- Email: [email protected]
Increased urotensin II plasma levels in patients with cirrhosis
Saturday, April 21,200l
18
and 125Ihippuran during three consecutive 30 minute periods. Renal sodium handling was determined by lithium and sodium clearance measurements and free water clearance by determination of osmolar clearance. Therapeutic plasma levels of octreotide along with a reduction of insulin-like growth factor I (IGF-I) (PC 0.01) and an increase of IGF binding protein 1 (PC 0.05) were demonstrated. No effect of octreotide was observed on GFR, ERPF or filtration fraction (GFR/ERPF). Changes in clearance and extraction fraction of sodium and lithium during octreotide treatment were not significantly different from those of placebo. In addition, no changes in free water clearance, urinary flow rate or 24h Na excretion were demonstrated. A significant increase of mean arterial pressure (+ 5 mmHg, P< 0.01) was observed after octreotide-LAR. In spite of increased arterial pressure octreotide-LAR has no significant effect on renal haemodynamics and tubular function in clinically stable oirrhotic patients with portal hypertension.
0
1449
NORADRENALIN FOR TREATMENT OF TYPE I HEPATORENAL SYNDROME (HRS)
C. Duvouxr , D. Zanditenas ‘, C. Hbode t , A. Chauvat*, J. Metreau I, D. Dhumeauxr . ’ Service d’H$atologie et de Gastmenthlogie; ‘Service de Cardiologie, Hbpital Hem-i Mondos Universite’ Paris XII, CrtQeil, France
Vasopressin analogs were shower to be efficient in the treatment of type I HRS. However, their use is limited by ischaemic side effects and a high cost. Our aim was to assess efficacy and tolerance of noradrenalin (NA) in the treatment of type I HRS. Patients and Methods: from May 1998 to July 2000, 12 patients with type I HRS (age: 54 f 11 years, 7 males, 5 females, Child-Pugh score: 11.3 f 1.7) were treated with NA. After a 48 hour-period of fluid expansion with human albumin, continuous infusion of NA was initiated (DO) at 0.5 mg/hour and progressively risen to a maximum of 3.0 mg/b according to clinical response, for a minimum of 5 days. Fluid expansion was continued to maintain central venous pressure (CVP) above 7 mmHg. From D-3 to DlO, daily urine output, natriuresis, serum creatinine, creatinine clearance, mean arterial pressure (MAP), CVP and liver tests were studied. In 9/12 patients, plasma renin activity (PRA) was assessed on DO, D3 and D5. In 6 of these 9 patients, systemic vascular resistances (SVR) were measured on DO and D5, using a non invasive technique. Results: NA was given for 10 f 3 days, with a mean dose of 0.8 f 0.3 mg/h. Renal function improved in 1002 cases, and this occurred after terlipressin failure in 2 cases. The effects of NA, are summarized in the table. In 1 patient, transient myocardial ischaemia occurred while treated with NA, 2 mg/h. NA was withdrawn for 36 h and reintroduced thereafter at 1 mg/h without ischaemic recurrence. With a 6 month-follow-up, 6 patients died, 3 were transplanted and 3 are alive without transplantation. The cost of a 10 day-course of NA was 52 f 15. Conclusions: These results suggest that continuous infusion of NA is effective in the treatment of type I I-IRS and acceptably tolerated. The efficacy and low cost of NA should lead to comparison with vasopressin analogs in the treatment of I-IRS.
I
2%
THALIDOMIDE BUT NOT PENTOXIFYLLINE LOWERS PORTAL PRESSURE IN HUMAN ALCOHOLIC CIRRHOSIS
A.S. Austin, Y.R. Mahida, S.D. Ryder, J.G. Freeman. University Hospital, Nottingham, UK, Department of Medicine, Derby City General Hospital, Derby, UK Introduction: Blockade of tumour necrosis factor alpha (TNFa) activity reduces portal pressure in portal vein-ligated rats. We investigated the ability of two inhibitors of TNFa production, thalidomide and pentoxifylline, to reduce portal pressure in humans. Methods: Abstinent stable alcoholic cirrhotic patients were treated with open-label pentoxifylline 18OOmg daily (n=9, median age 53 (45~64), median Child-Pugh score 6(5-10)) or thalidomide 200mg daily (n=lO, median age 53(41-72), median Child-Pugh score 6.5(5-13)). Portal and systemic haemodynamics were measured before and after two weeks treatment. Data are expressed as median (range) and analysed using Wilcoxon signed ranks test. Results: Thalidomide markedly reduced hepatic venous pressure gradient (HVPG) from 19.7 (9.3-23.5) to 12.2 (4.7-19.5) mmHg (p=O.O28). Moreover, HVPG fell by >20% in all but one patient (444% ($16-451%). Thalidomide increased hepatic blood flow (HBF) from 1164(738-2260) ml/mitt to 1505 (1054-2943) ml/mm. Pentoxifylline had no effect on HVPG, 19.2 (14.3-24.7) to 20.9 (18-22.8) mmHg; nor on HBF. There was no significant change in systemic haemodynamics, bilirubin, albumin, INR or creatinine in either treatment group. Seven patients did not complete the study due to drug side effects or unwillingness to continue. Conclusion: Short term anti-TNFa therapy with thalidomide effectively reduces portal pressure without compromising hepatic blood flow, renal or liver function.
0382
INCREASED UROTENSIN II PLASMA LEVELS IN PATIENTS WITH CIRRHOSIS
J. Heller, M. Schepke, M. Neef, R.P. Woitas, T. Sauerbruch. Department of Internal Medicine, Universiv of Bonn, Germany
Introduction: Patients with portal hypertension are characterized by splanchnic vasodilation and activation of endogenous vasoconstrictors. The “somatostatin-like” peptide Urotensin II (U-II) is the strongest endogeneous vasconstrictor of large arterial vessels discovered so far (Nature 1999;401:282). In contrast U-II relaxes rat mesenteric resistance vessels (Br J Pharmacol 2ooO,130:1865). The aim of this study was to determine plasma U-II levels in patients with cirrhosis and healthy control persons. Methods: Plasma U-II levels were measured by ELISA in 20 patients with cirrhosis and portal hypertension (wedged hepatic venous pressure gradient = 19fl mmHg) and in 10 aged matched healthy controls. Additionally, plasma U-II levels were compared between hepatic venous and portal venous blood of 10 patients with cirrhosis prior to TIPS insertion. Results: U-II plasma levels were significantly higher in cirrhotic patients (1064Of1751 pg/ml) compared to control persons (3921f889 pg/ml, pcO.005). In cirrhotic patients undergoing TIPS implantation hepatic
Abstract 1449: Table
D-3 Creatinine (pm&l) Creatinine Cl Mhnin) Urine output &l/d) ’ MAP (mm&) SVR (dyn.sec-’ .cm-‘) PRA (ngn) (N ==20) Prothrombin time (%)
240 f 16 f 697 f 63 f
99 14 555 7
29 f 15
D3
w 358 f 161 13 f 9 638 f 690 65 f 7 787 f 164 565 If: 989 26f 12
254 31 2300 74
f f f f
DlO
D5 145 17 840 12
324 f 598 26f 11
188 f 40 f 2453 f 74 f 838 f 164 f 27f
77 22 926 7 216 196 14
145 f 4Of 1982 f 73 f
P 78 15 917 9
27 f 13
<0.0001 to.001 0.0003 0.007 0.L ns
19
Working Party 6 - Novel aspects in basic and clinical hepatology
venous U-II plasma levels were significantly higher (14756f3500 pg/ml) compared to portal venous plasma levels (11931f2973 pg/ml, P
0
934
IMPAIRED TUFSIN ACTIVITY IN CIRRHOSIS. RELATIONSHIP WlT’H SPLENIC FUNCTION AND CLINICAL OUTCOME
F.G. Foschi, E. Castelli, M. Parazza, C. Melotti, E. Loggi, M. Bertelli, F. Trevisani, M. Bemardi. Semeiotica Medica, University of Bologna, Italy
Neutrophil granulocyte (NG) function is impaired in cirrhosis and its cause is unknown. Tuftsin, a peptide that stimulates the phagocyitc activity (PA), is deficient in diseases with impaired splenic function. It is unknown if tuftsin is deficient in cirrhosis. Aim: To determine if tuftsin activity (TA): 1) is deficient in cirrhosis; 2) contributes to the altered PA of NG; 3) affects patient survival and the occurrence of bacterial infections. Methods. 31 patients with cirrhosis and 31 healthy subjects were studied. TA was measured by assessing its ability to stimulate NG phagocytosis in vitro. Splenic function was assessed by counting pitted cells. PA was measured in 23 patients by a chemiluminescence method with the addition of either autologous or pooled sera from healthy subjects or tuftsin. Patients were followed-up until death or liver transplantation. Results: TA was lower in patients than in controls ([median; range] 8%; 3-24.5 vs 17%; 11.5-37; Pt0.001) while pitted red cell count was higher (2.4%; 1.0-9.8 vs 0.6%; 0.2-1.8; Pt0.001). TA was inversely correlated with both pitted cells (r=O.41; P=O.O2) and Child-Pugh score (t=-0.54; P=O.O02). 19 out of 23 patients showed a deficient PA, which was correlated with TA (r= 0.75; P-=0.001). Patient PA improved in all cases but one (becoming normal in 8) with the addition of serum from healthy subjects, and normalized with tuftsin. The survival of patients with normal TA did not differ from that of patients with reduced TA; however, bacterial infections were more frequent in the latter (P=O.O29). Comment: TA is reduced in cirrhosis and contributes to the impaired PA of NG. This abnormality is related to impaired splenic function and severity of cirrhosis, and may favor the occurrence of bacterial infections.
Background:
S21
Working Party 6 - Novel aspects in basic and clinical hepatology
I1007
ALENDRONATE VERSUS ETIDRONATE FOR OSTEOPENIC PATIENTS WITH PRIMARY BILIARY CIRRHOSIS: RESULTS AFTER TWO YEARS OF TREATMENT
A. Pares, N. Guanabens, I. Ros, F. Pans, L. Alvarez, L. Caballeria, A. Monegal, M. Rota, Juan Rodes. Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Spain
Etidronate prevents bone loss in patients with primary biliary cirrhosis (PBC), although it has not enough potential for increasing bone mass. Therefore, we have compared the effects of alendronate (10 mg/day) versus etidronate (400 mg/day during 14 days every 3 months) in 32 women with PBC (age: 57 f1.3 years). Bone mineral density (BMD)
of the lumbar spine and proximal femur as well as markers of bone turnover were measured initially and every 6 months. Development of bone fractures were also evaluated. Sixteen patients were randomly allocated into each group. Two patients with etidronate and one patient with alendronate left the trial because of gastrointestinal symptoms. Thirteen patients in each group completed two years. At the end of treatment BMD improvement at the lumbar spine and proximal femur were significantly higher (~~0.05) in patients taking alendronate than in those receiving etidronate (Lumbar: 5.8 f1.38 vs 1.9 f 1.1%; femoral neck: 3.5 f 0.9% vs 0.4 f 1.3%; Ward’s triangle: 2.3 f 1% vs -4.2 f 2.3%; trochanter: 5.1 f 1.6% vs 4.1 f 1.4%). No patient developed new vertebral fractures, but new peripheral fractures were detected in 2 patients under alendronate and in 1 receiving etidronate. Markers of bone turnover declined more markedly in patients under alendronate than in those under etidronate. Neither treatment impaired liver function. We conclude that alendronate is safe and more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis.
CROSS-REACTIVITY BETWEEN MYCOBACTERIUM GORDONAE AND PDC-E2, THE MAJOR TARGET OF ANTI-MlTOCHONDRIAL ANTIBODY, IS PRESENT IN SPANISH BUT NOT BRITISH PATIENTS WITH PBC
D.P. Bogdanos, A. Pares, U.C. Sharma, L. Caballeria, Y. Ma, A.K. Burroughs, J. Rodes, D. Vergani. Alcohol and Liver Units, Hospital Clinic, Barcelona, Spain; Znsitute of Hepatology, University College London Medical School and Hospitals; Liver Transplantation and Hepatobilia, London, UK
Previous studies on Spanish patients with primary biliary cirrhosis (PBC) have shown extensive cross-reactive immune responses between heat shock 65 kD protein (hsp65) of Mycobacterium gordonae and PDC-E2, the major target of antimitochondrial antibody (AMA). No evidence of exposure to mycobacteria was observed, however, in a UK study. Through protein database search we found extensive aa sequence similarity (82%) between hsp65 M.gordonae and the inner lipoyl domain core sequence - SEGDLLAEIETDK- the immunodominant AMA epitope on PDC-E2. Reactivity to peptides spanning the homologous hsp65 M.gordonae and PDC-E2 sequences was tested under code by ELISA in 43 PBC patients of the original Spanish series and in 50 PBC patients from the UK. Labelled anti-human Ig (G, M, A) class or IgG subclasses (IgGl-4) were used as revealing antisera. Double reactivity to the hsp65 and PDC-E2 peptides was found in 20/43 (47%) of the Spanish group but only in 2/50 (4%, p
1189
ROLE OF CASPASES IN ETHANOL-SIGNALLING APOPTOSIS
FOR
M.G. Neuman, K. Valentino. Clinical Pharmacology, Sunnybrook& Women’s College Health Sciences & Women’s College HSC, Toronto, Canada and IDUN Pharmaceuticals, La Jolla, CA, USA
Background: Caspases are protease inhibitors that play a role in apoptosis and repair. Aims: l-To assess the mechanism by which ethanol (EtOH) is signaling for apoptosis in a normal human primary hepatocyte (NHPH) culture. ~-TO delineate the role of tumor necrosis factor alpha (TNF) antibody (anti-TNF) and caspase-3 inhibitor (CAPI) in cell protection against
18
and 125Ihippuran during three consecutive 30 minute periods. Renal sodium handling was determined by lithium and sodium clearance measurements and free water clearance by determination of osmolar clearance. Therapeutic plasma levels of octreotide along with a reduction of insulin-like growth factor I (IGF-I) (PC 0.01) and an increase of IGF binding protein 1 (PC 0.05) were demonstrated. No effect of octreotide was observed on GFR, ERPF or filtration fraction (GFR/ERPF). Changes in clearance and extraction fraction of sodium and lithium during octreotide treatment were not significantly different from those of placebo. In addition, no changes in free water clearance, urinary flow rate or 24h Na excretion were demonstrated. A significant increase of mean arterial pressure (+ 5 mmHg, P< 0.01) was observed after octreotide-LAR. In spite of increased arterial pressure octreotide-LAR has no significant effect on renal haemodynamics and tubular function in clinically stable oirrhotic patients with portal hypertension.
0
1449
NORADRENALIN FOR TREATMENT OF TYPE I HEPATORENAL SYNDROME (HRS)
C. Duvouxr , D. Zanditenas ‘, C. Hbode t , A. Chauvat*, J. Metreau I, D. Dhumeauxr . ’ Service d’H$atologie et de Gastmenthlogie; ‘Service de Cardiologie, Hbpital Hem-i Mondos Universite’ Paris XII, CrtQeil, France
Vasopressin analogs were shower to be efficient in the treatment of type I HRS. However, their use is limited by ischaemic side effects and a high cost. Our aim was to assess efficacy and tolerance of noradrenalin (NA) in the treatment of type I HRS. Patients and Methods: from May 1998 to July 2000, 12 patients with type I HRS (age: 54 f 11 years, 7 males, 5 females, Child-Pugh score: 11.3 f 1.7) were treated with NA. After a 48 hour-period of fluid expansion with human albumin, continuous infusion of NA was initiated (DO) at 0.5 mg/hour and progressively risen to a maximum of 3.0 mg/b according to clinical response, for a minimum of 5 days. Fluid expansion was continued to maintain central venous pressure (CVP) above 7 mmHg. From D-3 to DlO, daily urine output, natriuresis, serum creatinine, creatinine clearance, mean arterial pressure (MAP), CVP and liver tests were studied. In 9/12 patients, plasma renin activity (PRA) was assessed on DO, D3 and D5. In 6 of these 9 patients, systemic vascular resistances (SVR) were measured on DO and D5, using a non invasive technique. Results: NA was given for 10 f 3 days, with a mean dose of 0.8 f 0.3 mg/h. Renal function improved in 1002 cases, and this occurred after terlipressin failure in 2 cases. The effects of NA, are summarized in the table. In 1 patient, transient myocardial ischaemia occurred while treated with NA, 2 mg/h. NA was withdrawn for 36 h and reintroduced thereafter at 1 mg/h without ischaemic recurrence. With a 6 month-follow-up, 6 patients died, 3 were transplanted and 3 are alive without transplantation. The cost of a 10 day-course of NA was 52 f 15. Conclusions: These results suggest that continuous infusion of NA is effective in the treatment of type I I-IRS and acceptably tolerated. The efficacy and low cost of NA should lead to comparison with vasopressin analogs in the treatment of I-IRS.
I
2%
THALIDOMIDE BUT NOT PENTOXIFYLLINE LOWERS PORTAL PRESSURE IN HUMAN ALCOHOLIC CIRRHOSIS
A.S. Austin, Y.R. Mahida, S.D. Ryder, J.G. Freeman. University Hospital, Nottingham, UK, Department of Medicine, Derby City General Hospital, Derby, UK Introduction: Blockade of tumour necrosis factor alpha (TNFa) activity reduces portal pressure in portal vein-ligated rats. We investigated the ability of two inhibitors of TNFa production, thalidomide and pentoxifylline, to reduce portal pressure in humans. Methods: Abstinent stable alcoholic cirrhotic patients were treated with open-label pentoxifylline 18OOmg daily (n=9, median age 53 (45~64), median Child-Pugh score 6(5-10)) or thalidomide 200mg daily (n=lO, median age 53(41-72), median Child-Pugh score 6.5(5-13)). Portal and systemic haemodynamics were measured before and after two weeks treatment. Data are expressed as median (range) and analysed using Wilcoxon signed ranks test. Results: Thalidomide markedly reduced hepatic venous pressure gradient (HVPG) from 19.7 (9.3-23.5) to 12.2 (4.7-19.5) mmHg (p=O.O28). Moreover, HVPG fell by >20% in all but one patient (444% ($16-451%). Thalidomide increased hepatic blood flow (HBF) from 1164(738-2260) ml/mitt to 1505 (1054-2943) ml/mm. Pentoxifylline had no effect on HVPG, 19.2 (14.3-24.7) to 20.9 (18-22.8) mmHg; nor on HBF. There was no significant change in systemic haemodynamics, bilirubin, albumin, INR or creatinine in either treatment group. Seven patients did not complete the study due to drug side effects or unwillingness to continue. Conclusion: Short term anti-TNFa therapy with thalidomide effectively reduces portal pressure without compromising hepatic blood flow, renal or liver function.
0382
INCREASED UROTENSIN II PLASMA LEVELS IN PATIENTS WITH CIRRHOSIS
J. Heller, M. Schepke, M. Neef, R.P. Woitas, T. Sauerbruch. Department of Internal Medicine, Universiv of Bonn, Germany
Introduction: Patients with portal hypertension are characterized by splanchnic vasodilation and activation of endogenous vasoconstrictors. The “somatostatin-like” peptide Urotensin II (U-II) is the strongest endogeneous vasconstrictor of large arterial vessels discovered so far (Nature 1999;401:282). In contrast U-II relaxes rat mesenteric resistance vessels (Br J Pharmacol 2ooO,130:1865). The aim of this study was to determine plasma U-II levels in patients with cirrhosis and healthy control persons. Methods: Plasma U-II levels were measured by ELISA in 20 patients with cirrhosis and portal hypertension (wedged hepatic venous pressure gradient = 19fl mmHg) and in 10 aged matched healthy controls. Additionally, plasma U-II levels were compared between hepatic venous and portal venous blood of 10 patients with cirrhosis prior to TIPS insertion. Results: U-II plasma levels were significantly higher in cirrhotic patients (1064Of1751 pg/ml) compared to control persons (3921f889 pg/ml, pcO.005). In cirrhotic patients undergoing TIPS implantation hepatic
Abstract 1449: Table
D-3 Creatinine (pm&l) Creatinine Cl Mhnin) Urine output &l/d) ’ MAP (mm&) SVR (dyn.sec-’ .cm-‘) PRA (ngn) (N ==20) Prothrombin time (%)
240 f 16 f 697 f 63 f
99 14 555 7
29 f 15
D3
w 358 f 161 13 f 9 638 f 690 65 f 7 787 f 164 565 If: 989 26f 12
254 31 2300 74
f f f f
DlO
D5 145 17 840 12
324 f 598 26f 11
188 f 40 f 2453 f 74 f 838 f 164 f 27f
77 22 926 7 216 196 14
145 f 4Of 1982 f 73 f
P 78 15 917 9
27 f 13
<0.0001 to.001 0.0003 0.007 0.L ns
19
Working Party 6 - Novel aspects in basic and clinical hepatology
venous U-II plasma levels were significantly higher (14756f3500 pg/ml) compared to portal venous plasma levels (11931f2973 pg/ml, P
0
934
IMPAIRED TUFSIN ACTIVITY IN CIRRHOSIS. RELATIONSHIP WlT’H SPLENIC FUNCTION AND CLINICAL OUTCOME
F.G. Foschi, E. Castelli, M. Parazza, C. Melotti, E. Loggi, M. Bertelli, F. Trevisani, M. Bemardi. Semeiotica Medica, University of Bologna, Italy
Neutrophil granulocyte (NG) function is impaired in cirrhosis and its cause is unknown. Tuftsin, a peptide that stimulates the phagocyitc activity (PA), is deficient in diseases with impaired splenic function. It is unknown if tuftsin is deficient in cirrhosis. Aim: To determine if tuftsin activity (TA): 1) is deficient in cirrhosis; 2) contributes to the altered PA of NG; 3) affects patient survival and the occurrence of bacterial infections. Methods. 31 patients with cirrhosis and 31 healthy subjects were studied. TA was measured by assessing its ability to stimulate NG phagocytosis in vitro. Splenic function was assessed by counting pitted cells. PA was measured in 23 patients by a chemiluminescence method with the addition of either autologous or pooled sera from healthy subjects or tuftsin. Patients were followed-up until death or liver transplantation. Results: TA was lower in patients than in controls ([median; range] 8%; 3-24.5 vs 17%; 11.5-37; Pt0.001) while pitted red cell count was higher (2.4%; 1.0-9.8 vs 0.6%; 0.2-1.8; Pt0.001). TA was inversely correlated with both pitted cells (r=O.41; P=O.O2) and Child-Pugh score (t=-0.54; P=O.O02). 19 out of 23 patients showed a deficient PA, which was correlated with TA (r= 0.75; P-=0.001). Patient PA improved in all cases but one (becoming normal in 8) with the addition of serum from healthy subjects, and normalized with tuftsin. The survival of patients with normal TA did not differ from that of patients with reduced TA; however, bacterial infections were more frequent in the latter (P=O.O29). Comment: TA is reduced in cirrhosis and contributes to the impaired PA of NG. This abnormality is related to impaired splenic function and severity of cirrhosis, and may favor the occurrence of bacterial infections.
Background:
S21
Working Party 6 - Novel aspects in basic and clinical hepatology
I1007
ALENDRONATE VERSUS ETIDRONATE FOR OSTEOPENIC PATIENTS WITH PRIMARY BILIARY CIRRHOSIS: RESULTS AFTER TWO YEARS OF TREATMENT
A. Pares, N. Guanabens, I. Ros, F. Pans, L. Alvarez, L. Caballeria, A. Monegal, M. Rota, Juan Rodes. Liver Unit, Hospital Clinic, IDIBAPS, University of Barcelona, Spain
Etidronate prevents bone loss in patients with primary biliary cirrhosis (PBC), although it has not enough potential for increasing bone mass. Therefore, we have compared the effects of alendronate (10 mg/day) versus etidronate (400 mg/day during 14 days every 3 months) in 32 women with PBC (age: 57 f1.3 years). Bone mineral density (BMD)
of the lumbar spine and proximal femur as well as markers of bone turnover were measured initially and every 6 months. Development of bone fractures were also evaluated. Sixteen patients were randomly allocated into each group. Two patients with etidronate and one patient with alendronate left the trial because of gastrointestinal symptoms. Thirteen patients in each group completed two years. At the end of treatment BMD improvement at the lumbar spine and proximal femur were significantly higher (~~0.05) in patients taking alendronate than in those receiving etidronate (Lumbar: 5.8 f1.38 vs 1.9 f 1.1%; femoral neck: 3.5 f 0.9% vs 0.4 f 1.3%; Ward’s triangle: 2.3 f 1% vs -4.2 f 2.3%; trochanter: 5.1 f 1.6% vs 4.1 f 1.4%). No patient developed new vertebral fractures, but new peripheral fractures were detected in 2 patients under alendronate and in 1 receiving etidronate. Markers of bone turnover declined more markedly in patients under alendronate than in those under etidronate. Neither treatment impaired liver function. We conclude that alendronate is safe and more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis.
CROSS-REACTIVITY BETWEEN MYCOBACTERIUM GORDONAE AND PDC-E2, THE MAJOR TARGET OF ANTI-MlTOCHONDRIAL ANTIBODY, IS PRESENT IN SPANISH BUT NOT BRITISH PATIENTS WITH PBC
D.P. Bogdanos, A. Pares, U.C. Sharma, L. Caballeria, Y. Ma, A.K. Burroughs, J. Rodes, D. Vergani. Alcohol and Liver Units, Hospital Clinic, Barcelona, Spain; Znsitute of Hepatology, University College London Medical School and Hospitals; Liver Transplantation and Hepatobilia, London, UK
Previous studies on Spanish patients with primary biliary cirrhosis (PBC) have shown extensive cross-reactive immune responses between heat shock 65 kD protein (hsp65) of Mycobacterium gordonae and PDC-E2, the major target of antimitochondrial antibody (AMA). No evidence of exposure to mycobacteria was observed, however, in a UK study. Through protein database search we found extensive aa sequence similarity (82%) between hsp65 M.gordonae and the inner lipoyl domain core sequence - SEGDLLAEIETDK- the immunodominant AMA epitope on PDC-E2. Reactivity to peptides spanning the homologous hsp65 M.gordonae and PDC-E2 sequences was tested under code by ELISA in 43 PBC patients of the original Spanish series and in 50 PBC patients from the UK. Labelled anti-human Ig (G, M, A) class or IgG subclasses (IgGl-4) were used as revealing antisera. Double reactivity to the hsp65 and PDC-E2 peptides was found in 20/43 (47%) of the Spanish group but only in 2/50 (4%, p
1189
ROLE OF CASPASES IN ETHANOL-SIGNALLING APOPTOSIS
FOR
M.G. Neuman, K. Valentino. Clinical Pharmacology, Sunnybrook& Women’s College Health Sciences & Women’s College HSC, Toronto, Canada and IDUN Pharmaceuticals, La Jolla, CA, USA
Background: Caspases are protease inhibitors that play a role in apoptosis and repair. Aims: l-To assess the mechanism by which ethanol (EtOH) is signaling for apoptosis in a normal human primary hepatocyte (NHPH) culture. ~-TO delineate the role of tumor necrosis factor alpha (TNF) antibody (anti-TNF) and caspase-3 inhibitor (CAPI) in cell protection against