Nutritional therapy for alcoholic hepatitis: are we there yet?
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Energy Intake↗
Biomedical subjects
C L Mendenhall
Publications and source records attributed to C L Mendenhall.
Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: their prevalence and clinical relevance. The VA Cooperative Study Group (No. 119)
Patients with overt alcoholic liver disease who had participated in a multicenter therapeutic trial and subgroups of controls (i.e., alcoholic patients without liver disease and patients with neither alcoholism nor liver disease) were tested for hepatitis B virus and hepatitis C virus antibodies to determine the prevalence of these antibodies to determine the prevalence of these antibodies and any clinical association in the progression and outcome of alcoholic liver disease. Antibodies to hepatitis B (anti-HBs and/or anti-HBc) were found in 29.2% of patients with alcoholic liver disease, in 26.1% of hospitalized alcoholic patients without liver disease and in 24.2% of hospitalized nonalcoholic patients without liver disease; frequencies were not significantly different from one another. HBsAg was not evaluated because HBsAg+ patients had been excluded from the original trial. The presence of these antibody markers correlated with ethnic origin of and immunoglobulin levels in the patients. In contrast, antibody to hepatitis C, as detected by enzyme immunoassay, was positive in 27.1%, 4.8% and 3.0% of the three groups, respectively, the first differing significantly from the other two. Antibody to hepatitis C virus positivity correlated significantly with clinical severity of the disease and with the presence of histological features that imply chronic viral infection (periportal inflammation, cirrhosis), despite the fact that the supplementary assay for antibody to hepatitis C virus, using recombinant immunoblot assay, reduced the positive rate by 79%.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Sex steroid regulation of autoimmunity.
The immune response of males and females is not identical but instead has been shown to be dimorphic in its nature, with females generally demonstrating a greater overall response than males. This dimorphism extends to both the humoral and cell mediated systems and appears to be mechanistically based on the differences in type and concentration of sex steroids in males vs females. Furthermore, growth hormone and prolactin secretions which are different in males and females may also be partly responsible for the observed dimorphism. Because autoimmune disease results from a pathological perturbation of normal immune function, it follows that expression of these diseases will also demonstrate a dimorphic pattern. Examples of this autoimmune dimorphism include (but are not limited to) lupus, rheumatoid arthritis and multiple sclerosis with the two former more prevalent in females than males and the latter more severe during pregnancy. To explain autoimmune dimorphism it therefore becomes necessary firstly to describe the cellular and hormonal interactions found in normal immune regulation and thereafter extrapolate these to autoimmune phenomena.
Autoimmune Diseases↗
Alpha-fetoprotein alterations in alcoholics with liver disease. V.A. Cooperative Study Groups.
Sera on 409 male alcoholics with liver injury were assayed for alpha-fetoprotein (AFP) as part of a VA co-operative study on the natural history and therapy of alcoholic liver disease. In 78% of the patients values below normal were observed and 42% had undetectable levels. Clinically the lowest AFP concentrations were observed in the more severely ill patients with the poorest 1 year survival. Furthermore, improvement in AFP was associated with improved survival. Correlation analysis showed a relationship of AFP to (1) visceral protein concentrations (i.e. albumin, transferrin, retinal binding protein); (2) variables related to hepatic fibrogenesis (i.e. Ito cell activity, quantitative estimates of fibrosis and Kupffer cell abnormalities); and (3) changes in immunoglobulin levels particularly IgG. These findings suggest that AFP is a good index of disease prognosis.
Alcoholism↗
Effects of controlled liver injury and ethanol pretreatment on monoethylglycine xylidide formation in the rat.
Measuring the monoethylglycine xylidide (MEGX) serum level 15-30 min after intravenous administration of lidocaine has been shown to be an accurate predictor of early success in liver transplants. This study evaluates the changes in the MEGX formation test associated with changes in liver mass and ethanol pretreatment in a rat model. Mean MEGX levels were significantly higher for the sham-operated group versus each of the partially hepatectomized groups at 15, 30, and 45 min after injection. No differences between mean MEGX levels for either of the surgically treated groups could be distinguished. Ethanol pretreatment and body weight had no effect on MEGX levels at any of the time points tested in this model.
Animals↗
Ito cell activation induced by chronic ethanol feeding in the presence of different dietary fats.
Bronfenmajer et al. (1966) first studied Ito cells in alcoholic hepatitis (AH) by light microscopy (LM). The number of Ito cells and the number of fat droplets were increased. Okanoue et al. (1983) found that Ito cells were reduced by LM but increased by electron microscopy (EM) in scars in AH. Ito cells were activated in scars (increased RER and decreased fat in Ito cells with transition to fibroblasts). Minato et al. (1983) showed that increased RER in Ito cells correlated with increased collagen synthesis of liver biopsies in vitro. Mak et al. showed increased RER correlated with the degree of fibrosis in alcoholic baboons (1984) and alcoholic cirrhosis in man (1988). French et al. (1988b) showed morphometrically that Ito cell fat was decreased and RER was increased only in scars but not in normal sinusoids so that Ito cell activation was restricted to the scars. There was no correlation of sinusoidally located Ito cell fat or RER with the amount of perisinusoidal collagen. In rats fed ethanol and a nutritionally adequate diet including corn oil (25% of calories) by intragastric cannula for five months the fatty liver progressed to focal central fibrosis, and Ito cell activation (fat/RER) was increased. When tallow was substituted for corn oil the Ito cells were not activated and the liver histology was normal. Thus, the type of dietary fat and the local environment (scars) are important factors in the activation of Ito cells by alcohol in vivo.
Alcoholism↗
Prognostic factors in alcoholic liver disease. VA Cooperative Study Group.
Two hundred eighty-one alcoholic patients were prospectively evaluated by clinical, biochemical, and histologic parameters during a 4-yr period to assess their prognosis. They were stratified into four categories of injury: 1) fatty liver (26 patients), 2) acute alcoholic hepatitis (106), 3) cirrhosis (39), and 4) cirrhosis with superimposed alcoholic hepatitis (111). The rate of survival and variables correlating with survival varied according to the group. At 48 months, 70% of the patients with fatty liver were alive, 58% in the alcoholic hepatitis group, 49% in cirrhosis, and 35% in alcoholic hepatitis superimposed upon cirrhosis. Within group one, deaths were due to causes unrelated to liver disease. In the alcoholic hepatitis group, factors significantly correlating with survival were ascites, alanine amino-transferase levels, grams of alcohol consumed, continuation of alcohol intake, and clinical severity of disease. Survival in patients of group three correlated significantly with prothrombin time and histologic severity score. Patients with combined cirrhosis and alcoholic hepatitis exhibited the worst prognosis, with the most significant predictors of survival being age, grams of alcohol consumed, the ratio of serum aminotransferases (AST:ALT) and the histologic and clinical severity of the disease. Although a different pattern of correlates was observed for each pathologic level of injury, knowledge of the various correlates aids in prognostic assessment.
Acute Disease↗
Host response to mycobacterial infection in the alcoholic rat.
Animals, chronically treated with alcohol, were inoculated with mycobacteria (bacillus Calmette-Guérin, 10.2 x 10(6) organisms) into the spleen to produce a granulomatous hepatitis. Before infection, chronic alcohol ingestion was associated with a depressed skin test response to phytohemagglutinin, 71.7% of baseline (P = 0.009). Mycobacterial (bacillus Calmette-Guérin) infection stimulated phytohemagglutinin skin test response to 417% of baseline in controls and 299% in alcoholics (P less than 0.001). The hepatic granuloma response was altered with smaller but more numerous granulomas (mean +/- SEM, 81.2 +/- 1.5 microns2 of area with a frequency of 1.8 granulomas per field in alcoholics vs. 129.8 +/- 5.71 microns2 and 1.2 granulomas per field in controls; P less than 0.001). These changes were associated with a 10-fold increase in colony-forming units per gram of liver (54.5 +/- 18.2 in alcoholics vs. 5.6 +/- 1.83 in controls; P = 0.0006). This model offers precise parameters for host response to infection and indicates that alcohol significantly impairs the clearing capacity for mycobacteria from the liver.
Alcoholism↗
Anabolic steroid effects on immune function: differences between analogues.
As an untoward effect of chronic anabolic steroid use, immunologic alterations may be induced. To evaluate this possibility five commercially available steroids with various types of structural differences were studied in male Sprague-Dawley rats. Animals were divided into five groups and treated with testosterone (Group 1), testosterone propionate (Group 2), testolactone (Group 3), oxandrolone (Group 4), and stanozolol (Group 5). Androgenic anabolic steroids were administered daily, subcutaneously dissolved in oil, at a dose of 1.1 mg/kg. Immune alterations were assessed by skin-test responses to phytohemagglutinin. After five days of treatment (1.1 mg/kg/day) a significant immuno-suppression was observed with all groups. However, by day 10, groups 3, 4, and 5 showed an immuno-stimulation. Using oxandrolone as the model stimulant, serum testosterone levels were significantly suppressed, while castration abolished the stimulatory effect. These observations indicate that immune alterations do occur with anabolic steroids which are immuno-suppressive when the steroid nucleus is intact and immuno-stimulatory with nuclear alterations. It appears that these changes are associated with altered gonadal testosterone release.
Anabolic Agents↗
Cell-mediated immunity in alcoholic liver disease. Veterans Administration Cooperative Study #275.
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Antigen-Presenting Cells↗
Nuclear progestin receptors in rat thymic tissue.
The thymus and its associated endothelial cells and lymphocytes act as an important immunological tissue. The endothelial cells of the thymus have been reported to synthesize cytoplasmic progestin receptor in response to estrogen priming. To measure nuclear progestin receptor, female rats were castrated and primed for 3 days with estradiol benzoate (30 micrograms/0.1 ml/d) and immediately before sacrifice injected subcutaneously with 0.2 mg of progesterone. By Scatchard plot analysis we found that specific progestin receptor (KA = 0.89 +/- 0.10 x 10(9) M-1) was present in the KCl-nuclear extract. The concentration of nuclear progestin receptor was found to be in the range of 312.6 +/- 49 fmole/g tissue (n = 9, 1 hour after progesterone injection) while the nuclear receptor was significantly reduced (approximately 44 fmol/g tissue) in the oil treated controls. This level verges on the limits of sensitivity for this assay. For cytoplasmic progestin receptor the concentration was 3.46 +/- 0.20 pmole/g tissue in oil treated controls (n = 14) and 3.36 +/- 0.20 pmole/g tissue in progesterone treated animals (n = 24). The KA of this thymic cytoplasmic progestin receptor was 1.35 +/- 0.06 x 10(9) M-1. By competition assay, the relative binding affinity of nuclear progestin receptor was: R5020 (a potent synthetic progestin) (100%), progesterone (9%), testosterone (0.56%), corticosterone (0.53%), estradiol-17 beta (0%). It is concluded that thymic reticuloepitheleal cells contain nuclear progestin receptor and this finding supports the hypothesis that progesterone, like other sex steroids may play a regulatory role in thymic cell function.
Animals↗
The interactions of insulin-like growth factor I(IGF-I) with protein-calorie malnutrition in patients with alcoholic liver disease: V.A. Cooperative Study on Alcoholic Hepatitis VI.
Plasma concentrations of insulin-like growth factor I (IGF-I) were measured in 95 alcoholic men with a spectrum of alcoholic liver injury and protein-calorie malnutrition (PCM). Circulating levels of IGF-I were depressed in the alcoholic patients (0.23 +/- 0.02 U/ml; mean +/- S.E.M.) compared to controls (1.0 +/- 0.07, P less than 0.0001). Plasma IGF-I levels declined progressively with falling indices of PCM (P less than 0.001) and correlated especially with the parameters relating to protein deficiency. While the severity of liver dysfunction and histopathologic alterations in the liver also related to plasma IGF-I concentration, partial correlation analysis showed that only PCM correlated significantly with IGF-I levels independent of the other factors. These findings indicate that IGF-I levels reflect nutritional status even in the presence of alcoholic liver disease.
Adult↗
Beef fat prevents alcoholic liver disease in the rat.
The amount and type of dietary fat is thought to be important in the pathogenesis of alcoholic liver disease (ALD). We investigated the role of different dietary fats in our rat model for ALD. Liver pathology was evaluated in rats fed ethanol and lard or tallow or corn oil over a period of 2 to 6 months. All experimental animals were pair-fed the same diet as controls except that glucose was isocalorically replaced by ethanol. Rats fed tallow and ethanol developed none of the features of ALD, those fed lard and ethanol developed minimal to moderate disease, rats fed corn oil and ethanol developed the most severe pathology. The degree of histopathological abnormality correlated with the linoleic acid content of fat in the diet (tallow 0.7%, lard 2.5%, corn oil 56.6%). We postulate that linoleic acid facilitates development of ALD and provides an explanation for our previous epidemiological observations.
Animals↗
Cell-mediated immune responses associated with short term alcohol intake: time course and dose dependency.
Using a rat model, we report here the duration of heavy drinking necessary to produce immunosuppression, the recovery time after such alcohol-induced immunosuppression, and the variations in immune response associated with varied amounts of alcohol consumption. Immune status was evaluated by means of delayed cutaneous hypersensitivity (DCH)-like responses to phytohemagglutinin. The daily consumption of 5 g of ethanol/kg body weight/d resulted in a prompt reduction in DCH-like responses which was significant by Day 3 (p = 0.03) and maximal by Day 11 (45% of baseline). These data were consistent with a similar reduction of migration inhibitory factor activity in spleen cells from ethanol fed rats. Cessation of ethanol resulted in a return to baseline within 4 days. In a second experiment ethanol was administered daily in doses ranging from 0.5 to 6.0 g/kg. Early (Day 5) low dose ethanol (0.5-2 g/kg) stimulated immune response (153-188% of baseline) while high dose (6.0 g/kg) suppressed (79% of baseline). Continued treatments resulted in a loss of stimulation at low dose and increased suppression at higher doses. The relationship of these animal studies to human binge drinking and the possible risk for infection in the alcoholic remains to be established.
Animals↗
Ethanol and soluble mediators of host response.
Lymphokines serve to modulate host inflammatory response by providing a communication link among cells involved in resistance to infection. In the alcoholic, this system may be impaired due to a combination of the direct effects of ethanol on immunocompetent cells and the soluble factors involved in cell-cell interactions. In this paper, we review the literature on this subject, describe an ethanol-related impairment of migration inhibitory factor activity in the rat, and present a possible mechanism for this alteration.
Alcoholism↗
Serum aspartate aminotransferase to alanine aminotransferase ratio in human and experimental alcoholic liver disease: relationship to histologic changes.
We studied the relationship between the ratio of serum aspartate aminotransferase (ASAT) to alanine aminotransferase (ALAT) and histologic changes in human and experimental alcoholic liver disease. The patient population included 52 hospitalized patients enrolled in a Veterans Administration Cooperative study. The experimental animal group consisted of male Wistar rats fed an ethanol-liquid diet. Of the 52 patients with alcoholic hepatitis, 33 had evidence of cirrhosis. The mean +/- SD for the ASAT/ALAT ratio in the group with alcoholic hepatitis and no cirrhosis was 1.47 +/- 0.84, the mean +/- SD in the group with hepatitis and cirrhosis was significantly higher (2.68 +/- 1.32, p less than 0.01). There was no difference in the ratio between the rats with and without liver fibrosis. The cause for the increased ASAT/ALAT ratio in serum in the presence of cirrhosis is unknown and may reflect more severe liver damage.
Alanine Transaminase↗
Phytohemagglutinin skin test responses to evaluate in vivo cellular immune function in rats.
It is often necessary to have a small animal model which permits the sequential evaluation of functional immune status over a period of time. We report here the in vivo, intradermal response to phytohemagglutinin which produces an area of induration that is histologically similar to a typical delayed cutaneous hypersensitivity response, and that provides fast, quantitative, reproducible results similar to those observed with standard but more laborious and variable in vitro tests of immune function. For small animal studies this has the advantage of permitting longitudinal evaluations over time without sacrificing the animal. Using phytohemagglutinin-microprotein (0.2 mg/0.1 ml), injected intradermally, a delayed cutaneous hypersensitivity-like response is induced which is maximal at 24 hr. When immune function was altered either by treatment with a chemical immunosuppressant (ethanol) or by hormonal manipulations (hypophysectomy and rat growth hormone), the delayed cutaneous hypersensitivity-like response (area of induration) correlated closely with both macrophage migration inhibitory factor changes (r = 0.98; P less than 0.001) and mixed lymphocyte reaction changes (r = 0.99; P less than 0.05). These observations suggest that this technique correlates well with standard in vitro measures of immune response and may thus permit an in vivo estimation of immune reactivity.
Animals↗
Age dependent alterations of host immune response in the ethanol-fed rat.
The interaction between ethanol and aging with respect to cellular immune response is unclear. For our studies, Sprague-Dawley rats were pair fed using a synthetic liquid control diet (LCD) or a diet in which ethanol was substituted for carbohydrate (LED). The special diets were started when the rats' age varied from 1-18 months and were continued for one, two, or three months. In a second set of experiments, rats were treated continuously with these diets for 24 months. At each study period blood was drawn for serum and the spleen cells removed. Immune response was assessed by the lymphocyte transformation test using combinations of cells and serum from each of the rat groups. When LCD or LED were started in aged rats (18 months), after three months, there was a significant decrease in the Concanavalin A induced lymphocyte transformation test using the serum from LCD rats compared to serum from LED rats with either cells from LCD (1,273 +/- 831 (DPM +/- SD) vs 302 +/- 139; p less than 0.04) or cells from LED animals (984 +/- 338 vs 420 +/- 196; p less than 0.02). When the diet started at younger age or for less than three months these effects were not seen. In the continuously LCD or LED fed rats, the blastogenic response peaked at three months of treatment (four months of age) and decreased at six months and remained constant over the remainder of the 24 month period. There was no difference in lymphocyte DNA synthesis comparing any of the serum or cell groups with respect to diet.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗