In consideration of the vast prevalence of schistosomiasis and heavy alcohol consumption in many parts of the world, the possibility of an interaction between these two conditions inducing liver disease was studied in mice infected with Schistosoma mansoni. Alcohol consumption significantly reduced by 25% the mean granuloma diameter and by about 60% the extent of fibrous tissue deposition determined chemically as hydroxyproline. DNA, as an expression of the inflammatory and cellular components of the granulomatous reaction in the infected animals, was also significantly reduced by alcohol consumption. These results indicate the need for epidemiological studies in the clinical manifestations and course of schistosomiasis in human alcoholics.

Alcoholism↗

PubMedDate not supplied

Assessment of prognostic factors in alcoholic liver disease: toward a global quantitative expression of severity.

The prognostic significance of a battery of clinical, laboratory, and histological indicators was assessed in relation to mortality risk in a 1-year study of 253 patients with alcoholic liver disease, of whom 51 died within such time. The relative risk associated with each abnormality was calculated. A number of abnormalities was found to be statistically associated with a higher risk of death. Among the clinical abnormalities, these were: collateral circulation, edema, ascites, encephalopathy, spider nevi, anorexia, and weakness. Among the laboratory tests, these were: albumin, bilirubin, hemoglobin, abnormal prothrombin time, and alkaline phosphatase. Two hundred and sixteen of these patients had liver biopsies in which the quantifiable abnormalities were scored. Among the histological findings, the alterations significantly related to mortality were necrosis, Mallory, and inflammation, while the presence of cirrhosis per se did not influence the mortality risk. The relative risk factors for mortality associated with the histological alterations were lower than those derived from clinical or laboratory measurements. The advantage of using only clinical and laboratory items to derive a global, quantitative expression of severity is discussed. The relative mortality risks provided a means of calculating a "unit of severity" for each clinical and laboratory abnormality. A combined clinical and laboratory index (CCLI) results when these mortality-risk units are added. Such a combined index had a quasi-linear relationship with the risk of mortality for the complete population. This method compared well with severity scores derived from computerized, linear step-wise discriminant function (SDF) analysis and from a logistic regression (LR) analysis. The factors chosen to have independent prognostic significance by the SDF analysis were: encephalopathy, albumin, prothrombin time, and hemoglobin, while only encephalopathy, albumin, and hemoglobin were chosen by the LR analysis. Within a range of values, LR can provide a good discrimination in relation to mortality, similar to that observed for the CCLI in its complete range. However, there are some advantages to the CCLI method vs. the LR or SDF analyses. The CCLI is less susceptible to being unduly influenced by a nonspecific effect of treatment on the items chosen than the SDF and LR analyses, as the CCLI contains a large number of factors. Obtaining a single-severity score such as the CCLI is of value in: (a) assessing the effectiveness of treatment modalities; (b) analyzing the success of randomization; (c) separating cohorts of different severity, and (d) comparing new liver tests, histological abnormalities, or specific biological events with the severity of alcoholic liver disease.

Age Factors↗

PubMedDate not supplied

Sinusoidal caliber in alcoholic and nonalcoholic liver disease: diagnostic and pathogenic implications.

Portal hypertension in alcoholic liver disease has been attributed to an increased resistance to blood flow either of sinusoidal or of postsinusoidal origin. The former should be accompanied by sinusoidal compression while the latter is expected to result in an increased or a normal sinusoidal diameter. Patients with alcoholic liver disease showed a marked reduction (p less than 0.001) in relative sinusoidal area (995 +/- 135 micron 2; n = 19) when compared to nonalcoholic patients with normal liver histology (5,100 +/- 389 micron 2; n = 6), or to patients with nonalcoholic liver disease (6,242 +/- 467 micron 2; n = 19). Hepatocyte surface area was significantly increased in patients with alcoholic liver disease when compared to hepatocytes from normal biopsies (563 +/- 32 micron 2 vs. 301 +/- 26 micron 2; p less than 0.001). Patients with nonalcoholic liver disease had hepatocyte surface areas within the normal range (327 +/- 14 micron 2). There was a significant inverse correlation between hepatocyte size and sinusoidal area (r = -0.63; p less than 10(-6); n = 44), indicating that larger hepatocytes were associated with sinusoidal compression. In the alcoholic patients, portal pressure correlated inversely (r = -0.77; p less than 0.01) with sinusoidal area only after the sinusoidal area was markedly reduced to areas below 20% of normal. Such a threshold was not reached in patients with nonalcoholic liver disease, in whom no correlation between sinusoidal area and portal pressure was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Ethanol-induced increase in portal hepatic blood flow: interference by anesthetic agents.

While a number of studies show that acute oral administration of ethanol results in increases in liver blood flow, a large body of evidence has also been presented in which such an effect is not observed. To shed light on this discrepancy, we have studied in rats, a number of variables that might modulate or inhibit the effect of ethanol. These included the use of three anesthetic agents studied at two different times after anesthetic administration and the effect of animal age, gender, batches and seasonal variation. Portal blood flows were determined by the radiolabeled microsphere method in 12 separate experiments in awake rats. Ethanol given at doses ranging from 0.5 to 4.0 gm per kg consistently increased portal vein blood flow by approximately 50% (42.2 +/- 3.5 to 63.4 +/- 6.5 ml per min per kg). The interexperiment variation was 2.4 to 3.0%, showing remarkable consistency, typical of an all-or-none effect at the doses employed. On the other hand, the ethanol-induced increase in portal blood flow was completely suppressed by ketamine (75 mg per kg), thiopental (50 mg per kg) and fentanyl (15 micrograms per kg) when given 15 min prior to blood flow determinations. This suppression was dependent on the dose and duration of anesthesia. These anesthetic agents had no effect on basal hepatic arterial or portal blood flows. Ethanol or the anesthetics were without effects on hepatic artery blood flow. Neither gender, weight (150 to 350 gm) nor animal batch had effect on the response to ethanol. Similarly, there was no effect of seasonal variation.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMedDate not supplied

Antibodies against acetaldehyde-modified protein epitopes in human alcoholics.

Acetaldehyde, the primary metabolite of ethanol, binds covalently to proteins forming condensation products which have been recently shown to be immunogenic. To assess whether an antibody response against acetaldehyde-modified protein epitopes is associated with alcoholic liver disease, the serum immunoreactivity against proteins modified in vitro by acetaldehyde and against the corresponding unmodified proteins was measured by an enzyme-linked immunosorbent assay in 58 alcoholics with varying degrees of liver damage. Alcoholics showed significantly higher titers against protein-acetaldehyde conjugates than against the unmodified protein, independent of the nature of the carrier protein. The highest titers occurred in alcoholic hepatitis patients. Sera of patients with chronic hepatitis of nonalcoholic origin and of healthy controls also reacted with acetaldehyde conjugates, but their titers were significantly lower than those in alcoholic hepatitis patients. Our data support the idea that binding of acetaldehyde to proteins in humans generates antigenic determinants which trigger a corresponding immune response against such epitopes and suggest that this humoral immune response may be implicated in autoantibody formation and liver damage associated with excessive alcohol consumption.

Acetaldehyde↗

PubMedDate not supplied

Studies on metabolic tolerance to alcohol, hepatomegaly and alcoholic liver disease.

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Alcohol Oxidoreductases↗

PubMedDate not supplied

Effect of alpha- and beta-blockers on ethanol metabolism.

The acute administration of propranolol or phentolamine resulted in a small (16-19%) but significant reduction in the rate of ethanol disappearance in vivo in the naive Wistar rat. A reduction of essentially similar magnitude was also observed in ethanol-treated rats and pair-fed (sucrose) control animals, following the administration of these blockers.

Alcohol Drinking↗

PubMedDate not supplied

The inhibitory effect of testosterone on the development of metabolic tolerance to ethanol.

We have investigated the mechanism(s) of metabolic tolerance to ethanol in a rat strain (spontaneously hypertensive or SH) in which liver alcohol dehydrogenase (ADH) levels are very low due to a marked inhibitory effect of testosterone on ADH. Chronic ethanol administration resulted in marked increases in the rate of ethanol metabolism and in ADH activity (+65 to 90%). Oxygen consumption measured in the perfused livers of the ethanol-fed rats was also elevated (+40%). The administration of 6-n-propyl-2-thiouracil (PTU), which was previously found to reduce hepatic oxygen consumption and to increase ADH activity, resulted in no change in the rate of ethanol metabolism in the ethanol-fed rats and an increase in the sucrose-fed controls, suggesting that increased ADH activity is more important for the development of metabolic tolerance to ethanol, in the male SH rat, than increased oxygen consumption. The activity of the microsomal ethanol-oxidizing system (MEOS) in vitro was induced by chronic ethanol treatment (+95%), but it may only account for a small part (32%) of the increase in ethanol metabolism in vivo. Serum testosterone concentrations were lower in the ethanol-fed rats at peak blood ethanol levels, relative to those found in controls. Concurrent chronic administration of ethanol and testosterone abolished about one-third of the absolute increases in ethanol metabolism and in ADH activity in the ethanol-fed rats. In conclusion, most of the metabolic tolerance to ethanol, in the male SH rat, appears to occur mainly due to a testosterone-independent increase in ADH activity and to a lesser degree to an increase in ADH activity produced by a reduction in testosterone levels in the ethanol-fed rats.

Alcohol Oxidoreductases↗

PubMedDate not supplied

Alcohol dehydrogenase is not a major determinant of alcohol preference in mice.

We present evidence that in MRL/Mp mice, difference in one gene affects the activity of alcohol dehydrogenase. MRL/Mp- + show high alcohol dehydrogenase (ADH) activity in the range of that found in C57BL/6, while MRL/Mp-lpr show ADH values in the range of non-drinker strains such as DBA/1, BALB/c, A, SJL, CBA and C3H/He. Voluntary alcohol consumption in MRL/Mp- + is 30-40% higher than that in the MRL/Mp-lpr. However, alcohol preference of both congenic strains is markedly lower than those of C57BL/6 mice. Our findings lead us to conclude that although alcohol dehydrogenase levels do relate to alcohol preference in mice, they are responsible for only a minor fraction of inter-strain differences.

Alcohol Dehydrogenase↗

PubMedDate not supplied

Gamma-glutamyl transferase ectoactivity in the intact rat liver: effect of chronic alcohol consumption.

The localization of gamma-glutamyl transferase (GGT) in the intact rat liver was studied by a new approach in which the chromogenic gamma-glutamyl donor substrate of GGT gamma-glutamyl-p-nitroanilide is perfused through the portal vein to yield p-nitroaniline, which is monitored spectrophotometrically. GGT activity was markedly increased by the gamma-glutamyl acceptors glycyl-glycine, cystine and methionine, following Michaelis-Menten kinetics. Infusion of glutathione (GSH), the natural substrate of GGT, was shown to markedly reduce or to abolish the formation of p-nitroaniline without entering the liver cells, indicating the existence of a GGT ectoactivity accessible to the sinusoidal circulation. This ectoenzyme was shown to remove significant amounts of GSH from the circulation, amounting, in the naive rat, to 20-25% of the net rate at which GSH is contributed by the liver into the circulation. Chronic alcohol consumption is known to increase hepatic GGT activity, although the biological significance of such an effect remains unknown. Present studies show that chronic administration of alcohol to rats leads to a significant (40-75%) increase in hepatic GGT ectoactivity. GGT ectoactivity significantly correlates with total liver GGT, both in control and alcohol-treated animals (r = .76 and r = .90, respectively). Livers of alcohol-fed rats showed an increased (80-110%) capacity to remove circulating GSH which strongly correlated with total liver GGT (r = .96; p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

1-Carboxyglutamic Acid↗