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Terlipressin for hepatorenal impairment in alcoholic hepatitis
Nutrition, metabolism, alcoholic liver disease, pharmacology
[ P/C08/09 ]
[ P/C08/11 I
EFFECT OF CIRRHOSIS ON HEPATIC GLYCOGEN METABOLISM IN HUMANS C. Langl, C. Seller2, A. Zimmermann3, S. Kr~ihenbfihll, L. Kr/ihenb0hl2 IDepartment of Clinical Pharmacology,UniversityHospital, Berne, Switzerland. 2Department of Visceral Surgery, University Hospital, Berne, Switzerland.3Department of Pathology,UniversityHospital, Berne, Switzerland. Background." In most text books of hepatology liver cirrhosis is associated with reduced hepatic glycogen stores. This statement is largely based on determinations in 8 patients with alcoholic cirrhosis and 2 control subjects (Owen Jet al. J Clin Invest 1981;68:240-252). Aims: To determine hepatic glycogen in patients with different types of cirrhosis, to relate it to hepatoeellular volume and to investigate potential mechanisms for impaired hepatic glycogen metabolism. Methods: Patients had alcohohc (ALC, n=7), biliary (BIL, n=8) or viral cirrhosis (VIR, n=7) and underwent liver transplantation or hepatic resection, Control subjects (CON) underwent resection of benign tumors or single liver metastases. Liver biopsies were obtained in the postabsorptive state during surgery from cancer-free liver. Results: Hepatic glycogen (by speetrophotometry) was 25.7+ 18.8 in eirrhoties (CIR) and 44.7+17.3 mg/g liver in CON (p<0.05). The activities of glycogen synthase and phosphorylase were not different between CIR and CON. Stereologieal analysis of the livers revealed reduced hepatoeellular volume fraction in CIR (0.64+0.09 vs. 0.87+0.04, p<0.05). Glycogen per mL of hepatocytes was 50.0+_20.5 in CON and 39.3+_26.7 rag in CIR (not different). Regarding subgroups, hepatocellular glycogen (mg/mL) was decreased in ALC (26.9+_5.8) and BIL (28.2+_23.6) but maintained in VIR (64.5+96.6). Conclusions: Hepatic glycogen content is decreased in alcoholic and biliary cirrhosis per g liver and per mL hepatoeytes. Maintained activities of glycogen synthase and phosphorylase suggest that not hormonal, but mechanisms intrinsic to the liver, are responsible.
TNF-MEDIATED APOPTOSIS IN ALCOHOLIC HEPATITIS A. Tagami, H. Ohnishi, H. Moriwakil, M.G. Phillips, R.D. Hughes2 IFirst Department of Internal Medicine, Gifu, Japan. 2Institute of Liver Studies, Guy's King's and St Thomas' School of Medicine,London, UK. Blood levels of TNFc~ and IgA are increased in patients with alcoholic liver disease (ALD). IgA stimulates TNF secretion by monocytes from patients with ALD (Deviere et al 1991, Hepatology 13:670). The aim of this study was to investigate TNF-mediated apoptosis in relationship to IgA in patients with ALD. Liver tissue was obtained from 11 patients with acute alcoholic hepatitis (AAH), 11 patients with alcoholic cirrhosis (AC) and 7 normal donor livers. Fresh samples were frozen in liquid Nz and stored at -70°C. Protein was extracted for immunoblot analysis of expression of TNFa, TNF receptor (TNF-R1), the intracellular death domain FADD and IgA. The hepatic protein expression of TNFc¢ was significantly increased in patients with AAH compared to normal controls and patients with AC (Sheffe's F test: p=0.0189 and p=0.0098 respectively). Expression of TNF-R1 in patients with AAH was also significantly increased compared to normal controls and patients with AC (p<0.0001 and p=0.0001). There were significant positive correlations between expression of IgA and TNFc~ (p=0.0170), IgA and TNF-R1 (p=0.0003), TNFct and FADD (p<0.0001) and TNFR1 and FADD (p<0.0001). These findings in AAH could be the result of activation of Kupffer cells by IgA in portal venous blood to produce TNFcq which in turn induces apoptosis in adjacent hepatocytes.
I P/C08/10 I NTBI lS PRESENT IN CHRONIC ALCOHOL ABUSERS T.M. De Feo, L. Duca, M. Mattioli, G. Fiorelli, S. Fargion Dip. di Med. Int, Osp. Magg. IRCCS, Univ. Di Milano, Italy. Background: non-transferrin-bound iron (NTBI) has been found in rats fed either with ethanol and iron or with ethanol diet only. Aim: to evaluate i) whether NTBI is present in the serum of chronic alcohol abusers with and without liver cirrhosis and ii) investigate the behavior of NTBI according to active alcohol intake or withdrawal. Patients and methods: 43 chronic active alcohol abusers with or without cirrhosis (29 and 14) studied at presentation and 35 after one month of follow-up. Ten healthy subjects with daily alcohol intake < 10g. NTBI concentration was measured in serum using mtrilotri-acetic acid (NTA), ulUafiltration and UV detection with HPLC. Results: at presentation NTBI was present in the serum of 26/29 (89.6%) pts. with cirrhosis and of 10/14 (71.4%) pts. without cirrhosis, whereas it was undetectable in all controls. Moreover, NTBI values were significantly (P =0.01) higher in pts. with cirrhosis than without (2.22=k2.49pM vs. 0.59~1.64pM). Between pts. with and without cirrhosis a statistically significant ( P = 0.01) difference was found in TS (67±27 vs. 47±22%) while a higher, hut not statistically significant daily alcohol intake, was observed in pts. with cirrhosis (110g vs. 80g). After one month NTBI was present in 21/22 (95.4%) active drinkers and absent in 11/13 (84.6%) abstinents. Conclusions: NTBI is present in the serum of chronic alcohol abusers, either with than without cirrhosis, disappearing after withdrawal. In chronic alcohol abusers NTBI is detected also in presence of normal or mildly elevated TS. NTBI could play a role in alcohol toxicity.
P/C08/12 ] TERLIPRESSIN FOR HEPATORENAL IMPAIRMENT IN ALCOHOLIC HEPATITIS M.D. Rutter, S. Agarwal, C.O. Record, C.P. Day, O.EW.James, M. Hudson Liver Unit, Freeman Hospital, Newcastle-on-Tyne,UK. BACKGROUND: Hepatorenal impairment is a common complication of alcoholic hepatitis and carries a poor prognosis. Pathogenesis is mediated by profound renal vasoconstriction in response to systemic vasodilatation (predominantly splanchnic). Recent reports suggest terlipressin may be beneficial. AIM: To evaluate the benefit of terlipressin in patients with alcoholic hepatitis and hepatorenal impairment in the absence of hypotension or obstructive uropathy. METHODS: 12 consecutive patients with alcoholic hepatitis and renal impairment were treated with terlipressin (1-3 mg/day in divided doses) and plasma volume expansion with albumin to a central venous pressure of 7-12 mmHg. Infection was actively sought and treated appropriately. RESULTS: 8/12 patients (66%) showed evidence of response to tedipressin at 7 days: fall in baseline serum creatinine from 209 (159-386)~moF1 to 137(87-373)prooF1 [p=0.003]. Maddrey score did not fall significantly. 4 patients showed no response: baseline creatinine 494(466-643)pmol/1 rising to 721(562-880)lxrnol/1 at 7 days. 30-day mortality in responding group was 25%, compared to 100% in the non-responders. The 6 deaths were sepsis-related. CONCLUSION: Terlipressin may be of benefit in patients with alcoholic hepatitis and renal impairment The beneficial effect of terlipressin was most striking when in~oduc~ early, before the serum creatinine had reached 400 pmoFl.
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[ P/C08/09 ]
[ P/C08/11 I
EFFECT OF CIRRHOSIS ON HEPATIC GLYCOGEN METABOLISM IN HUMANS C. Langl, C. Seller2, A. Zimmermann3, S. Kr~ihenbfihll, L. Kr/ihenb0hl2 IDepartment of Clinical Pharmacology,UniversityHospital, Berne, Switzerland. 2Department of Visceral Surgery, University Hospital, Berne, Switzerland.3Department of Pathology,UniversityHospital, Berne, Switzerland. Background." In most text books of hepatology liver cirrhosis is associated with reduced hepatic glycogen stores. This statement is largely based on determinations in 8 patients with alcoholic cirrhosis and 2 control subjects (Owen Jet al. J Clin Invest 1981;68:240-252). Aims: To determine hepatic glycogen in patients with different types of cirrhosis, to relate it to hepatoeellular volume and to investigate potential mechanisms for impaired hepatic glycogen metabolism. Methods: Patients had alcohohc (ALC, n=7), biliary (BIL, n=8) or viral cirrhosis (VIR, n=7) and underwent liver transplantation or hepatic resection, Control subjects (CON) underwent resection of benign tumors or single liver metastases. Liver biopsies were obtained in the postabsorptive state during surgery from cancer-free liver. Results: Hepatic glycogen (by speetrophotometry) was 25.7+ 18.8 in eirrhoties (CIR) and 44.7+17.3 mg/g liver in CON (p<0.05). The activities of glycogen synthase and phosphorylase were not different between CIR and CON. Stereologieal analysis of the livers revealed reduced hepatoeellular volume fraction in CIR (0.64+0.09 vs. 0.87+0.04, p<0.05). Glycogen per mL of hepatocytes was 50.0+_20.5 in CON and 39.3+_26.7 rag in CIR (not different). Regarding subgroups, hepatocellular glycogen (mg/mL) was decreased in ALC (26.9+_5.8) and BIL (28.2+_23.6) but maintained in VIR (64.5+96.6). Conclusions: Hepatic glycogen content is decreased in alcoholic and biliary cirrhosis per g liver and per mL hepatoeytes. Maintained activities of glycogen synthase and phosphorylase suggest that not hormonal, but mechanisms intrinsic to the liver, are responsible.
TNF-MEDIATED APOPTOSIS IN ALCOHOLIC HEPATITIS A. Tagami, H. Ohnishi, H. Moriwakil, M.G. Phillips, R.D. Hughes2 IFirst Department of Internal Medicine, Gifu, Japan. 2Institute of Liver Studies, Guy's King's and St Thomas' School of Medicine,London, UK. Blood levels of TNFc~ and IgA are increased in patients with alcoholic liver disease (ALD). IgA stimulates TNF secretion by monocytes from patients with ALD (Deviere et al 1991, Hepatology 13:670). The aim of this study was to investigate TNF-mediated apoptosis in relationship to IgA in patients with ALD. Liver tissue was obtained from 11 patients with acute alcoholic hepatitis (AAH), 11 patients with alcoholic cirrhosis (AC) and 7 normal donor livers. Fresh samples were frozen in liquid Nz and stored at -70°C. Protein was extracted for immunoblot analysis of expression of TNFa, TNF receptor (TNF-R1), the intracellular death domain FADD and IgA. The hepatic protein expression of TNFc¢ was significantly increased in patients with AAH compared to normal controls and patients with AC (Sheffe's F test: p=0.0189 and p=0.0098 respectively). Expression of TNF-R1 in patients with AAH was also significantly increased compared to normal controls and patients with AC (p<0.0001 and p=0.0001). There were significant positive correlations between expression of IgA and TNFc~ (p=0.0170), IgA and TNF-R1 (p=0.0003), TNFct and FADD (p<0.0001) and TNFR1 and FADD (p<0.0001). These findings in AAH could be the result of activation of Kupffer cells by IgA in portal venous blood to produce TNFcq which in turn induces apoptosis in adjacent hepatocytes.
I P/C08/10 I NTBI lS PRESENT IN CHRONIC ALCOHOL ABUSERS T.M. De Feo, L. Duca, M. Mattioli, G. Fiorelli, S. Fargion Dip. di Med. Int, Osp. Magg. IRCCS, Univ. Di Milano, Italy. Background: non-transferrin-bound iron (NTBI) has been found in rats fed either with ethanol and iron or with ethanol diet only. Aim: to evaluate i) whether NTBI is present in the serum of chronic alcohol abusers with and without liver cirrhosis and ii) investigate the behavior of NTBI according to active alcohol intake or withdrawal. Patients and methods: 43 chronic active alcohol abusers with or without cirrhosis (29 and 14) studied at presentation and 35 after one month of follow-up. Ten healthy subjects with daily alcohol intake < 10g. NTBI concentration was measured in serum using mtrilotri-acetic acid (NTA), ulUafiltration and UV detection with HPLC. Results: at presentation NTBI was present in the serum of 26/29 (89.6%) pts. with cirrhosis and of 10/14 (71.4%) pts. without cirrhosis, whereas it was undetectable in all controls. Moreover, NTBI values were significantly (P =0.01) higher in pts. with cirrhosis than without (2.22=k2.49pM vs. 0.59~1.64pM). Between pts. with and without cirrhosis a statistically significant ( P = 0.01) difference was found in TS (67±27 vs. 47±22%) while a higher, hut not statistically significant daily alcohol intake, was observed in pts. with cirrhosis (110g vs. 80g). After one month NTBI was present in 21/22 (95.4%) active drinkers and absent in 11/13 (84.6%) abstinents. Conclusions: NTBI is present in the serum of chronic alcohol abusers, either with than without cirrhosis, disappearing after withdrawal. In chronic alcohol abusers NTBI is detected also in presence of normal or mildly elevated TS. NTBI could play a role in alcohol toxicity.
P/C08/12 ] TERLIPRESSIN FOR HEPATORENAL IMPAIRMENT IN ALCOHOLIC HEPATITIS M.D. Rutter, S. Agarwal, C.O. Record, C.P. Day, O.EW.James, M. Hudson Liver Unit, Freeman Hospital, Newcastle-on-Tyne,UK. BACKGROUND: Hepatorenal impairment is a common complication of alcoholic hepatitis and carries a poor prognosis. Pathogenesis is mediated by profound renal vasoconstriction in response to systemic vasodilatation (predominantly splanchnic). Recent reports suggest terlipressin may be beneficial. AIM: To evaluate the benefit of terlipressin in patients with alcoholic hepatitis and hepatorenal impairment in the absence of hypotension or obstructive uropathy. METHODS: 12 consecutive patients with alcoholic hepatitis and renal impairment were treated with terlipressin (1-3 mg/day in divided doses) and plasma volume expansion with albumin to a central venous pressure of 7-12 mmHg. Infection was actively sought and treated appropriately. RESULTS: 8/12 patients (66%) showed evidence of response to tedipressin at 7 days: fall in baseline serum creatinine from 209 (159-386)~moF1 to 137(87-373)prooF1 [p=0.003]. Maddrey score did not fall significantly. 4 patients showed no response: baseline creatinine 494(466-643)pmol/1 rising to 721(562-880)lxrnol/1 at 7 days. 30-day mortality in responding group was 25%, compared to 100% in the non-responders. The 6 deaths were sepsis-related. CONCLUSION: Terlipressin may be of benefit in patients with alcoholic hepatitis and renal impairment The beneficial effect of terlipressin was most striking when in~oduc~ early, before the serum creatinine had reached 400 pmoFl.
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