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SUMMARIES

similar degree as atropine but produce fewer side effects. Preliminary studies suggest that pirenzepine, at a dose of 100-150 mgiday, is equally efficacious as histamine HZ-receptor antagonists in healing gastric and duodenal ulcers [Stand J Gastroenterol 1982; 17(Suppl 81):1-40; Dig Dis Sci 1986;31:21OS; Stand J Gastroenterol 1986;21:806-8081. At these doses, the most frequent side effects are dry mouth and blurred vision, occurring in 14% and 6% of patients, respectively [Stand J Gastroenterol 1982;17(Suppl 72):237-2461. The discovery of the selective muscarinic M,-receptor antagonists pirenzepine and telenzepine has advanced our knowledge of the pharmacology of muscarinic receptors and should advance our understanding of the neural regulation of gastric acid secretion. Initial enthusiasm for the use of these agents, either as single or adjunctive therapy for acid-peptic disorders, has been tempered by recent approval of more potent histamine HZ-receptor antagonists and the H’,K’-ATPase inhibitor omeprazole for clinical use. The Ml-receptor antagonists are already powerful research tools-their role in patient care remains to be determined. M. L. SCHUBERT, M.D.

INTERLEUKIN-10

AND

COUNTING

. . .

Hsu D-H, de Waal Walefyt R, Fiorentino DF, et al. (Departments of Immunology and Human Immunology, DNAX Research Institute, Palo Alto, California). Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF-1. Science 1990;250:830-832 (November]. Cytokine synthesis-inhibitory factor [CSIF; interleukin-10 (IL-lo)], a product of mouse Th2 T-cell clones that inhibits synthesis of cytokines by mouse Thl T-cell clones, exhibits extensive sequence similarity to an uncharacterized open reading frame in the Epstein-Barr virus genome, termed BCRF-1 [Science 1990;248:1230-1234).The predicted protein-coding region of the BCRF-1 gene was cloned and transfected into COS-7 cells. The supernatants of the COS-7 transfectants contained an approximately 17kilodalton polypeptide not present in supernatants from mock-transfected cells. These transfectant supernatants inhibited interferon-y (IFN-y) synthesis by antigen-stimulated mouse Thl clones in the presence of syngeneic antigen-presenting cells in a manner similar to the effects of mouse IL-lo. Interestingly, the BCRF-l-protein-containing supernatants inhibited interferon production by human cells stimulated either with phytohemagglutinin, antibodies to CD3, or IL-2. Thus, recombinant BCRF-1 protein mimics the activity of IL-10 on both mouse and human cells, which suggests that in vivo BCRF-1 may have a role in the interaction of the virus with the host immune system. Comment. The identification of new cytokines continues to rapidly progress. We are now at IL-lo, and a number of additional candidates for interleukin designation are waiting in the wings. Interleukin is a term that was coined to denote molecules produced by lymphoid cells that act on other cells of the lymphoid series. It was meant to encompass and replace terms such as “monokine” and “lymphokine.” It has been subsequently realized that interleukins have effects on a much broader array of cells outside the immune system, so the term “cytokines” has been developed, although the terms “interleukin” and “cytokine” are often used interchangeably. To get the interleukin designation, the gene for that molecule must have been cloned and the derived protein

Vol. 100, No. 6

sequence proved to be distinct from that of any known cytokine. Many teams of researchers are actively doing just that, and the numbers of interleukins continue to climb. One can only guess what the total number will turn out to be. In previous commentaries, the existence of murine helper T cells that make a restricted pattern of cytokines was discussed. This distinction is particularly evident in T-cell clones and hybridomas that have been carried in prolonged culture in vitro. Thl-type helper T cells produce IFN-y and IL-Z, whereas ThZ-type T cells produce IL-4 and IL-5. Both types produce a wide variety of other cytokines including IL-3, tumor necrosis factorcx, and granulocytemacrophage colony-stimulating factor. These patterns of cytokine synthesis seem to correlate with different functions carried out by these subsets. Thl clones are less efficient in providing help for B-cell responses but are very active in inducing macrophage activation and delayed hypersensitivity; Th2 clones’ major function seems to be to provide help for B-cell antibody responses. This divergence in function between the two types of helper cells parallels and may underlie the well-recognized divergence of immune responses into those that are predominantly humoral and those that are predominantly cellular (DTH). In a previous selected summary (Gastroenterology 98;536:1990), work was discussed that showed that the pattern of Thlvs. Th2-helper response to Leishmanio major in mice largely determined whether mice resisted the infection and recovered or were susceptible to the infection and succumbed. It now appears that there are reciprocal interactions between Thl- and Th2-helper cells, mediated by IFN-y and IL-IO, whose net effect determines which type of response, humoral or cellular, will predominate: IFN-7 produced by Thl cells inhibits the proliferation of Th2 clones: conversely, IL-10 produced by Th2 cells inhibits the synthesis of cytokines such as IFN-y by Thl cells. The mechanism of IL-10 action is not yet understood, but its effects appear to be mediated through antigen-presenting cells: Antigen-presenting cells pulsed with IL-lo, washed, and added to Thl clones inhibit IFN-y production. There is some recent additional evidence that IL-10 may play a crucial role in vivo in directing the pattern of immune response in that in susceptible mice, schistosome egg antigen triggers an IL-10 response which inhibits a protective Thl response and allows a nonprotective Th2 response to dominate (FASEB J 1990;4:A2191). In a previous publication (Science 1990;248:1230-12341, these authors reported cloning of the IL-10 gene. When its sequence was compared with known sequences of genes already cloned, it turned out to have a strong homology to an open reading frame of a gene from Epstein-Barr virus. In this particular report they went on to express the Epstein-Barr virus gene and show that its product has IL-10 activity for both murine and human cells. The implication is that the virus may have captured an important cytokine sequence with which to divert the immune system to its advantage. Assuming that humans have a similar divergence of function in their helper T cells (which so far has not been demonstrated], the net effect of the expression of this gene with IL-lo-like activity by this virus would be to decrease the IFN-y-dominated DTH response in vivo. The human IL-10 gene has been cloned and found to be 90% homologous to murine IL-10 (FASEB J 1990;4:A2172), and thus the present results may well be relevant to the human response to Epstein-Barr virus, whose host, of course, is the human. C. 0. ELSON, M.D.

PROPHYLAXIS

FOR VARICEAL

BLEEDING

Andreani T, Poupon RE, Balkau B], et al. (Hapita SaintAntoine, Paris, France; INSERM Unit6 21, Villejuif, France; HBpital first

Jean

Verdier,

gastrointestinal

Bondy, bleeding

France). in

Preventive patients

with

therapy cirrhosis:

of

June

1991

results of a controlled trial comparing propranolol, endoscopic sclerotherapy and placebo. Hepatology 1990;12:14131419 (December). Two Paris centers evaluated prophylaxis of the first episode of upper gastrointestinal bleeding in 126 patients with cirrhosis between November 1985 and February 1988. Patients were randomized according to Child-Pugh score to three treatment regimens: 43 received propranolol, 42 were treated with sclerotherapy, and 41 received placebo (vitamin K). Patients were excluded for the following reasons: follow-up deemed not feasible, hepatocellular carcinoma, other cancers, previous variceal treatment, moribundity, contraindication of propranolol, and refusal to participate. At one of the two centers, we are told that only 47% of consecutive patients could actually be enrolled, with the rest excluded for the above reasons. Varices were graded by size on a scale of I-III, and patients with all sizes of varices were included in the study. Thirty-five to forty-eight percent of the patients in the three treatment groups had grade I varices, 35%-56% had grade II, and 9%-18% had grade III. The severity of liver disease in the three treatment groups was 23%-24% Child-Pugh class A, 45%-54% class B, and 23%-31% class C. The etiology of liver disease was alcohol in 80% of the patients. Patients were seen 1 month after inclusion and then at 3-month intervals for 2 years. The patients randomized to sclerotherapy received 1% or 2% pilodocanol (mean, 22 mL) by intravariceal and paravariceal injections every 1-2 weeks until obliteration was achieved (mean, 3 sessions). Injections were repeated every 3 months if varices reformed. Fourteen patients were lost to follow-up (propranolol, 6; sclerosis, 6, and placebo, 2). Three patients had treatment discontinued due to severe complications [all in the propranolol group) and 11 patients refused to continue or initiate treatment (all in the sclerotherapy group). Nine patients did not take their propranolol regularly. Twenty-four patients had bleeding during the study, 18 from esophageal varices, 3 from erosive gastritis, 2 from gastric ulcer, and 1 from fundic varices. The l- and 2-year bleeding rates were, respectively, 30% and 39% in the placebo group, 23% and 31% in the sclerotherapy group, and 6% and 6% in the propranolol group. The differences were significant between the propranolol and placebo groups and between the propranolol and sclerotherapy groups. We are told that these results would not be affected if only patients having started treatment or those having completed treatment were considered. Gastrointestinal bleeding was the cause of death in 7 of the 24 patients (29%). The l- and 2-year survival rates were, respectively, 66% and 54% in the placebo group, 71% and 52% in the sclerotherapy group, and 79% and 66% in the propranolol group. There was no significant difference in survival between the three treatment groups although a trend toward improved survival appeared in the propranolol group. The multivariate Cox model indicated that size of varices and Child-Pugh class were predictive of onset of bleeding and that female sex and Child-Pugh class were predictive of survival. Comment. It has been suggested that physicians respond to variceal bleeding irrationally, with reliance on unproven therapies

SELECTED SUMMARIES

1779

for an event with high initial mortality instead of emphasizing prevention (Hepatology 1988;8:167-170). A lack of enthusiasm for preventive treatment may be based on the early experience with prophylactic portal-systemic shunts which prevented bleeding but failed to improve, or even worsened, survival (Medicine 1982;51:2740). The past 5 years have given us several studies of two newer prophylactic therapies, sclerotherapy and propranolol. It appears that propranolol is effective in decreasing the incidence of first hemorrhage, although widespread application of prophylactic therapy has not yet occurred. This study concurs with previous ones regarding the frequency of first upper gastrointestinal hemorrhage (13 of 39 patients on placebo over a 2-year follow-up, or 31%) in cirrhotic patients (Hepatology 1986;6:1407-1413). Significant mortality (30%) was associated with this first bleed, which included three nonvariceal upper gastrointestinal bleeding episodes. Previous studies report mortality rates of 28%-71%. Given the frequency and gravity of these bleeding episodes, the issue of prophylaxis is important. This study is the fifth controlled trial of B-blockers for bleeding prophylaxis in cirrhotic patients. All have found decreased bleeding risk with P-blockers (Hepatology 1988;8:6-9; N Engl J Med 1987;317: 856-8611, although two of these studies had efficacy limited to patients compliant with the medication (J Hepatol 1988;7:118-125) or those with mild cirrhosis (J Hepatol 1989;9:75-83). Note that most patients in the present study also had mild cirrhosis (74% class A or B). In contrast, eight controlled studies of sclerotherapy prophylaxis are not in agreement. Four studies show reduced risk of first bleeding (Endoscopy 1986;18:40-43; Endoscopy 1982;14: 4-5; Hepatology 1988;8:1495-1500; Lancet 1985;1:773-775) while three studies (including this one) show no modification of bleeding risk (Gut 1989;30:873-879; N Engl J Med 1988;319:8-15) and one demonstrates increased risk of bleeding in the sclerosed patients (N Engl J Med 1988;318:814-818). Propranolol appears superior to sclerotherapy for prevention of the first hemorrhage in cirrhotic patients. One of the reasons physicians have been slow to embrace propranolol for prevention of the first bleeding episode is that efficacy for prevention of rebleeding was not confirmed after the initial promising report by Lebrec et al. (N Engl J Med 1983;309: 1539-1542). In contrast, sclerotherapy compared favorably with both medical therapy and surgical shunting, often making it the treatment of choice for the prevention of rebleeding. It was difficult to understand why propranolol would be more effective in the prevention of the first bleeding episode than it is in rebleeding. One explanation for this could be that propranolol takes longer to work, which makes it less effective for prevention of rebleeding because rebleeding risk is greatest soon after the initial bleeding episode. Two recent reports support the initial favorable results of the study of Lebrec et al. on propranolol in the prevention of rebleeding by showing equal efficacy for sclerotherapy and propranolol (Hepatology 1990;11:353-359; Hepatology 1987;7:355-361). An attractive feature of propranolol for prophylaxis of the first bleeding episode is that it is inexpensive and noninvasive compared with sclerotherapy. The ideal prophylaxis would also be without complications. Unfortunately, propranolol is not tolerated by all patients, and most trials have serious side effect rates (hypotension or asthma) similar to the present study (12%). In addition, some patients were excluded from entry because of (12% of consecutive potential candipropranolol contraindication dates) or were not regularly compliant with the medication (21%). One important difference between this study and previous ones is that patients with all degrees of severity of underlying liver disease and all sizes of varices were included. Many authors have included only high-risk patients with large varices. Scoring systems predictive of bleeding risk have been developed (N Engl J Med 1988;319:983-989). This study showed efficacy for prevention of bleeding even in patients with grade I varices and Child-Pugh class

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GASTROENTEROLOGY Vol. 100, No. 6

A and B. If this finding is confirmed, it could obviate the need for an initial endoscopic examination for scoring of variceal size before the institution of prophylaxis. The most important end point for any of the prophylactic treatments is improved survival. Despite success in the prevention of first hemorrhage, only one of the previous four trials found significantly improved survival (N Engl J Med 1987;317:856-861). Similarly, the present study found no significant difference in survival between the propranolol-treated placebo-treated groups, although there was a trend toward improvement. The authors suggest that this may be attributable to small study size. Unfortunately, this has been a recurrent theme in all treatments of variceal bleeding; even when the bleeding is controlled or prevented, the patient goes on to die of other complications of the liver disease. Do we now have enough information to support prophylactic treatment for upper gastrointestinal bleeding in cirrhotic patients? Propranolol has been shown to be effective in the prevention of the first bleeding episode in five studies. It is inexpensive, noninvasive, and fairly well tolerated. Despite its lack of clear efficacy in improving survival, I believe that its routine use is justified, especially in patients listed and waiting for transplantation. Whether all cirrhotic patients, or only those with large varices, should be treated remains uncertain. G. H. ELTA. M.D.

ERCG: THE FINAL FRONTIER IN GALLSTONE DISSOLUTION? Foerster EC, Mate.4 W, Domschke W (Department of Medicine I, University of Erlangen-Nuremberg, Erlangen, Germany). Endoscopic retrograde cannulation of the gallbladder: direct dissolution of gallstones. Gastrointest Endosc 1990;36:444-450 (September/October]. The authors performed endoscopic retrograde cannulation of the gallbladder (ERCG) with the aim of instilling methyl teti-butyl ether (MTBE) into the gallbladder lumen, dissolving the stones contained therein. To accomplish this, they developed a new catheter system (using a conventional duodenoscope) that fairly reliably allows placement of a catheter through the cystic duct into the gallbladder lumen without the need for a sphincterotomy. Twenty-two patients were included in the study; all had symptomatic gallbladder stones and either had refused surgery or were considered at high risk for surgery. There was no size or number limitation on the stones, but computed tomographic [CT) scanning was performed before treatment in all patients to ascertain that the stones were not calcified. The procedure used to catheterize the cystic duct and gallbladder was performed using conscious sedation and involved the use of several specially designed catheters and a steerable guide wire manipulated through an intact papilla. Once the guide wire was placed in the gallbladder lumen, an MTBE-instillation catheter with a double pigtail tip was passed and looped in the fundus so it encircled as many stones as possible; this catheter was then brought out through the nose as a cystonasal catheter. Methyl tert-butyl ether was instilled (mean volume, 40 mL) manually and aspirated in 3-5-minute cycles. In 4 of 22 patients (18%) cannulation attempts failed, in 3 cases due to cystic duct blockage by a stone. In one case the cystic duct was perforated and a cholecystectomy was subsequently per-

formed. In the remaining 18 patients (82%) a cystonasal catheter was able to be placed, and in 14 of these MTBE dissolution therapy was performed for a mean of 5.6 hours (range, 2.5-16 hours]. Based on catheter cholecystography, at least 95% of the stone mass was dissolved in 10 of the 14 patients. The 4 relative failures were related to higher acute gallstone density on CT scan. One patient developed cholecystitis 2 weeks posttreatment and underwent cholecystectomy; the residual debris in the gallbladder consisted of cholesterol-free pigment material. In 8 patients, ultrasonography obtained immediately after the procedure showed no residual stone debris, while in the remaining 6 residual debris was seen (4 with > 50% and 2 with > 95% reduction in stone mass). These 6 patients were treated with oral bile salt therapy, and 1 became stone-free after 3 months. Comment. Investigation into the nonsurgical treatment of gallstones continues on a variety of fronts. Nonsurgical therapy can be broadly categorized into noninvasive (oral bile salts alone or combined with lithotripsy) and invasive (percutaneous cholecystolithotomy or percutaneous instillation of MTBE into the gallbladder] forms of treatment. Oral bile salt therapy has been extensively evaluated over the past decade and, although safe and welltolerated, requires several months to several years to achieve a success rate of about 40%-50%, somewhat higher if floating stones are involved (Gastroenterology 1989;96:220-229). The combination of bile salts with extracorporeal shock-wave lithotripsy (ESWL) continues to be investigated in an attempt to increase its efficacy. Extracorporeal shock-wave lithotripsy is reasonably well tolerated and safe but often requires more than one treatment long-term oral bile salt therapy afterward, particularly

session and when larger

single stones or multiple stones are being treated (N Engl J Med 1988;318:393-397). Percutaneous cholecystolithotomy is a procedure performed during a several-day hospital stay and involves some significant patient inconvenience due to the cholecystostomy catheter as well as significant risks (Gastroenterology 1990;98: A243). The percutaneous transhepatic instillation of MTBE into the gallbladder is performed over 1 or more days and also involves potentially significant risks (N Engl J Med 1989;320:633-639). Thus, looking at the noninvasive and invasive modes of therapy in a very general sense, the trade-off with the percutaneous procedures is rapidity of dissolution against some increased risks and discomfort whereas the trade-off for the noninvasive therapies is increased safety and convenience against a somewhat lower dissolution rate. One emerging surgical

can also include in this technique of laparoscopic

broad perspective cholecystectomy

the as a

procedure that has a high yield in terms of efficacy and prevention of stone recurrence but still involves some risk of complications and mortality (Endosk Heute 1990;3:30-32; Gastroenterology 1990; 99:1529). The ideal nonsurgical treatment would involve a relatively brief, well-tolerated, low-risk procedure or therapy that would completely clear the gallbladder of stones, leaving the gallbladder free of residual material that could cause symptoms or serve as a nidus for future stone growth. This paradigm is probably not achievable in the foreseeable future. Efforts to date to reach this goal have involved a variety of approaches, either oral, percutaneous, or transcutaneous (the latter in the case of ESWL), as noted above. The technique of ERCG with MTBE instillation detailed in the current report is a novel one that seems to fall in between strictly noninvasive therapy and invasive percutaneous procedures: perhaps one could view it as “moderately invasive.” Endoscopic retrograde catheterization of the gallbladder has, of course, always been fraught with technical difficulties. As all