Alcoholic hepatitis.
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Hepatitis, Alcoholic↗
Biomedical subjects
A D Thomson
Publications and source records attributed to A D Thomson.
Alcoholic liver disease.
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Disease Susceptibility↗
Clubbing associated with oesophageal adenocarcinoma.
A patient with an oesophageal adenocarcinoma, recent onset of digital clubbing, and evidence of increased oestrogen synthesis is presented. In the discussion, some of the theories of the pathogenesis of clubbing are reviewed, together with previous reports of clubbing in gastro-oesophageal disorders. A possible unifying theory is proposed for our case which we believe is the first report of this triple association.
Adenocarcinoma↗
The genesis of alcoholic brain tissue injury.
1. Acetaldehyde has been implicated in the pathogenesis of alcohol-related liver damage by two mechanisms. Adduct formation with many tissue constituents, especially proteins, makes them immunologically foreign or reduces enzyme activity and formation of cytotoxic free radicals from acetaldehyde metabolism. Adduct formation damage to microtubule associated proteins and to hepatocyte membranes impedes protein movement into, out of and around the cell. 2. Evidence that these mechanisms also have a role in alcoholic brain damage includes raised blood acetaldehyde in alcoholics, especially in those chemically dependent, or in other abnormal states; effects of extra-hepatic free radical toxicity, including induction of superoxide dismutase activity and damaged, abnormal variants of the thiamin-dependent enzyme transketolase and extrahepatic acetaldehyde-adduct formation with haemoglobin. That acetaldehyde-mediated impairment of microtubule systems also damages the brain is suggested by its importance for the maintenance by protein transport of often greatly extended brain cell processes. 3. Oxygen-derived free radicals can damage brain tissue, the effects including cerebral oedema, neuronal loss and damage to the blood-brain barrier, all changes also reported in the brains from alcoholic patients. Alcohol-related pathology in the brain differing from that in the liver, shows sharper regional variations in vulnerability and adverse effects due to nutritional deficiencies, especially of B-group vitamins. Even though some such deficits are capable of causing encephalopathy in the non-alcoholic, the strong association between them and chronic alcoholism points to possible aggravation by metabolic interactions at various levels between acetaldehyde and thiamin or other B-vitamins. Selective regional vulnerability may reflect differences in ease of acetaldehyde access or to important metabolic differences. Alteration of animal behaviour by acetaldehyde points to a need to correlate clinical evidence of acetaldehyde central nervous cytotoxicity with the incidence of different types of cognitive defect.
Acetaldehyde↗
The age dependence of the activity and activation of human red blood cell transketolase.
Erythrocyte transketolase has been measured in normal controls and non-alcoholic patients not at risk from nutritional deficiency and without signs of brain damage. The enzyme activity declines steadily with age over a range from 18 to 90 years with a statistically significant fall of 25% over this period. Since this decline is apparent whether or not thiamin diphosphate is added in vitro to activate the apoenzyme, the activation ratios are independent of the age effect. The decline is seen in both sexes in patients and normal subjects. It is concluded that the reliability of the specific transketolase activity as an indicator of marginal thiamin deficiency will be improved if the results are expressed as a percentage of the mean normal value corrected for age with values less than 60% of the age adjusted mean taken to indicate possible deficiency.
Adolescent↗
Superoxide dismutase in the erythrocytes of acute alcoholics during detoxification.
The activity of erythrocyte superoxide dismutase in acute alcoholic patients on admission does not form a single population but clusters in two groups either above or below the normal range. The values in both groups revert towards the normal after a week of treatment. The divergent activities of this free radical scavenging enzyme between the two groups could not be explained by differences in age, haematology or liver function tests but are likely to be acute responses, possibly to diverse drinking patterns in the period immediately preceding admission.
Adult↗
The effect of di-isopropyl 1,3 dithiol-2-ylidenemalonate (malotilate) on the hepatic changes induced by ethanol administration in the rat.
The sulphur-containing drug, di-isopropyl-1,3-dithiol-2-ylidenemalonate (Malotilate) protects against the increase in hepatic triglyceride concentration after acute ethanol administration (either 6 g/kg p.o. or 2 g/kg i.p.) in rats. The compound had no influence on the increased hepatic NADH:NAD ratio (measured as the lactate:pyruvate and 3-hydroxybutyrate:acetoacetate ratios) after acute ethanol dosing (2 g/kg i.p.), but was found to lower hepatic acetaldehyde concentrations and prevent some of the disturbances in lipid metabolism observed in liver slices from ethanol-treated animals (e.g. decreased oxidation of [1-14C]palmitate to 14CO2) after this ethanol dose. The drug did not inhibit ethanol metabolism in this acute experiment. Administration of Malotilate to Wistar rats (100 mg/kg/day orally) during chronic feeding of ethanol as 36% of the total calorie intake in a liquid diet, resulted in a lower intake of the alcohol-containing diet by ethanol-fed animals and reduced body weight gain in rats which received the drug, without blood ethanol levels or the ethanol intake (expressed in g/kg body weight/day) being affected. In ethanol-fed animals, Malotilate prevented the production of fatty liver and the adaptive increase in the ethanol elimination rate (EER) normally seen in ethanol-fed animals, although the drug actually caused a slight increase in EER in glucose pair-fed controls. Malotilate did not significantly decrease the degree of induction of microsomal cytochrome P-450 by ethanol, but the increase in aniline hydroxylation was much less marked in animals receiving ethanol and Malotilate, suggesting that the activity of the inducible microsomal ethanol oxidising system (MEOS) may be reduced by the compound. Determination of hepatic acetaldehyde concentrations during ethanol feeding, and during an acute ethanol challenge test following long-term ethanol treatment showed that the compound significantly lowered the level of this ethanol metabolite in the liver under both circumstances. This reduction of hepatic acetaldehyde concentrations, probably resulting in part from the reduced EER as well as increased low-Km aldehyde dehydrogenase activities and glutathione contents seen in the livers of Malotilate-treated rats, are possible mechanisms by which the drug protects against triglyceride accumulation after ethanol administration.
Aldehyde Dehydrogenase↗
Alcohol and brain damage.
1. The safe limits of alcohol intake are difficult to define because of individual variations in susceptibility to damage. The present recommendations are based largely on epidemiological studies of liver damage. 2. Recent investigations indicate that alcoholic brain damage is much more common than previously suspected. More information is required about its natural history and the characteristics of individuals most likely to suffer damage. 3. Thiamin (vitamin B1) deficiency has long been associated with brain damage and may result from a number of additive causes in the alcoholic patient. New information indicating damage to the protein moeity of some of the thiamin-using enzymes has been reviewed, as have possible mechanisms of brain cell necrosis.
Alcohol Drinking↗
The activation of red blood cell transketolase in groups of patients especially at risk from thiamin deficiency.
Erythrocyte transketolase activation by thiamin diphosphate has been studied in elderly patients with moderate or severe chronic dementia, acute alcoholic admissions and chronic alcoholics with evidence of brain damage, mostly of the Wernicke-Korsakoff type. Significantly more patients in each group than controls showed abnormal activation of transketolase, not only by 0.3 mM thiamin diphosphate (TDP) but also in further activation by increase to 3 mM. This indicated the presence in a proportion of the alcoholic and the demented patients of an abnormal enzyme variant, similar to that previously found in vitro. The modified transketolase activation test may warn not only of marginal thiamin deficiency but also independently, of susceptibility to brain damage in patients at risk.
Adult↗
Possible role of toxins in nutritional deficiency.
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Alcohol Amnestic Disorder↗
Nutrition and alcoholic encephalopathies.
An assessment has been made of metabolic factors possibly causing or contributing to the brain damage associated with chronic alcoholism, especially thiamin lack or disturbance of amino acid metabolism. Abnormalities in the thiamin-dependent enzyme, transketolase, provide evidence of a high incidence of thiamin deficiency as well as of disturbed thiamin metabolism in chronic alcoholics, which are likely to be caused by reduced vitamin intake as well as impaired absorption. A grossly disturbed pattern of amino acids in the blood of patients undergoing treatment for alcohol withdrawal syndromes is likely to be caused by loss of hepatic function and may well aggravate brain damage caused by B group vitamin deficiency. A hypothesis is proposed of how chronic thiamin lack can lead to brain damage.
Alcoholism↗
Palmitoyl-catechin for alcoholic liver disease: results of a three-month clinical trial.
A prospective randomized double-blind trial of 3-palmitoyl-(+)-catechin at a dose of 1500 mg daily (500 mg t.d.s.) for 3 months vs placebo has failed to demonstrate statistically significant clinical, biochemical or histological benefit in patients with biopsy-proven alcoholic liver disease. Nevertheless, this trial has confirmed the beneficial effect of a reduction in the rate of alcohol consumption on alcoholic liver disease. Apart from clinical evidence of a higher rate of alcohol consumption by patients receiving the active drug during the trial, no adverse side-effects were identified and for this reason, it is suggested that a further trial should be considered with the daily dosage so far used in man (20 mg/kg) increased toward that (100 mg/kg) employed with benefit in animal experiments.
Alcohol Drinking↗
Effects of cysteine and antioxidants on the hepatic redox-state, acetaldehyde and triglyceride levels after acute ethanol dosing.
Cysteine and the synthetic antioxidants butylated hydroxytoluene (BHT) and N,N'-diphenyl-phenylenediamine (DPPD) have been found to protect against the increase in hepatic triglycerides caused by acute ethanol administration (2 g/kg/i.p.) in rats. None of these agents affected the ethanol-induced increase in the hepatic redox-state, measured as lactate/pyruvate and 3-hydroxybutyrate/acetoacetate ratios, and there was no influence of any of the compounds on ethanol metabolism. Of the three agents tested, only cysteine was found to lower the liver acetaldehyde concentration after ethanol administration, confirming reports that trapping of acetaldehyde can protect against ethanol hepatotoxicity. The protective action of the anti-oxidants suggests that lipid peroxidation (probably initiated by acetaldehyde) is an important event in the pathogenesis of acute alcoholic fatty liver.
Acetaldehyde↗
Changes in the activation of red blood cell transketolase of alcoholic patients during treatment.
Erythrocyte transketolase activation by thiamin diphosphate has been studied in alcoholic patients on admission and after treatment, which included vitamin therapy. The high proportion of the patients who showed an abnormal activation of transketolase, not only by 0.3 mM thiamin diphosphate but also further activation by increasing the thiamin diphosphate to 3 mM, was reduced considerably after treatment. A few patients, however, still showed continuing abnormalities even after treatment. Further study of the enzyme activation in vitro confirmed the presence of an enzyme variant, abnormal both in the ease with which the thiamin diphosphate could be removed and in requiring a high concentration of thiamin diphosphate for activation. Since the modified transketolase activation test appears not only to monitor the effectiveness of thiamin therapy but also independently to warn of persisting enzyme abnormalities, it could prove to be of general use in alcohol detoxification units.
Adult↗
The role of the hepatocellular redox state in the hepatic triglyceride accumulation following acute ethanol administration.
The role of the increased hepatocellular redox-state [( NADH]/[NAD+] ratio) as a mechanism underlying hepatic triglyceride deposition after acute ethanol dosing has been investigated in the rat. Following a single dose of ethanol (2 g/kg i.p.) in fasted rats, increases were observed at 1.5 hr in the hepatic [lactate]/[pyruvate] (133%), [3-hydroxybutyrate]/[acetoacetate] (69%) ratios, and the liver triglyceride concentration (129%). At the same time point, ethanol increased radioactivity incorporated into hepatic total lipid and triglyceride, after an injection of [U-14C] palmitic acid, by 76% and 158% respectively. Treatment of animals with Naloxone hydrochloride (2 mg/kg i.p.) at 1.0 hr and 2.5 hr after ethanol abolished these ethanol-mediated redox-state changes, without inhibiting ethanol oxidation or affecting hepatic acetaldehyde levels. This, however, did not prevent completely the triglyceride accumulation in the liver or reverse the enhanced uptake of radio-labelled palmitate caused by ethanol. Administration of sorbitol (3.5 g/kg i.p.) caused 109%, 57% and 200% increases in the hepatic [lactate]/[pyruvate], [3-hydroxybutyrate]/[acetoacetate] ratios and glycerol-3-phosphate concentrations respectively. However, the hepatic triglyceride concentration and the incorporation of [U-14C] palmitic acid into hepatic lipids were not influenced by this treatment. In vitro studies in which rat liver slices were incubated with [1-14C] palmitic acid also indicated that the altered [NADH]/[NAD+] ratio was not responsible for the decreased rate of fatty acid oxidation seen after ethanol administration or after the addition of ethanol to the incubation medium. In conclusion, these experiments indicate that increases in the hepatic [NADH]/[NAD+] ratio resulting from ethanol oxidation may not be directly implicated in the altered hepatic fatty acid utilisation and triglyceride deposition observed after acute ethanol administration in rats.
Acetaldehyde↗
Inhibition of ethanol induced hepatic vitamin A depletion by administration of N,N'-diphenyl-p-phenylene-diamine (DPPD).
The administration of ethanol as 36% of the total calories in a nutritionally adequate liquid diet for three weeks to male Wistar rats caused a 36% decrease in hepatic vitamin A levels (P less than 0.001) when compared with glucose pair-fed control rats, without affecting serum levels of the vitamin. Simultaneous administration of a synthetic antioxidant, DPPD (N,N'-diphenyl-p-phenylene-diamine) to ethanol-fed rats caused a 73% decrease in the extent of the ethanol induced hepatic vitamin A depletion (P less than 0.001). DPPD administration did not affect weight gain, dietary (and hence ethanol) intake or serum ethanol and vitamin A levels in ethanol-fed rats, nor did it affect hepatic or serum vitamin A levels in pair-fed controls. Increased hepatic catabolism of retinoic acid due to induction of cytochrome P450 by ethanol has been suggested as a mechanism of depletion. In the current study, DPPD administration to ethanol-fed rats did not reverse the ethanol induced increase in microsomal cytochrome P450 concentrations or aniline hydroxylase activity. These findings indicate that the ethanol induced hepatic vitamin A depletion can be largely dissociated from the induction of cytochrome P450. In view of the potent free radical scavenging activity of vitamin A, and the protective effect of DPPD against ethanol induced hepatic loss of the vitamin, this study suggests that increased free radical generation and direct peroxidation of vitamin A may be an important mechanism by which ethanol induced hepatic vitamin A depletion occurs in the rat.
Alcoholism↗
Reduced stability of rat brain transketolase after conversion to the apo form.
The stability of rat brain transketolase, whether measured at 37 or 0 degree C, was reduced after conversion to the apo form by removal of thiamine diphosphate, as shown by a decline in the activity recovered when assayed in the presence of thiamine diphosphate. Both the shape of the breakdown curve and the failure to recover the full activity, even after incubation with thiamine diphosphate, showed that the breakdown of the apotransketolase was complex. The initial rate of breakdown of the apoenzyme was sharply pH dependent, being minimal at 37 degrees C at a pH value of 7.6, close to that likely to exist in vivo. The rate rose sharply with deviation of the pH in either direction. The stability of the enzyme on storage at 0 degree C showed a similar pattern of pH dependence, provided that allowance is made for temperature effects on dissociation constants. These findings provide further support for the hypothesis that differences in brain transketolase may play a part in the etiology of Wernicke-Korsakoff's syndrome.
Animals↗
The effect of methylene blue on the hepatocellular redox state and liver lipid content during chronic ethanol feeding in the rat.
Feeding of ethanol in a liquid diet to male Wistar rats caused decreases in the hepatic cytosolic and mitochondrial [NAD+]/[NADH] ratios. This redox-state change was attenuated after 16 days of feeding ethanol as 36% of the total energy intake. Supplementation of the ethanol-containing liquid diet with Methylene Blue largely prevented the ethanol-induced redox state changes, but did not significantly decrease the severity of the hepatic lipid accumulation that resulted from ethanol ingestion. Methylene Blue did not affect body-weight gain, ethanol intake or serum ethanol concentrations in ethanol-fed rats, nor did the compound influence the hepatic redox state or liver lipid content of appropriate pair-fed control animals. These findings suggest that the altered hepatic redox state that results from ethanol oxidation is not primarily responsible for the production of fatty liver after long-term ethanol feeding in the rat.
Animals↗