Vol. 12, No. 3, 1990
625
CORRESPONDENCE
trial comparing somatostatin and injection sclerotherapy in the control of acute variceal haemorrhage [Abstract].Br J Surg 1990; 77:A702. 8. Kleber G, Sauerbruch T, Fisher C, Paumgartner G. Somatostatin does not reduce oesophageal variceal pressure in liver cirrhotics. Gut 1988;29:153-156. 9. Yates J , Nott D, Ellenbogen S, Cooke T, Shields R, Jenluns SA.
Effects of somatostatin, sandostatin and vasopressin on portal pressure and collateral blood flow in portal hypertensive rats [Abstract]. Gut 1989;30:A1498. 10. Bosch J, Kravetz D, Mastai R, Bruix J, Rigau J, Mes J . Azygos blood flow in cirrhosis: effects of balloon tamponade, vasopressin, somatostatin and propranolol [Abstractl. HEPATOLOGY 1983;3: 855.
Acute Variceal Bleeding: Still Searching for the Right Treatment To the Editor: We have read with interest the article of Valenzuela et al. (1) suggesting that somatostatin administered under their study conditions is ineffective, but it is most striking that placebo is successful in 34 of 41 (83%) patients. These conclusions led us to emphasize two points. First, the only study in which placebo has been as effective is the study of Walker et al. (2). In their placebo group, 80% of the patients stopped bleeding, but balloon tamponade was used in 20 of 25 patients (75%). In fact, if a real placebo-controlled trial (3)is considered, the controlled bleeding rate is 35% at 6 hr and 45% at 24 hr after initiation of the treatment. It is more likely that in the Valenzuela et al. study (1) some bias in the inclusion criteria may have occurred. These authors described in great detail their inclusion criteria. In most studies (4, 5 ) like ours (61, the description is shorter: an emergency esogastroduodenoscopy demonstrates active bleeding from a varix and the treatment is applied right away. Efficacy of the considered treatment is evaluated within 12 hr after initiation of therapy, that is to say, almost 12 hr after seeing an active hemorrhage during endoscopy. In the Valenzuela et al. study (11, some delay might have occurred between the onset of the variceal bleeding and the initiation of the treatment. This might constitute a bias because a spontaneous stop in bleeding could have happened and so would explain the discrepancy between their results and the others. The second point is that to demonstrate that a treatment is more effective with a rate of 90% than a placebo with a rate of 80%with a subsequent a risk of 5% and p risk of 5%, 640 patients must be included in the two groups to be studied. Besides, if the lowest limit is taken into account (a = 5%, p = 20961, 370 patients would still be necessary. Thus, small groups of patients may lead to imprudent conclusions. On the other side, who would be able to demonstrate that a designated treatment is
Reply: We thank Drs. Shields and Jenkins and Dr. Silvain et al. for their interest and comments on our article (1).We are pleased to offer our points of view on the interesting issues that were raised. We do not believe that our results are contrary to earlier reports (2-4) that compared somatostatin-effects to those of vaso-
better than placebo when such a large number of patients is needed to reach a statistically significant effective rate? Finally, under these conditions, endoscopic sclerosis performed in the emergency department (4)seems actually to be the more beneficial treatment. In the future, we should emphasize that comparisons between studies would be feasible only if everyone used the same methodology.
CHRISTINESILVAIN, M.D. ERICFORT,M.D. PIERRE INGRAND, M.D. MICHEL BEAUCHANT, M.D. Hepatogastroenterology Unit Hbpital La MilBtrie 86000 Poitiers, France REFERENCES 1. Valenzuela JE, Schubert T, Fogel MR, Strong RM, Levine J , Mills PR, Fabry TL. A multicenter, randomized, double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varices. HEPATOLOGY 1989;10:958-961. 2. Walker S, Stiehl A, Raedsch R, Kommerell B. Terlipressin in bleedmg esophageal varices: a placebo-controlled, double-blind 1986;6:112-115. study. HF,PATOLOGY 3. Fogel MR, Knauer CM, Andres LL, Mahal AS, Stein DET, Kemeny MJ, Rink MM, et al. Continuous intravenous vasopressin in active upper gastrointestinal bleeding: a placebo-controlled trial. Ann Intern Med 1982;96:565-569. 4. Westaby D, Hayes PC, Gimson AES, Polson RT, Williams R. Controlled clinical trial of injection sclerotherapy for active variceal bleeding. HEPATOLOGY 1989;9:274-277. 5. Tmi XT, Lay CS, Lai KH, Ng WW, Yeh YS, Wang JY,Chiang TT, et al. Controlled trial of vasopressin plus nitroglycerin vs. vasopressin alone in the treatment of bleeding eeophageal varices. 1986;6:406-409. HEPATOLOGY 6. Fort E, Sautereau D, Silvain C, Ingrand P, Pillegand B, Eeauchant M. A randomized trial of terlipressin plus nitroglycerin vs. balloon tamponade in the control of acute variceal hemorrhage. HEPATOLOGY 1990;11:678-681.
pressin or cimetidine. It is true that in the preliminary report by Burroughs et al. ( 5 ) the placebo response was only 41% compared with our 83% response. Because the report by Burroughs et al. is available only as an abstract, we cannot elaborate on the possible emlanations and unwblished data. However, we were surprised by the k g h success rate
626
CORRESPONDENCE
of our placebo group and alluded to this in the discussion of our report. Dr. Shields and Jenkins, however, raise a salient point related to the selection criteria. We cannot express an opinion regarding selection criteria in other studies, but in our protocol consecutive patients were considered and only those not fulfilling the entrance criteria were dismissed. We estimate that approximately an equal number of patients were excluded because they were initially treated by house staff with other drugs or modalities, possibly because of a lack of awareness of this protocol. We believe our criteria assured a proper analysis of results and comparison among groups. We conducted a double-blind study, and there were no significant differences in the characteristics of patients in the two treatment arms. Thus we believe that our carefully worded comment that “somatostatin administered under our study conditions is ineffective, or perhaps harmful, in the treatment of acute gastrointestinal hemorrhage due to esophageal varices” is justified. Regarding the comments of Dr. Silvain et al., we believe it is extremely important to explain clearly, but succinctly,the inclusion criteria in a study of this nature because this will facilitate comparison with other studies, as has been the case.The treatment, placebo or somatohtin, was initiated in our study within hours, in most cases less than 6 hr and in no instance after 12 hr after completion of diagnostic endoscopy. We believe our study emphasizes the importance of prospective double-blind controlled studies. Analysis of treatment success without a placebo arm may lead to
HEPrnLOGY
invalid conclusions. In this particular case, it remains to be seen whether other groups will have similar success with placebo treatment in similar clinical conditions.
JORGE E. VALENZUELA, M.D.
TIMOTHYSCHUBERT, M.D. JAMES POSILLICO, Ph.D. LORENWE, M.D. Department of Medicine Section of Gastroenterology University of Southern California School of Medicine Los Angeles, CA 90033 REFERENCES 1. Valenzuela JE, Schubert T, Fogel MR, Strong RM,Levine J, Mills PR, Fabry TL. A multicenter, randomised double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varices. HEPATOLQGY 1989;10:958-961. 2. Kravetz D, Bosch J, Teres J, Bruix J, Rimola A, Rod68 J. Comparisonof intravenous somatostatinand vasopressin infusions in treatment of acute esophageal variceal hemorrhage. HEPATOLQGY 1984;4:442-446. 3. Jenkins SA, Baxter JN,Corbett W, Devitt P, Ware J, Shields R. A prospective randomised controlled trial hemorrhage. Br Med J 1985;290:275-278. 4. Testoni PA, Masci E, Passaretti A, Malesci A, Tittobello A, Comin U, Ballarin E, et al. Comparison of somatostatin and cimetidine in the treatment of acute bleeding esophageal varices. CUR Ther Res 1986;39:758-766. 5. Burroughs AK, McCormick PA, Sprengers D, Hughes M, D’Heygere FR, McIntyre E, et al. Randomised double-blind placebo controlled study of somatostatin for control of variceal bleeding [Abstract].Gut 1988;29A1495.
Experimental Autoimmune Hepatitis in the Mouse: A Promising Model To the Editor: I read with great interest the paper entitled “Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity” by Lohse and colleagues that appeared in the January 1990 issue of Hepatology (1). The authors were able to successfully induce experimental autoimmune hepatitis (EAH) in C57BW6 mice by intraperitoneal immunization with syngeneic soluble liver proteins. Moreover, disease in this murine model not only could be transferred by spleen cells but was also unequivocally shown to be the result of a type IV autoimmune reaction mediated by the T lymphocyte. Over the past several years, I have been particularly interested in a number of antigens prepared from the cytosol, that is, the soluble liver fraction of mouse (2), human (3, 4) and more recently of rat (Manuscripts in preparation). Consequently, by virtue of experimentation, the crude antigenic material used by Lohse et al. (1)has been repeatedly used in our studies for immu-
nizing mice with both allogeneic and syngeneic material. The livers of the recipient mice were routinely examined by light microscopy. When mice were immunized withallogeneic liver extracts, their liver histological findings were not different from those of control animals, despite the fact that a strong antibody (anti-F) response could be deteded in their sera. Unfortunately, our efforts were unsuccessful, even when syngeneic liver extracts were used as immunogens as shown in Table 1. Only 11 of 72 animals immunized with the 100,000g supernatant of syngeneic livers showed a minor inflammatory infiltrate with no evidence of liver cell necrosis or enzyme elevations. What seems to be the primary reason for the difference between our results and those reported by Lohse et al. (1)is perhaps the selection in mice strain. It is quite obvious from their experiments that C57BW6 mice represent the most susceptible strain for the development of EAH. In an earlier work, Lane and Silver ( 5 ) immunized a very similar mouse strain (C57BW10) with syngeneic liver extracts in an effort to better define
625
CORRESPONDENCE
trial comparing somatostatin and injection sclerotherapy in the control of acute variceal haemorrhage [Abstract].Br J Surg 1990; 77:A702. 8. Kleber G, Sauerbruch T, Fisher C, Paumgartner G. Somatostatin does not reduce oesophageal variceal pressure in liver cirrhotics. Gut 1988;29:153-156. 9. Yates J , Nott D, Ellenbogen S, Cooke T, Shields R, Jenluns SA.
Effects of somatostatin, sandostatin and vasopressin on portal pressure and collateral blood flow in portal hypertensive rats [Abstract]. Gut 1989;30:A1498. 10. Bosch J, Kravetz D, Mastai R, Bruix J, Rigau J, Mes J . Azygos blood flow in cirrhosis: effects of balloon tamponade, vasopressin, somatostatin and propranolol [Abstractl. HEPATOLOGY 1983;3: 855.
Acute Variceal Bleeding: Still Searching for the Right Treatment To the Editor: We have read with interest the article of Valenzuela et al. (1) suggesting that somatostatin administered under their study conditions is ineffective, but it is most striking that placebo is successful in 34 of 41 (83%) patients. These conclusions led us to emphasize two points. First, the only study in which placebo has been as effective is the study of Walker et al. (2). In their placebo group, 80% of the patients stopped bleeding, but balloon tamponade was used in 20 of 25 patients (75%). In fact, if a real placebo-controlled trial (3)is considered, the controlled bleeding rate is 35% at 6 hr and 45% at 24 hr after initiation of the treatment. It is more likely that in the Valenzuela et al. study (1) some bias in the inclusion criteria may have occurred. These authors described in great detail their inclusion criteria. In most studies (4, 5 ) like ours (61, the description is shorter: an emergency esogastroduodenoscopy demonstrates active bleeding from a varix and the treatment is applied right away. Efficacy of the considered treatment is evaluated within 12 hr after initiation of therapy, that is to say, almost 12 hr after seeing an active hemorrhage during endoscopy. In the Valenzuela et al. study (11, some delay might have occurred between the onset of the variceal bleeding and the initiation of the treatment. This might constitute a bias because a spontaneous stop in bleeding could have happened and so would explain the discrepancy between their results and the others. The second point is that to demonstrate that a treatment is more effective with a rate of 90% than a placebo with a rate of 80%with a subsequent a risk of 5% and p risk of 5%, 640 patients must be included in the two groups to be studied. Besides, if the lowest limit is taken into account (a = 5%, p = 20961, 370 patients would still be necessary. Thus, small groups of patients may lead to imprudent conclusions. On the other side, who would be able to demonstrate that a designated treatment is
Reply: We thank Drs. Shields and Jenkins and Dr. Silvain et al. for their interest and comments on our article (1).We are pleased to offer our points of view on the interesting issues that were raised. We do not believe that our results are contrary to earlier reports (2-4) that compared somatostatin-effects to those of vaso-
better than placebo when such a large number of patients is needed to reach a statistically significant effective rate? Finally, under these conditions, endoscopic sclerosis performed in the emergency department (4)seems actually to be the more beneficial treatment. In the future, we should emphasize that comparisons between studies would be feasible only if everyone used the same methodology.
CHRISTINESILVAIN, M.D. ERICFORT,M.D. PIERRE INGRAND, M.D. MICHEL BEAUCHANT, M.D. Hepatogastroenterology Unit Hbpital La MilBtrie 86000 Poitiers, France REFERENCES 1. Valenzuela JE, Schubert T, Fogel MR, Strong RM, Levine J , Mills PR, Fabry TL. A multicenter, randomized, double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varices. HEPATOLOGY 1989;10:958-961. 2. Walker S, Stiehl A, Raedsch R, Kommerell B. Terlipressin in bleedmg esophageal varices: a placebo-controlled, double-blind 1986;6:112-115. study. HF,PATOLOGY 3. Fogel MR, Knauer CM, Andres LL, Mahal AS, Stein DET, Kemeny MJ, Rink MM, et al. Continuous intravenous vasopressin in active upper gastrointestinal bleeding: a placebo-controlled trial. Ann Intern Med 1982;96:565-569. 4. Westaby D, Hayes PC, Gimson AES, Polson RT, Williams R. Controlled clinical trial of injection sclerotherapy for active variceal bleeding. HEPATOLOGY 1989;9:274-277. 5. Tmi XT, Lay CS, Lai KH, Ng WW, Yeh YS, Wang JY,Chiang TT, et al. Controlled trial of vasopressin plus nitroglycerin vs. vasopressin alone in the treatment of bleeding eeophageal varices. 1986;6:406-409. HEPATOLOGY 6. Fort E, Sautereau D, Silvain C, Ingrand P, Pillegand B, Eeauchant M. A randomized trial of terlipressin plus nitroglycerin vs. balloon tamponade in the control of acute variceal hemorrhage. HEPATOLOGY 1990;11:678-681.
pressin or cimetidine. It is true that in the preliminary report by Burroughs et al. ( 5 ) the placebo response was only 41% compared with our 83% response. Because the report by Burroughs et al. is available only as an abstract, we cannot elaborate on the possible emlanations and unwblished data. However, we were surprised by the k g h success rate
626
CORRESPONDENCE
of our placebo group and alluded to this in the discussion of our report. Dr. Shields and Jenkins, however, raise a salient point related to the selection criteria. We cannot express an opinion regarding selection criteria in other studies, but in our protocol consecutive patients were considered and only those not fulfilling the entrance criteria were dismissed. We estimate that approximately an equal number of patients were excluded because they were initially treated by house staff with other drugs or modalities, possibly because of a lack of awareness of this protocol. We believe our criteria assured a proper analysis of results and comparison among groups. We conducted a double-blind study, and there were no significant differences in the characteristics of patients in the two treatment arms. Thus we believe that our carefully worded comment that “somatostatin administered under our study conditions is ineffective, or perhaps harmful, in the treatment of acute gastrointestinal hemorrhage due to esophageal varices” is justified. Regarding the comments of Dr. Silvain et al., we believe it is extremely important to explain clearly, but succinctly,the inclusion criteria in a study of this nature because this will facilitate comparison with other studies, as has been the case.The treatment, placebo or somatohtin, was initiated in our study within hours, in most cases less than 6 hr and in no instance after 12 hr after completion of diagnostic endoscopy. We believe our study emphasizes the importance of prospective double-blind controlled studies. Analysis of treatment success without a placebo arm may lead to
HEPrnLOGY
invalid conclusions. In this particular case, it remains to be seen whether other groups will have similar success with placebo treatment in similar clinical conditions.
JORGE E. VALENZUELA, M.D.
TIMOTHYSCHUBERT, M.D. JAMES POSILLICO, Ph.D. LORENWE, M.D. Department of Medicine Section of Gastroenterology University of Southern California School of Medicine Los Angeles, CA 90033 REFERENCES 1. Valenzuela JE, Schubert T, Fogel MR, Strong RM,Levine J, Mills PR, Fabry TL. A multicenter, randomised double-blind trial of somatostatin in the management of acute hemorrhage from esophageal varices. HEPATOLQGY 1989;10:958-961. 2. Kravetz D, Bosch J, Teres J, Bruix J, Rimola A, Rod68 J. Comparisonof intravenous somatostatinand vasopressin infusions in treatment of acute esophageal variceal hemorrhage. HEPATOLQGY 1984;4:442-446. 3. Jenkins SA, Baxter JN,Corbett W, Devitt P, Ware J, Shields R. A prospective randomised controlled trial hemorrhage. Br Med J 1985;290:275-278. 4. Testoni PA, Masci E, Passaretti A, Malesci A, Tittobello A, Comin U, Ballarin E, et al. Comparison of somatostatin and cimetidine in the treatment of acute bleeding esophageal varices. CUR Ther Res 1986;39:758-766. 5. Burroughs AK, McCormick PA, Sprengers D, Hughes M, D’Heygere FR, McIntyre E, et al. Randomised double-blind placebo controlled study of somatostatin for control of variceal bleeding [Abstract].Gut 1988;29A1495.
Experimental Autoimmune Hepatitis in the Mouse: A Promising Model To the Editor: I read with great interest the paper entitled “Experimental autoimmune hepatitis: disease induction, time course and T-cell reactivity” by Lohse and colleagues that appeared in the January 1990 issue of Hepatology (1). The authors were able to successfully induce experimental autoimmune hepatitis (EAH) in C57BW6 mice by intraperitoneal immunization with syngeneic soluble liver proteins. Moreover, disease in this murine model not only could be transferred by spleen cells but was also unequivocally shown to be the result of a type IV autoimmune reaction mediated by the T lymphocyte. Over the past several years, I have been particularly interested in a number of antigens prepared from the cytosol, that is, the soluble liver fraction of mouse (2), human (3, 4) and more recently of rat (Manuscripts in preparation). Consequently, by virtue of experimentation, the crude antigenic material used by Lohse et al. (1)has been repeatedly used in our studies for immu-
nizing mice with both allogeneic and syngeneic material. The livers of the recipient mice were routinely examined by light microscopy. When mice were immunized withallogeneic liver extracts, their liver histological findings were not different from those of control animals, despite the fact that a strong antibody (anti-F) response could be deteded in their sera. Unfortunately, our efforts were unsuccessful, even when syngeneic liver extracts were used as immunogens as shown in Table 1. Only 11 of 72 animals immunized with the 100,000g supernatant of syngeneic livers showed a minor inflammatory infiltrate with no evidence of liver cell necrosis or enzyme elevations. What seems to be the primary reason for the difference between our results and those reported by Lohse et al. (1)is perhaps the selection in mice strain. It is quite obvious from their experiments that C57BW6 mice represent the most susceptible strain for the development of EAH. In an earlier work, Lane and Silver ( 5 ) immunized a very similar mouse strain (C57BW10) with syngeneic liver extracts in an effort to better define
