcholine and linoleic acid had no such action. We concluded that (a) polyunsaturated lecithin selectively prevents the acetaldehyde-induced increase in collagen accumulation in lipocyte cultures, whereas other phospholipids or linoleate have no such effect; and (b) polyunsaturated lecithin does not modify the acetaldehyde-mediated increase in alpha-1 (I) procollagen mRNA, but it increases collagenase activity, suggesting that the protective effect exerted by polyunsaturated lecithin against alcohol induced fibrosis in vivo is due at least in part to stimulation of collagenase activity, which may prevent excess collagen accumulation by offsetting increased collagen production.
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PMID:Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in cultured lipocytes. 137 80

Two types of factors can theoretically modulate alcohol metabolism toward increased acetaldehyde production. These factors are the following: (a) individual, genetically determined isoenzymes with distinct catalytic properties, and (b) modifications of enzyme activity induced by alcohol itself or liver damage. To investigate the respective roles of these factors in white individuals, we studied the alcohol dehydrogenase phenotype, together with liver alcohol dehydrogenase and aldehyde dehydrogenase activities, in 161 patients. Patients with alcoholic cirrhosis (n = 31) were compared with three types of controls: patients with nonalcoholic cirrhosis (n = 25) and excessive (n = 62) and moderate drinkers (n = 43) without liver disease. No association between alcohol dehydrogenase-3 phenotype and alcoholic cirrhosis was found. The prevalence of atypical alcohol dehydrogenase in the four groups was less than 1%. Patients with cirrhosis, regardless of its cause, had significantly lower alcohol dehydrogenase activity than the patients without cirrhosis (p less than 0.05 and p less than 0.01 vs. excessive and moderate drinkers, respectively). Among the noncirrhotic patients, alcohol dehydrogenase activity was significantly lower in the excessive drinkers than in the moderate drinkers (p less than 0.001). Aldehyde dehydrogenase activity was not different between cirrhosis-free excessive and moderate drinkers; in contrast, compared with these two groups, it was significantly lower in the two cirrhosis groups (p less than 0.01). These results suggest that no phenotypic pattern of alcohol dehydrogenase-3 associated with alcoholic cirrhosis in white patients exists, that liver alcohol dehydrogenase activity falls as a consequence of both alcohol abuse and cirrhosis and that liver aldehyde dehydrogenase activity is unaffected by alcohol abuse and only falls after the onset of cirrhosis.
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PMID:Polymorphism of alcohol dehydrogenase, alcohol and aldehyde dehydrogenase activities: implication in alcoholic cirrhosis in white patients. The French Group for Research on Alcohol and Liver. 832 17

In vitro models have shown that metabolites of ethanol (acetaldehyde and lactate) stimulate collagen synthesis, thereby, suggesting that they may be important as fibrogenic mediators. The relevance of these findings for fibrogenesis in the human liver in vivo, however, has not as yet been demonstrated. Serum markers for collagen (PIIINP, using radioimmunoassays employing polyclonal antibodies and Fab-fragments (PIIINP-Fab), respectively) and basement membrane (laminin) metabolism were therefore investigated in 25 alcoholic cirrhotics (Pugh-Score: 6.7 +/- 1.9 S.D.) and in 19 comparable nonalcoholic cirrhotics (Pugh-Score: 6.3 +/- 1.5, n.s.) with only slight evidence for inflammation: GOT 28 +/- 22 vs. 24 +/- 21 U/l; GPT 24 +/- 23 vs. 31 +/- 28 U/l; gamma-globulins 24 +/- 8 vs. 22 +/- 5%, respectively (all n.s.). Severity of the disease was assessed by quantitative liver function tests. Levels of PIIINP, PIIINP-Fab and laminin measured by RIA were 21 +/- 19 micrograms/l, 90 +/- 42 micrograms/l and 2.5 +/- 0.8 U/ml in alcoholic cirrhosis and 10 +/- 6 micrograms/l, 61 +/- 10 micrograms/l and 1.9 +/- 0.4 U/ml in nonalcoholic cirrhosis, respectively (all p less than 0.01). Differences on PIIINP and PIIINP-Fab remained significant even after accurate matching for galactose elimination capacity, aminopyrine breath test and hepatic sorbitol clearance. Laminin levels were higher in alcoholic cirrhosis only after matching for the hepatic sorbitol clearance (p less than 0.01). The higher levels of serum markers for collagen and basement membrane metabolism in alcoholic vs. nonalcoholic patients with cirrhosis at equal severity of the disease and with only minimal signs of inflammation may be the clinical reflection of a specific fibrogenic effect of ethanol metabolites.
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PMID:Higher levels of serum aminoterminal type III procollagen peptide, and laminin in alcoholic than in nonalcoholic cirrhosis of equal severity. 173 19

To clarify the pathogenetic role of acetaldehyde in the development of alcoholic liver disease, genotyping of aldehyde dehydrogenase-2 genes was performed and the clinical features of the alcoholic liver disease patients with different genotypes were compared. Genotyping of aldehyde dehydrogenase-2 was performed in 47 patients with alcoholic liver disease using the polymerase chain reaction and slot-blot hybridization. Of the 47 patients with alcoholic liver disease, 40 were homozygous for the normal aldehyde dehydrogenase-2 gene and the remaining seven cases were heterozygous for the normal and mutant aldehyde dehydrogenase-2 genes. No homozygote was found for the mutant aldehyde dehydrogenase-2 genes. Daily alcohol intake was less than 100 gm in all heterozygotes without relation to the type of alcoholic liver disease. On the other hand, all but four patients homozygotic for the normal aldehyde dehydrogenase-2 gene drank more than 100 gm alcohol/day. The mean daily alcohol intake in the heterozygotes was significantly lower than that in the normal homozygotes. The incidence of alcoholic fibrosis tended to be lower in the heterozygotes than in the normal homozygotes (14.2% vs. 52.5%). On the other hand, the incidence of alcoholic hepatitis and/or cirrhosis tended to be higher in the heterozygotes than in the normal homozygotes. These results indicate that alcoholic liver disease develops even with moderate amounts of alcohol intake in heterozygotes of the aldehyde dehydrogenase-2 genes, in which acetaldehyde metabolism in the liver is impaired and liver damage in the heterozygotes is more severe than that in the normal homozygotes, suggesting that habitual drinkers who are heterozygotes of the aldehyde dehydrogenase-2 genes may be at high risk for alcoholic liver disease.
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PMID:Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes. 205 Mar 24

Alcoholic liver disease includes steatosis, alcoholic hepatitis and cirrhosis. Other liver diseases of genetic origin, but with a curious association with alcohol intake, are hemochromatosis and porphyria cutanea tarda. The attribution of chronic hepatitis to alcohol intake remains speculative, and the association may reflect hepatitis C infection. Hepatic injury attributed to alcohol includes the changes reported in the fetal alcohol syndrome. Steatosis, the characteristic consequence of excess alcohol intake, is usually macrovesicular and rarely microvesicular. Acute intrahepatic cholestasis, which in rare instances accompanies steatosis, must be distinguished from other causes of intrahepatic cholestasis (e.g., drug-induced) and from mechanical obstruction of the intrahepatic bile ducts (e.g., pancreatitis, choledocholithiasis) before being accepted. Alcoholic hepatitis (steatonecrosis) is characterized by a constellation of lesions: steatosis, Mallory bodies (with or without a neutrophilic inflammatory response), megamitochondria, occlusive lesions of terminal hepatic venules, and a lattice-like pattern of pericellular fibrosis. All these lesions mainly affect zone 3 of the hepatic acinus. Other changes, observed at the ultrastructural level, are of importance in progression of the disease. They include widespread cytoplasmic shedding, and capillarization and defenestration of sinusoids. Progressive fibrosis complicating alcoholic hepatitis eventually leads to cirrhosis that is typically micronodular but can evolve to a mixed or macronodular pattern. Hepatocellular carcinoma occurs in 5 to 15% of patients with alcoholic liver disease. The clinical syndrome of alcoholic liver disease is the result of three factors--parenchymal insufficiency, portal hypertension and the clinical consequences of extrahepatic damage produced by alcohol. At the several phases of the life history of alcoholic liver disease, the individual factors play a different role. The clinical manifestations of alcoholic steatosis are mainly extrahepatic in origin. Those of alcoholic hepatitis reflect mainly parenchymal insufficiency and those of cirrhosis are mainly those of portal hypertension. Alcoholic liver injury appears to be generated by the effects of ethanol metabolism and the toxic effects of acetaldehyde, perhaps the immune responses to alcohol- or acetaldehyde-altered proteins, and questionably enhanced by viral hepatitis. Alcoholic hepatitis may be mimicked histologically, and to a varying degree clinically, by a number of conditions (obesity, diabetes, several drug-induced injuries, jejunoileal bypass, and related "shortcircuiting" of the bowel). Perhaps the most important facet of the hepatotoxicity of alcohol is its enhancement of the effects of a number of other hepatotoxic agents, among which acetaminophen is the prime example.
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PMID:Alcoholic liver disease: pathologic, pathogenetic and clinical aspects. 205 45


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