Nonalcoholic Subjects Research Articles

Ethanol metabolism and aging: the role of "first pass metabolism" and gastric alcohol dehydrogenase activity.

To investigate the effect of age and gender on ethanol metabolism, first-pass metabolism (FPM) and gastric alcohol-dehydrogenase (ADH) activity were compared in 32 elderly and 30 young adult nonalcoholic subjects. The FPM was obtained from the difference between the area under the curve of ethanol blood concentration after intravenous or oral administration of ethanol 0.3 g/Kg b.w. The ADH activity was determined in samples of gastric mucosa obtained during diagnostic endoscopy. In the young adult group the FPM was higher in men than in women (3.3 +/- 2.3 vs 1.2 +/- 0.9 mmol/l/h, respectively, p < .01). In aged subjects FPM was found to be very low for men (1.1 +/- 0.8 mmol/l/h, p < .001); conversely, FPM was not significantly reduced in women (1.7 +/- 0.8 mmol/l/h, p = n.s.). The gastric ADH activity was significantly (p < .01) higher in young adult men than women, whereas in aged subjects the activities were low (p < .0001) in both sexes. Thus, gender-related FPM differences equalize in the elderly or are even reversed, most likely because of gastric mucosal atrophy, which occurs more in men than women.

Serum secretory IgA and secretory component in patients with non-cirrhotic alcoholic liver diseases

Elevated levels of secretory IgA in serum have been demonstrated in several liver dysfunctions such as hepatic cytolysis and cholestasis. However, these possible alterations at an eary stage of liver diseases have not yet been investigated. We studied a cohort of chronic alcoholic patients without cirrhosis in order to assess the changes in serum secretory IgA and other forms of secretory component, the split product of the polymeric Ig-receptor of epithelial cells. The possible diagnostic value of these measurements in the assessment of alcoholic disease was compared to that of serum gamma-glutamyl transpeptidase activity.Serum levels of secretory IgA and IgM and free secretory component, were quantified by an enzyme-linked immunosorbent assay in 71 patients with chronic alcoholic liver disease without cirrhosis and in 45 healthy controls. Patients were divided into two groups according to the severity of the liver abnormalities. In addition, the reversibility of serum secretory IgA, IgM and free secretory component abnormalities after alcohol withdrawal was evaluated in 15 patients.Serum levels of the three molecular forms of secretory component were significantly higher than those measured in control subjects, both in the whole population of patients and in the two groups of alcoholic patients without cirrhosis. In all groups, serum secretory IgA levels were correlated to free secretory component but not to total IgA levels. Serum secretory IgA levels were as discriminative as gammaglutamyl transferase activity in distinguishing between chronic alcoholic patients without cirrhosis and non-alcoholic subjects. The abnormalities of serum secretory IgA concentrations were reversible after alcohol withdrawal.The results of this study demonstrate that serum secretory IgA and free secretory component levels are significantly increased in patients with chronic alcoholic liver disease, even at a very early stage of the disease, and decrease after alcohol withdrawal. Serum secretory IgA could therefore be used as an additional marker of mild liver abnormalities in chronic alcoholic subjects, and of the effectiveness of alcohol withdrawal. Release of polymeric Ig-receptor into the serum could share a similar physiopathological mechanism with gamma-glutamyl transpeptidase.

Abstracting capacity in cirrhotic alcoholics: negative findings.

Alcoholic and nonalcoholic cirrhotics and normal controls were compared to determine the extent to which the cognitive deficits frequently observed in alcoholics are attributable to hepatic encephalopathy. A battery of neuropsychological tests was administered measuring verbal and nonverbal abstracting capacity. No significant differences between the three groups were observed. Both the alcoholic (n = 43) and nonalcoholic (n = 63) subjects performed comparably to normal controls (n = 21) and the former two groups performed comparably to each other on seven indicators of abstracting capacity. Deficits in reasoning ability are not invariably associated with chronic alcoholism. In addition, low grade hepatic encephalopathy concomitant to cirrhosis in both alcoholics and nonalcoholics does not impact adversely on abstracting capacity.

GENETIC POLYMORPHISM OF LIVER ALCOHOL DEHYDROGENASE IN SPANTSH SUBJECTS: SIGNIFICANCE OF ALCOHOL CONSUMPTION AND LIVER DISEASE

Class I alcohol dehydrogenase (ADH) phenotypes have been studied by starch gel electrophoresis and activity analysis in liver tissue obtained at necropsy from 61 non-alcoholic subjects with normal liver (controls), and in biopsies from 60 chronic alcoholics with liver disease and from 24 subjects with non-alcoholic liver disease. Twenty-three per cent of controls exhibited the ADH2 phenotype, which represents the highest frequency for atypical ADH found in a Caucasian population. Both alcoholic and non-alcoholic patients with liver disease showed a lower frequency of the atypical phenotype (6.6% and 8.8%, respectively). No differences in the ADH2 locus were detected among groups of patients with different severity of alcoholic and non-alcoholic liver disease. The allele frequencies of the ADH3 locus for the controls (ADH3 = 0.63, ADH3 = 0.37) are common to those of other Caucasian populations. Similar ADH3 allele frequencies were observed in patients with alcoholic and non-alcoholic liver disease. Discrepancies between the various phenotyping and genotyping studies now known for several populations suggest that local differences may exist in the distribution of the ADH polymorphism in even geographically close regions, and that the effect of ADH polymorphism on vulnerability towards alcohol may not be identical in different populations.

Interrelationships of alcohol intake with blood vitamin status in nonalcoholic subjects

The vitamin status was investigated in 157 healthy men, aged 20 to 60 years and recruited in the Centre for Preventive Medicine of Dijon (France), by means of a dietary survey and biochemical studies. Subjects were grouped according to their usual alcohol intake: 0 g/d, 0.1–39 g/d, 40–79 g/d, and 79+ g/d. The 1992 French Recommended Dietary Allowance (FRDA) was used to assess adequacy of intake. Drinkers had similar intakes of total calories than nondrinkers. Calories derived from ingested alcohol appeared to replace carbohydrate as a source of energy in drinkers. Thiamin, riboflavin, folate, and vitamin A mean intakes decreased significantly when alcohol intake increased. The serum concentration of retinol and retinol-binding protein was significantly higher in drinkers than in nondrinkers. Drinkers did not have a higher risk rate for a biochemical vitamin deficiency of thiamin, riboflavin, vitamin B 6, folate, vitamin B 12, vitamin C, vitamin A, and vitamin E than the nondrinkers. The percentage of subjects with plasma 25(OH)D < 10 nmol/L was high (≈33%) in subjects drinking 79+ g alcohol/d, which indicated a high risk of deficiency of vitamin D in this group.

Differential expression of guanosine triphosphate binding proteins in men at high and low risk for the future development of alcoholism.

We evaluated G-proteins that are components of adenylyl cyclase (AC) signal transduction in erythrocyte and lymphocyte membranes from 26 family history positive (FHP) non-alcoholic and 26 family history negative (FHN) nonalcoholic subjects. Subjects were classified as FHP if their father met criteria for alcohol dependence; as FHN, if there was no history of alcoholism in any first or second degree relatives. Immunoblot analysis indicated that levels of erythrocyte membrane Gs alpha from FHP subjects were greater than levels in FHN subjects (171 +/- 11 vs 100 +/- 6, P < 0.001). To confirm the results of the immunoblot analysis, Gs alpha was quantitated by cholera toxin-dependent [32P]ADP-ribosylation. Levels of erythrocyte [32P]ADP-ribose-Gs alpha from FHP subjects were greater than levels in FHN subjects (236 +/- 28 vs 100 +/- 14, P < 0.001). Gs alpha levels did not correlate with age or alcohol consumption. By contrast to differences in Gs alpha, immunoblot analysis showed similar levels of Gi(2)alpha and Gi(3)alpha in erythrocyte membranes of FHP and FHN subjects. Pertussis toxin-catalyzed [32P]ADP-ribosylation of Gi-like G-proteins confirmed the immunoblot observations. Lastly, compared to FHN subjects, FHP subjects had enhanced Gs alpha expression in lymphocyte membranes as well (138 +/- 11 vs 100 +/- 5.5; P < 0.02). In summary, compared to FHN nonalcoholic men, FHP nonalcoholic men had greater levels of the stimulatory G-protein, Gs alpha, in erythrocyte and lymphocyte membranes. Enhanced expression of Gs alpha may be a marker of increased risk for the future development of alcoholism.

Collagen–Acetaldehyde Adducts in Alcoholic and Nonalcoholic Liver Diseases

ABSTRACT Alcoholic and, to a lesser extent, nonalcoholic patients with liver disease have serum antibodies to acetaldehyde–protein adducts produced in vitro. These antibodies presumably reflect the presence of adducts in the liver, but the protein that triggers this immune response has not been identified. To study this, we measured the reactivity of cytosolic proteins to rabbit IgG developed against a P–450 2E1—acetaldehyde adduct, isolated from alcohol–fed rats, that recognizes acetaldehyde–modified epitopes in proteins. Adducts were determined on Western blots by scanning densitometry of antibody–linked alkaline phosphatase activity in 4 normal livers and in needle biopsy specimens from subjects with liver disease, 17 alcoholic and 14 nonalcoholic. In all livers, except for a normal one, we found a reactive protein of at least 200 kD, similar to the collagen–acetaldehyde adduct we reported to be markedly increased in rats with experimentally induced cirrhosis. The immunostaining intensity in the alcoholic patients with liver disease was eightfold (p&lt;0.01) and that in nonalcoholic patients with liver disease was fourfold, greater (p&lt;0.02) than the weak staining in normal livers; it correlated with the degree of inflammation and serum AST or γ–glutamyl transpeptidase activities. The adduct was reproduced on incubation of normal cytosolic proteins with 2.5 mmol/L acetaldehyde, whereas higher concentrations yielded many additional adducts; the adduct also reacted with IgG antibody to rat collagen type I and disappeared after digestion with collagenase, suggesting that the target protein is a form of collagen. The association of this collagen–acetaldehyde adduct with parameters of liver disease activity suggests that the adduct reflects the liver injury and may even contribute to its development, both in alcoholic and in nonalcoholic subjects. (Hepatology 1994;20:111-118.)

CORRELATIONS BETWEEN ACETALDEHYDE-MODIFIED HAEMOGLOBIN, CARBOHYDRATE-DEFICIENT TRANSFERRIN (CDT) AND HAEMATOLOGICAL ABNORMALITIES IN CHRONIC ALCOHOLISM

Serum levels of carbohydrate-deficient transferrin (CDT), the proportions of eight haemoglobin fractions separated by cation exchange liquid chromatography, indices of liver function and various haematological parameters were determined in most of a group of 49 chronic alcoholics who had misused alcohol for at least the preceding 3 months and in 15 healthy non-alcoholic control subjects. The percentages of alcoholics giving abnormally high values for gamma-glutamyl transferase (GGT) activity, CDT levels, GGT activity or CDT levels or both, and aspartate aminotransferase (AST) activity were, respectively, 73.0, 71.0, 87.1 and 64.4. The percentages of patients giving abnormally high values for the proportion of HbA1a, proportion of HbA1ach, proportion of HbA1a or HbA1ach or both, MCH, MCV and red cell distribution width (RDW) were, respectively, 46.8, 25.5, 55.3, 55.3, 36.2 and 29.8. Reduced values for the red cell folate concentration, lymphocyte count and platelet count were found in 36.2%, 6.4% and 17.0%, respectively, of the alcoholics. When compared with the control subjects, the group of alcoholics showed statistically significant increases in the mean values for the MCV, MCH, MCHC and RDW and statistically significant decreases in the mean values for the haemoglobin distribution width (HDW) and the logarithms of the holo-transcobalamin II concentrations and the platelet count. The logarithms of the CDT values correlated directly with the MCV and MCH and inversely with the logarithms of the lymphocyte or platelet counts and the HDW, suggesting but not proving that the haematological changes in chronic alcoholism may be at least partly related to defective glycosylation of the constituents of developing blood cells or, possibly, of haemopoietic growth factors.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ethanol on energy expenditure.

The thermogenic response induced by ethanol ingestion in humans has not been extensively studied. This study was designed to determine the thermic effect of ethanol added to a normal diet in healthy nonalcoholic subjects, using indirect calorimetry measurements over a 24-h period in a respiration chamber. The thermic effect of ethanol was also measured when ethanol was ingested in the fasting state, using a ventilated hood system during a 5-h period. Six subjects ingested 95.6 +/- 1.8 (SE) g ethanol in 1 day partitioned over three meals; there was a 5.5 +/- 1.2% increase in 24-h energy expenditure compared with a control day in which all conditions were identical except that no ethanol was consumed. The calculated ethanol-induced thermogenesis (EIT) was 22.5 +/- 4.7% of the ethanol energy ingested. Ingestion of 31.9 +/- 0.6 g ethanol in the fasting state led to a 7.4 +/- 0.6% increase in energy expenditure over baseline values, and the calculated EIT was 17.1 +/- 2.2%. It is concluded that in healthy nonalcoholic adults ethanol elicits a thermogenic response equal to approximately 20% of the ethanol energy. Thus the concept of the apparently inefficient utilization of ethanol energy is supported by these results which show that only approximately 80% of the ethanol energy is used as metabolizable energy for biochemical processes in healthy nonalcoholic moderate ethanol consumers.

Atypical Liver Alcohol Dehydrogenase in the Spanish Population: Its Relation with the Development of Alcoholic Liver Disease

The presence of atypical liver alcohol dehydrogenase (ADH) was determined in samples of liver tissue from 222 alcoholic and nonalcoholic subjects to determine its prevalence in the Spanish population, and to evaluate the possible relationship between the presence of this isoenzyme and the development of alcoholism and alcoholic liver disease. Alcoholic patients were classified into the following groups: control subjects, with normal liver pathology (group 1), patients with noncirrhotic liver disease (group 2), and patients with cirrhosis of the liver (group 3). Nonalcoholic subjects were also divided, following the same criteria, into groups 4, 5, and 6, respectively. The prevalence of atypical ADH in the population analyzed was 16.2%. Atypical ADH was present in 14.9% of alcoholics and in 17.4% of nonalcoholics (p = NS). There were no significant differences when the prevalence of atypical ADH of alcoholic and nonalcoholic patients with similar degrees of liver pathology was compared (group 1 vs. 4, group 2 vs. 5, and group 3 vs. 6). The prevalence of atypical ADH was also similar in cirrhotic patients with respect to those of noncirrhotic liver disease and control patients, either in alcoholic or nonalcoholic groups. Our findings indicate that the prevalence of atypical ADH in the Spanish population is similar to that reported for other Caucasian groups. Moreover, the presence of atypical ADH does not play a role in the development of alcoholism nor in the development of alcoholic liver disease in the population analyzed.

Cerebral trauma and alcohol abuse.

We report results of clinical examinations, computed tomography, quantitative electroencephalography (QEEG), and cerebral blood flow measurements performed on a series of 56 consecutive brain injury patients including 15 alcohol abusers and 41 non-alcoholic subjects. Greater volumes of intracranial haemorrhage were noted in the alcoholics for a similar severity of injury and local brain atrophy became more pronounced in them during a follow-up of 1 year. After this time, the third ventricle width, distance between frontal horns, the sum of lateral ventricle dimensions and cortical sulci were all markedly larger in the alcoholics. The QEEG results also indicated a weaker improvement in the alcoholics. The cerebral blood flow at the site of the injury was initially slow in the alcoholics when compared to the contralateral region of the other hemisphere, although these differences disappeared during the follow-up. Permanent occupational disability was also found to be associated with pretraumatic alcohol abuse. The findings indicate that ethanol abuse is not only commonly associated with cerebral trauma but is also a risk factor for a more severe brain damage following the injury.

Social contingencies and the effects of punishment in alcoholics and nonalcoholics

Okulitch and Marlatt (1972) have argued that alcoholics show a differential tolerance for punishment relative to nonalcoholics. However, the studies purporting to support this assertion failed to control for the effects of social factors on alcoholics' tolerance of punishment. The present study compared alcoholics' and nonalcoholics' tolerance for punishment under two conditions. In the private condition, subjects were led to believe that no one would know how they responded to a task involving punishment. In the public condition, it was made clear that the subjects' responses would be known to the experimenter. In the public condition, alcoholic subjects made more punished responses than nonalcoholic subjects. In the private condition, neither group responded in the presence of punishment.

The dose-dependency of alcohol-induced hypoparathyroidism, hypercalciuria, and hypermagnesuria

Ingestion of alcohol evokes hypoparathyroidism, hypercalciuria, and hypermagnesuria. The dose-dependency of these changes has not been assessed before. We measured the serum concentrations of intact parathyroid hormone (PTH), and serum and urine calcium and magnesium in six normal men before and at intervals up to 6 h after the ingestion of fruit juice (control) and 0.5, 1.0 and 1.3 g of alcohol per kg of body weight. As compared with the control experiment the maximum reductions in the mean PTH concentration were 31% (P = 0.19), 31% (P = 0.20) and 45% (P = 0.01) with the three alcohol doses, respectively. After stopping drinking, the urinary excretion of calcium was 85%, 142% and 207% higher during the three alcohol experiments than during the control session (P < 0.05, < 0.01 and < 0.01, respectively), also urinary magnesium increased up to threefold. We conclude that in nonalcoholic subjects acute alcohol intake induces hypoparathyroidism, hypercalciuria, and hypermagnesuria, the latter two being dose-dependent. The direct renal effects of alcohol are the major mechanisms for hypercalciuria and hypermagnesuria, but hypoparathyroidism contributes to hypercalciuria at high levels of alcohol intoxication.

Drug-induced hepatic injury: an analysis of 1100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987.

The Danish Committee on Adverse Drug Reactions received 1100 reports of suspected drug-induced hepatic injury during the decade 1978-1987. The causal relationship between drug and hepatic injury was classified as definite in 57 (5.2%) reports, probable in 989 (89.9%) reports, possible in 50 (4.5%) reports and unclassifiable in four (0.4%) reports. Hepatic injuries accounted for 5.9% of all adverse drug reactions reported, and 14.7% of the lethal adverse drug reactions. A total of 47.2% were classified as acute cytotoxic, 16.2% as acute cholestatic and 26.9% as abnormal hepatic function. In 52 (4.7%) cases the hepatic injury was lethal; only 14 (1.3%) cases were chronic. Halothane accounted for 25% of the cases. The incidence of halothane-induced hepatic injury is decreasing, and only one lethal case has been reported since 1981. Next to halothane, sulfasalazine was the drug most often suspected during the last 2 years of the decade. Based on consumption data, the incidence of hepatic injury due to sulindac was estimated to be 18-fold higher than that due to ibuprofen. Paracetamol was reported to induce acute cytotoxic as well as cholestatic reactions in non-alcoholic subjects taking therapeutic doses.

Diazepam- and chlordiazepoxide-mediated increases in erythrocyte aldehyde dehydrogenase activity and its possible implications

Erythrocyte ALDH activity was assayed in alcoholic ( n = 70) and nonalcoholic ( n = 40) subjects. In general, alcoholics without any prior medications ( n = 57) were found to have a decreased ALDH activity (mean ± SD: 3.38 ± 1.7 mU; p < 0.001) as compared to control group (5.10 ± 1.57 mU). However, a group of alcoholics who were detoxified with benzodiazepines ( n = 13) prior to blood collection for enzyme assay were found to have higher ALDH activity (4.92 ± 2.46 mU; p < 0.05) as compared to alcoholics who were not detoxified. In vitro experiments demonstrated that both diazepam (DZM) and chlordiazepoxide (CDP) could activate the ALDH. The magnitude of enzyme activation by DZM and CDP appear to correlate with their relative potency of tranquilizing effect. Further, the observed ability of DZM to reverse the inhibition of ALDH mediated by disulfiram may explain the biochemical basis of the reported ability of benzodiazepines (BDZ) to reduce the intensity of disulfiram ethanol reaction (DER).

Acute ethanol intoxication may not alter alpha 2-adrenoceptors in the human brain.

The specific binding of the alpha 2-adrenoceptor agonists [3H]clonidine and [3H]bromoxidine (UK 14304) was measured in the postmortem brain of ethanol intoxicated nonalcoholic subjects (blood ethanol concentration: 1.37 +/- 0.30 g/l) and matched controls. In the frontal cortex, the density of binding sites for [3H]clonidine (Bmax = 58 +/- 7 fmol/mg protein) and [3H]bromoxidine (UK 14304) (Bmax = 49 +/- 7 fmol/mg protein) in ethanol intoxicated subjects did not differ from those in the control groups (Bmax = 68 +/- 4 and 56 +/- 8 fmol/mg protein for the respective radioligand). The dissociation constants (KD) were also similar in both groups. The binding capacities (Bmax) and KD values for both radioligands also were found unchanged in the hypothalamus, amygdala, head of caudate, hippocampus and cerebellum. The results demonstrate that, contrary to the beta-adrenoceptor, the presence of ethanol in the human brain does not alter the high-affinity state of the alpha 2-adrenoceptor in the frontal cortex and possibly also in other brain regions.

Alcoholism

This descriptive study attempted to determine if significant differences in temporal adaptation existed between alcoholic and non-alcoholic subjects, through an evaluation of interests and use of time. Kielhofner's conceptual framework of temporal adaptation (1977) and Kielhofner and Burke's (1980) Model of Human Occupation served as the theoretical foundation for this research. Two measurement instruments-an adaptation of Matsutsuyu's (1969) Interest Checklist and the Hourly Time Log-were administered to a group of twenty-five alcoholics in a rehabilitation program and to twenty-five non-alcoholic volunteers from the working community. Data analysis revealed statistically significant differences between the two groups in several dimensions.

Allelic Association of the D2 Dopamine Receptor Gene With Receptor-Binding Characteristics in Alcoholism or Gene ism

The allelic association of the human D2 dopamine receptor gene with the binding characteristics of the D2 dopamine receptor was determined in 66 brains of alcoholic and non-alcoholic subjects. In a blinded experiment, DNA from the cerebral cortex was treated with the restriction endonuclease Taql and probed with a 1.5-kilobase (kb) digest of a clone (lambda hD2G1) of the human D2 dopamine receptor gene. The binding characteristics (Kd [binding affinity] and Bmax [number of binding sites]) of the D2 dopamine receptor were determined in the caudate nuclei of these brains using tritiated spiperone as the ligand. The adjusted Kd was significantly lower in alcoholic than in nonalcoholic subjects. In subjects with the A1 allele, in whom a high association with alcoholism was found, the Bmax was significantly reduced compared with the Bmax of subjects with the A2 allele. Moreover, a progressively reduced Bmax was found in subjects with A2/A2, A1/A2, and A1/A1 alleles, with subjects with A2/A2 having the highest mean values, and subjects with A1/A1, the lowest. The polymorphic pattern of the D2 dopamine receptor gene and its differential expression of receptors suggests the involvement of the dopaminergic system in conferring susceptibility to at least one subtype of severe alcoholism.

Abnormal sympathetic skin response in alcoholic subjects

Although the impairment of autonomic function has been described in alcoholic subjects, there is no evidence for such a dysfunction to be due to damage of autonomic centers or peripheral small caliber fibers. To investigate the function of peripheral fibres of the autonomic nervous system, we have carried out an electrophysiological study of the sympathetic skin response (SSR) in the hands and feet in 70 alcoholic and in 33 non-alcoholic subjects. In the hand, SSR recordings were done simultaneously in the palm and finger tip by stimulating the median nerve at the wrist. A conventional electrophysiological study performed in the same patients was used to classify them according to the presence or absence of electrophysiological criteria for peripheral polyneuropathy (ECPN). In analyzing the results of the SSR test, we found absent responses in the finger tip with present responses in the palm in 18 patients, 13 of them with ECPN. Absent responses in the feet were observed in 37 patients, 28 of them with ECPN. From our findings, it is concluded that alcoholics suffer from a dysfunction of sympathetic sudomotor activity due to axonal involvement of the most distal segments of the nerves.

Hepatic effects of dietary weight loss in morbidly obese subjects

This prospective study was carried out in order to evaluate the influence on liver morphology and function of a very-low-calorie formula diet. Fourty-one morbidly obese, non-alcoholic subjects had liver biopsy performed before and after a median weight loss of 34 kg. Fatty change improved ( p < 0.001), but 24% of the patients developed slight portal inflammation ( p = 0.039) or slight portal fibrosis ( p = 0.063). Patients developing portal fibrosis had a higher degree of fatty change at entry ( p = 0.029), a more pronounced reduction of fatty change ( p = 0.014) and a faster weight loss ( p = 0.026). Liver biochemistry, which was of no individual diagnostic value, improved. It is concluded that morbidly obese subjects with a high degree of hepatic fatty change are at risk of developing portal inflammation and fibrosis when undergoing very fast dietary weight reductions.