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Pharmacologic therapy for mallory bodies in liver disease
Al108
AASLD ABSTRACTS
P H A R M A C O L O G I C T H E R A P Y FOR M A L L O R Y BODIES IN L I V E R DISEASE. C.B. Leevy, P.J. Gaglio, P. Zweil and M. Patel. U M D - N J M S L i v e r Center, Newark, N.J. M a l l o r y b o d i e s (MBs), p o s t t r a n s c r i p t i o n m o d i f i c a t i o n of cytokeratins, d i s a p p e a r w i t h imp r o v e m e n t of l i v e r injury, but m a y p e r s i s t w i t h p r o g r e s s i v e disease. E f f e c t i v e n e s s of a v a i l a b l e t h e r a p y was e v a l u a t e d b y use of NMB-3 m o n o c l o n a l a n t i b o d i e s to q u a n t i f y MBs; h y b r i d i z a t i o n p r o b e s to assess gene expression; and i n c o r p o r a t i o n of H3T to d e t e r m i n e D N A synthesis. The increase in MBs i n d u c e d b y G r i s e o f u l v i n (G) in c u l t u r e d CRL 7154 human liver cells w a s b l o c k e d by v i t a m i n D 3 a n d r e t i n o i c a c i d (RA). This was a s s o c i a t e d w i t h a r e d u c t i o n in VDR, RAR, c-myc mRNA, and D N A synthesis. Untreated Treated Treated with G with G + D3 + RA MBs/103 Cells 0 ii0 ± i0 0 c-myc m R N A mm2 2 ~ 0.5 6 ± 2 2 ± 0.5 V D R m R N A mm2 0 3 & 1 0 RAR m R N A ram2 2 ~ 1 4 ± 1 1 ± 0.5 D N A syn c p m 5 ± 2 15 ± 1 4 ± 2 R e s p o n s e to t r e a t m e n t of 33 m a l n o u r i s h e d p a t i e n t s w i t h M B s a n d a l c o h o l i c liver d i s e a s e d e p e n d e d on its severity. Subjects w i t h m i l d to m o d e r a t e d i s e a s e (22) were i m p r o v e d b y abstinence, v i t a m i n supplements, adrenal steroids, anabolic steroids a n d / o r p r o s t a g l a n d i n s . None of 8 p a t i e n t s w i t h p r o g r e s s i v e e n d - s t a g e disease responded. One of this g r o u p r e c e i v e d a liver t r a n s p l a n t a f t e r 6 months of abstinence. The explant e x h i b i t e d MBs, n e g l i g i b l e D N A s y n t h e s i s w i t h o u t r e d u c t i o n in VDR, R A R or o-myc mRNA. In contrast, p h a r m a c o l o g i c doses of D 3 a n d R A g i v e n d a i l y for 1 m o n t h dec r e a s e d l e u k o c y t e M I F r e s p o n s e to MBs and interr u p t e d p r o g r e s s i v e liver failure in 2 of 3 such patients. Conclusion: Cognate r e s p o n s e e l e m e n t s of the o s t e o c a l c i n gene w h i c h m o d i f y c y t o k e r a t i n s m a y also d e c r e a s e MBs, gene e x p r e s s i o n and D N A synthesis in liver injury.
EARLY CYTOLYSIS AND WORSENING OF LIVER FUNCTION AFTER TIPS PLACEMENT: EVIDENCE FOR INDUCED LIVER ISCHEMIA. O Le Moine, M Ghysels, P Van der Linden, J Devi&e Service de Gastroent6rologie0 H6pital Erasme, ULB, Bruxelles, Belgique TIPS can be useful in the prevention of recurrent variceal bleeding (RB). Its benefit in management of uncontrolled variceal bleeding (UB) or refractory ascites (RA) is still questioned. Liver failure is one of the main cause of death after TIPS. The mechanisms leading to this severe complication are still undetermined. One hypothesis might be that it results from decreased oxygen supply to the liver consecutive to derived portal blood flow through the shunt. We therefore reviewed AST levels and Prothrombin Time in 38 patients with daily blood sampling after TIPS. The procedure was performed for RB in 24, RA in 11 and AB in 3. Thirty one of them had significant early increase of AST levels (median: 29 IU before, vs 60, 66 and 41 IU at days 1,2 and 7 after TIPS) with concomitant decrease of Prothrombin Time (median: 60% vs 47, 48 and 54%). This pattern was not correlated with Pugh score (median 8 vs 8.5), age (median 65 vs 59 years) or decrease in porto-atrial gradient (median 11 vs 11 mmHg). It was, however, significantly associated with the reason for performing TIPS (100 % in RA and AB vs 70% in RB; p<0.05). All patients dying from liver failure (7/15) presented this pattern but increased AST levels were not significantly associated with overall mortality. To ascertain the hypothesis of liver ischemia we prospectively measured hepatic oxygen venous saturation before and after stent opening in seven patients during the procedure and found a significant oxygen desaturatiun (median decrease of 10%). We conclude that TIPS is often associated with transient signs of liver ischemia. This may be relevant to the development of liver failure after TIPS in patients with already compromised liver oxygen supply.
GASTROENTEROLOGY,Vol. 108, No. 4
• DEFECTIVE INTERLEUKIN 10 PRODUCTION BY LPS STIMULATED MONOCYTES IN ALCOHOLIC CIRRHOSIS. O Le Moine, A Marchant, M Goldman, J Devi&e Service de Gastroent&ologie et d'Immlmologie, H6pital Erasme, ULB, Bmxeiles, Belgique. Monocytes of patients with alcoholic liver cirrhosis are known to produce higher amounts of tumor necrosis factor-alpha after llpopolysaechatide stimulation. The mechanisms of this overproduction remain undefined. Interleukin-10 is an antiinIhmmatory cytokine known to dowuregulate tumor necrosis factor-alpha secretion by monocytes. The present study analyses interleukin-10 plasma levels in septic cirrhotic patients and its LPS-induced production by monocytes isolated from non infected patients with alcoholic cirrhosis. In vivo, sinfdar interleukin-10 plasma levels were found at the onset of infectiun in patients with (n=ll) or without (n=21) cirrhosis (median: 17 pg/ml, range: 11-203 vs llpg/ml, range: 11-46, respectively) while tumor necrosis factor-alpha plasma levels were much higher in cirrhotic patients (median: 115 pg/ml, range: 24-350 vs 34 pg/ml, range: 10-110, respectively). In vitro, lipopolysaccharide-stimulated monocyte-enriched cell populations from alcoholic cirrhotics (n=6) showed decreased interleuldn-10 ( mean ± SEM: 253 + 51 pg/ml vs 638 :~ 144 pg/ml, p<0.05) contrasting with increased tumor necrosis factor-alpha secretion ( 17593 ± 3693 pg/ml vs 7193 ± 1729 pg/ml, p<0.05)compared to controls (n=6). Cells from cirrhotic patients were normally responsive to recombinant intedeukin-10 which induced a dose dependent decrease of tumor necrosis factor-alpha secretion and abolished the differences between monoeytes from eirrhotics and controls. In conclusion, stimulated monocytes from alcoholic cirrhotic patients exhibit a defective interleukin10 production which contrasts with and could be involved in the characteristic tumor necrosis factor-alpha hyperproduction observed in these patients.
HIGH MORTALITY ASSOCIATED WITH TIPS IN REFRACTORY ASCITES AND ACTIVE VARICEAL BLEEDING. O Le Moine, J Devi6re, M Ghysels, P Van der Linden, N Bourgeois, M Adler. Service de Gastroent&ologie, H6pital Erasme, ULB, Bruxelles, Belgique TIPS remains the last solution for patients with compficated portal hypertension and severe liver disease who failed to respond to conventional therapies. The indication is often variceal rebleeding after faihzre of sclerotherepy. In refractory ascites and uncontrollable bleeding little is known concerning the therapeutic success of TIPS. We therefore analyzed the 57 patients treated by TIPS in our Institution between January 92 to November 94. Indications were variceal rebleeding despite sclerotherapy in 37 (R), uncontrollable variceal bleeding in 6 (U) and refractory ascites in 18 (A). Eight percents were Child A, 59% Child B and 32% Child C. Portoatrial gradient was reduced from 21 + 5 to 10 ± 3 mmHg after stent implantation. No procedural mortafity occurred. Twenty patients (35%) died during the follow-up period (323 :~ 242 days). Death occurred in the first month following TIPS in 10 patients. Mortality was related to liver failure in 8 patients (40%), bacterial infection in 7 (35%), variceal rebleeding in 2 (10%) and other in 3 (15%). Overall mortality rate was related to three variables in univariate analysis: Pugh score before TIPS (8 vs 9.5 for patients who will die; p<0.05), age (52 vs 62 years; p<0.05) and the indication for TIPS ( 19%, 83% and 50% mortality for the IL U and A groups, respectively; p<0.05). During the follow-up period, ascites disappeared within one month in all patients in group 1L disappeared or was easily controlled in all but one surviving patients in group A. Forty seven percent of TIPS had to be revised (in 75% of the cases stent dysfunction was diagnosed only on the basis of hemodynamic measurements and Doppler sonography). We conclude that patients proposed for TIPS should be carefully selected with particular caution in refractory aseites and acute uncontrolled variceal bleeding.
AASLD ABSTRACTS
P H A R M A C O L O G I C T H E R A P Y FOR M A L L O R Y BODIES IN L I V E R DISEASE. C.B. Leevy, P.J. Gaglio, P. Zweil and M. Patel. U M D - N J M S L i v e r Center, Newark, N.J. M a l l o r y b o d i e s (MBs), p o s t t r a n s c r i p t i o n m o d i f i c a t i o n of cytokeratins, d i s a p p e a r w i t h imp r o v e m e n t of l i v e r injury, but m a y p e r s i s t w i t h p r o g r e s s i v e disease. E f f e c t i v e n e s s of a v a i l a b l e t h e r a p y was e v a l u a t e d b y use of NMB-3 m o n o c l o n a l a n t i b o d i e s to q u a n t i f y MBs; h y b r i d i z a t i o n p r o b e s to assess gene expression; and i n c o r p o r a t i o n of H3T to d e t e r m i n e D N A synthesis. The increase in MBs i n d u c e d b y G r i s e o f u l v i n (G) in c u l t u r e d CRL 7154 human liver cells w a s b l o c k e d by v i t a m i n D 3 a n d r e t i n o i c a c i d (RA). This was a s s o c i a t e d w i t h a r e d u c t i o n in VDR, RAR, c-myc mRNA, and D N A synthesis. Untreated Treated Treated with G with G + D3 + RA MBs/103 Cells 0 ii0 ± i0 0 c-myc m R N A mm2 2 ~ 0.5 6 ± 2 2 ± 0.5 V D R m R N A mm2 0 3 & 1 0 RAR m R N A ram2 2 ~ 1 4 ± 1 1 ± 0.5 D N A syn c p m 5 ± 2 15 ± 1 4 ± 2 R e s p o n s e to t r e a t m e n t of 33 m a l n o u r i s h e d p a t i e n t s w i t h M B s a n d a l c o h o l i c liver d i s e a s e d e p e n d e d on its severity. Subjects w i t h m i l d to m o d e r a t e d i s e a s e (22) were i m p r o v e d b y abstinence, v i t a m i n supplements, adrenal steroids, anabolic steroids a n d / o r p r o s t a g l a n d i n s . None of 8 p a t i e n t s w i t h p r o g r e s s i v e e n d - s t a g e disease responded. One of this g r o u p r e c e i v e d a liver t r a n s p l a n t a f t e r 6 months of abstinence. The explant e x h i b i t e d MBs, n e g l i g i b l e D N A s y n t h e s i s w i t h o u t r e d u c t i o n in VDR, R A R or o-myc mRNA. In contrast, p h a r m a c o l o g i c doses of D 3 a n d R A g i v e n d a i l y for 1 m o n t h dec r e a s e d l e u k o c y t e M I F r e s p o n s e to MBs and interr u p t e d p r o g r e s s i v e liver failure in 2 of 3 such patients. Conclusion: Cognate r e s p o n s e e l e m e n t s of the o s t e o c a l c i n gene w h i c h m o d i f y c y t o k e r a t i n s m a y also d e c r e a s e MBs, gene e x p r e s s i o n and D N A synthesis in liver injury.
EARLY CYTOLYSIS AND WORSENING OF LIVER FUNCTION AFTER TIPS PLACEMENT: EVIDENCE FOR INDUCED LIVER ISCHEMIA. O Le Moine, M Ghysels, P Van der Linden, J Devi&e Service de Gastroent6rologie0 H6pital Erasme, ULB, Bruxelles, Belgique TIPS can be useful in the prevention of recurrent variceal bleeding (RB). Its benefit in management of uncontrolled variceal bleeding (UB) or refractory ascites (RA) is still questioned. Liver failure is one of the main cause of death after TIPS. The mechanisms leading to this severe complication are still undetermined. One hypothesis might be that it results from decreased oxygen supply to the liver consecutive to derived portal blood flow through the shunt. We therefore reviewed AST levels and Prothrombin Time in 38 patients with daily blood sampling after TIPS. The procedure was performed for RB in 24, RA in 11 and AB in 3. Thirty one of them had significant early increase of AST levels (median: 29 IU before, vs 60, 66 and 41 IU at days 1,2 and 7 after TIPS) with concomitant decrease of Prothrombin Time (median: 60% vs 47, 48 and 54%). This pattern was not correlated with Pugh score (median 8 vs 8.5), age (median 65 vs 59 years) or decrease in porto-atrial gradient (median 11 vs 11 mmHg). It was, however, significantly associated with the reason for performing TIPS (100 % in RA and AB vs 70% in RB; p<0.05). All patients dying from liver failure (7/15) presented this pattern but increased AST levels were not significantly associated with overall mortality. To ascertain the hypothesis of liver ischemia we prospectively measured hepatic oxygen venous saturation before and after stent opening in seven patients during the procedure and found a significant oxygen desaturatiun (median decrease of 10%). We conclude that TIPS is often associated with transient signs of liver ischemia. This may be relevant to the development of liver failure after TIPS in patients with already compromised liver oxygen supply.
GASTROENTEROLOGY,Vol. 108, No. 4
• DEFECTIVE INTERLEUKIN 10 PRODUCTION BY LPS STIMULATED MONOCYTES IN ALCOHOLIC CIRRHOSIS. O Le Moine, A Marchant, M Goldman, J Devi&e Service de Gastroent&ologie et d'Immlmologie, H6pital Erasme, ULB, Bmxeiles, Belgique. Monocytes of patients with alcoholic liver cirrhosis are known to produce higher amounts of tumor necrosis factor-alpha after llpopolysaechatide stimulation. The mechanisms of this overproduction remain undefined. Interleukin-10 is an antiinIhmmatory cytokine known to dowuregulate tumor necrosis factor-alpha secretion by monocytes. The present study analyses interleukin-10 plasma levels in septic cirrhotic patients and its LPS-induced production by monocytes isolated from non infected patients with alcoholic cirrhosis. In vivo, sinfdar interleukin-10 plasma levels were found at the onset of infectiun in patients with (n=ll) or without (n=21) cirrhosis (median: 17 pg/ml, range: 11-203 vs llpg/ml, range: 11-46, respectively) while tumor necrosis factor-alpha plasma levels were much higher in cirrhotic patients (median: 115 pg/ml, range: 24-350 vs 34 pg/ml, range: 10-110, respectively). In vitro, lipopolysaccharide-stimulated monocyte-enriched cell populations from alcoholic cirrhotics (n=6) showed decreased interleuldn-10 ( mean ± SEM: 253 + 51 pg/ml vs 638 :~ 144 pg/ml, p<0.05) contrasting with increased tumor necrosis factor-alpha secretion ( 17593 ± 3693 pg/ml vs 7193 ± 1729 pg/ml, p<0.05)compared to controls (n=6). Cells from cirrhotic patients were normally responsive to recombinant intedeukin-10 which induced a dose dependent decrease of tumor necrosis factor-alpha secretion and abolished the differences between monoeytes from eirrhotics and controls. In conclusion, stimulated monocytes from alcoholic cirrhotic patients exhibit a defective interleukin10 production which contrasts with and could be involved in the characteristic tumor necrosis factor-alpha hyperproduction observed in these patients.
HIGH MORTALITY ASSOCIATED WITH TIPS IN REFRACTORY ASCITES AND ACTIVE VARICEAL BLEEDING. O Le Moine, J Devi6re, M Ghysels, P Van der Linden, N Bourgeois, M Adler. Service de Gastroent&ologie, H6pital Erasme, ULB, Bruxelles, Belgique TIPS remains the last solution for patients with compficated portal hypertension and severe liver disease who failed to respond to conventional therapies. The indication is often variceal rebleeding after faihzre of sclerotherepy. In refractory ascites and uncontrollable bleeding little is known concerning the therapeutic success of TIPS. We therefore analyzed the 57 patients treated by TIPS in our Institution between January 92 to November 94. Indications were variceal rebleeding despite sclerotherapy in 37 (R), uncontrollable variceal bleeding in 6 (U) and refractory ascites in 18 (A). Eight percents were Child A, 59% Child B and 32% Child C. Portoatrial gradient was reduced from 21 + 5 to 10 ± 3 mmHg after stent implantation. No procedural mortafity occurred. Twenty patients (35%) died during the follow-up period (323 :~ 242 days). Death occurred in the first month following TIPS in 10 patients. Mortality was related to liver failure in 8 patients (40%), bacterial infection in 7 (35%), variceal rebleeding in 2 (10%) and other in 3 (15%). Overall mortality rate was related to three variables in univariate analysis: Pugh score before TIPS (8 vs 9.5 for patients who will die; p<0.05), age (52 vs 62 years; p<0.05) and the indication for TIPS ( 19%, 83% and 50% mortality for the IL U and A groups, respectively; p<0.05). During the follow-up period, ascites disappeared within one month in all patients in group 1L disappeared or was easily controlled in all but one surviving patients in group A. Forty seven percent of TIPS had to be revised (in 75% of the cases stent dysfunction was diagnosed only on the basis of hemodynamic measurements and Doppler sonography). We conclude that patients proposed for TIPS should be carefully selected with particular caution in refractory aseites and acute uncontrolled variceal bleeding.