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)

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 mechanisms responsible for the increased hepatic collagen deposition in alcoholic cirrhosis remain unknown. The question of whether ethanol or acetaldehyde has a direct effect on collagen and noncollagen protein production was investigated in human fibroblasts with no detectable activity of alcohol dehydrogenase to distinguish the effects of these metabolites. To eliminate environmental factors, protein production by confluent human skin, fetal and hepatic fibroblasts was studied after three passages. Cells were labeled with [5-3H]proline for 4 hr in the presence of 0.2 mM ascorbate alone or with addition of either ethanol (50 mM) or acetaldehyde (0 to 300 microM). Rates of protein production were calculated from the radioactivities of collagenase-sensitive and collagenase-resistant proteins. Skin fibroblasts from alcoholic individual either with cirrhosis or without liver disease have comparable rates of collagen and noncollagen protein production. Acetaldehyde, in a concentration found in the liver during ethanol abuse, significantly increased collagen production by human skin fibroblasts (up to 140%), fetal fibroblasts (up to 240%) and hepatic fibroblasts (up to 70%) but the addition of ethanol had no significant effect on basal collagen production. The effect of acetaldehyde was dose-related and affected noncollagen protein production in a similar manner. Acetaldehyde did not cause changes in either proline transport or the specific activity of the proline precursor pool. This newly recognized stimulation of collagen production by acetaldehyde may be a possible mechanism of fibrogenesis in alcoholic individuals.
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PMID:Acetaldehyde stimulates collagen and noncollagen protein production by human fibroblasts. 647 53

During 1961-75, 128 cases of primary liver carcinoma (PLC) in the Radiation Effects Research Foundation life-span study extended sample and 301 cases of liver cirrhosis in the pathology study sample were observed. The presence of hepatitis B surface antigen (HBsAg) was assessed in all of the cases with the use of orcein and aldehyde fuchsin stains and was confirmed by the immunofluorescence technique. The incidence of PLC was two times higher in Nagasaki than in Hiroshima, which was statistically significant, but little difference was noted in the prevalence of cirrhosis in the two cities. Findings that might possibly explain the higher PLC incidence in Nagasaki were 1) the 2.3 times higher presence in Nagasaki than in Hiroshima of HBsAg in the livers of subjects without liver disease and 2) the two times higher prevalence in Nagasaki than in Hiroshima of cirrhosis with PLC. We believe that the higher incidence of PLC in Nagasaki is attributable to hepatitis B virus infection, although other factors (e.g., immunologic competence affected by radiation) cannot be excluded. In both cities, a suggestive relationship of radiation dose to cirrhosis prevalence, but not to PCL prevalence, was noted. To clarify possible radiation effects on cirrhosis prevalence, further follow-up of the populations of these two cities is necessary.
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PMID:Primary liver carcinoma and liver cirrhosis in atomic bomb survivors, Hiroshima and Nagasaki, 1961-75, with special reference to hepatitis B surface antigen. 675 25

Acetaldehyde in non-toxic doses (15.6 micrograms per start) causes in the inhibition test of the migration of leucocytes an inhibition of the migration in 6/13 of the patients with alcoholic hepatitis, a stimulation of the migration in 6/11 of alcohol cirrhoses. Healthy (n = 16) persons, patients with alcoholic fatty degeneration of the liver (n = 3) as well as non-alcoholic liver diseases (chronic persisting hepatitis, n = 11; chronic active hepatitis, n = 8, cirrhosis, n = 7) did not show this cellular immune reagibility. The inhibition of the migration and the stimulation of the migration, respectively, might develop by hapten autoantigen complexes (altered cytoskeleton?) with release of the factors of inhibition of migration and stimulation of migration, in which case the role of a hapten belongs to acetaldehyde. The results of the tests did not correlate with functional and histological findings of the liver, with the actual consumption of alcohol and also not with haptoglobin phaenotypes. When it is postulated that by acetaldehyde also the release of further lymphokines is mediated, origin and progression of alcoholic hepatitis and alcoholic cirrhosis might be explained immunopathogenetically.
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PMID:[Acetaldehyde-induced leukocyte migration inhibition in alcoholic liver diseases]. 712 38

Inherited variations in alcohol and aldehyde dehydrogenases, the principal enzymes of ethanol metabolism, have been implicated in determining susceptibility to alcoholism and alcohol-related organ damage. An association between an RFLP for the alcohol dehydrogenase-2 (ADH2) gene and alcohol-induced liver damage was demonstrated in a Caucasian population. Genotyping studies revealed an increase in the ADH3(2) allele in patients with alcohol-induced cirrhosis. PCR studies of the ALDH5 gene have demonstrated diverse polymorphism within a short segment of its coding region, with marked inter-racial variation in allele frequencies. In addition, the Caucasian alcohol-induced flushing reaction has been characterised and its relationship with phenotypic polymorphism of ALDH1 examined.
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PMID:Alcohol and acetaldehyde dehydrogenase gene polymorphism and alcoholism. 791 53

Lysyl oxidase (EC 1.4.3.13), a copper-dependent enzyme which catalyses the formation of aldehyde cross-links, and acts primarily on collagen and elastin, is known to be increased during wound healing and in fibrotic disorders including liver cirrhosis and atherosclerosis, and to be decreased in some hereditary connective tissue diseases and in malignant cell lines. A recent study showed that lysyl oxidase might possess tumour suppressor activity as an antioncogene for ras. Little is known about the localization of this enzyme in human skin. In this study, we determined immunohistochemically the localization of lysyl oxidase in normal skin of young and elderly subjects obtained from sun-exposed and unexposed regions of the body. All skin samples tested had similar distributions of lysyl oxidase. The enzyme was present both extracellularly and intracellularly. Extracellularly, a few granular aggregates of immunoreactants were observed along collagen and elastic fibres. These granules were more common in the adventitial portion of the dermis than in the reticular portion. Of all sun-exposed and unexposed regions studied, the skin of the face displayed the greatest amount of extracellular immunoreactants. Immunopositive granules were observed intracellularly in fibroblasts, vascular endothelial cells, sweat glands, sebaceous glands, arrector pili muscles and some keratinocytes. These findings provide evidence that, as suggested in recent reports, lysyl oxidase may have a variety of intracellular functions.
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PMID:Immunohistochemical localization of lysyl oxidase in normal human skin. 791 5

The location of acetaldehyde binding sites in the axial unit cell of tendon collagen was investigated by neutron diffraction. Acetaldehyde forms spontaneous cross-links with specific residues in collagen. The use of deuterated acetaldehyde increased the neutron scattering length of these groups. The introduction of deuterated acetaldehyde at specific locations allowed the acetaldehyde-reacted collagen to be treated as multiple isomorphous derivatives for neutron fibre diffraction. The low resolution axially projected structure was determined using amplitudes of the first eight meridional reflections (d = 67 nm). Results indicate that the process of acetaldehyde labelling takes place at different rates at different sites within the collagen fibril. The position of acetaldehyde attachment correlates well with the position of lysine and hydroxylysine residues especially in the regions of the molecular termini. This information is relevant to the process of cirrhosis and fibrosis of the liver since adduction of collagen by acetaldehyde may interfere with normal Schiff base cross-link formation at the C- and N-termini. This may result in subsequent alterations in the intra- and inter-molecular cross-linking pattern of collagen molecules.
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PMID:The in vitro binding of acetaldehyde to collagen studied by neutron diffraction. 798 77

There are genetic and exogenous factors responsible for alpha 1-antitrypsin (alpha 1-AT) deficiency which may lead to cirrhosis of the liver and emphysema. The present study was initiated on a biochemical level in order to determine whether acetaldehyde, the major product of ethanol metabolism, is capable of influencing the physiological effect of alpha 1-AT upon elastase, an enzyme which is capable of inducing emphysema. The effects of acetaldehyde and ethanol upon elastase and alpha 1-AT were tested. Acetaldehyde at 0.3-M and 1.2-M concentrations inhibited the anti-elastase activity of alpha 1-AT. Acetaldehyde at 0.03-M and 0.07-M concentrations did not affect elastase activity and had a slight effect at 0.12-M levels. Equivalent amounts of ethanol were without influence upon elastase activity or alpha 1-AT function. These data provide biochemical support for the possibility that heterozygous males with lower than normal alpha 1-AT levels may be at much higher risk to develop liver disease, emphysema, and alpha 1-AT deficiency as a consequence of chronic exposure to ethanol and concomitant circulating acetaldehyde levels.
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PMID:Acetaldehyde inhibits the anti-elastase activity of alpha 1-antitrypsin. 806 May 17

In alcoholic liver disease, it is well-known that ethanol and its metabolites induce hepatic fibrosis. With progress in injury, the accumulation of extracellular matrix, which consists of type I, III, IV collagen and laminine, occurs in the area of hepatic central vein and perihepatocytes. In these fibrotic areas, the activated lipocytes (transitional cell and myofibroblast, etc), which may be transformed from Ito cell by fibrogenic cytokines, are increased and may play an important role in the progression of alcoholic hepatic fibrosis. Actually, a recent study indicates that chronic ethanol consumption sensitizes the response of lipocytes to TGF beta. It is observed that acetaldehyde and lactate stimulate collagen production and that acetaldehyde increases collagen mRNA expression and collagen gene transcription in cultured human fibroblast. The extracellular matrix is degraded by matrix metalloproteinases (MMPs). The collagenase activity is decreased in progression of liver cirrhosis and is regulated by fibrogenic cytokines. Acetaldehyde decreases by 50% of the collagenase mRNA expression in fibroblast. It is clear that hepatic fibrosis may progress under the balance of collagen production and degradation, which are associated with fibrogenic cytokines. Thus, in the search for mechanism of alcoholic hepatic fibrosis, it is important to elucidate how ethanol and its metabolites influence the activation of lipocytes through fibrogenic cytokines.
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PMID:[Alcoholic liver cirrhosis]. 811 91

The modifying action of experimentally induced chronic liver injury on diethylnitrosamine (DEN) hepatocarcinogenesis was investigated using a minimal treatment protocol. A single dose of DEN (15 mg/kg b.w.) was administered as a carcinogen to 1-day-old Sprague-Dawley rats. From 3 weeks of age rats received repeated intraperitoneal injections of carbon tetrachloride (CCl4), or 10% ethanol or 5% acetaldehyde in the drinking water for 9 weeks. Combinations of CCl4 and ethanol or acetaldehyde were also tested. Morphology, immunohistochemistry for glutathione S-transferase-placental form, and incidence and quantity of preneoplastic lesions of the livers were studied. The chronic CCl4 administration produced complete or incomplete liver cirrhosis and exerted a strong promoting effect on the development of neoplastic nodules. Ethanol alone revealed no cirrhogenous or tumor-promoting effect, but enhanced both actions of CCl4. Acetaldehyde increased only the cirrhogenous effect of CCl4.
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PMID:Effects of carbon tetrachloride, ethanol and acetaldehyde on diethylnitrosamine-induced hepatocarcinogenesis in rats. 833 Feb 98


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