Severe Alcoholics Research Articles

Receptor binding sites and uptake activities mediating GABA neurotransmission in chronic alcoholics with Wernicke encephalopathy

Superior frontal cortex (SFC) and primary motor cortex tissue was obtained at autopsy from thirteen severe chronic alcoholics with neuropathologically confirmed Wernicke Encephalopathy (WE) and 22 controls. Cases with both WE and cirrhosis showed markedly fewer neurones in SFC than did WE cases without cirrhosis. The extent of the apparent neuronal loss corresponded to an increase in post-synaptic GABA A receptor sites, as assessed by the binding of [ 3H]muscimol to synaptic membranes. Increased [ 3H]muscimol binding was not accompanied by an increase in ‘central-type’ benzodiazepine binding sites: as assessed by [ 3H]flunitrazepam binding, these sites were apparently unaltered, while as assessed by [ 3H]diazepam binding, they were decreased. The affinities of the two benzodiazepine ligands varied differently with disease. These discrepancies between [ 3H]flunitrazepam and [ 3H]diazepam binding could not be accounted for, either by the presence of a second, diazepam-preferring, ‘central-type’ benzodiazepine binding site, or by loss of ‘peripheral-type’ sites. The changes in the post-synaptic GABA A benzodiazepine receptor sites did not reflect any regional, disease-related deficit of afferent GABAergic terminals, as assessed by synaptosomal high-affinity [ 3H]GABA uptake. On a number of indices, it appears most likely that the data reflect both a loss of receptor sites, and a change in the population of receptor sub-types.

Polymorphism at the P450IIE1 Locus Is Not Associated with Alcoholic Liver Disease in Caucasian Men

Because alcoholic hepatitis and cirrhosis, well-known complications of alcohol abuse, do not occur in all alcoholics, genetic factors such as differences in alcohol-metabolizing enzymes may play a role in the development of alcoholic liver disease. Cytochrome P450IIE1 catalyzes the oxidation of ethanol, producing acetaldehyde and free radicals capable of reacting with and peroxidizing cell membranes. Polymorphisms have been identified in the 5'-flanking region of the P450IIE1 gene that may alter the transcriptional activity of the gene. In this study, we analyzed the P450IIE1 genotypes at the polymorphic PstI and RsaI restriction enzyme sites in 53 Caucasians with severe alcoholic liver disease to determine if there is an association between these polymorphisms and alcoholic liver disease. Subjects that tested positive for the hepatitis C virus were eliminated from the study. To identify the type A (homozygous for the c1 gene), type B (heterozygous for the c1 and c2 genes), and type C (homozygous for the c2 gene) genotypes at the P450IIE1 locus, DNA encompassing the polymorphisms was amplified by polymerase chain reaction, slot-blotted, and probed with allele-specific oligonucleotides. Allele frequencies for the c1 allele were 0.95 for alcoholics with severe liver disease, 0.95 for alcoholics without liver disease, and 0.98 for the general population. No differences in allele frequencies between alcoholic patients with severe liver disease and alcoholics without liver disease were observed.

D<sub>2</sub> DOPAMINE RECEPTOR <italic>Taq</italic>I ALLELES IN MEDICALLY ILL ALCOHOLIC AND NONALCOHOLIC PATIENTS

The prevalence of TaqI A alleles of the D2 dopamine receptor (DRD2) gene was examined in two subgroups of medically ill nonalcoholics (more prevalent and less prevalent substance users, MPSU and LPSU, respectively) and in two subgroups of medically ill alcoholics (more severe and less severe alcoholics, MSA and LSA, respectively). The prevalence of the A1 allele in the 80 nonalcoholic and 73 alcoholic patients was 30.0% and 52.1%, respectively (P = 0.009). In the four subgroups of these patients, the prevalence of this allele was: LPSU = 18.2%, MPSU = 34.5%, LSA = 44.4% and MSA = 58.3%. Linear trend analysis showed that as the use of substances and severity of alcoholism increase, so does A1 prevalence (P = 0.001). Specific, subgroup comparisons showed A1 prevalence in MSA to be about 3-fold (P = 0.007) and 1.5-fold (P = 0.04) higher than in LPSU and MPSU subgroups, respectively. Similarly, in a combined analysis of independent studies, A1 prevalence in MSA was higher when compared to LSA (P < 5 x 10(-3), MPSU (P < 10(-4) and LPSU (P < 10(-8) subgroups. There was virtually no difference in the prevalence of the A1 allele between LSA and MPSU subgroups. None of the specific medical or neuropsychiatric complications of alcoholism was associated with the A1 allele. In conclusion, the severity of alcohol dependence in alcoholics and of substance use behaviors in controls are important variables in DRD2 allelic association. The present report and converging lines of evidence suggest that the DRD2 locus could represent a prominent gene risk factor for susceptibility to severe alcoholism. However, other genes and environmental factors, when combined, still play the larger role.

Prognostic validity of short-term abstinence in alcoholism.

A demonstrated period of abstinence is often viewed as a good prognostic sign in alcoholism. For example, short-term abstinence is one factor often considered important as a selection criteria for alcoholics who are being evaluated as liver transplant candidates. However, the prognostic validity of short-term abstinence is unclear. We evaluated the effects of 3 and 6 months of abstinence on readmission rates in a series of 299 alcoholics following discharge from inpatient treatment. Readmission rates were stratified using a 3-factor model of alcoholism severity. This 3-factor model defined groups with 1-year readmission rates, ranging from 15.8% to 62.7%. Short-term abstinence did not have strong effects on readmission rates for the most severe alcoholics, nor did short-term abstinence produce clinically significant reduction for readmission rates for the least severe alcoholics. We conclude that short-term abstinence has minimal effect on prognosis for alcoholics with various levels of baseline severity.

The genetic transmission of alcoholism: implications for prevention

Evidence obtained from adoption and twin studies suggests an important hereditary component in alcoholism. Following our initial observation that the A1 allele of the D2 dopamine receptor (DRD2) gene was associated with alcoholism, a number of studies, both in the United States and abroad, have attempted to replicate and extend this finding in different Caucasian populations. In eight independent studies containing a total of 444 heterogeneous alcoholics (less severe and severe) and 495 heterogeneous controls (alcoholics excluded or not excluded), the prevalence of the A1 allele was 45.5% in the former group compared to 25.7% in the latter group (p < 10-7). In 176 severe alcoholics and 176 controls free of alcoholism, the prevalence of the A1 allele was 49.4% in the former group compared to 17.0% in the latter group (p < 10-8). The severity of alcoholism and the types of controls used are key determinants in A1 allelic association with alcoholism. The total evidence at hand suggests that the DRD2 A1 allele may represent the most prominent single gene determinant of susceptibility to severe alcoholism. However, the larger role is still played by environmental factors and other genes.

The A1 Allele at the D2 Dopamine Receptor Gene and Alcoholism

An allelic association between the TaqI "A" system A1 allele at the D2 dopamine receptor locus (DRD2) and either alcoholism or severe alcoholism has been proposed. Our purpose was to evaluate whether, based on all of the accumulated evidence, this association could be considered to be proven. We considered data from all published reports of DRD2 allele frequency in alcoholics, controls, or both. We concentrated on the issue of replication. We therefore considered all data reported (on white samples, because DRD2 allele frequency varies by race and ethnicity) since the first report by Blum et al in 1990. We analyzed the set of data for differences in allele frequencies between alcoholics and controls, and for heterogeneity among samples. We also investigated the influence of the data from the first group to report an association (including a subsequent report from that group) on the findings. Our analysis shows that, when all studies subsequent to the original study are considered, there is no significant difference in DRD2 A1 allele frequency between alcoholics and controls, there is significant heterogeneity among reported alcoholics and reported controls, and there is no significant difference in DRD2 A1 allele frequency between severe and not severe alcoholics. Also, the two reports of Blum et al account for all of the (nonsignificant) differences seen between controls, alcoholics, and severe alcoholics. In general, heterogeneity among studies (for alcoholics or controls) is considerably greater than differences between alcoholics and controls overall. The findings to date can best be explained by more conservative interpretations than a confirmed physiologically important allelic association between DRD2 alleles and alcoholism. These other possibilities include sampling error and ethnic variation in those studies that individually showed a large effect.

The D2 dopamine receptor gene: A review of association studies in alcoholism

Following our initial observation that the Al allele of the D2 dopamine receptor (DRD2) gene was associated with alcoholism, a number of studies, both in the United States and abroad, have attempted to replicate and extend this finding in different Caucasian populations. In nine independent studies containing a total of 491 heterogeneous alcoholics (less severe and severe) and 495 heterogeneous controls (assessed and unassessed for alcoholism), the prevalence of the Al allele was 43.0% in the former group compared to 25.7% in the latter group (odds ratio = 2.18, p < 10(-7)). The prevalence of the Al allele increased to 56.3% in a more homogeneous sample of 158 severe alcoholics (odds ratio = 3.32, p < 10(-8)). Moreover, the Bl allele of the DRD2 gene was also found to be significantly associated with severe alcoholism. Additional data are accruing which also implicate the DRD2 Al and Bl alleles in substance use disorders other than alcoholism. If further studies continue to support the results currently at hand, they would indicate that the DRD2 gene is the most prominent single gene determinant of susceptibility to severe substance abuse. However, the larger role still appears to be played by a combination of environmental factors and as yet unidentified genes.

Are severe alcoholics genetically predisposed?

Are severe alcoholics genetically predisposed?

Genetic predisposition in alcoholism: Association of the D 2 dopamine receptor TaqI B1 RFLP with severe alcoholics

Previous studies have shown an association of the 3′ Taq1 A1 allele of the D 2 dopamine receptor (DRD2) gene with severe alcoholism. The recent demonstration of a new polymorphism located closer to the regulatory regions of this gene, permits an associational analysis of these 5′ Taq1 B alleles with alcoholism and a comparison with the 3′ Taq1 A alleles. Restriction fragment length polymorphism methodology was used to analyze a total of 133 blood samples of nonalcoholics, less severe alcoholics, and severe alcoholics. In white subjects ( n = 115), no significant difference in the prevalence of the B1 allele is found between nonalcoholics ( n = 30) and less severe alcoholics ( n = 36). However, the prevalence of this allele is significantly higher in severe alcoholics ( n = 49 when compared to either nonalcoholics ( p = 0.008) or less severe alcoholics ( p = 0.005). When Taq1 B and Taq1 A alleles of the DRD2 gene are compared in whites, the prevalence of the A1 allele is significantly higher than the B1 allele only in the severe alcoholic group. In conclusion, alleles in both the 5′ and 3′ region of the DRD2 gene associate with severe alcoholism. This suggests that the DRD2 gene may have an etiological role in some severe alcoholics.

Association between severity of alcoholism and the A1 allele of the dopamine D2 receptor gene TaqI A RFLP in Japanese

The allelic association of TaqI A restriction fragment length polymorphism (RFLP) of the dopamine D2 receptor gene with alcoholism was examined in 78 Japanese alcoholics and compared with Japanese controls. A significantly higher frequency of the A1 allele (0.42) was found in 100 Japanese unscreened controls compared with those reported in white populations. Among 70 alcoholics whose severities were determined, the A1 allele was present in 77% of 43 more severe alcoholics and in 59% of 27 less severe alcoholics. The A1 allele was present significantly less frequently in the alcoholics at the age of 60 or older (42%), compared with those under the age of 60 (74%). In the subjects under the age of 60, the A1 allele was present in 83% of the 35 more severe alcoholics, being significantly more frequent than in 60% of the 35 nonalcoholic controls. All of the 7 alcoholics homozygous for the A1 allele were classified as severe. The average severity of alcoholism increased in the order A2/A2, A1/A2, and A1/A1 genotypes. These data suggest that the A1 allele is associated with severe alcoholism in the Japanese population and that the effect is related to or has a linkage disequilibrium with a genetic factor that has a small but not negligible additive effect on alcoholism.

Association of the A1 allele of the D 2 dopamine receptor gene with severe alcoholism

In a blinded study, 159 subjects composed of nonalcoholics (N = 43), less severe alcoholics (N = 44), severe alcoholics (N = 52) and young children of alcoholics (CoAs, N = 20) were studied for their allelic association with the D2 dopamine receptor (D2DR) gene utilizing peripheral lymphocytes as the DNA source. The combined alcoholic group compared to the nonalcoholic group showed a significantly greater association with the A1 allele of the D2DR gene. Furthermore, an even more robust association was found when severe alcoholics were compared to nonalcoholics. CoAs also showed a significantly greater association with the A1 allele than nonalcoholics but not when compared to alcoholics. Analysis of risk of alcoholism severity suggests that it comprises of two independent components: family history of alcoholism and presence of the A1 allele. Genotype and allelic frequency of the D2DR gene were also analyzed with respect to race. A higher percentage of blacks compared to whites had the A1/A1 genotype, and A1 allelic frequency in the total sample of blacks was significantly greater than in the total sample of whites. Moreover, frequency of the A1 allele was significantly greater in severe alcoholics compared to nonalcoholics in both whites and blacks. However, due to the small sample size of blacks, these racial differences need to be further studied. This study, of the largest sample of alcoholics to date, strongly affirms association of severe alcoholism with the A1 allele of the D2DR gene.

Cerebral lipids and alcohol abuse in humans

Abstract: A necropsy study of the lipid profiles of the cerebral white matter was undertaken in an attempt to identify the mechanisms underlying brain shrinkage associated with alcohol abuse. Three groups of cases were studied — those with low (control), moderate and heavy alcohol intakes. Results suggest the possibility of a biphasic change in that some of the lipid values are significantly reduced in the alcoholic group whereas in the moderate group the lipids appear to be increased. Since the moderate drinkers are more likely to have reversible changes in the brain than severe alcoholics, this difference may be of some importance and should be studied in more detail. There may well prove to be two different pathological changes in the white matter as a result of alcohol abuse — an irreversible component due to neuronal death and subsequent Wallerian degeneration and a reversible component which may relate to subtle structural changes which can not be identified by normal subjective histological examination of human material.

CONTROLLED TRIAL OF ACUPUNCTURE FOR SEVERE RECIDIVIST ALCOHOLISM

In a placebo-controlled study, 80 severe recidivist alcoholics received acupuncture either at points specific for the treatment of substance abuse (treatment group) or at nonspecific points (control group). 21 of 40 patients in the treatment group completed the programme compared with 1 of 40 controls. Significant treatment effects persisted at the end of the six-month follow-up: by comparison with treatment patients more control patients expressed a moderate to strong need for alcohol, and had more than twice the number of both drinking episodes and admissions to a detoxification centre.

Alcoholism, Alcoholics Anonymous attendance, and outcome in a prison system.

The purpose of this study was to assess the relationship between attendance at meetings of Alcoholics Anonymous (AA) and follow-up status in a sample of prison inmates. Subjects (N = 102) were administered three self-report measures of alcoholism: the MAST, CAGE, and Rosett Quantity-Frequency tests. AA attendance during incarceration was recorded. One-year follow-up status, ranging from transfer to a more secure facility to discharge from the prison system, was used as an outcome indicator. ResuLts revealed that 56% of the subjects met the criteria for alcoholism on at least one measure, and that scores on the alcoholism measures were significantly correlated with AA attendance. Thus, the most severe alcoholics were the best AA attenders. The hypothesis that greater AA attendance would predict follow-up outcome was not confirmed. However, the extent of drinking reported prior to admission (average alcohol quantity per week) was related to security status at 1-year follow-up. The greater the drinking quantity, the more likely the inmate was to be in a more secure facility. Possible explanations for the findings and the need for a longer follow-up period are discussed.

The prevalence of alcoholic cerebellar atrophy: A morphometric and histological study of an autopsy material

The Purkinje cell densities in the cerebellar vermis were determined in 31 male alcoholics and 34 non-alcoholic controls under 70 years of age. In addition, all cases were examined histologically for atrophy of the superior vermis. All analyses were performed independently of each other and on randomized slides. The alcoholics had significantly lower Purkinje cell densities than the controls in the superior and middle segments of the vermis. Histologically verified atrophy of the superior vermis was found in 13 of the alcoholics (42%) and in 3 of the controls (9%). There was a good accordance between the morphometric data and the histologic diagnoses. The cause of the cerebellar atrophy in the 3 control cases is uncertain. It could be due to hidden alcoholism or to premature ageing. In a series of non-alcoholic control cases above 70 years, one third of the cases showed atrophy of the superior vermis similar to that of alcoholics. The diagnosis alcoholic cerebellar atrophy should therefore be made with great caution in cases over 70 years. From previous morphometric data on symptomatic cases (Victor et al. 1959), it can be assumed that the majority of the present cases with histologically verified atrophy had overt clinical symptoms. It is concluded that almost one half of all severe alcoholics have atrophy of the superior vermis which can be recognized morphologically and probably also clinically.

Ability of Calcium bis-Acetyl Homotaurine, a GABA Agonist, to Prevent Relapse in Weaned Alcoholics

After they had been weaned off alcohol in hospital 85 severe alcoholics (above 200 g alcohol/day) were included in a double-blind study of calcium bis acetyl homotaurine (Ca AOTA, 25 mg/kg/day), a new gamma-aminobutyric acid agonist, versus placebo. Patients were treated as outpatients during the 3-month study. The only other treatment that patients received was meprobamate, 800 to 1200 mg/day, in the first month. The criterion for success was abstinence at 3 months (with normal gamma-glutamyl transpeptidase being one of the criteria). Of the 70 patients who completed the study, 33 received Ca AOTA and 37 placebo. 20 patients on Ca AOTA did not relapse, compared with 12 on placebo (p less than 0.02 by X2 test). Side-effects were noted by 7 patients on Ca AOTA and 2 on placebo. The results suggest that Ca AOTA may be useful in helping severe alcoholics who have been weaned off alcohol not to relapse.

Lipomatosis of the neck (Madelung's neck).

Benign symmetrical lipomatosis of the neck is a rare disease that has to be differentiated from goiter, sialadenitis, obesity or a lymphatic tumor. Most patients are severe alcoholics, but they may have other endocrine disorders, such as diabetes mellitus, hyperuricemia, or hyperlipidemia. Aside from the cosmetic disfigurement and consequent psychological stress, respiratory distress may be the indication for surgical treatment. Excision of the lipomatosis requires technical skill because the extensive and sometimes infiltrative growth makes dissection of muscle and nerves difficult. The computer tomogram provides good information on the extent of the disease. Three of our 5 patients died 2 1/2 to 6 years after the first operation because of their primary disease.

Role of alcohol in clinical nephrology.

Different nephrological derangements are observed in severe alcoholics. Until now the direct toxicity of ethanol is only shown in the fetal alcohol syndrome with various malformations of the genitourinary tract. In the adult the kidney is often involved in the development, maintenance and counterregulation of complex electrolyte disturbances like phosphate and potassium hypoglycemia etc. The alcohol associated retention of urate, induced by hyperlactatemia and/or increased beta-hydroxybutyrate concentration is only rarely complicated by urate nephropathy. Alcohol intoxication (acute and chronic) predisposes to rhabdomyolysis with the risk of acute renal failure. There are some hints that chronic alcoholism with myopathy increases the vulnerability of the kidney for further toxic agents. In rats glycerol induced renal failure is enhanced by alcohol pretreatment. Finally, regular alcohol consumption raises the blood pressure, which per se is a risk factor for renal damage.

NATURAL HISTORY OF THE FETAL ALCOHOL SYNDROME: A 10-YEAR FOLLOW-UP OF ELEVEN PATIENTS

Of the eleven children who were the first to be diagnosed as having the fetal alcohol syndrome ten years ago, two are now dead, one is lost to follow-up, and the remaining eight continue to be growth deficient and dysmorphic. With menarche, which occurred with normal timing, the female patients developed increased body fat. The mothers were all severe chronic alcoholics. Four of the eight known survivors are of borderline intelligence and have needed some remedial teaching. The other four are severely handicapped intellectually and need complete supervision outside the home. The degree of growth deficiency and intellectual handicap was directly

ABILITY OF CALCIUM BIS ACETYL HOMOTAURINE, A GABA AGONIST, TO PREVENT RELAPSE IN WEANED ALCOHOLICS

After they had been weaned off alcohol in hospital 85 severe alcoholics (above 200 g alcohol/day) were included in a double-blind study of calcium bis acetyl homotaurine (Ca AOTA, 25 mg/kg/day), a new γ-aminobutyric acid agonist, versus placebo. Patients were treated as outpatients during the 3-month study. The only other treatment that patients received was meprobamate, 800 to 1200 mg/day, in the first month. The criterion for success was abstinence at 3 months (with normal γ-glutamyl transpeptidase being one of the criteria). Of the 70 patients who completed the study, 33 received Ca AOTA and 37 placebo. 20 patients on Ca AOTA did not relapse, compared with 12 on placebo (p<0·02 by χ2 test). Side-effects were noted by 7 patients on Ca AOTA and 2 on placebo. The results suggest that Ca AOTA may be useful in helping severe alcoholics who have been weaned off alcohol not to relapse.