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Endoscopic variceal ligation compared with injection sclerotherapy in patients with hepatocellular carcinoma
April 1995
• RETREATMENT WITH RECOMBINANT BETA INTERFERON OF PATIENTS WITH CHRONIC HEPATITIS B WHO FAILED TO RESPOND TO ALPHA INTERFERON. F. HabersetzerJ~ F. Nevens2, P. Marcellin 3, N. Boyer3, JL. Payen4, JP. Pascal4, SH. YapZ, J. Alam5, S Erlinger 3, C. Tr6po I , J. Fevery 2. Liver Units : Lyon 1, Clichy 3 & Toulouse 4, France; Leuven, Belgium2 .Biogen, MA, USs. The aim of the study was to evaluate the efficacy and tolerance of recombinant beta interferon (r 13 IFN) in chronic hepatitis B pts who had failed to respond to alpha interferon (IFN cz). Methods :thirty five pts with CAH B received SC tiw 9 MU (15 pts) or 12 MU (11 pts) r !B IFN (Biogen) for 16 wksor 15 MU for 24 wks (9 pts). 27 pts were male, mean age was 42 years (range 20-64). All except 1 were caucasien. All lots had elevated ALT values, HBe Ag and HBV DNA in serum for greater than 6 mths. 25 had CAH and 9 had active cirrhosis on pretreatment liver biopsy. None reacted With anti HIV, anti HCV or anti Delta. All had unsuccessfully been treated with IFN a and 8 also received adenine-S' monophophate (last injection at least 6 mths prior). Results: HBV DNA was cleared during treatmenffin 12 pts (34%) with HBeAg negativation and seroconversion to anti-HBe in 7 (20%). In one pt, anti-HBe seroconversion was associated with reappearance of low level of HBV DNA suggesting the emergence of a mutant strain. During a 6 mths follow up period, HBV DNA reappeared in 2 other pts and became negative in one; an additional one lost HBe Ag. All pts completed therapy without dose reduction. Moderate side effects included: flue-like syndrome, fatigue, anorexia, anxiety, insomnia, headache and erythema at the injection Site. Results did not seem to be better with the higher dose. In conclusion: r LBIFN at a dose of 9 to 15 MU tiw was well tolerated for 16 or 24 wks, and triggered clearance of HBV DNA in 34 % (31% at 6 mths follow up) and seroconversion of HBe Ag in 20 % of pts with CAH B who previouly had failed to respond to IFN a. This research was funded in part by the Biogen Corporation, Cambridge, MA.
• ENDOSCOPIC VARICEAL LIGATION COMPARED WITH INJECTION SCLEROTHERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA. E. Hamada. K. Ogura, M. Takahashi, S. Matsukawa*, T. Kawase*, M. Nomura*, T. Kawabe, S. eta, M. Omata. The 2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan. *)The Division of Internal Medicine, Kanto Chuo Hospital, Tokyo, Japan. Hepatocellular carcinoma (HCC) has been reported to arise mainly from liver cirrhosis based on viral infection. In those cases, bleeding from esophageal varices has been demonstrated to be one of the important causes of their death. Therefore, prevention or coiatrol of esop~hageal variceal bleeding may improve the prognosis of the patients with HCC. While e n d o s c o p i c v a r i e e a l l i g a t i o n (EVL) is a new method for the treatment of esophageal varices, the efficacy and safety of EVL for the patients with HCC has not been assessed in the previous study. We compared EVL and endoscopic injection sclerotherapy (EIS) in nonrandomised study. We underwent endoscopic treatment to esophageal varices in forty cirrhotic patients with HCC. Twenty-four patients received EIS and sixteen patients received EVL. The two patient groups were well matched with respect to age, sex, the severity of liver disease, cause of disease and other clinical indexes. Both treatments were highly effective in eradicating varices (93.8% in the EVL group and 95.8% in the EIS group) and recurrence of varices was similar (31.2% vs 33.3%). Rebleeding rate was lower in the EVL group than in the EIS group (27.0% vs 41.1%). Excluding the patients with portal vein tumor thrombus made the rebleeding rate lower (16.1% in the EVL group and 27.3% in the EIS group). There were no critical complications in the EVL group and only esophageal ulcers at the banding points were seen, while pulmonary embolism occurred in one patient in the EIS group. Endoscopic variceal ligation is a safe and effective technique, which eradicates esophageal varices with a lower rebleeding rate than endoscopic injection sclerotherapy even in the patients with HCC.
AASLD A1079
HCV RNA SCREENING IN BLOOD DONNERS P.Halfon(1), D.Ouzan.(2), H.Khiri(1), C.Tirtaine(3), I,M Feryn(1), P.Ledinh(1), J,P.I--Ialimi(1), R.Follana(3) a n d C.Sayada(4). (1)Laboratoire d e b i o l o g i c m o l e c u l a i r e A l p h a b i o , Marseille. (2) Departement d'h~patogastroenterologie,(3)Centre Departemental de T r a n s f u s i o n S a n g u i n e , I n s t i t u t A r n a u l t Tzanck St. L a u r e n t d u Var.(4) Roche Diagnostic Systems, N e u i l l y , France. H e p a t i t i s C v i r u s (HCV) d e t e c t i o n in b l o o d d o n o r s (BDs) is b a s e d o n a n t i b o d i e s d e t e c t i o n , i n c l u d i n g b o t h E.I.A. s c r e e n i n g a n d i m m u n o b l o t v a l i d a t i o n tests. In a d d i t i o n to s e r o p o s i t i v e BDs, those w i t h e l e v a t e d ALT are d i s c a r d e d from b l o o d donation. The aim of this s t u d y w a s to d e t e r m i n e w h e t h e r H C V R N A d e t e c t i o n could m a x i m i z e H C V infection d i a g n o s i s b y c o m p l e t i n g the lack of serological tests for these BDs. For this p u r p o s e , w e e v a l u a t e d the p r e d i c t i n g factor v a l u e of e l e v a t e d ALT v e r s u s n o r m a l ALT, for H C V R N A d e t e c t i o n i n s e r o n e g a t i v e BDs. METHODS: s a m p l e s from 400 H C V s e r o n e g a t i v e (Elisa 3, O r t h o D i a g n o s t i c System) BDs, w e r e t e s t e d for HHCV R N A d e t e c t i o n u s i n g the , n e w l y d e v e l o p e d A m p l i c o r TM H C V R N A q u a l i t a t i v e a s s a y (Roche M o l e c u l a r S y s t e m s , USA)~, 5% of t h e m w e r e anti HBc positive. These Samples w e r e s e p a r a t e d i n t o t w o g r o u p s a c c o r d i n g ALT levels: g r o u p I i n d u e d 200 n o r m a l ALT BDs ( N o r m a l < ULN), and g r o u p II w i t h 200 e l e v a t e d ALT BDs (1 to 4 ULN). All s a m p l e s were firstly i n c l u d e d in the u s u a l serological r o u t i n e tests of the Blood Bank (BB) a n d t h e n stored at -80°C. Then, they w e r e t h a w e d once b e f o r e H C V R N A d e t e c t i o n . RESULTS: 2 of the g r o u p I s a m p l e s w e r e f o u n d A m p l i c o r p o s i t i v e (1%) w h e r e a s 4 s a m p l e s in g r o u p II w e r e f o u n d p o s i t i v e (2%). N o n e of these six A m p l i c o r p o s i t i v e s a m p l e s w e r e anti-HBc positive. R e p r o d u c t i b i l i t y of the positive RT-PCR s a m p l e s w a s a c h i e v e d b y r e p e a t i n g the extraction step once a n d the RT-PCR s t e p !n triplicate. C O N C L U S I O N S : 1)HCV R N A w a s f o u n d i n s e r o n e g a t i v e BDs w i t h n o r m a l or elevated ALT. 2)ALT a p p e a r as a n usefull tool for the screening of s e r o n e g a t i v e HCV. i n f e c t i o n i n BDs. 3 ) H C V R N A w a s d e t e c t e d w i t h o u t anti H C V i n a p p a r e n t l y n o n i m m u n o s u p p r e s s e d subjects. 4)HCV R N A A r n p l i c o r a s s a y c o u l d m a x i m i z e the d e t e c t i o n of H C V infection in BDs a n d i m p r o v e the t r a n s f u s i o n safety.
• INTESTINAL PERMEABILITYAS MEASUREDWITH POLYETHYLENE GLYCOL 600 IN PATIENTS WITH CIRRHOSIS: CLINICAL INVESTIGATION. R. H~md~ni, R. Chapparella, R. Stauber, S. Wood, D. Framer, E. Rosenblum, M. Kondraclfi, D.H. Van-Thiel. Departments of Critical Care Medicine/Anesthesiology and Surgery, University of Pittsburgh, Pittsburgh, PA; University of Iowa, Iowa City, IA. BACKGROUND: Patients with cirrhosis have an increased incidence of bacterial infections (Hepatol 1984;4:53-8). Bacterial translocation, which occurs as result of altered intestinal permsability (J Trauma 1988;28:896-906), may play a role in this increased incidence of infections. Intestinal permeability can be measured using PEG polymers (Gastro 1977;73:241-257). METHODS: A total of 39 cirrhotic patients and 21 normal controls were given 10 Gins of PEG 600. The 24 hour urine recovery of each of the seven principle polymers tiiat comprise PEG 600 was determined using HPLC. Differences in the recovery of each polymer and the mean recovery of the higher molecular weight polymers were compared between the cirrhotic patients and controls using Helmert contrasts. Medical records were reviewed retrospectively for 6 months or until OLTX, whichever came first. Age, etiology of liver disease, child class and incidence of bacterial infections was obtained. RESIdLT~: The mean age was 47 (16-68) years. Of the 39 patients, alcohol was the etiology in 12, post necrotic inl3, PBC in 6, PSC in 4 and miscellaneous in 4. Ten of the patients were in child class A, 13 in B and 16 in C. The mean recovery is shown in the table below, The first significantdifference was noted between the % recovery of polymer 590 and the higher polymers (p = 0.01). An exclusionindex defined as the difference between the recovery of polymers 590 and 722 was determined for each patient. The index of patients in child class A and B (N23) vs class C (N15) was 3.92_.+0.75vs 3.14_+1.62(p =0.92), patients without varices (NS) and those with (N23) was 3.05+ 1.09 vs 3.41_+1.90(p=0.42). The index in patients with infections (N$) and those without (N22) was 1.04+1.29 vs 4.21_+1.15(p=0.005). pOLYMER MW502 MW546 MW590 MW634 MW678 MW722
PATIENTS (39) CONTROLS(21) 16.81%+1.35% 22.40%+1.67% 15.87%+1.19% 21.81%+1.48% 13.86%+1.09% 19.62%+1.34% 13.01%+0.99% 1'/.58%+1.23% 10.88%+0.93% 15.33%+1.16% 10.10%+0.88% 13.06%_.+1.08%
P VALUE 0.61 0.08 0.015 0.16 0.008 ---
CONCLUSION: The intestinal absorption of PEG 600 is altered in patients with cirrhosis. There is an inability of the intestinal epithelium to exclude larger molecular weight polymers. More importantly, a low PEG 600 exclusion index is associated with bacterial infections.
• RETREATMENT WITH RECOMBINANT BETA INTERFERON OF PATIENTS WITH CHRONIC HEPATITIS B WHO FAILED TO RESPOND TO ALPHA INTERFERON. F. HabersetzerJ~ F. Nevens2, P. Marcellin 3, N. Boyer3, JL. Payen4, JP. Pascal4, SH. YapZ, J. Alam5, S Erlinger 3, C. Tr6po I , J. Fevery 2. Liver Units : Lyon 1, Clichy 3 & Toulouse 4, France; Leuven, Belgium2 .Biogen, MA, USs. The aim of the study was to evaluate the efficacy and tolerance of recombinant beta interferon (r 13 IFN) in chronic hepatitis B pts who had failed to respond to alpha interferon (IFN cz). Methods :thirty five pts with CAH B received SC tiw 9 MU (15 pts) or 12 MU (11 pts) r !B IFN (Biogen) for 16 wksor 15 MU for 24 wks (9 pts). 27 pts were male, mean age was 42 years (range 20-64). All except 1 were caucasien. All lots had elevated ALT values, HBe Ag and HBV DNA in serum for greater than 6 mths. 25 had CAH and 9 had active cirrhosis on pretreatment liver biopsy. None reacted With anti HIV, anti HCV or anti Delta. All had unsuccessfully been treated with IFN a and 8 also received adenine-S' monophophate (last injection at least 6 mths prior). Results: HBV DNA was cleared during treatmenffin 12 pts (34%) with HBeAg negativation and seroconversion to anti-HBe in 7 (20%). In one pt, anti-HBe seroconversion was associated with reappearance of low level of HBV DNA suggesting the emergence of a mutant strain. During a 6 mths follow up period, HBV DNA reappeared in 2 other pts and became negative in one; an additional one lost HBe Ag. All pts completed therapy without dose reduction. Moderate side effects included: flue-like syndrome, fatigue, anorexia, anxiety, insomnia, headache and erythema at the injection Site. Results did not seem to be better with the higher dose. In conclusion: r LBIFN at a dose of 9 to 15 MU tiw was well tolerated for 16 or 24 wks, and triggered clearance of HBV DNA in 34 % (31% at 6 mths follow up) and seroconversion of HBe Ag in 20 % of pts with CAH B who previouly had failed to respond to IFN a. This research was funded in part by the Biogen Corporation, Cambridge, MA.
• ENDOSCOPIC VARICEAL LIGATION COMPARED WITH INJECTION SCLEROTHERAPY IN PATIENTS WITH HEPATOCELLULAR CARCINOMA. E. Hamada. K. Ogura, M. Takahashi, S. Matsukawa*, T. Kawase*, M. Nomura*, T. Kawabe, S. eta, M. Omata. The 2nd Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan. *)The Division of Internal Medicine, Kanto Chuo Hospital, Tokyo, Japan. Hepatocellular carcinoma (HCC) has been reported to arise mainly from liver cirrhosis based on viral infection. In those cases, bleeding from esophageal varices has been demonstrated to be one of the important causes of their death. Therefore, prevention or coiatrol of esop~hageal variceal bleeding may improve the prognosis of the patients with HCC. While e n d o s c o p i c v a r i e e a l l i g a t i o n (EVL) is a new method for the treatment of esophageal varices, the efficacy and safety of EVL for the patients with HCC has not been assessed in the previous study. We compared EVL and endoscopic injection sclerotherapy (EIS) in nonrandomised study. We underwent endoscopic treatment to esophageal varices in forty cirrhotic patients with HCC. Twenty-four patients received EIS and sixteen patients received EVL. The two patient groups were well matched with respect to age, sex, the severity of liver disease, cause of disease and other clinical indexes. Both treatments were highly effective in eradicating varices (93.8% in the EVL group and 95.8% in the EIS group) and recurrence of varices was similar (31.2% vs 33.3%). Rebleeding rate was lower in the EVL group than in the EIS group (27.0% vs 41.1%). Excluding the patients with portal vein tumor thrombus made the rebleeding rate lower (16.1% in the EVL group and 27.3% in the EIS group). There were no critical complications in the EVL group and only esophageal ulcers at the banding points were seen, while pulmonary embolism occurred in one patient in the EIS group. Endoscopic variceal ligation is a safe and effective technique, which eradicates esophageal varices with a lower rebleeding rate than endoscopic injection sclerotherapy even in the patients with HCC.
AASLD A1079
HCV RNA SCREENING IN BLOOD DONNERS P.Halfon(1), D.Ouzan.(2), H.Khiri(1), C.Tirtaine(3), I,M Feryn(1), P.Ledinh(1), J,P.I--Ialimi(1), R.Follana(3) a n d C.Sayada(4). (1)Laboratoire d e b i o l o g i c m o l e c u l a i r e A l p h a b i o , Marseille. (2) Departement d'h~patogastroenterologie,(3)Centre Departemental de T r a n s f u s i o n S a n g u i n e , I n s t i t u t A r n a u l t Tzanck St. L a u r e n t d u Var.(4) Roche Diagnostic Systems, N e u i l l y , France. H e p a t i t i s C v i r u s (HCV) d e t e c t i o n in b l o o d d o n o r s (BDs) is b a s e d o n a n t i b o d i e s d e t e c t i o n , i n c l u d i n g b o t h E.I.A. s c r e e n i n g a n d i m m u n o b l o t v a l i d a t i o n tests. In a d d i t i o n to s e r o p o s i t i v e BDs, those w i t h e l e v a t e d ALT are d i s c a r d e d from b l o o d donation. The aim of this s t u d y w a s to d e t e r m i n e w h e t h e r H C V R N A d e t e c t i o n could m a x i m i z e H C V infection d i a g n o s i s b y c o m p l e t i n g the lack of serological tests for these BDs. For this p u r p o s e , w e e v a l u a t e d the p r e d i c t i n g factor v a l u e of e l e v a t e d ALT v e r s u s n o r m a l ALT, for H C V R N A d e t e c t i o n i n s e r o n e g a t i v e BDs. METHODS: s a m p l e s from 400 H C V s e r o n e g a t i v e (Elisa 3, O r t h o D i a g n o s t i c System) BDs, w e r e t e s t e d for HHCV R N A d e t e c t i o n u s i n g the , n e w l y d e v e l o p e d A m p l i c o r TM H C V R N A q u a l i t a t i v e a s s a y (Roche M o l e c u l a r S y s t e m s , USA)~, 5% of t h e m w e r e anti HBc positive. These Samples w e r e s e p a r a t e d i n t o t w o g r o u p s a c c o r d i n g ALT levels: g r o u p I i n d u e d 200 n o r m a l ALT BDs ( N o r m a l < ULN), and g r o u p II w i t h 200 e l e v a t e d ALT BDs (1 to 4 ULN). All s a m p l e s were firstly i n c l u d e d in the u s u a l serological r o u t i n e tests of the Blood Bank (BB) a n d t h e n stored at -80°C. Then, they w e r e t h a w e d once b e f o r e H C V R N A d e t e c t i o n . RESULTS: 2 of the g r o u p I s a m p l e s w e r e f o u n d A m p l i c o r p o s i t i v e (1%) w h e r e a s 4 s a m p l e s in g r o u p II w e r e f o u n d p o s i t i v e (2%). N o n e of these six A m p l i c o r p o s i t i v e s a m p l e s w e r e anti-HBc positive. R e p r o d u c t i b i l i t y of the positive RT-PCR s a m p l e s w a s a c h i e v e d b y r e p e a t i n g the extraction step once a n d the RT-PCR s t e p !n triplicate. C O N C L U S I O N S : 1)HCV R N A w a s f o u n d i n s e r o n e g a t i v e BDs w i t h n o r m a l or elevated ALT. 2)ALT a p p e a r as a n usefull tool for the screening of s e r o n e g a t i v e HCV. i n f e c t i o n i n BDs. 3 ) H C V R N A w a s d e t e c t e d w i t h o u t anti H C V i n a p p a r e n t l y n o n i m m u n o s u p p r e s s e d subjects. 4)HCV R N A A r n p l i c o r a s s a y c o u l d m a x i m i z e the d e t e c t i o n of H C V infection in BDs a n d i m p r o v e the t r a n s f u s i o n safety.
• INTESTINAL PERMEABILITYAS MEASUREDWITH POLYETHYLENE GLYCOL 600 IN PATIENTS WITH CIRRHOSIS: CLINICAL INVESTIGATION. R. H~md~ni, R. Chapparella, R. Stauber, S. Wood, D. Framer, E. Rosenblum, M. Kondraclfi, D.H. Van-Thiel. Departments of Critical Care Medicine/Anesthesiology and Surgery, University of Pittsburgh, Pittsburgh, PA; University of Iowa, Iowa City, IA. BACKGROUND: Patients with cirrhosis have an increased incidence of bacterial infections (Hepatol 1984;4:53-8). Bacterial translocation, which occurs as result of altered intestinal permsability (J Trauma 1988;28:896-906), may play a role in this increased incidence of infections. Intestinal permeability can be measured using PEG polymers (Gastro 1977;73:241-257). METHODS: A total of 39 cirrhotic patients and 21 normal controls were given 10 Gins of PEG 600. The 24 hour urine recovery of each of the seven principle polymers tiiat comprise PEG 600 was determined using HPLC. Differences in the recovery of each polymer and the mean recovery of the higher molecular weight polymers were compared between the cirrhotic patients and controls using Helmert contrasts. Medical records were reviewed retrospectively for 6 months or until OLTX, whichever came first. Age, etiology of liver disease, child class and incidence of bacterial infections was obtained. RESIdLT~: The mean age was 47 (16-68) years. Of the 39 patients, alcohol was the etiology in 12, post necrotic inl3, PBC in 6, PSC in 4 and miscellaneous in 4. Ten of the patients were in child class A, 13 in B and 16 in C. The mean recovery is shown in the table below, The first significantdifference was noted between the % recovery of polymer 590 and the higher polymers (p = 0.01). An exclusionindex defined as the difference between the recovery of polymers 590 and 722 was determined for each patient. The index of patients in child class A and B (N23) vs class C (N15) was 3.92_.+0.75vs 3.14_+1.62(p =0.92), patients without varices (NS) and those with (N23) was 3.05+ 1.09 vs 3.41_+1.90(p=0.42). The index in patients with infections (N$) and those without (N22) was 1.04+1.29 vs 4.21_+1.15(p=0.005). pOLYMER MW502 MW546 MW590 MW634 MW678 MW722
PATIENTS (39) CONTROLS(21) 16.81%+1.35% 22.40%+1.67% 15.87%+1.19% 21.81%+1.48% 13.86%+1.09% 19.62%+1.34% 13.01%+0.99% 1'/.58%+1.23% 10.88%+0.93% 15.33%+1.16% 10.10%+0.88% 13.06%_.+1.08%
P VALUE 0.61 0.08 0.015 0.16 0.008 ---
CONCLUSION: The intestinal absorption of PEG 600 is altered in patients with cirrhosis. There is an inability of the intestinal epithelium to exclude larger molecular weight polymers. More importantly, a low PEG 600 exclusion index is associated with bacterial infections.