Hypothalamic-Pituitary-Thyroid (HPT) Axis in Chronic Alcoholism. I. HPT Axis in Chronic Alcoholics During Withdrawal and After 3 Weeks of Abstinence

Thyroxine (T₄), free T₄ (fT₄), triiodothyronine (T₃ free T₃ (fT₃), reverse T₃ (rT₃), thyrotropine (TSH), thyroxine binding globulin (TBG), and T₃ uptake were measured in 14 chronic alcoholics during withdrawal and after 21 days of abstinence. Results were compared with those of 16 healthy volunteers. During withdrawal, the fT₄ and fT₃ concentrations were subnormal, whereas the respective protein-bound fractions were normal. T₄, T₃, and TBG increased during the abstinence period, T₃ and TBG being significantly higher than in normals at the second measuring time. T₃ uptake values fell, but remained well within the normal range at both measuring times. During abstinence, the fT₃ levels remained significantly lower than in healthy subjects. rT₃ concentrations decreased, but not significantly. The TSH values were normal throughout. These results showed numerous abnormalities in the hypothal-amic-pituitary-thyroid axis in alcoholics, the reasons for which are as yet unclear. The following possible interpretations are suggested: 1. The abnormally low serum fT₃ and ff₄ levels during withdrawal might reflect an increase in tissue uptake. 2. The increases in T₄-and partty those in T₃-during abstinence seem to reflect increased binding by TBG, the level of which rose markedly for reasons as yet unknown. 3. If increases in TBG during abstinence are taken into account, the decreases in rT₃ concentrations may reach the level of statistical significance. These falls in rT₃ concentrations may reflect an increase in rT₃ metabolization (deiodination) in various tissues, including the CNS, leading to a reduction in serum rT₃ bioavail-ability. 4. Factors such as liver disease, protein caloric malnutrition, and “psychological stress” do not fully explain all these abnormalities. A direct effect of ethanol on intracellular thyroid hormone metabolism and/or function seems conceivable.     

Determinants of Ethanol and Acetaldehyde Metabolism in Chronic Alcoholics

We have studied the factors determining the rate of ethanol and acetaldehyde metabolism in a group of 25 alcoholics with varying degrees of liver lesion (from normal liver to cirrhosis) and in six nonalcoholic cirrhotics. In alcoholics the ethanol metabolic rate was related to hepatic function, estimated either by the aminopyrine breath test ( r = 0.70, p < 0.001) or the indocyanine green clearance ( r = 0.76, p < 0.01), and was independent of the activity of hepatic alcohol dehydrogenase and hepatic blood flow. In nonalcoholic cirrhotics blood acetaldehyde was always below the detection limit (0.5 μM), but elevated levels were found in 14 out of the 25 alcoholics. Alcoholics with elevated blood acetaldehyde showed a significantly higher ethanol metabolic rate than alcoholics with undetectable acetaldehyde (120 ± 17 mg/kg/hr vs 104 ± 11 mg/kg/hr, p < 0.02), but no differences were observed in the activities of alcohol and aldehyde dehydrogenases. Peak blood acetaldehyde levels were directly related to the ethanol metabolic rate ( r = 0.48, p < 0.02), but not to activities of hepatic alcohol or aldehyde dehydrogenases. These results indicate that in chronic alcoholics the main determinant of the ethanol metabolic rate is hepatic function, while the rise of blood acetaldehyde is mainly dependent on the ethanol metabolic rate. Alcohol and aldehyde dehydrogenase activities do not seem to be rate-limiting factors in the oxidation of ethanol or acetaldehyde.     

Selective Acceleration of Auditory Processing in Chronic Alcoholics during Abstinence

Simultaneous auditory processing between the hemispheres was studied with a whole-head magnetometer in 13 abstinent chronic alcoholics and 10 healthy control subjects. Auditory stimuli were presented monaurally with interstimulus intervals of 0.5 and 2.5 sec in different blocks. The N100m response, which contributes to stimulus detection, was significantly accelerated in the hemisphere ipsilateral to the ear stimulated in abstinent alcoholics. The MMNm response reflecting automatic stimulus-change detection peaked earlier in alcoholics, and the ipsilateral N100m latency correlated significantly with the abstinence duration. These results suggest that auditory processing is accelerated in the auditory cortex ipsilateral to the stimulated ear in chronic abstinent alcoholics and that the accelerated processing is at least partly reversible. This may be caused by the hyperexcitation in the brain related to the ethanol withdrawal.     

Effect of Cigarette Smoking on ACTH/Cortisol Secretion in Alcoholics After Short- and Medium-Term Abstinence

BACKGROUND: To gain a better insight into the alterations of the hypothalamic-pituitary-adrenal axis in alcoholism, we evaluated the ACTH response to nicotine inhaled from cigarette smoking (two nonfilter cigarettes in succession within 10 min) in nine nonalcoholic men and nine age- and weight-matched alcoholic men who had been addicted to alcohol for at least 8 years. All subjects were regular cigarette smokers. METHODS: Alcoholic men were tested after 2 weeks of abstinence, when the possible interferences because of alcohol assumption or the acute withdrawal period had completely ceased, and again after 12 weeks of abstinence. RESULTS: At both 2 and 12 weeks of abstinence, basal plasma ACTH and cortisol levels were not significantly different in the alcoholic men from those observed in the control group. In the control group subjects, cigarette smoking induced a striking increase in the circulating concentrations of ACTH and cortisol, with peak responses 1.4 and 1.5 times higher than baseline at 20 and 30 min, respectively. In contrast, no significant ACTH/cortisol increase was observed in alcoholic subjects at any time after cigarette smoking in any test. CONCLUSION: These data suggest that alterations of nicotinic cholinergic transmission occur in the control of ACTH secretion in the alcoholic men, providing further evidence of modification of the hypothalamic-pituitary-adrenal axis in alcoholism.     

Cyanamide-Induced Liver Dysfunction After Abstinence in Alcoholics: A Long-Term Follow-Up Study on Four Cases

Background: Cyanamide, an aversive agent widely used in Japan, is known to induce various degrees of hepatic lesion with ground-glass inclusion bodies. When cyanamide-treated alcoholics relapse into drinking, more severe inflammation develops in the liver. However, it is controversial whether progressive hepatic lesions develop in complete abstainers as a result of long-term cyanamide treatment. Case Reports: Case 1: A 53-year-old male alcoholic received cyanamide treatment for 4.5 months and completely abstained without cyanamide treatment for 6 years. A liver biopsy shortly after abstinence showed extensive pericellular fibrosis, but a biopsy after 6 years showed very mild fibrosis. Case 2: A 43-year-old male alcoholic remained completely abstinent with cyanamide treatment for 5 years and complained of general fatigue. His serum transaminases were slightly elevated and hepatic hyperechogenicity was observed on ultrasonography. Only mild pericellular fibrosis was present in the liver biopsy specimen obtained shortly after abstinence, but after 5 years the second liver biopsy showed that thin septum-like fibrosis that formed portal-to-portal and portal-to-central linkage had developed and ground-glass hepatocytes had emerged extensively. Case 3: A 29-year-old female alcoholic complained of general fatigue and a slight fever after 1.5 years of abstinence with cyanamide treatment. Slight elevation of serum transaminases and hepatic hyperechogenicity were observed. The liver biopsy showed extensive ground-glass hepatocytes and thin septum-like fibrosis that formed portal-to-portal linkage. Case 4: A 61-year-old male alcoholic who remained completely abstinent while taking cyanamide for 3 years showed slight elevation of serum transaminases. Liver biopsy showed extensive ground-glass hepatocytes and extension of thin septum-like fibers from portal tract to the lobule. Ultrasonography revealed hepatic hyperechogenicity. Conclusion: In some abstainers who take cyanamide for several years, thin septum-like liver fibrosis progresses along with the emergence of ground-glass hepatocytes. Hepatic hyperechogenicity on ultrasonography and slight elevation of serum transaminases might erroneously lead to a diagnosis of hepatic steatosis without liver histology.     

Anger in an Inpatient Treatment Sample of Chronic Alcoholics

Four measures of anger were investigated in sober male and female alcoholics and nonalcoholic peers. The relationships among anger variables, past drinking behavior, and substance abuse consequences in alcoholics were explored. Additionally, the interrelationships among anger, depression, and anxiety in the groups were examined, and the relationships between an overall dysphoria index and drinking behavior and substance abuse consequences were determined. 104 alcoholics (sober 21 to 45 days) and 70 community controls, aged 21 to 56, were given the Spielberger Anger Expression Inventory, the Beck Depression Inventory, and the Spielberger State Anxiety Inventory. Alcoholics scored higher than controls on Trait Anger, Anger-In, and Anger-Out, but not on State Anger. There were no main effects of sex. Anger-In was significantly negatively correlated with the Quantity-Frequency Index in alcoholic males. Anger-In was significantly positively correlated with depression in male and female alcoholics and with substance abuse consequences in the latter group. The depression measure was significantly correlated with consequences in female, but not in male alcoholics. These data have treatment implications, especially for female alcoholics.     

Withdrawal Severity After Chronic Intermittent Ethanol in Inbred Mouse Strains

Background: To study withdrawal, ethanol is usually administered chronically without interruption. However, interest has recurred in models of episodic exposure. Increasing evidence suggests that chronic intermittent exposure to ethanol leads to a sensitization effect in both withdrawal severity and ethanol consumption. The goal of the present study was to examine mouse inbred strain differences in withdrawal severity following chronic intermittent exposure using the handling‐induced convulsion as the behavioral endpoint. We also sought to compare the withdrawal responses of inbred strains across acute, chronic continuous, and chronic intermittent exposure regimens. Methods: Male mice from 15 standard inbred strains were exposed to ethanol vapor for 16 hours each day for 3 days and removed to an air chamber during the intervening 8 hours. Mice in the control groups were handled the same, except that they were exposed only to air. Daily blood ethanol concentrations were averaged for each mouse to estimate total dose of ethanol experienced. Results: Across strains, mice had an average daily blood ethanol concentration (BEC) of 1.45 ± 0.02 mg/ml and we restricted the range of this value to 1.00–2.00 mg/ml. To evaluate strain differences, we divided data into two dose groups based on BEC, low dose (1.29 ± 0.1 mg/ml) and high dose (1.71 ± 0.02 mg/ml). After the third inhalation exposure, ethanol‐exposed and air‐exposed groups were tested hourly for handling‐induced convulsions for 10 hour and at hour 24 and 25. Strains differed markedly in the severity of withdrawal (after subtraction of air control values) in both dose groups. Conclusion: The chronic intermittent exposure paradigm is sufficient to elicit differential withdrawal responses across nearly all strains. Data from the high‐dose groups correlated well with withdrawal data derived from prior acute (single high dose) and chronic continuous (for 72 hours) ethanol withdrawal studies, supporting the influence of common genes on all three responses.     

Ethanol, acetaldehyde, acetate, and lactate levels after alcohol intake in white men and women: effect of 4-methylpyrazole

BACKGROUND: 4-Methylpyrazole (4-MP), a selective inhibitor of alcohol dehydrogenase (ADH), recently has been approved for clinical use in humans. The objective was to evaluate the use of 4-MP in human alcohol research and to study the effect of 4-MP on various parameters of alcohol metabolism during alcohol intoxication. METHODS: 4-MP (10-15 mg/kg orally) or placebo was given in double-blind fashion to 22 premenopausal women, 12 of whom were using oral contraceptives, and 13 men followed by intake of alcohol (0.5 g/kg orally) or placebo. RESULTS: A 30% to 40% decrease in the ethanol elimination rate was observed in the different groups during pretreatment with 4-MP. The alcohol-induced increase in plasma acetate was partially inhibited by 4-MP. A significant positive correlation was observed between the effect of 4-MP on the alcohol-induced lactate and acetate elevations. The acetaldehyde was nondetectable (<1 micromol/liter) in the peripheral venous blood during alcohol intoxication in both women and men. During alcohol intoxication, a decrease in breath acetaldehyde was found with 4-MP pretreatment in women but not in men. CONCLUSION: The alcohol-induced elevation in blood acetate level is caused, in part, by ADH-mediated ethanol oxidation. Although no evidence was found for measurable acetaldehyde levels in the peripheral venous blood during alcohol intoxication, the effect of 4-MP on breath acetaldehyde in women supports the view that ADH-mediated acetaldehyde elevations reflected in the airways, but too low to be detected in the peripheral venous blood, may occur in women during alcohol intoxication in the present experimental conditions.     

Chronic Ethanol Feeding Impairs Glucose Tolerance But Does Not Produce Skeletal Muscle Insulin Resistance in Rat Epitrochlearis Muscle

Herein, we have investigated whether male Wistar rats develop impaired glucose tolerance after ethanol feeding. Rats were fed a liquid diet providing 35% calories from ethanol (EF) or a control diet that isocalorically replaced ethanol with maltose-dextrins for 4 weeks. Intravenous glucose tolerance was impaired in EF rats compared with pair-fed (PF), but not ad libitum (AL) controls. Areas under the intravenous glucose tolerance test curve were 5476 ± 516 mm², 3056 ± 421 mm², and 4199 ± 613 mm² ( p < 0.05) for AL, PF, and EF rats, respectively. Initial plasma insulin concentrations in EF rats were comparable with PF rats; however, 15 min after a dextrose challenge, plasma insulin levels in EF rats were 39% lower than PF rats. Because skeletal muscle is the primary sink for insulin-mediated glucose disposal, the development of skeletal muscle insulin resistance after ethanol feeding could contribute to impaired glucose tolerance. Total GLUT1 was not affected by diet in either red or white muscle. No difference in the total quantity of insulin-responsive glucose transporter, GLUT4, was observed in red muscle. In contrast, GLUT4 was 20% lower in white muscle from EF rats, compared with PF and AL rats. However, insulin-stimulated glucose transport into the epitrochlearis, a white muscle group, was not impaired with ethanol feeding. These data demonstrate that chronic ethanol feeding impairs glucose tolerance; impaired glucose tolerance was associated with an inability to maintain plasma insulin levels, rather than the development of skeletal muscle insulin resistance.     

Alterations in Brain Glucose Utilization Accompanying Elevations in Blood Ethanol and Acetate Concentrations in the Rat

Background: Previous studies in humans have shown that alcohol consumption decreased the rate of brain glucose utilization. We investigated whether the major metabolite of ethanol, acetate, could account for this observation by providing an alternate to glucose as an energy substrate for brain and the metabolic consequences of that shift. Methods: Rats were infused with solutions of sodium acetate, ethanol, or saline containing ¹³C‐2‐glucose as a tracer elevating the blood ethanol (BEC) and blood acetate (BAcC) concentrations. After an hour, blood was sampled and the brains of animals were removed by freeze blowing. Tissue samples were analyzed for the intermediates of glucose metabolism, Krebs’ cycle, acyl‐coenzyme A (CoA) compounds, and amino acids. Results: Mean peak BEC and BAcC were approximately 25 and 0.8 mM, respectively, in ethanol‐infused animals. Peak blood BAcC increased to 12 mM in acetate‐infused animals. Both ethanol and acetate infused animals had a lower uptake of ¹³C‐glucose into the brain compared to controls and the concentration of brain ¹³C‐glucose‐6‐phosphate varied inversely with the BAcC. There were higher concentrations of brain malonyl‐CoA and somewhat lower levels of free Mg²⁺ in ethanol‐treated animals compared to saline controls. In acetate‐infused animals the concentrations of brain lactate, α‐ketoglutarate, and fumarate were higher. Moreover, the free cytosolic [NAD⁺]/[NADH] was lower, the free mitochondrial [NAD⁺]/[NADH] and [CoQ]/[CoQH₂] were oxidized and the ΔG′ of ATP lowered by acetate infusion from ?61.4 kJ to ?59.9 kJ/mol. Conclusions: Animals with elevated levels of blood ethanol or acetate had decreased ¹³C‐glucose uptake into the brain. In acetate‐infused animals elevated BAcC were associated with a decrease in ¹³C‐glucose phosphorylation. The co‐ordinate decrease in free cytosolic NAD, oxidation of mitochondrial NAD and Q couples and the decrease in ΔG′ of ATP was similar to administration of uncoupling agents indicating that the metabolism of acetate in brain caused the mitochondrial voltage dependent pore to form.     

Excretion of β-Carbolines Harman and Norharman in 24-Hour Urine of Chronic Alcoholics During Withdrawal and Controlled Abstinence

Animal experiments suggest that endogenous substances that could result from the interaction between neurotransmitters (dopamine and indoleamines) and ethanol and its metabolite acetaldehyde might be involved in the pathogenesis and maintenance of alcohol dependence. Therefore, aromatic β-carbolines (norharman and harman) were investigated repeatedly in 24-hr urine of 13 male severe alcoholics without any psychiatric comorbidity during a controlled inpatient abstention program of up to 8 weeks. Harman excretion was ˜2-fold above levels in control subjects, with a steady decline after 3 weeks of abstinence and lower levels in patients with a longer duration of alcohol dependence. Severity of withdrawal symptoms and actual feelings of anxiety/depression were negatively associated with urinary harman excretion. Positive associations could be established with daily ethanol consumption the month before admission and the score on the scale "reward dependence" according to Cloninger's Tridimensional Personality Questionnaire. Moreover, patients without alcohol-dependent first-degree relatives and higher "reward dependence" exhibited an increased excretion of harman. Therefore, harman levels might characterize a distinct subgroup of alcoholic patients, who in part resemble the so-called type I alcoholics of Cloninger. However, this awaits further study in a larger number of individuals. In contrast, norharman excretion was elevated up to 6-fold, compared with nonalcoholics over 6 to 8 weeks of controlled abstention. No correlations to demographic or clinical variables could be observed. Therefore, increased norharman levels might be proposed as a "residual marker" or a trait variable. Whether the observed changes are specific markers of at least certain aspects of alcoholism or dependence remain to be elucidated.     

Adrenocorticotropin Responses Following Administration of Ethanol and Ovine Corticotropin-Releasing Hormone in the Sons of Alcoholics and Control Subjects

Alcoholism is a familial disorder with both genetic and environmental determinants. The sons of alcoholic fathers have been documented to have alterations in several neuroendocrine measures. We investigated the ACTH/cortisol response to ovine corticotropin-releasing hormone (oCRH) and ethanol in men with and without a family history of alcoholism. Men were defined as family history positive (FHP) ( n = 7) if their father was alcoholic; as family history negative (FHN) ( n = 16), if their father was nonalcoholic. Ethanol (0.75 g/kg) or placebo was ingested over 15 min, 1 μg/kg oCRH was administered, and plasma ACTH/cortisol levels were determined at –20, 0, 15, 30, 60, and 90 min after oCRH. Following placebo, FHP men had lower peak ACTH response to oCRH than did FHN men (12 ± 2 vs 20 ± 2 pmol/liter, P = 0.04). In FHN men, plasma ACTH response to oCRH was blunted during the ethanol session compared to the placebo session (13 ± 1 vs 20 ± 2 pmol/liter; P = 0.006). In contrast, FHP men had similar ACTH responses to oCRH during ethanol and placebo sessions. Cortisol responses to oCRH were similar in both groups during both sessions. In summary, FHP and FHN nonalcoholic men had different plasma ACTH responses following the administration of oCRH.     

Six- and Twelve-Month Abstinence Rates in Inpatient Alcoholics Treated with Aversion Therapy Compared with Matched Inpatients from a Treatment Registry

Two hundred forty-nine patients who were treated for alcoholism in an inpatient multimodal treatment program that included aversion therapy were matched post hoc on 17 baseline variables with patients from a national treatment outcome registry. The latter patients received inpatient treatment that emphasized individual and group counseling as the primary therapeutic elements but did not include aversion therapy for alcohol. Six- and 12-month abstinence rates from alcohol and all mood-altering chemicals are reported. The patients treated with aversion therapy for alcohol had higher alcohol abstinence rates at 6 and 12 months (p less than 0.01). The abstinence rates from all mood-altering chemicals were higher in the aversion group at 6 months (p less than 0.05) but not at 12 months. The largest differences between treatment groups in 6-month alcohol abstinence rates were noted for males (p less than 0.001), those over 35 (p less than 0.001), daily drinkers (p less than 0.001), and those with alcohol-related work performance problems (p less than 0.05).     

Nutritional Status and Body Fluid Distribution in Chronic Alcoholics Compared With Controls

BACKGROUND: At present few data are available on the total body water (TBW) content and in particular on the distribution of water in the intra- and extracellular compartments (ICW and ECW) of alcoholics. The aim of this study was to evaluate TBW, ICW, and ECW in chronic alcoholic patients. METHODS: Thirty-six alcoholics meeting DSM-III-R criteria for diagnosis (20 men, 16 women; body mass index [BMI] 22.3+/-2.57 kg/m2) were enrolled. Fifty-four healthy social drinkers (31 men, 23 women; BMI 23.7+/-1.68 kg/m2) matched for age and height were used as controls. Systolic and diastolic blood pressure was measured for all cases. All patients were assessed using specific anthropometric measurements. The waist-to-hip ratio (WHR) was used as an indicator of body fat distribution. TBW was measured by isotopic dilution by giving 100 microCi of tritiated water. ICW and ECW were assessed by multifrequence bioelectric impedance analysis (BIA). Basal metabolic rate (BMR) was measured by indirect calorimetry. RESULTS: Body weight was lower in the alcoholics than in the controls (61.9+/-5.5 kg vs. 65.8+/-5.2 kg;p < 0.01), essentially due to a reduction in fat mass. Significantly higher WHR values were found in both male (p < 0.001) and female (p < 0.001) alcoholics than in healthy subjects. A higher ECW/TBW ratio was found in the alcoholics compared with the controls, both as a whole (0.53+/-0.04 vs. 0.41+/-0.03; p < 0.0001) and separated by gender (p < 0.001). CONCLUSIONS: The increased ECW could derive from an increase in cellular permeability related to endothelial damage linked to the vasoconstriction present in the alcoholics and/or to a direct toxic effect of ethanol on cellular membranes. In addition, because the high ECW volumes correlated positively with WHR in the alcoholics, a potential association of these two factors in determining an increased risk of liver disease, hypertension, and cardiovascular disease may exist. Finally, the lower TBW characteristic of women may be one of the reasons for the observed greater rate of toxic effects of ethanol that occur in women.     

Glucose Transporters and Glucose Utilization in Rat Brain after Acute Ethanol Administration

In the normal adult brain, glucose provides 90% of the energy requirements as well as substrate for nucleic acid and lipid synthesis. In the present study, effects of ethanol on glucose transporters (GLUT) and glucose utilization were examined in rat brain. Male Sprague-Dawley rats weighing 250-300 gms were given either ethanol 3 gm/kg BW or saline IP 4 hrs prior to the animal sacrifice and removal of the cerebral cortical tissue. The cortical plasma membranes analyzed by cytochalasin B binding assay showed a decrease in GLUT number but not in GLUT affinity in the ethanol treated rats as compared to the control rats. The estimated Ro values were 70 ± 8.9 Vs 91 ± 8.9 pmoles/mg protein (p < 0.05 N=4) and the estimated Kd values were 0.37 ± 0.03 and 0.28 ± 0.05 M (p: NS) in ethanol and control experiments respectively. Immunoblots of purified cerebral plasma membranes and low density microsomal fraction showed 17% and 71% decrease for GLUT1 and 54% and 21% (p<0.05 or less; n=6) for GLUT3 respectively in ethanol treated rats than in control animals. Immunofluoresence studies also showed reduction of GLUT1 immunoreactively in choroid plexus and cortical microvessels of ethanol treated rats as compared to control rats. The effect of ethanol on regional cerebral metabolic rates for glucose (CMR_Gle) was studied using [6-¹⁴C] glucose and showed statistically insignificant decrease in brain glucose utilization. These data suggest that ethanol invivo decrease GLUT number and protein content in rat cerebral cortex     

Tyrosine Hydroxylase and Dopamine D4 Receptor Allelic Distribution in Scandinavian Chronic Alcoholics

Associations of polymorphic genetic markers at the tyrosine hydroxylase (TH) and dopamine D4 receptor (DRD4) loci were examined in Scandinavian chronic alcoholics ( n = 72) and control subjects ( n = 67). Patients were divided into subgroups with regard to the presence of parental alcoholism and age of onset. Neither the TH nor the DRD4 allele distributions were significantly different when alcoholic samples were compared with control subjects. However, a tendency to high prevalence for 1 of the 5 TH alleles assayed (TH-K3) was observed in a subsample of 44 alcoholics characterized by late onset when compared with control subjects (27.3% vs. 10.6%, p = 0.041). Results suggest that no major influence on alcoholism is exerted through genes associated with the DRD4 or TH allelic markers examined.