Interaction between alcohol and nutrition in the pathogenesis of alcoholic liver disease.
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Deficiency Diseases↗
Biomedical subjects
E Mezey
Publications and source records attributed to E Mezey.
Trauma in cirrhosis: an indicator of the pattern of alcohol abuse in different societies.
While some morbidities associated with the excessive use of alcohol are related to the total amount of alcohol consumed--cirrhosis being an example--other pathologies, such as trauma and those of psycho-social origin, are mainly related to the frequency of acute alcoholic intoxication rather than to the total amount consumed. The balance between these two types of alcohol-associated morbidities can provide an indication of the relative frequency of intoxication, and thus of the pattern of alcohol abuse in a population. Since trauma is highly associated with acute alcoholic intoxication, the prevalence of bone fractures was determined in cirrhotics in nine countries. The prevalence of rib and vertebral fractures on routine chest x-rays showed a 17-fold variation in the different countries, from 2% and 6% in Spain and Italy to 30% and 34% in Canada and the USA, suggesting marked differences in the pattern of alcohol abuse to intoxication. Conversely, the prevalence of cirrhosis is twice as high in Spain and Italy than in Canada and the USA. A strong positive correlation between per capita consumption and cirrhosis mortality (r = 0.86; p less than 0.01) exists among the nine countries studied, while the correlation between per capita alcohol consumption and the prevalence of trauma is not statistically significant (r = 0.40). Supporting a strong association between trauma and alcoholic intoxication, the prevalence of trauma was found to be highly correlated: r = 0.88, p less than 0.002, with the degree of concern for the psycho-social consequences of alcohol abuse in the different countries. Data indicate that trauma can be used as an objective indicator to assess the pattern of alcohol abuse in a population.
Alcohol Drinking↗
Altered expression of HLA antigens and CD16 Fc receptors on leukocytes of alcoholic subjects and uremic patients.
The possible influences of ethanol and its metabolic product acetate on the surface expression of HLA class I and class II antigens and CD16 Fc receptors were examined. Fluorescent-labeled monoclonal antibodies and flow cytometry were used to measure these antigens on leukocytes from reference controls, subjects admitted for alcohol detoxification, uremic patients undergoing hemodialysis using Cu-prophan dialyzers and fluids containing 4 to 37 mM acetate, and uremic patients that were not hemodialyzed. In comparison to the controls, the mean intensity of staining for class I antigens was not changed significantly on lymphocytes or monocytes from alcoholics but was depressed on cells from eight of 12 uremic patients. Interferon-gamma above 5 units/ml was detected in less than 15% of plasma samples from controls, uremic patients or alcoholics on admission but was detected in four of eight samples from alcoholics at discharge (2-4 days after admission). The intensity of staining for class II antigens was depressed by more than 50% on lymphocytes from alcoholics and uremic patients. The expression of HLA class I and class II antigens was depressed whether uremic patients were hemodialyzed or not. The percentage of lymphocytes expressing CD16 was depressed in three of seven alcoholics and five of seven hemodialyzed patients. In contrast, the percentage of monocytes expressing CD16 was increased in six of seven hemodialyzed patients and three of five uremic patients not undergoing hemodialysis suggesting activation of monocytes in these patients. Plasma levels of beta 2-microglobulin were elevated by 61% in alcoholics, 50-fold in hemodialyzed patients, and 26-fold in nonhemodialyzed uremic patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Coexpression of vasopressin and oxytocin in hypothalamic supraoptic neurons of lactating rats.
Magnocellular hypothalamic neurons in the rat supraoptic nucleus (SON) normally produce either vasopressin (VP) or oxytocin (OT). Here we demonstrate that many magnocellular neurons in the SON of lactating rats synthesize both hormones at the same time. We show the colocalization of the messenger (m) RNA that encodes the VP precursor with OT-neurophysin; OT mRNA with VP-neurophysin, the C-terminal glycopeptide of the VP precursor, and VP itself, and the presence of both mRNAs in the same cell. At the light microscopic level quantitative studies show that on the second day of lactation, 17% of the SON neurons produce both hormones, on the fifth day 13%, and on the ninth day 9%. Two days after lactation the number of cells that are positive for both hormones returns to the control level (2-3%). We also show by means of electron microscopic immunohistochemistry that both peptides (or their precursors) are present in the same neurosecretory vesicles in nerve endings in the posterior lobe of lactating rats. At the electron microscopic level quantitative studies show that on the second day of lactation 21% of the terminals contain mixed vesicles; this number increases to 24% by the fourth day and is down to 5% by the 15th day, a level similar to that found in control rats. Since the double-labeled cells seemed to be producing additional VP as opposed to OT, we hypothesized that the former should affect urinary osmolality. Urine samples of lactating rats show a significant (5-fold) increase in urine osmolality during lactation (highest on the second day). The increase in osmolality correlated with the increase in the number of VP positive cells during lactation. We suggest that magnocellular neurons that ordinarily synthesize little or no VP can produce this antidiuretic hormone to help the animal compensate for the loss of water associated with lactation.
Animals↗
Approaches to treatment of fibrogenesis in alcoholic liver disease.
Alcoholic hepatitis is associated with progressive hepatic fibrosis and the development of cirrhosis. The increased fibrosis is principally the result of increased collagen synthesis which exceeds lesser increases in collagen degradation. No proven therapy exists for progressive hepatic fibrosis in alcoholic liver disease. Sobriety increases long-term survival, but there is no evidence that it affects the process of fibrogenesis once initiated. Corticosteroids increase hospital survival in severe alcoholic hepatitis, while long-term propylthiouracil therapy increased survival in moderately severe alcoholic hepatitis. However, neither therapy was found to decrease hepatic fibrosis. By contrast, long-term therapy with colchicine improved survival and decreased hepatic fibrosis in a few patients with cirrhosis. Potential new therapies which have been shown to decrease fibrosis in animals or by cells in vitro include prostaglandin E2, gamma interferon, and inhibitors of proline hydroxylation.
Animals↗
Effect of parenteral amino acid supplementation on short-term and long-term outcomes in severe alcoholic hepatitis: a randomized controlled trial.
The effect of parenteral amino acid administration on nutritional state, liver function and mortality was assessed in patients with severe alcoholic hepatitis. Twenty-eight patients received 2 l/day of a solution of dextrose (65 gm/L) and amino acids (25.8 gm/L) for 1 mo, whereas 26 received only the dextrose solution. All patients were allowed to eat a standard hospital diet. During the month in the hospital, there were six deaths in the treatment group and five deaths in the control group. Nitrogen balance improved in the treated group, but not in the control group. Creatinine-height index, triceps skin fold measurement and levels of serum albumin and prealbumin increased similarly in both groups. Serum retinol binding protein increased more in the treatment group than it did in the control group, and transferrin was increased only in the treatment group. Serum bilirubin, type III amino-terminal procollagen peptide and aminopyrine clearance improved more in the treatment group than in the control group, whereas serum AST and prothrombin time improved in the treatment group but not in the control group. Cumulative 2-yr survival rates from the day of entry into the study were 42% and 38% in the treatment and control groups, respectively. Patients who survived 2 yr and patients in the treatment group who died during the 2-yr follow-up had continued improvement in serum retinol binding protein, transferrin, bilirubin and prothrombin time. These parameters were unchanged in patients in the control group who died during follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Ethanol increases the formation of NADP+ in rat hepatocytes.
The acute effects of ethanol on total (bound + free) pyridine dinucleotides were determined in freshly isolated rat hepatocytes. Pyridine dinucleotides and adenine nucleotides were determined by high-performance liquid chromatography. Exposure of the hepatocytes to 8 mmol/L ethanol resulted in a decrease in NAD+ and an increase in NADP+ after 2 min incubation. There were no significant changes in NADH and NADPH. Ethanol decreased ATP and increased AMP after 2 min, whereas an increase in ADP was only apparent after 15 min of incubation. Ethanol 8 mmol/L and 100 mmol/L resulted in an increased incorporation of [32P] into NADP+ from [32P]-prelabeled NAD+ and ATP. Ethanol increased hepatocyte NAD+ kinase activity; this effect was blocked by 4-methylpyrazole but reproduced by 10 mumol acetaldehyde. These observations indicate that ethanol increases the synthesis of NADP+ and that this effect is most likely the result of increased NAD+ kinase activity. The ethanol-induced decrease of NAD+ may limit ADP ribosylation of nuclear proteins, whereas increases in NADP+ may stimulate the pentose phosphate cycle.
Adenine Nucleotides↗
Ethanol-induced increases in [Ca2+]i and inositol (1,4,5) triphosphate in rat hepatocytes.
Rat hepatocytes were studied for [Ca2+]i with Fura-2 at the single cell level using a microfluorometer-imaging system which showed that both the number of cells elevating [Ca2+]i and the magnitude of [Ca2+]i increase were directly dependent upon ethanol concentration between 50 mM and 1 M. Peak [Ca2+]i increases ranged from 27 nM with 50 mM ethanol to 57 nM after 1 M ethanol. Ethanol appeared to initiate calcium release from intracellular stores and caused a dose dependent production of inositol(1,4,5) triphosphate (Ins(1,4,5)P3) in hepatocytes. Low concentrations of ethanol (50-100 mM) did not significantly raise Ins(1,4,5)P3 although 300 mM-1 M increased Ins(1,4,5)P3 comparable to that found with vasopressin (5 nM). In summary, physiologic amounts of ethanol raise [Ca2+]i in rat hepatocytes, although at lower levels (50-100 mM) the changes may or may not be related to an Ins(1,4,5)P3 pathway.
Animals↗
Effect of epinephrine on ethanol metabolism by isolated rat hepatocytes.
The effect of epinephrine on ethanol metabolism was determined in isolated rat hepatocytes. Epinephrine (10 microM) enhanced an initial rapid rate of ethanol elimination observed in the first 5 min. Thereafter, between 5 and 90 min, the rate of ethanol elimination was slower and not affected by epinephrine. Epinephrine resulted in higher acetaldehyde concentrations at 2 min, but not thereafter. Acetaldehyde production in the presence and absence of epinephrine was inhibited by 4-methylpyrazole, by a low free extracellular calcium concentration, and by the alpha 1-adrenergic blocker prazosin. Ethanol alone and epinephrine alone increased oxygen consumption, but the effects were not additive. The ethanol-induced decreases in the cytosolic NAD-/NADH and NADP++NADPH ratios and in the mitochondrial NAD+/NADH ratio were delayed by the presence of epinephrine. An accelerated initial alcohol dehydrogenase activity sufficient to account for the rapid initial rate of ethanol elimination shown with epinephrine was demonstrated by coupling ethanol oxidation with lactaldehyde reduction, a system which increases the rate of dissociation of NADH from the enzyme and its oxidation back to NAD+. The findings in this study indicate that an increased reoxidation of NADH during ethanol oxidation by alcohol dehydrogenase is the basis for the rapid transient increase in ethanol elimination produced by epinephrine.
Acetaldehyde↗
Effect of insulin-like growth factor I on rat alcohol dehydrogenase in primary hepatocyte culture.
The effect of insulin-like growth factor I (IGF-I) on the activity of alcohol dehydrogenase was determined in primary hepatocyte culture from male rats. Continuous exposure of hepatocytes to IGF-I (30 nM) resulted in increases in alcohol dehydrogenase activity on Days 3-6 of culture. The increase in enzyme activity was preceded by increased alcohol dehydrogenase mRNA, indicating that the effect of IGF-I was at the pretranslational level. The effect of IGF-I was observed only in the presence of pharmacological concentrations of insulin in the media. Insulin alone had no effect on alcohol dehydrogenase activity. The permissive influence of insulin was correlated with the ability of insulin to maintain a steady high number of IGF-I binding receptors in the hepatocytes during culture. The response of alcohol dehydrogenase to IGF-I is similar to that previously demonstrated for growth hormone and suggests the possibility that the effect of growth hormone on this enzyme may be mediated by IGF-I.
Alcohol Dehydrogenase↗
Neuropeptide content and connectivity of the rat claustrum.
The rat claustrum has a homogeneous distribution of the neuropeptides somatostatin (SOM), cholecystokinin (CCK) and vasoactive intestinal polypeptide (VIP) along its rostrocaudal axis. In general, neuropeptide levels are comparable to those of overlying pyriform cortex. Visualization of mRNA encoding SOM, CCK and VIP in cell bodies of the claustrum by in situ hybridization histochemistry demonstrates that all 3 neuropeptides are contained in intrinsic claustral neurons. Mid-coronal section of the claustrum itself, or interruption of potential rostral, caudal or medial connections between the claustrum and the rest of the brain did not significantly alter levels of VIP, SOM or CCK in claustrum, cerebral cortex, or basal ganglia. Isolation of the claustrum from the cerebral cortex immediately dorsal to it along its rostrocaudal aspect caused no change in peptide levels in claustrum indicating that VIP, SOM and CCK projections to claustrum do not arrive from dorsal cortical areas. Transection of the external capsule above the claustrum caused a 50-100% elevation of all 3 peptides on the contralateral side of the lesion, suggesting that VIP, SOM and CCK synthesis and/or release within the claustrum may be regulated by projections from the contralateral side. VIP, SOM and CCK are candidates for neurotransmitters contained in neurons whose cell bodies are within the claustrum and possibly also immediately overlying lateral neocortex, and have their terminals mainly within the claustrum itself.
Animals↗
Distribution of carboxypeptidase H messenger RNA in rat brain using in situ hybridization histochemistry: implications for neuropeptide biosynthesis.
Carboxypeptidase H is an exopeptidase which is highly specific for C-terminal basic amino acids and thought to play a role in neuropeptide biosynthesis. The distribution of carboxypeptidase H mRNA was examined in adult rat brain using in situ hybridization histochemistry. Enzyme transcripts were detected in all major brain areas. Very high levels of carboxypeptidase H mRNA were found in the hippocampus associated with pyramidal cells. Other brain regions showed varied levels of labelling, ranging from high levels in the magnocellular cells of hypothalamic nuclei to very low levels in the striatum. The appearance of enzyme transcripts throughout brain supports a role for this enzyme in the biosynthesis of many neuropeptides. The expression of transcripts in certain ventricular ependymal cells identified them as a new potential peptidergic cell type. The variations in levels of expression of carboxypeptidase H mRNA may reflect differences in peptidergic activity in different neuronal systems.
Animals↗
Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis.
Plasma tumor necrosis factor alpha (TNF alpha), interleukin 1 alpha (IL-1 alpha), and interleukin 1 beta (IL-1 beta) were measured in plasma samples obtained from 23 patients with severe alcoholic hepatitis on admission and after 30 days of hospitalization. Over a 2-year follow-up period, 14 patients died at a mean time of 8 months following discharge. The presence of elevated plasma TNF alpha either at admission or discharge from the hospital was associated with death in 82% (14/17) of patients. By contrast absence of elevated plasma TNF alpha was associated with survival in 100% (6/6). The difference in survival with and without detectable plasma TNF alpha was significant at p = 0.0022. Plasma TNF alpha was not elevated in alcoholic patients without clinically apparent liver disease, with alcoholic cirrhosis, or in nonalcoholic healthy controls. Plasma IL-1 alpha was also significantly increased in alcoholic hepatitis whereas IL-1 beta was not. Neither IL-1 alpha nor beta was correlated with outcome in the alcoholic hepatitis group. It is concluded that the presence of elevated plasma TNF alpha is a significant predictor of decreased long-term survival in patients with severe alcoholic hepatitis.
Adult↗
Influence of growth hormone on the synthesis of rat liver alcohol dehydrogenase in primary hepatocyte culture.
Growth hormone has previously been shown to increase the activity of alcohol dehydrogenase in primary hepatocyte culture from male rats. In this study, continuous exposure of cultured hepatocytes to growth hormone (1 microgram/ml) resulted in parallel increased in the enzyme activity of alcohol dehydrogenase and immunoreactive protein. Growth hormone increased the incorporation of [3H]leucine into alcohol dehydrogenase protein relative to the incorporation into cytosolic protein. The abundance of alcohol dehydrogenase mRNA increased on Days 3 and 4 of continuous exposure of the hepatocytes to growth hormone and returned to control levels on Day 5 of culture. Growth hormone increased the rate of transcription of the alcohol dehydrogenase gene as demonstrated by nuclear runoff experiments. These observations indicate that the effect of growth hormone in enhancing alcohol dehydrogenase activity is due to increased synthesis of the enzyme which is initiated at the level of gene transcription.
Actins↗
Analysis of pyridine dinucleotides in cultured rat hepatocytes by high-performance liquid chromatography.
An isocratic reverse-phase high-performance liquid chromatography method for the separation and quantitation of total pyridine dinucleotides in hepatocyte cultures is described. Cells are extracted with cold 3 M perchloric acid or 0.5 N sodium hydroxide containing 50% (v/v) ethanol and 35% cesium chloride for the determination of the oxidized or reduced pyridine dinucleotides, respectively. Pyridine dinucleotides in the neutralized extracts were separated on an Excellopak ODS C18 (4.6 X 150 mm) column with 0.1 M potassium phosphate, pH 6.0, containing 3.75% methanol as the mobile phase. NAD+ and NADP+ were detected spectrophotometrically at 254 nm. The response was linear from 5 to 4000 pmol with recoveries of NAD+ and NADP+ of 98 and 101.1%, respectively. NADH and NADPH were monitored fluorometrically by activation at 370 nm and emission in the 400-700 nm range. The reduced pyridine dinucleotides had a linear response from 7.5 to 60 pmol with recoveries of NADH and NADPH of 99.4 and 101.3%, respectively. The coefficients of variation for all of the pyridine dinucleotide standards were less than 3.5%.
Adenosine Diphosphate↗
Distribution of serotonin 5-HT1C receptor mRNA in adult rat brain.
Based on in situ hybridization histochemistry (ISHH), we describe the anatomical distribution of the serotonin 5-HT1C receptor mRNA. In addition to the very high levels in epithelial cells of the choroid plexus, 5-HT1C receptor mRNA is found throughout the limbic system, in catecholaminergic cells and in serotonergic neurons. Receptor transcripts are also present in the hypothalamus, numerous motor nuclei and the subthalamus. Our results correlate well with serotonin (5-HT) innervation and receptor binding. Receptor mRNA is present in many brain structures in addition to regions previously shown to have 5-HT1C receptor binding. The distribution of this receptor mRNA suggests that the 5-HT1C receptor may mediate a number of the central effects of 5-HT.
Animals↗
Cloning of the rat adrenal medullary phenylethanolamine-N-methyltransferase.
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Adrenal Medulla↗
Animal models for alcoholic liver disease.
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Animals↗