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Endoscopic blockade to prevent resurfacing of esophageal varices
GASTROENTEROLOGY 2003;124:1545–1555
SELECTED SUMMARIES Henry J. Binder, M.D. Selected Summaries Editor Yale University School of Medicine New Haven, Connecticut
STAFF OF CONTRIBUTORS Laurence Blendis, Tel-Aviv, Israel Robert Bresalier, Detroit, MI Glenn T. Furuta, Boston, MA William L. Hasler, Ann Arbor, MI Sreenivasa Jonnalagadda, St. Louis, MO Cyrus Kapadia, New Haven, CT Saul J. Karpen, Houston, TX
Ronald L. Koretz, Sylmar, CA Kris V. Kowdley, Seattle, WA James D. Lewis, Philadelphia, PA Gary R. Lichtenstein, Philadelphia, PA Douglas B. Nelson, Minneapolis, MN Richard M. Peek, Nashville, TN G. S. Raju, Galveston, TX
ENDOSCOPIC BLOCKADE TO PREVENT RESURFACING OF ESOPHAGEAL VARICES Cipolletta L, Bianco MA, Rotondano G, Marmo R, Meucci C, and Piscopo R (Maresca Hospital, Torre del Greco, Naples, Italy). Argon plasma coagulation prevents variceal recurrence after band ligation of esophageal varices: preliminary results of a prospective randomized trial. Gastrointest Endosc 2002;56:467– 471. In this prospective study, patients with cirrhosis and previous esophageal variceal bleeding who had undergone eradication of esophageal varices by endoscopic variceal band ligation were randomized to undergo argon plasma coagulation (APC) or to observation according to a computer-generated list. Medical therapy for portal hypertension (e.g., nonselective betablocker agents and nitrates) was not permitted. Patients with hepatocellular carcinoma, portal vein thrombosis, advanced cirrhosis (Child–Pugh score ⬎11), and chronic ingestion of alcohol were excluded. Eradication of varices was defined as complete disappearance of varices or the presence of trivial varices without red color signs. Variceal recurrence was defined as the development of varices that occupy less than one third of the esophageal lumen (F1, according to the North Italian Endoscopy Club [NIEC] classification). From April 1999 to August 2001, 30 patients with postviral cirrhosis and esophageal varices eradicated by endoscopic variceal band ligation were randomized to either APC (n ⫽ 16) or to control (n ⫽ 14) groups. The 2 groups were comparable for demographics, severity of cirrhosis and esophageal varices, and presence of gastric varices and degree of portal hypertensive gastropathy. APC (probe: 7 French; settings: power output of 60 W; gas flow rate: 1.5 to 2.0 liters per minute; and technique: create longitudinal parallel “stripes” of coagulation of the distal 5 cm of the esophagus) was initiated within 30 days of variceal ligation and continued at 1–2-week intervals, attempting to treat each half of the esophageal circumference at one time, until complete coagulation of the entire circumference of the distal 5 cm of the esophagus was achieved. After APC, patients were treated with omeprazole (20 mg per day)
Don C. Rockey, Durham, NC Fergus Shanahan, Cork, Ireland Nicholas J. Shaheen, Chapel Hill, NC Brad Warner, Cincinnati, OH David C. Whitcomb, Pittsburgh, PA Stephen D. Zucker, Cincinnati, OH
to promote healing of the coagulated tissue. Endoscopy was done at 1 month in the APC treatment group to assess healing and at 3-month intervals in both groups to check for esophageal variceal recurrence. Two sessions of APC (range, 1–3) were required to ablate the distal esophageal mucosa. At 1 month, the mucosal damage healed completely. Compared with 43% esophageal variceal recurrence in the control group, there was no esophageal variceal recurrence in the APC group during a follow-up of 16 months (range, 9 –28 months; P ⬍ 0.04). In the control group, there was one recurrence of variceal bleeding (7.2%), but no recurrent bleeding occurred in the APC group. The APC group did not have any major complications, such as stricture, perforation, and overt bleeding, but did have transient fever (⬎38° C), dysphagia, and retrosternal pain, all of which resolved in 24 hours. Neither gastric varices developed nor portal hypertensive gastropathy worsened in either group. Comment. Anatomy is the only solid foundation of medicine; it is to the physician and surgeon what geometry is to the astronomer. —William Hunter, circa 1750 After paying homage to William Hunter, let us review the venous anatomy of esophagus to evaluate the works of Cipolletta’s group. Without it, we will be lost at sea. Where shall we start? Kitano’s esophageal venous anatomy dissections at Cape Town, South Africa, done under the tutelage of Professor Terblanche (Br J Surg 1986;73: 525–531) are truly a masterpiece. It should be kept on a must-read list of all the novices venturing into endoscopic therapy of varices. In addition, it provides us with an opportunity to think “outside the box” and explore novel options for the prevention of variceal recurrence. Our current endoscopic practice of repeated sclerotherapy or ligation of varices has not made an impact on the prevention of variceal recurrence. Will cementing the free space around the obliterated varices with fibrosis (a concept tested by the application of APC in the report by Cipolletta et al.) prevent variceal recurrence? If so, why does it work? Before we address these issues, let us examine Kitano’s artwork demonstrating the minutest details of venous anatomy of the esophagus in health and in portal hypertension. This was done using microvascular resin casts. Five normal human cadavers and 5 known cases of portal hypertension with esophageal varices due to alcoholic cirrhosis were studied. Four layers of veins were identified in the
1546
SELECTED SUMMARIES
esophagus: the first layer, intra-epithelial channels drain into a superficial venous plexus, with the second layer connecting to the third layer of larger deep intrinsic veins. The first 3 layers of veins are located in the mucosa and submucosa. Both the superficial venous plexus and the deep intrinsic veins communicate directly with their counterpart veins in the stomach. In addition, perforating veins connect the deep intrinsic veins with the adventitial plexus, the fourth layer. All of these 4 layers of veins were significantly dilated in patients with portal hypertension, anywhere between 2 to 6 times compared to normal. The esophageal varices arose from the deep intrinsic veins, which communicated directly with gastric varices (Br J Surg 1986;73:525–531). After studying Kitano’s venous mapping of the esophagus, can we do any better with the endoscopic management of portal hypertension? First of all, a brief review of basic concepts of esophageal variceal development is also required. Portal hypertension and increased flow is the driving force that leads to the surfacing of the varices secondary to engorgement of microvascular channels in the submucosal free space of esophagus. Endoscopic therapy aims at obliterating the varices either by sclerosing or banding of the varices. However, neither of these endoscopic techniques is uniformly successful in the prevention of variceal recurrence because the basic pathophysiologic defect, i.e., the portal hypertension, remains unabated by endoscopic therapy. Rarely, endoscopic sclerosis of esophageal varices may open up bypass routes and lead to the development of large natural shunts (spleno-renal-caval shunts), which divert the driving force of portal hypertension away from the esophagus and prevent recurrence of varices (Gastroenterology 1989;97:421– 426). Opening up of natural shunts is not a predictable phenomenon, and one cannot rely on this mechanism to prevent recurrence of varices. Are there any other options available to prevent variceal recurrence? A close look at the Kitano’s chart provides some insights into how we can prevent resurfacing of varices after their eradication. Let me present my simplistic viewpoint—an endoscopist viewpoint—thinking like a plumber! Esophageal varices are (a) enlarged veins (b) in the submucosal space (c) opened up by portal hypertension. The pressure is transmitted transmurally through the perforating veins running across the esophageal wall and through the communicating veins between the stomach and the esophagus. Current therapeutic modalities, whether they are endoscopic, pharmacologic, or shunt therapies, address just 1 of the 3 above problems. Endoscopic therapy targets the vessels in the mucosa and submucosa directly. Both medical therapy and shunt therapy address the pressure issue. Embolization by interventional radiologists focuses on cutting off the blood flow from outside through the perforator veins. It is widely acknowledged that the current endoscopic techniques, neither sclerotherapy nor banding, on their own are successful in the prevention of recurrence of varices. Is there something else that the endoscopists can do to prevent variceal recurrence? Options are limited. One option is to cut off the blood supply from the perforator veins using endoscopic ultrasound guidance. Lahoti et al. have shown that dynamic endoscopic ultrasonography color doppler guided sclerotherapy of the esophageal perforator veins may be achieved (Gastrointest Endosc 2000;51:331– 333). Although an attractive high-tech option, this is not going to work because there too many patients with varices floating around for sonar-guided therapy. Prevention of resurfacing of varices is another option, which can be achieved by removing the surfacing zone, i.e.,
GASTROENTEROLOGY Vol. 124, No. 5
mucosa and submucosa, and replacing it with fibrous tissue. This concept of removal of the esophageal mucosa to prevent recurrence of varices, originally reported by Kitano’s group, has been left on the wayside for almost 15 years. Kitano et al. injected ethanolamine oleate into the mucosa after obliteration of the varices to create superficial ulcers in the lower esophagus as an endpoint of therapy. After total elimination of esophageal mucosa by sclerotherapy-induced ulceration, there was no recurrence of esophageal varices or bleeding over a mean follow-up of 16.3 months (range, 7–27 months; n ⫽ 119 survivors). Unfortunately, this was an uncontrolled observational study (Hepatology 1987;7:810 – 815). Furukawa et al. have evaluated the role of supplemental consolidation therapy of APC of the distal esophagus following eradication of varices with endoscopic banding. Eleven patients with esophageal varices underwent endoscopic variceal ligation. After disappearance or decrease of variceal size from F3 (largest sized varices) to F1 (straight), APC of the distal 5 centimeters of esophagus (settings, 1.8 L/min and 60 Watts) was performed. There was no recurrence of varices during a follow-up of 637.4 ⫾ 56.5 days (SD). Except for transient heartburn (73%), dysphagia (54%), and esophageal stenosis (18%) for a few days, there were no serious complications. None of the patients developed deep ulcers, and there were no other complications such as pleural effusion, mediastinitis, or pneumonia during the study (Hepatology Research 2002;23:220 –225). Nakamura et al. showed the usefulness of a combination of endoscopic variceal ligation and APC therapy in a small-randomized controlled study (Endoscopy 2001;33: 210 –215). Coming to the Cipolletta’s study, the preliminary results of APC in the prevention of variceal recurrence after band ligation are very encouraging. There was no recurrence of varices or variceal hemorrhage in the APC-treated group during a follow-up of 16 months. Neither were there any serious side effects with the consolidation therapy using APC. If these encouraging pilot data stand the test of time, this supplemental therapy will certainly become part of our routine practice because it is simple to deliver. My gut feeling is that the blockade of resurfacing of varices will certainly find its niche in endoscopic therapeutic strategies for prevention of variceal recurrence. GOTTUMUKKALA S. RAJU, M.D.
LEPTIN SIGNALING AND OBESITY: WEIGHT AND SEE Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, Soukas AA, Sharma R, Hudgins LC, Ntambi JM, Friedman JM (Laboratory of Molecular Genetics, Center for Studies in Physics and Biology, Rogosin Institute, Howard Hughes Medical Institute, The Rockefeller University, New York, New York; and Departments of Biochemistry and Nutritional Sciences, University of Wisconsin, Madison, Wisconsin). Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 2002;297:240 –243. Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, Attie AD (Departments of Biochemistry, Nutritional Sciences, Biostatistics and Medical Informatics, and Statistics and Horticulture, University of Wisconsin, Madison, Wisconsin; and Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The
SELECTED SUMMARIES Henry J. Binder, M.D. Selected Summaries Editor Yale University School of Medicine New Haven, Connecticut
STAFF OF CONTRIBUTORS Laurence Blendis, Tel-Aviv, Israel Robert Bresalier, Detroit, MI Glenn T. Furuta, Boston, MA William L. Hasler, Ann Arbor, MI Sreenivasa Jonnalagadda, St. Louis, MO Cyrus Kapadia, New Haven, CT Saul J. Karpen, Houston, TX
Ronald L. Koretz, Sylmar, CA Kris V. Kowdley, Seattle, WA James D. Lewis, Philadelphia, PA Gary R. Lichtenstein, Philadelphia, PA Douglas B. Nelson, Minneapolis, MN Richard M. Peek, Nashville, TN G. S. Raju, Galveston, TX
ENDOSCOPIC BLOCKADE TO PREVENT RESURFACING OF ESOPHAGEAL VARICES Cipolletta L, Bianco MA, Rotondano G, Marmo R, Meucci C, and Piscopo R (Maresca Hospital, Torre del Greco, Naples, Italy). Argon plasma coagulation prevents variceal recurrence after band ligation of esophageal varices: preliminary results of a prospective randomized trial. Gastrointest Endosc 2002;56:467– 471. In this prospective study, patients with cirrhosis and previous esophageal variceal bleeding who had undergone eradication of esophageal varices by endoscopic variceal band ligation were randomized to undergo argon plasma coagulation (APC) or to observation according to a computer-generated list. Medical therapy for portal hypertension (e.g., nonselective betablocker agents and nitrates) was not permitted. Patients with hepatocellular carcinoma, portal vein thrombosis, advanced cirrhosis (Child–Pugh score ⬎11), and chronic ingestion of alcohol were excluded. Eradication of varices was defined as complete disappearance of varices or the presence of trivial varices without red color signs. Variceal recurrence was defined as the development of varices that occupy less than one third of the esophageal lumen (F1, according to the North Italian Endoscopy Club [NIEC] classification). From April 1999 to August 2001, 30 patients with postviral cirrhosis and esophageal varices eradicated by endoscopic variceal band ligation were randomized to either APC (n ⫽ 16) or to control (n ⫽ 14) groups. The 2 groups were comparable for demographics, severity of cirrhosis and esophageal varices, and presence of gastric varices and degree of portal hypertensive gastropathy. APC (probe: 7 French; settings: power output of 60 W; gas flow rate: 1.5 to 2.0 liters per minute; and technique: create longitudinal parallel “stripes” of coagulation of the distal 5 cm of the esophagus) was initiated within 30 days of variceal ligation and continued at 1–2-week intervals, attempting to treat each half of the esophageal circumference at one time, until complete coagulation of the entire circumference of the distal 5 cm of the esophagus was achieved. After APC, patients were treated with omeprazole (20 mg per day)
Don C. Rockey, Durham, NC Fergus Shanahan, Cork, Ireland Nicholas J. Shaheen, Chapel Hill, NC Brad Warner, Cincinnati, OH David C. Whitcomb, Pittsburgh, PA Stephen D. Zucker, Cincinnati, OH
to promote healing of the coagulated tissue. Endoscopy was done at 1 month in the APC treatment group to assess healing and at 3-month intervals in both groups to check for esophageal variceal recurrence. Two sessions of APC (range, 1–3) were required to ablate the distal esophageal mucosa. At 1 month, the mucosal damage healed completely. Compared with 43% esophageal variceal recurrence in the control group, there was no esophageal variceal recurrence in the APC group during a follow-up of 16 months (range, 9 –28 months; P ⬍ 0.04). In the control group, there was one recurrence of variceal bleeding (7.2%), but no recurrent bleeding occurred in the APC group. The APC group did not have any major complications, such as stricture, perforation, and overt bleeding, but did have transient fever (⬎38° C), dysphagia, and retrosternal pain, all of which resolved in 24 hours. Neither gastric varices developed nor portal hypertensive gastropathy worsened in either group. Comment. Anatomy is the only solid foundation of medicine; it is to the physician and surgeon what geometry is to the astronomer. —William Hunter, circa 1750 After paying homage to William Hunter, let us review the venous anatomy of esophagus to evaluate the works of Cipolletta’s group. Without it, we will be lost at sea. Where shall we start? Kitano’s esophageal venous anatomy dissections at Cape Town, South Africa, done under the tutelage of Professor Terblanche (Br J Surg 1986;73: 525–531) are truly a masterpiece. It should be kept on a must-read list of all the novices venturing into endoscopic therapy of varices. In addition, it provides us with an opportunity to think “outside the box” and explore novel options for the prevention of variceal recurrence. Our current endoscopic practice of repeated sclerotherapy or ligation of varices has not made an impact on the prevention of variceal recurrence. Will cementing the free space around the obliterated varices with fibrosis (a concept tested by the application of APC in the report by Cipolletta et al.) prevent variceal recurrence? If so, why does it work? Before we address these issues, let us examine Kitano’s artwork demonstrating the minutest details of venous anatomy of the esophagus in health and in portal hypertension. This was done using microvascular resin casts. Five normal human cadavers and 5 known cases of portal hypertension with esophageal varices due to alcoholic cirrhosis were studied. Four layers of veins were identified in the
1546
SELECTED SUMMARIES
esophagus: the first layer, intra-epithelial channels drain into a superficial venous plexus, with the second layer connecting to the third layer of larger deep intrinsic veins. The first 3 layers of veins are located in the mucosa and submucosa. Both the superficial venous plexus and the deep intrinsic veins communicate directly with their counterpart veins in the stomach. In addition, perforating veins connect the deep intrinsic veins with the adventitial plexus, the fourth layer. All of these 4 layers of veins were significantly dilated in patients with portal hypertension, anywhere between 2 to 6 times compared to normal. The esophageal varices arose from the deep intrinsic veins, which communicated directly with gastric varices (Br J Surg 1986;73:525–531). After studying Kitano’s venous mapping of the esophagus, can we do any better with the endoscopic management of portal hypertension? First of all, a brief review of basic concepts of esophageal variceal development is also required. Portal hypertension and increased flow is the driving force that leads to the surfacing of the varices secondary to engorgement of microvascular channels in the submucosal free space of esophagus. Endoscopic therapy aims at obliterating the varices either by sclerosing or banding of the varices. However, neither of these endoscopic techniques is uniformly successful in the prevention of variceal recurrence because the basic pathophysiologic defect, i.e., the portal hypertension, remains unabated by endoscopic therapy. Rarely, endoscopic sclerosis of esophageal varices may open up bypass routes and lead to the development of large natural shunts (spleno-renal-caval shunts), which divert the driving force of portal hypertension away from the esophagus and prevent recurrence of varices (Gastroenterology 1989;97:421– 426). Opening up of natural shunts is not a predictable phenomenon, and one cannot rely on this mechanism to prevent recurrence of varices. Are there any other options available to prevent variceal recurrence? A close look at the Kitano’s chart provides some insights into how we can prevent resurfacing of varices after their eradication. Let me present my simplistic viewpoint—an endoscopist viewpoint—thinking like a plumber! Esophageal varices are (a) enlarged veins (b) in the submucosal space (c) opened up by portal hypertension. The pressure is transmitted transmurally through the perforating veins running across the esophageal wall and through the communicating veins between the stomach and the esophagus. Current therapeutic modalities, whether they are endoscopic, pharmacologic, or shunt therapies, address just 1 of the 3 above problems. Endoscopic therapy targets the vessels in the mucosa and submucosa directly. Both medical therapy and shunt therapy address the pressure issue. Embolization by interventional radiologists focuses on cutting off the blood flow from outside through the perforator veins. It is widely acknowledged that the current endoscopic techniques, neither sclerotherapy nor banding, on their own are successful in the prevention of recurrence of varices. Is there something else that the endoscopists can do to prevent variceal recurrence? Options are limited. One option is to cut off the blood supply from the perforator veins using endoscopic ultrasound guidance. Lahoti et al. have shown that dynamic endoscopic ultrasonography color doppler guided sclerotherapy of the esophageal perforator veins may be achieved (Gastrointest Endosc 2000;51:331– 333). Although an attractive high-tech option, this is not going to work because there too many patients with varices floating around for sonar-guided therapy. Prevention of resurfacing of varices is another option, which can be achieved by removing the surfacing zone, i.e.,
GASTROENTEROLOGY Vol. 124, No. 5
mucosa and submucosa, and replacing it with fibrous tissue. This concept of removal of the esophageal mucosa to prevent recurrence of varices, originally reported by Kitano’s group, has been left on the wayside for almost 15 years. Kitano et al. injected ethanolamine oleate into the mucosa after obliteration of the varices to create superficial ulcers in the lower esophagus as an endpoint of therapy. After total elimination of esophageal mucosa by sclerotherapy-induced ulceration, there was no recurrence of esophageal varices or bleeding over a mean follow-up of 16.3 months (range, 7–27 months; n ⫽ 119 survivors). Unfortunately, this was an uncontrolled observational study (Hepatology 1987;7:810 – 815). Furukawa et al. have evaluated the role of supplemental consolidation therapy of APC of the distal esophagus following eradication of varices with endoscopic banding. Eleven patients with esophageal varices underwent endoscopic variceal ligation. After disappearance or decrease of variceal size from F3 (largest sized varices) to F1 (straight), APC of the distal 5 centimeters of esophagus (settings, 1.8 L/min and 60 Watts) was performed. There was no recurrence of varices during a follow-up of 637.4 ⫾ 56.5 days (SD). Except for transient heartburn (73%), dysphagia (54%), and esophageal stenosis (18%) for a few days, there were no serious complications. None of the patients developed deep ulcers, and there were no other complications such as pleural effusion, mediastinitis, or pneumonia during the study (Hepatology Research 2002;23:220 –225). Nakamura et al. showed the usefulness of a combination of endoscopic variceal ligation and APC therapy in a small-randomized controlled study (Endoscopy 2001;33: 210 –215). Coming to the Cipolletta’s study, the preliminary results of APC in the prevention of variceal recurrence after band ligation are very encouraging. There was no recurrence of varices or variceal hemorrhage in the APC-treated group during a follow-up of 16 months. Neither were there any serious side effects with the consolidation therapy using APC. If these encouraging pilot data stand the test of time, this supplemental therapy will certainly become part of our routine practice because it is simple to deliver. My gut feeling is that the blockade of resurfacing of varices will certainly find its niche in endoscopic therapeutic strategies for prevention of variceal recurrence. GOTTUMUKKALA S. RAJU, M.D.
LEPTIN SIGNALING AND OBESITY: WEIGHT AND SEE Cohen P, Miyazaki M, Socci ND, Hagge-Greenberg A, Liedtke W, Soukas AA, Sharma R, Hudgins LC, Ntambi JM, Friedman JM (Laboratory of Molecular Genetics, Center for Studies in Physics and Biology, Rogosin Institute, Howard Hughes Medical Institute, The Rockefeller University, New York, New York; and Departments of Biochemistry and Nutritional Sciences, University of Wisconsin, Madison, Wisconsin). Role for stearoyl-CoA desaturase-1 in leptin-mediated weight loss. Science 2002;297:240 –243. Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, Attie AD (Departments of Biochemistry, Nutritional Sciences, Biostatistics and Medical Informatics, and Statistics and Horticulture, University of Wisconsin, Madison, Wisconsin; and Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The