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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Development of cirrhosis of liver tissue did not influence the intensity of glycolysis, with glucose as a substrate, in supernatant fraction of liver homogenate in chronic intoxication with CCL4. In preparations of cirrhotic liver, as compared with liver from the intact animals, more distinct activation of glycolysis was caused by addition of ATP and NAD at the stage of 3-week intoxication and also by addition of hexokinase, glyceraldehydephosphate dehydrogenase and lactate dehydrogenase at the stage of distinct cirrhosis of liver (6 weeks of CCL4 intoxication). Km values for glucose-6-phosphate dehydrogenase increased over all the periods of intoxication.
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PMID:[Change in the glycolytic and glucose-6-phosphate dehydrogenase activity in experimental cirrhosis of the liver]. 16 85

It is evident that ethanol by itself or one of its metabolites produces alterations in transport, metabolism and disposition of carbohydrates. Ethanol acts via changes in the redox state of co-factors; e.g. ethanol-induced hypoglycemia is due, partly, to the inhibition of hepatic gluconeogenesis by ethanol as a consequence of the increased NADH2/NAD ratio in patients whose glycogen stores are already depleted. On the other hand, hyperglycemia has also been described in patients with alcoholism. Although its mechanism is still obscure, abnormal hormonal secretion of insulin, catecholamines and glucocorticoids has been incriminated. Finally, structural changes of the liver and pancreas such as cirrhosis and pancreatitis produced by chronic alcohol consumption should also be considered as pathogenetic factors in a variety of clinical states involving deranged carbohydrate metabolism.
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PMID:Alcohol induced changes of carbohydrate metabolism [author's transl]. 70 66

In western industrialized countries ethanol is an important etiologic factor in the development of cirrhosis of the liver. Metabolic, immunologic and physico-chemical alterations of the hepatocyte due to ethanol are involved in the pathogenesis of alcoholic liver disease. However, the mechanisms by which ethanol damages the liver are far from clear. During the last two decades, the effect of ethanol on multiple biochemical pathways of the hepatocyte has been investigated intensively. The present paper is focusing on the metabolic aspects of alcoholic liver disease. In the first part of the review, special emphasis has been led on the metabolites of ethanol oxidation, while in the second part microsomal enzyme induction due to alcohol has been discussed. More than 90% of ethanol metabolism takes place in the liver via cytoplasmic alcoholdehydrogenase (ADH) and via a microsomal ethanol oxidizing system (MEOS). The products of these reactions are reduced nicotinadenine dinucleotide phosphate (NADH), acetaldehyde and acetate. NADH alters the redox state of the liver cell favouring all reductive processes. This shift in metabolic pathways results in hyperlactacidaemia, lactacidosis, ketosis and hyperuricaemia. Disturbances of the carbohydrate metabolism may lead either to hypo- or hyperglycaemia. The altered redox state also influences the metabolic pathways of lipid metabolism leading to lipid accumulation within the hepatocyte which can be morphologically observed as alcoholic fatty liver. In addition, porphyrin and collagen metabolism is also affected by the increased NADH/NAD+ ratio. On the other hand, acetaldehyde damages the microtubular system and the mitochondria. Acetaldehyde may also be responsible for the increased lipidperoxidation after chronic ethanol ingestion.
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PMID:[Metabolic aspects of alcoholic liver damage: 1984/5 update. 1. Epidemiology and alcohol metabolism]. 639 85

The chronic ingestion of ethanol results in liver-cell damage, and characteristic features of this injury are the marked alterations in both the functions and morphology of the mitochondria. Morphologically, the changes observed in human alcoholics and experimental animals appear similar. Bizarrely shaped mitochondria and megamitochondria are detected at the fatty liver stage and persist as the disease progresses. As yet, however, no correlation has been found between the severity of these morphological changes and the development of cirrhosis. Analysis of the mitochondrial membranes indicates that ethanol consumption produces changes in both the protein and lipid composition of the membrane. Profound decreases in the components of the respiratory chain have been detected, and these changes are associated with marked depressions in the activity of NAD+-linked dehydrogenases, cytochrome oxidase, and the ATP synthetase complex. On the other hand, no consistent pattern has emerged as to the effect of chronic ethanol consumption on the composition of the membrane phospholipids. Many of the changes appear to be dependent on the sex of the animal, the dietary status, and the duration of ethanol intake, and are suggestive of changes in fatty acid desaturase activity. Mitochondria isolated from ethanol-fed rats displayed impaired respiration and a lowered steady-state rate of ATP synthesis. Whether or not these functional changes are directly related to alterations in the physical properties of the membranes remains to be resolved. This marked depression of respiratory functions in isolated mitochondria was not reflected by a significant decrease in O2 consumption by the livers of ethanol-fed animals.
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PMID:Alcohol-induced mitochondrial changes in the liver. 672 59

Hepatic ethanol metabolism in the liver from carbon tetrachloride (CCl4)- treated animals was studied using non-recirculating hemoglobin-free liver perfusion system. CCl4-administration decreased ethanol uptake by the liver to 56% and 30% of the control values following the acute (24 hrs. after treatment) and chronic (8-12 weeks) treatments, respectively. In addition, 4 mM fructose, a well-known agent to increase ethanol metabolism in the liver, did not increase the hepatic uptake of ethanol in CCl4-treated livers. Hepatic alcohol dehydrogenase activity was not changed following acute and chronic CCl4 treatments. The lactate/pyruvate (cytosolic NADH/NAD) ratio as well as beta-hydroxybutyrate/acetoacetate (mitochondrial NADH/NAD) ratio significantly increased, whereas both hepatic oxygen uptake and oxidation of NADH in mitochondria remarkably decreased in parallel with the magnitude of liver injury induced by CCl4. Histological studies revealed that the liver had centrilobular coagulative necrosis with fatty droplet formations at acute phase, while bridging fibrosis between central and portal areas and the pattern of cirrhosis with conspicuous changes in the mitochondria were seen at chronic phase. These data indicate that CCl4-treatment significantly reduces hepatic ethanol metabolism via the inhibition of reoxidation of NADH, a rate limiting step of ethanol metabolism in the liver.
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PMID:Alteration of hepatic ethanol metabolism in CCL4-intoxicated rats: analysis using isolated liver perfusion system. 676 60

The main pathway for the hepatic oxidation of ethanol to acetaldehyde proceeds via ADH and is associated with the reduction of NAD to NADH; the latter produces a striking redox change with various associated metabolic disorders. NADH also inhibits xanthine dehydrogenase activity, resulting in a shift of purine oxidation to xanthine oxidase, thereby promoting the generation of oxygen-free radical species. NADH also supports microsomal oxidations, including that of ethanol, in part via transhydrogenation to NADPH. In addition to the classic alcohol dehydrogenase pathway, ethanol can also be reduced by an accessory but inducible microsomal ethanoloxidizing system. This induction is associated with proliferation of the endoplasmic reticulum, both in experimental animals and in humans, and is accompanied by increased oxidation of NADPH with resulting H2O2 generation. There is also a concomitant 4- to 10-fold induction of cytochrome P4502E1 (2E1) both in rats and in humans, with hepatic perivenular preponderance. This 2E1 induction contributes to the well-known lipid peroxidation associated with alcoholic liver injury, as demonstrated by increased rates of superoxide radical production and lipid peroxidation correlating with the amount of 2E1 in liver microsomal preparations and the inhibition of lipid peroxidation in liver microsomes by antibodies against 2E1 in control and ethanol-fed rats. Indeed, 2E1 is rather "leaky" and its operation results in a significant release of free radicals. In addition, induction of this microsomal system results in enhanced acetaldehyde production, which in turn impairs defense systems against oxidative stress. For instance, it decreases GSH by various mechanisms, including binding to cysteine or by provoking its leakage out of the mitochondria and of the cell. Hepatic GSH depletion after chronic alcohol consumption was shown both in experimental animals and in humans. Alcohol-induced increased GSH turnover was demonstrated indirectly by a rise in alpha-amino-n-butyric acid in rats and baboons and in volunteers given alcohol. The ultimate precursor of cysteine (one of the three amino acids of GSH) is methionine. Methionine, however, must be first activated to S-adenosylmethionine by an enzyme which is depressed by alcoholic liver disease. This block can be bypassed by SAMe administration which restores hepatic SAMe levels and attenuates parameters of ethanol-induced liver injury significantly such as the increase in circulating transaminases, mitochondrial lesions, and leakage of mitochondrial enzymes (e.g., glutamic dehydrogenase) into the bloodstream. SAMe also contributes to the methylation of phosphatidylethanolamine to phosphatidylcholine. The methyltransferase involved is strikingly depressed by alcohol consumption, but this can be corrected, and hepatic phosphatidylcholine levels restored, by the administration of a mixture of polyunsaturated phospholipids (polyenylphosphatidylcholine). In addition, PPC provided total protection against alcohol-induced septal fibrosis and cirrhosis in the baboon and it abolished an associated twofold rise in hepatic F2-isoprostanes, a product of lipid peroxidation. A similar effect was observed in rats given CCl4. Thus, PPC prevented CCl4- and alcohol-induced lipid peroxidation in rats and baboons, respectively, while it attenuated the associated liver injury. Similar studies are ongoing in humans.
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PMID:Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases. 889 26

NMR spectroscopy was used to examine hepatic metabolism in cirrhosis with a particular focus on markers of functional cellular hypoxia. (31)P and (1)H NMR spectra were obtained from liver extracts from control rats and from rats with carbon tetrachloride-induced cirrhosis. A decrease of 34% in total phosphorus content was observed in cirrhotic rats, parallelling a reduction of 40% in hepatocyte mass as determined by morphometric analysis. Hypoxia appeared to be present in cirrhotic rats, as evidenced by increased inorganic phosphate levels, decreased ATP levels, decreased ATP:ADP ratios (1.72 +/- 0.40 vs 2.48 +/- 0.50, p < 0.01), and increased inorganic phosphate:ATP ratios (2.77 +/- 0.48 vs 1.62 +/- 0.24, p < 0.00001). When expressed as a percentage of the total phosphorus content, higher levels of phosphoethanolamine and lower levels of NAD and glycerophosphoethanolamine were detected in cirrhotic rats. Cirrhotic rats also had increased phosphomonoester:phosphodiester ratios (5.73 +/- 2.88 vs 2.53 +/- 0.52, p < 0.01). These findings are indicative of extensive changes in cellular metabolism in the cirrhotic liver, with many findings attributable to the presence of intracellular hypoxia.
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PMID:31P and 1H NMR spectroscopic studies of liver extracts of carbon tetrachloride-treated rats. 1051 22

Alcoholic fatty liver is a potentially pathologic condition which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. Alcohol exposure may induce fatty liver by increasing NADH/NAD(+) ratio, increasing sterol regulatory element-binding protein-1 (SREBP-1) activity, decreasing peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity, and increasing complement C3 hepatic levels. Alcohol may increase SREBP-1 activity by decreasing the activities of AMP-activated protein kinase and sirtuin-1. Tumor necrosis factor-alpha (TNF-alpha) produced in response to alcohol exposure may cause fatty liver by up-regulating SREBP-1 activity, whereas betaine and pioglitazone may attenuate fatty liver by down-regulating SREBP-1 activity. PPAR-alpha agonists have potentials to attenuate alcoholic fatty liver. Adiponectin and interleukin-6 may attenuate alcoholic fatty liver by up-regulating PPAR-alpha and insulin signaling pathways while down-regulating SREBP-1 activity and suppressing TNF-alpha production. Recent studies show that paracrine activation of hepatic cannabinoid receptor 1 by hepatic stellate cell-derived endocannabinoids also contributes to the development of alcoholic fatty liver. Furthermore, oxidative modifications and inactivation of the enzymes involved in the mitochondrial and/or peroxisomal beta-oxidation of fatty acids could contribute to fat accumulation in the liver.
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PMID:Molecular mechanisms of alcoholic fatty liver. 1903 84

[1-(13)C]pyruvate is a readily polarizable substrate that has been the subject of numerous magnetic resonance spectroscopy (MRS) studies of in vivo metabolism. In this work (13)C-MRS of hyperpolarized [1-(13)C]pyruvate was used to interrogate a metabolic pathway involved in neither aerobic nor anaerobic metabolism. In particular, ethanol consumption leads to altered liver metabolism, which when excessive is associated with adverse medical conditions including fatty liver disease, hepatitis, cirrhosis, and cancer. Here we present a method for noninvasively monitoring this important process in vivo. Following the bolus injection of hyperpolarized [1-(13)C]pyruvate, we demonstrate a significantly increased rat liver lactate production rate with the coadministration of ethanol (P = 0.0016 unpaired t-test). The affect is attributable to increased liver nicotinamide adenine dinucleotide (NADH) associated with ethanol metabolism in combination with NADH's role as a coenzyme in pyruvate-to-lactate conversion. Beyond studies of liver metabolism, this novel in vivo assay of changes in NADH levels makes hyperpolarized [1-(13)C]pyruvate a potentially viable substrate for studying the multiple in vivo metabolic pathways that use NADH (or NAD(+)) as a coenzyme, thus broadening the range of applications that have been discussed in the literature to date.
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PMID:In vivo measurement of ethanol metabolism in the rat liver using magnetic resonance spectroscopy of hyperpolarized [1-13C]pyruvate. 1952 98


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