Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 evaluate changes in liver metabolic zonation during development of juvenile cirrhosis, zonal activities of succinate dehydrogenase, glutamate dehydrogenase, glucose-6-phosphatase, and nicotinamide adenine dinucleotide phosphate (NADPH) dehydrogenase were measured by quantitative cytochemistry in the liver of developing rats intoxicated with carbon tetrachloride and phenobarbitone. During treatment, activities were most decreased in perivenular zones and subsequently at the periphery of the cirrhotic nodules for succinate dehydrogenase and glucose-6-phosphatase, whereas glutamate dehydrogenase and NADPH dehydrogenase were less affected. In the periportal zones, enzyme activities decreased less. After stopping intoxication, the rats remained cirrhotic, but enzyme activities returned to control perivenular levels at the periphery of the cirrhotic nodule and to control periportal levels at its center. It is concluded that a metabolic zonation persists in carbontetrachloride/phenobarbitone-induced juvenile cirrhosis and that enzyme activities can recover despite persisting cirrhosis. In this model, afferent vessels seem to be located at the center of the cirrhotic nodules, and efferent vessels, at their periphery. A different metabolic zonation may exist in other human and animal liver cirrhosis that could be related to the site of initial liver damage.
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PMID:Adaptative changes of metabolic zonation during the development of cirrhosis in growing rats. 216 52

The cerebro-hepato-renal syndrome is a rare familial malady with cerebral, renal, and skeletal abnormalities, severe hypotonia, cirrhosis, iron and lipid storage, and death within 6 months. Correlated electron microscopic, histochemical, and biochemical studies demonstrate defects in two oxidative organelles. Peroxisomes cannot be found in hepatocytes and renal proximal tubules. In hepatocytes and cortical astrocytes, mitochondria are distorted in their appearance and glycogen stores are increased. Oxygen consumnption of brain and liver mitochondrial preparations with succinate and with substrates reducing nicotinamide adenine dinucleotide is markedly diminished, but the consumption is normal with ascorbate and tetramethylphenylenediamine, which suggests a defect in electron transport prior to the cytochromes. Histochemical studies of mitochondrial oxidation point to a defect between the succinate dehydrogenase flavoprotein and coenzyme Q, possibly in the region of nonheme iron protein.
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PMID:Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome. 473 55

Methylation reactions play an important role in the transformation of endogenous and exogenous substances. Up to 85% of all transmethylation reactions occur in the liver. Several studies have shown that these metabolic processes are greatly influenced by the presence of hepatic diseases. We investigated the methylation of nicotinamide in 16 control subjects and in 29 patients with cirrhosis (19 Child A, 10 Child B). The basal serum value of N-methyl-nicotinamide was measured in all subjects. In seven controls and in nine patients with cirrhosis (5 Child A and 4 Child B), the serum levels and urinary excretion (5 and 24 h) of N-methyl-nicotinamide were also evaluated after oral administration of nicotinamide (1.5 mg/kg body weight). The basal serum levels of N-methyl-nicotinamide were significantly (p < 0.05) higher in patients with cirrhosis (Child A: median 34 ng/ml, 16th percentile 24, 84th percentile 61; Child B median 45, 16th percentile 34, 84th percentile 81) than in controls (median 22, 16th percentile 13, 85th percentile 28). After the nicotinamide load the urinary excretion and the time course of serum N-methyl-nicotinamide in cirrhosis were also higher (p < 0.05) than in controls (24 h urinary excretion = 66.2 mg +/- 5 S.D. in cirrhosis; 47.2 +/- 10.3 in controls) (area under the serum concentration versus time curve = 68 micrograms.ml-1.min-1 +/- 22 S.D. in cirrhosis; 32 +/- 15 in controls). In conclusion, our results show that cirrhosis does not impair the efficiency of nicotinamide methylation.
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PMID:Nicotinamide methylation in patients with cirrhosis. 820 Dec 15

Alcohol causes primary malnutrition by displacing nutrients in the diet and secondary malnutrition via malabsorption and cellular injury through direct cytotoxicity. Hepatotoxicity results from metabolic disturbances associated with the oxidation of ethanol via liver alcohol dehydrogenase (ADH) and the redox changes produced by the generated NADH (the reduced form of nicotinamide adenine dinucleotide), which in turn affects the metabolism of lipids, carbohydrates, proteins, and purines. Ethanol is also oxidized in liver microsomes by an ethanol-inducible cytochrome P450, which contributes to the alcoholic's tolerance and his increased vulnerability to the toxicity of industrial solvents, anesthetics, commonly prescribed drugs, over-the-counter analgesics, chemical carcinogens, and retinoids. Increased acetaldehyde generation, with formation of protein adducts, results in antibody production, enzyme inactivation, decreased DNA repair, impaired utilization of oxygen, glutathione depletion, free radical-mediated toxicity, lipid peroxidation, and increased collagen synthesis. Therapy may eventually improve with the use of supernutrients such as S-adenosyl-L-methionine, which replenishes glutathione, restores methylation, and attenuates liver injury, as well as dilinoleoylphosphatidylcholine, which prevents cirrhosis.
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PMID:Herman Award Lecture, 1993: a personal perspective on alcohol, nutrition, and the liver. 823 56

Administration of vitamins or metals may cause severe side effects. Retinoids (derivatives of vitamin A) used for the treatment of various skin disorders are teratogenic, hepatotoxic and may induce a substantial increase in serum lipids. A case report demonstrates that vitamin D supplementation in a patient under total parenteral nutrition can cause hypercalcemia. The isolated administration of vitamin B1, without concomitant vitamin B6 and nicotinamide may precipitate potentially life-threatening pellagra encephalopathy. Repeat blood transfusions may produce clinically overt organ hemosiderosis, e.g. cirrhosis of the liver, diabetes mellitus or myocardiopathy. The literature contains reports on a few cases of sarcoma associated with orthopedic metal implants. The controversial issue of the potential dangers of dental amalgams is briefly mentioned.
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PMID:[Vitamins and metals: possible hazards for humans]. 866 74

Little is known about the alterations of metabolic organization of the human liver tissue in chronic liver diseases. We therefore compared the distribution of the following zonal metabolic markers in 10 samples of normal liver tissue, 10 samples of fibrotic tissue, and 22 samples of cirrhotic tissue: (a) the enzymatic activities of glucose-6-phosphatase (G6P), lactate dehydrogenase (LDH), succinate dehydrogenase (SDH), nicotinamide-adenine-dinucleotide-phosphate [NAPH] dehydrogenase (ND), beta-hydroxybutyrate dehydrogenase (HBDH), and glutamate dehydrogenase (GDH); (b) the protein glutamine synthetase (GLS); and (c) albumin messenger RNA (mRNA). The normal human hepatic lobule was characterized by the periportal predominance of G6P and SDH enzymatic activities and albumin mRNAs, the perivenous predominance of ND and GDH, the restriction of GLS to a small perivenous compartment, and the predominanc of beta-HBDH at the contact of both portal tracts and centrilobular veins. In fibrosis, the overall metabolic organization of the normal liver tissue was retained. The expression of periportal markers predominated around enlarged portal tracts and that of perivenous markers around residual centrilobular veins. GLS was constantly detected at the contact of centrilobular veins. In cirrhotic nodules, no zonation was observed for most enzymatic activities or for albumin. Only G6P usually predominated at the periphery of the nodules. GLS was constantly undetectable. No difference accordingly to the etiology of the underlying disease was observed. In conclusion, the normal human hepatic lobule presents a marked metabolic zonation, preserved in fibrotic lesions, but lost in cirrhotic nodules. The alterations of the metabolic organization observed in cirrhosis might contribute to the pathogenesis of some of the metabolic disorders associated with advanced liver disease.
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PMID:The metabolic organization of the adult human liver: a comparative study of normal, fibrotic, and cirrhotic liver tissue. 870 47

We investigated the change of tryptophan-niacin metabolism induced by carbon tetrachloride (CCl4) in rats with liver cirrhosis. The rats were injected with CCl4 (0.5 or 1 mL of 50% olive oil solution/kg body weight) twice a week for 1 or 2 mo and given phenobarbital water simultaneously. The urinary excretions of nicotinamide (Nam) and its metabolites were assayed. As the result, the urinary excretion of Nam, N1-methyl-4-pyridone-3-carboxamide (4-Py), Nam + N1-methylnicotinamide (MNA) + N1-methyl-2-pyridone-5-carboxamide (2-Py) + 4-Py was lower in the CCl4-treated groups than in the non-treated group (control) regardless of the experimental period (1 mo and 2 mo) or dosing amount of CCl4 (0.5 and 1 mL). Moreover, we investigated which pathway of tryptophan-niacin metabolism was affected in CCl4-treated rat. As the result, the possibility that the MNA-->4-Py reaction is inhibited by CCl4 treatment was suggested in this experiment.
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PMID:Tryptophan-niacin metabolism in liver cirrhosis rat caused by carbon tetrachloride. 1057 36

Apoptosis plays an important role in the progression of alcohol-induced liver disease to cirrhosis. Oxidative stress is an early event in the development of apoptosis. The major aim of this study was to study the conditions in which oxidative stress occurs in chronic alcoholism and its relationship with apoptosis of hepatocytes. We have found that oxidative stress is associated with chronic ethanol consumption in humans and in rats, in the former independently of the existence of alcohol-induced liver disease. Ethanol or acetaldehyde induces apoptosis in hepatocytes isolated from alcoholic rats, but not in those from control rats. Inhibition of aldehyde dehydrogenase, but not of cytochrome P450 2E1, prevents ethanol-induced cell death. Ethanol-induced apoptosis is caused by increased reactive oxygen species (ROS) driven by increased availability of the reduced form of nicotinamide-adenine dinucleotide (NADH) owing to mitochondrial acetaldehyde metabolism and it is prevented by blocking the opening of mitochondrial permeability transition (MPT) pores with cyclosporine A. Inhibition of nitric oxide (NO) synthase or addition of antioxidant vitamins C and E completely prevented ethanol-induced apoptosis. Mitochondrial oxidative stress, which occurs during chronic alcoholism, renders hepatocytes susceptible to apoptosis. On the other hand, the CD95 ligand expression was up-regulated by acetaldehyde. In conclusion, ethanol induces apoptosis via 2 different pathways: MPT and up-regulation of the expression of CD95-Fas ligand. The overproduction of ROS by mitochondria, driven by acetaldehyde metabolism, is a common trigger of both mechanisms.
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PMID:Mitochondrial oxidative stress and CD95 ligand: a dual mechanism for hepatocyte apoptosis in chronic alcoholism. 1198 71

Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase-mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinucleotide (NADH), which promotes steatosis by stimulating the synthesis of fatty acids and opposing their oxidation. Steatosis is also promoted by excess dietary lipids and can be attenuated by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1 activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism by means of this pathway generate release of free radicals, which cause oxidative stress, with peroxidation of lipids and membrane damage, including altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis, which are further increased through diminished feedback inhibition of collagen synthesis because acetaldehyde forms adducts with the carboxyl-terminal propeptide of procollagen in hepatic stellate cells. Acetaldehyde is also toxic to the mitochondria, and it aggravates their oxidative stress by binding to reduced glutathione and promoting its leakage. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of the proinflammatory cytokine tumor necrosis factor-alpha in the Kupffer cells. These are activated by induction of their CYP2E1 as well as by endotoxin. The endotoxin-stimulated tumor necrosis factor-alpha release is decreased by dilinoleoylphosphatidylcholine, the active phosphatidylcholine (PC) species of polyenylphosphatidylcholine (PPC). Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid-binding protein (L-FABPc). Accordingly, the intracellular concentration of free fatty acids may become high enough to injure membranes, thereby contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis. Eventually, hepatic S-adenosylmethionine and PCs become depleted in the alcoholic, with impairment of their multiple cellular functions, which can be restored by PC replenishment. Thus, prevention and therapy opposing the development of steatosis and its progression to more severe injury can be achieved by a multifactorial approach: control of alcohol consumption, avoidance of obesity and of excess dietary long-chain fatty acids, or their replacement with medium-chain fatty acids, and replenishment of S-adenosylmethionine and PCs by using PPC. Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment.
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PMID:Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. 1567 Jun 60

It is generally assumed that neuronal cell death is minimal in liver failure and is insufficient to account for the neuropsychiatric symptoms characteristic of hepatic encephalopathy. However, contrary to this assumption, neuronal cell damage and death are well documented in liver failure patients, taking the form of several distinct clinical entities namely acquired (non-Wilsonian) hepatocerebral degeneration, cirrhosis-related Parkinsonism, post-shunt myelopathy and cerebellar degeneration. In addition, there is evidence to suggest that liver failure contributes to the severity of neuronal loss in Wernicke's encephalopathy. The long-standing nature of the thalamic and cerebellar lesions, over 80% of which are missed by routine clinical evaluation, together with the probability that they are nutritional in origin, underscores the need for careful nutritional management (adequate dietary protein, Vitamin B(1)) in liver failure patients. Mechanisms identified with the potential to cause neuronal cell death in liver failure include NMDA receptor-mediated excitotoxicity, lactic acidosis, oxidative/nitrosative stress and the presence of pro-inflammatory cytokines. The extent of neuronal damage in liver failure may be attenuated by compensatory mechanisms that include down-regulation of NMDA receptors, hypothermia and the presence of neuroprotective steroids such as allopregnanolone. These findings suggest that some of the purported "sequelae" of liver transplantation (gait ataxia, memory loss, confusion) could reflect preexisting neuropathology.
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PMID:Neuronal cell death in hepatic encephalopathy. 1785 42


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