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Steroids vs enteral nutrition in severe alcoholic hepatitis. Interim results of a prospective, randomized, multicentric trial
129 NUTRITION,
METABOLISM,
ALCOHOLIC
LIVER DISEASE,
PHARMACOLOGY 1 P/CO8/003
OBESITY AND NOT ALCOHOL INTAKE IS THE MAIN CAUSE OF LIVER STEATOSIS. BBellentani. GSaccoccio. F Masutti. L.Croce’. CTiribelli. Fondo Studi Fegato, Modena-Trieste, Italy. The role of obesity in inducing liver steatosis is still a matter of controversies, especially when is associated with alcohol (EtOH) abuse. Nowadays, all data available have been collected from selected series. Aim: To compare the role of obesity and alcohol consumption in inducing liver steatosis. Methods: We performed an intra-cohort case-control studv within the Dionysos population (Hepatology 20:1442,1994). Twohundred and eightyfive (285) HBV and HCV negative, apparently healty subiects. aged 12-65. divided in 4 groups pair-matched for age and alcohol intake, belonging to the Dionysos cohort were enrolled in this study. The 4 groups were composed as follows: & 87 teetotallers with normal body mass index (BMl).used as controls (C); b) 71 teetotallers obese (BMI > 30) (0); c) 71 heavy drinkers (> 60 g of EtOH/day) with normal BMI (HD); d) 56 subjects both obese and heavy drinkers (O+HD). All the subjects underwent a detailed history, physical examination and hepato-biliarysplenic ultrasound (US). Serum ALT, AST, GGT, glucose, trigliceryde (TG) and cholesterol assay were also performed. Results: The risk of having hepatic steatosis at US, and AST and TG levels above the normal values, expressed as Odd Ratio (OR) and 95% confidence intervals, are reported in the table. GROUP
STFATOSIS
HD 0 O+HD
3.1 (1:5-6)* 10.0 (520)# 43.5 (14-135)#
’ p NS
l
~~0.02 or #
BSI 3.0 (I-8)’ 1.2 (0.4-4.0)” 4.1 (1.4-11.5)#
IE 1 .o (033.3)’ 3.4 (I.38.9)# 9.1 (3.0-28)#
p
In the general population, the risk for an obese of having either steatosis at US or an alteration of TG is significantly higher than for an heavy drinkers. When obese is also an heavy drinker the risk of having liver damage is further significantly increased. Concfusions: These data indicate that obesity more than alcohol consumption induces fatty liver in apparently normal healthy subjects.
1
REVERSES INTRAPORTAL ACETYLCHOLINE INSULIN RESISTANCE CAUSED BY CHRONIC BILE DUCT LIGATION W.W. Lautt. H Xie Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, R3E 0W3. Responsiveness to insulin is regulated by hepatic parasympathetic nerves. Insulin resistance is produced by hepatic denervation or intraportal atropine and is restored by intraportal but not intravenous acetylcholine (ACh) (Xie & Lautt, 1996, Am J Physiol 271:E587-E592). We tested the hypothesis that the liver disease model of chronic bile duct ligation (BDL) would lead to insulin resistance secondary to hepatic parasympathetic neuropathy that could be reversed by intraportal ACh. Rats underwent BDL or sham operation. After 10 days, insulin sensitivity was determined using the rapid insulin sensitivity test (RIST) with the RIST index being the amount of glucose (mg/kg) required to be infused in order to maintain euglycemia following administration of 50 mU insulin/kg. The sham group had a RIST index of 483 in control state, 476 during ACh and 240 after atropine. The BDL group had a RIST index of 199 and showed reversal to normal levels (364) during intraportal ACh (2.5 ug/kg/min) and did not become more resistant after atropine (194). We conclude that chronic BDL causes hepatic parasympathetic neuropathy resulting in insulin resistance that can be fully restored by administration of ACh into the portal vein.
1 P/CO8/002 1 STEROIDS vs ENTERAL NUTRITION IN SEVERE ALCOHOLIC HEPATITIS. INTERIM RESULTS OF A PROSPECTIVE, RANDOMIZED, MULTICENTRIC TRIAL. E.Cabr-? in behalf of the SDanish G~IID for the Studv of Alcoholic Heoatitis (‘Dept. Gastro.,Hosp.GermansTriasi Pujol.08916 Badalona,Spain)
EFFECT OF SEROTONIN ON CELL VOLUME REGULATION IN RESTING EARLY CULTURE RAT HEPATIC STELLATE CELLS
Steroids are the standard therapy for severe alcoholic hepatitis (SAH), but it has been claimed that nutrition support could also be effective in these cases. However, both therapies have not been compared yet. &?J To assess the effectiveness and safety of total enteral nutrition (TEN), in comparison to steroids, as primary therapy in SAH. Melhw’s: 51 patients with SAH (Maddrey’s Index [Ml] ~32 and/or hepatic encephalopathy [HE]) were randomized to receive prednisolone (40 mgl day) (STE group, n=24) or TEN (2000 KcaVday) continuously infused through a nasoenteral tube (Silk type)(TEN group, n=27) for 28 days, Randomization was stratified by sex and the presence of HE. Major endpoints were mortality and development of infections during therapy. For
Introduction: Serotonin (5HT) is a vasoactive biogenic amine released into the portal circulation from enterochromaffin cells of the intestinal mucosa and can get in touch with hepatic stellate cells (HSC) of the liver. We examined the expression of 5-HTreceptors in HSC and the effect of 5-HT on HSC volume regulation. Methods: Isolation of rat HSC according to De Leeuw. HSC were examined at day 2 afler isolation. Demonstration of 5 HT receptor subtypes with RT-PCR using subtype-specific primers. For single cell volume measurement we used fluorescein derivative Calcein-AM according to the method of Crowe et al. (Neuroscience 69, 283-96, 1995) using a Zeiss LSM 410 confocal microscope. Results: 5-HT (0.1-10 umolll) concentration-dependently mduced a shrinking of HSC (EC50: 0.4 umol/l, maximum effect: 15.15 &1.7%, n=lO). In controls the shrinkina of resting HSC was maximally 5% (n=lO). The calcium - ionophore ionomycin (10 umolll) reduced the cell volume by 14.05 *3.7% (n=lO), too. The adenvlate cvclase activator forskolin (I -1 Oumol/l) did not affect cell volume of HSC. In the presence of dantrolene (10 umolll), an inhibitor of intracellular calcium release, the effect of .5-HT (10 umolll) was blocked. RT-PCR revealed amplificates of 5-HT2A and 5-HT2B-receptors. Discussion: The reduction of cell volume of restina HSC bv a vasoactive substance like 5-HT implies a participation of th-ese cells in the regulation of hepatic circulation via changes of the sinusoidal diameter. The effect of 5-HT probably mediated by the activation of 5-HT2 receptors depends on the release of calcium from the endoplasmatic reticulum. The failure of forskolin to induce cell volume changes in HSC contradicts the involvement of CAMPsystem.
each end-point, survival curves (Kaplan-Meier) were compared according to the treatment, and baseline features (log-rank test). Those variables significantly associated to each end-point were included in a stepwise Cox regression model to identify independent predictors of the event. The treatment effect on each end-point was then adjusted for these covatiates. Resulfsl Groups were homogeneous, except for the MI, that was higher in the TEN group (56*4 vs. 46+3, p=.O52). However, no differences were found in the probability of surviving (78% in STE vs 65% in TEN group;
p=.24) or developing infections (45% vs 47% ; p=.70). Independent predictors (Cox model) included MI, HE, age, hematocnt, and serum sodium for survival, and total bilirubin and ALT for infections. No differences between treatments were found after adjusting their effects to these covariates (p=.64 for mortality, and p=.65 for infections). Cunclusio~ These preliminary results suggest that TEN may be as effective as steroids in the treatment of SAH.
Fischer
T, Schworer H, Raddatz D, Knittel T, Saile B, Ramadori G Dept. of Medicine, University of Gottingen, Germany
METABOLISM,
ALCOHOLIC
LIVER DISEASE,
PHARMACOLOGY 1 P/CO8/003
OBESITY AND NOT ALCOHOL INTAKE IS THE MAIN CAUSE OF LIVER STEATOSIS. BBellentani. GSaccoccio. F Masutti. L.Croce’. CTiribelli. Fondo Studi Fegato, Modena-Trieste, Italy. The role of obesity in inducing liver steatosis is still a matter of controversies, especially when is associated with alcohol (EtOH) abuse. Nowadays, all data available have been collected from selected series. Aim: To compare the role of obesity and alcohol consumption in inducing liver steatosis. Methods: We performed an intra-cohort case-control studv within the Dionysos population (Hepatology 20:1442,1994). Twohundred and eightyfive (285) HBV and HCV negative, apparently healty subiects. aged 12-65. divided in 4 groups pair-matched for age and alcohol intake, belonging to the Dionysos cohort were enrolled in this study. The 4 groups were composed as follows: & 87 teetotallers with normal body mass index (BMl).used as controls (C); b) 71 teetotallers obese (BMI > 30) (0); c) 71 heavy drinkers (> 60 g of EtOH/day) with normal BMI (HD); d) 56 subjects both obese and heavy drinkers (O+HD). All the subjects underwent a detailed history, physical examination and hepato-biliarysplenic ultrasound (US). Serum ALT, AST, GGT, glucose, trigliceryde (TG) and cholesterol assay were also performed. Results: The risk of having hepatic steatosis at US, and AST and TG levels above the normal values, expressed as Odd Ratio (OR) and 95% confidence intervals, are reported in the table. GROUP
STFATOSIS
HD 0 O+HD
3.1 (1:5-6)* 10.0 (520)# 43.5 (14-135)#
’ p NS
l
~~0.02 or #
BSI 3.0 (I-8)’ 1.2 (0.4-4.0)” 4.1 (1.4-11.5)#
IE 1 .o (033.3)’ 3.4 (I.38.9)# 9.1 (3.0-28)#
p
In the general population, the risk for an obese of having either steatosis at US or an alteration of TG is significantly higher than for an heavy drinkers. When obese is also an heavy drinker the risk of having liver damage is further significantly increased. Concfusions: These data indicate that obesity more than alcohol consumption induces fatty liver in apparently normal healthy subjects.
1
REVERSES INTRAPORTAL ACETYLCHOLINE INSULIN RESISTANCE CAUSED BY CHRONIC BILE DUCT LIGATION W.W. Lautt. H Xie Department of Pharmacology & Therapeutics, University of Manitoba, Winnipeg, Manitoba, R3E 0W3. Responsiveness to insulin is regulated by hepatic parasympathetic nerves. Insulin resistance is produced by hepatic denervation or intraportal atropine and is restored by intraportal but not intravenous acetylcholine (ACh) (Xie & Lautt, 1996, Am J Physiol 271:E587-E592). We tested the hypothesis that the liver disease model of chronic bile duct ligation (BDL) would lead to insulin resistance secondary to hepatic parasympathetic neuropathy that could be reversed by intraportal ACh. Rats underwent BDL or sham operation. After 10 days, insulin sensitivity was determined using the rapid insulin sensitivity test (RIST) with the RIST index being the amount of glucose (mg/kg) required to be infused in order to maintain euglycemia following administration of 50 mU insulin/kg. The sham group had a RIST index of 483 in control state, 476 during ACh and 240 after atropine. The BDL group had a RIST index of 199 and showed reversal to normal levels (364) during intraportal ACh (2.5 ug/kg/min) and did not become more resistant after atropine (194). We conclude that chronic BDL causes hepatic parasympathetic neuropathy resulting in insulin resistance that can be fully restored by administration of ACh into the portal vein.
1 P/CO8/002 1 STEROIDS vs ENTERAL NUTRITION IN SEVERE ALCOHOLIC HEPATITIS. INTERIM RESULTS OF A PROSPECTIVE, RANDOMIZED, MULTICENTRIC TRIAL. E.Cabr-? in behalf of the SDanish G~IID for the Studv of Alcoholic Heoatitis (‘Dept. Gastro.,Hosp.GermansTriasi Pujol.08916 Badalona,Spain)
EFFECT OF SEROTONIN ON CELL VOLUME REGULATION IN RESTING EARLY CULTURE RAT HEPATIC STELLATE CELLS
Steroids are the standard therapy for severe alcoholic hepatitis (SAH), but it has been claimed that nutrition support could also be effective in these cases. However, both therapies have not been compared yet. &?J To assess the effectiveness and safety of total enteral nutrition (TEN), in comparison to steroids, as primary therapy in SAH. Melhw’s: 51 patients with SAH (Maddrey’s Index [Ml] ~32 and/or hepatic encephalopathy [HE]) were randomized to receive prednisolone (40 mgl day) (STE group, n=24) or TEN (2000 KcaVday) continuously infused through a nasoenteral tube (Silk type)(TEN group, n=27) for 28 days, Randomization was stratified by sex and the presence of HE. Major endpoints were mortality and development of infections during therapy. For
Introduction: Serotonin (5HT) is a vasoactive biogenic amine released into the portal circulation from enterochromaffin cells of the intestinal mucosa and can get in touch with hepatic stellate cells (HSC) of the liver. We examined the expression of 5-HTreceptors in HSC and the effect of 5-HT on HSC volume regulation. Methods: Isolation of rat HSC according to De Leeuw. HSC were examined at day 2 afler isolation. Demonstration of 5 HT receptor subtypes with RT-PCR using subtype-specific primers. For single cell volume measurement we used fluorescein derivative Calcein-AM according to the method of Crowe et al. (Neuroscience 69, 283-96, 1995) using a Zeiss LSM 410 confocal microscope. Results: 5-HT (0.1-10 umolll) concentration-dependently mduced a shrinking of HSC (EC50: 0.4 umol/l, maximum effect: 15.15 &1.7%, n=lO). In controls the shrinkina of resting HSC was maximally 5% (n=lO). The calcium - ionophore ionomycin (10 umolll) reduced the cell volume by 14.05 *3.7% (n=lO), too. The adenvlate cvclase activator forskolin (I -1 Oumol/l) did not affect cell volume of HSC. In the presence of dantrolene (10 umolll), an inhibitor of intracellular calcium release, the effect of .5-HT (10 umolll) was blocked. RT-PCR revealed amplificates of 5-HT2A and 5-HT2B-receptors. Discussion: The reduction of cell volume of restina HSC bv a vasoactive substance like 5-HT implies a participation of th-ese cells in the regulation of hepatic circulation via changes of the sinusoidal diameter. The effect of 5-HT probably mediated by the activation of 5-HT2 receptors depends on the release of calcium from the endoplasmatic reticulum. The failure of forskolin to induce cell volume changes in HSC contradicts the involvement of CAMPsystem.
each end-point, survival curves (Kaplan-Meier) were compared according to the treatment, and baseline features (log-rank test). Those variables significantly associated to each end-point were included in a stepwise Cox regression model to identify independent predictors of the event. The treatment effect on each end-point was then adjusted for these covatiates. Resulfsl Groups were homogeneous, except for the MI, that was higher in the TEN group (56*4 vs. 46+3, p=.O52). However, no differences were found in the probability of surviving (78% in STE vs 65% in TEN group;
p=.24) or developing infections (45% vs 47% ; p=.70). Independent predictors (Cox model) included MI, HE, age, hematocnt, and serum sodium for survival, and total bilirubin and ALT for infections. No differences between treatments were found after adjusting their effects to these covariates (p=.64 for mortality, and p=.65 for infections). Cunclusio~ These preliminary results suggest that TEN may be as effective as steroids in the treatment of SAH.
Fischer
T, Schworer H, Raddatz D, Knittel T, Saile B, Ramadori G Dept. of Medicine, University of Gottingen, Germany