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The treatment of incidental esophageal varices
GASTROENTEROLOGY 2004;127:1645–1651
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten and submitted electronically to www.gastro-central.org. Please be sure to send 2 hard copies of any figures to the editorial office.
Primary Biliary Cirrhosis in Genetically Identical Twins Dear Sir: The study by Selmi et al.1 further confirms the critical importance of inherited factors in primary biliary cirrhosis (PBC) by showing high concordance rates in their monozygotic twin pairs. A similar concordant occurrence of this chronic liver disease was recorded in twin sisters with PBC that were HLA-identical over a decade ago.2 This earlier report of genetically identical twins from Canada documented their life-long clinical course including a transient episode of childhood jaundice (both, age 10 years), possibly due to an infectious agent or shared environmental factor, followed by a long asymptomatic phase (for both, almost 40 years) in largely different geographic locales. Eventually, both became symptomatic with their liver disease, presenting independently only months apart to university teaching hospitals in different provinces (both, age 51 years). Subsequently, both died with progressive liver failure in the same year (both, age 56 years) after liver transplantations were declined for religious reasons. Although their suggestion that an international study employing inheritance by descent methodology might be useful for further definition of the genetic basis of PBC, this also may represent a unique opportunity to define the life-long clinical courses of their genetically well-documented twin pairs with PBC. This may permit comparison of possible differences in the natural clinical histories of either monozygotic or dizygotic twins with this intriguing chronic liver disease. HUGH J. FREEMAN Professor of Medicine (Gastroenterology) University of British Columbia Vancouver, British Columbia, Canada 1. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, Gordon SC, Wright HI, Zweiban B, Podda M, Gershwin ME. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004;127:485– 492. 2. Freeman HJ, Bailey RJ. Primary biliary cirrhosis in HLA-identical twin sisters. Can J Gastroenterol 1994;8:88 –91. doi:10.1053/j.gastro.2004.08.044
Reply. We are grateful to Dr. Freeman for bringing to our attention his 1994 report of an additional HLA-identical twin set that was concordant for PBC, particularly since his manuscript/ data could not be found on PubMed. Even though Dr. Freeman’s conclusion agrees with ours, we should note that his definition of zygosity was based solely on HLA, while we used more extensive molecular methods for zygosity determination in our recent paper.1 Importantly, however, the observation by Dr. Freeman prompts us to renew our belief that a worldwide effort in collecting larger numbers of twins would allow a better estimation of concordance rates in such unique patients and of epigenetic influ-
ence on disease susceptibility. Lastly, since acceptance of our manuscript we became aware of one additional dizygotic twin set that was as expected discordant for PBC. CARLO SELMI, MD, PhD M. ERIC GERSHWIN, MD Division of Rheumatology Allergy and Clinical Immunology University of California Davis, California Division of Internal Medicine Department of Medicine, Surgery, and Dentistry San Paolo School of Medicine University of Milan Milan, Italy 1. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, Gordon SC, Wright HI, Zweiban B, Podda M, Gershwin ME. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004;127:485– 492. doi:10.1053/j.gastro.2004.08.044
The Treatment of Incidental Esophageal Varices Dear Sir: We read with interest the review article by De Franchis that was published in the June 2004 issue of GASTROENTEROLOGY.1 This review article has updated recent advances in the prophylaxis of esophageal varices that have never bled. We would like to address some comments on this issue. Dr. De Franchis listed the mechanisms of action of treatments for portal hypertension in Table 3 and concluded that endoscopic treatments aimed at obliterating the varices without influencing portal pressure. Actually, an increase of portal pressure has been noted in approximately 70% of patients receiving chronic endoscopic sclerotherapy or banding ligation to prevent rebleeding.2–3 This is the rationale underlying the combination of banding ligation with -blockers to prevent variceal rebleeding.4 Although the portal pressure was measured in patients who have bled from esophageal varices, we believe that similar impact on the portal pressure may occur after endoscopic therapy for prophylaxis of first bleed from esophageal varices. It is well accepted that high-risk esophageal varices should receive prophylactic therapy to prevent first variceal bleed. De Franchis suggested to start with -blockers if there are no contraindications. If the patient has a contraindication to -blockers or cannot tolerate side effects or is unwilling to embark in a lifelong treatment, banding ligation would be offered. Currently, this approach is very reasonable and acceptable by both the patients and gastroenterologists. However, not all patients with high-risk esophageal varices should receive either -blockers or banding ligation to prevent first variceal bleed. As we all know, patients of Child–Pugh’s C class are predisposed to a high risk of variceal bleeding5 and hepatic failure. Decompensated cir-
1646
CORRESPONDENCE
rhotic patients should be evaluated for the possibility of liver transplantation.6 Most studies that evaluate risk of first variceal bleeding generally excluded those patients with high Child–Pugh’s scores.7–9 No study has ever been carried out to investigate which therapy is suitable for preventing first variceal bleeding in patients with a high Child–Pugh’s score. Hemodynamic studies have suggested that propranolol has little effect in patients with advanced cirrhosis.10 Also, the safety of banding ligation in Child class C patients has been questioned.11 Thus, cirrhotic patients associated with high-risk esophageal varices and signs of impending hepatic failure, such as hepatorenal syndrome, deep jaundice, refractory ascites, severe hepatic encephalopathy, or advanced hepatocellular carcinoma with main portal vein thrombosis, the safety and effectiveness of employing either -blockers or banding ligation should be seriously considered. GIN-HO LO, MD KWOK-HUNG LAI, MD Division of Gastroenterology Department of Medicine Kaohsiung Veterans General Hospital National Yang-Ming University Kaohsiung, Taiwan 1. De Franchis R. Incidental esophageal varices. Gastroenterology 2004;126:1860 –1867. 2. Korula J, Ralls P. The effects of chronic endoscopic variceal sclerotherapy on portal pressure in cirrhotics. Gastroenterology 1991;101:800 – 805. 3. Lo GH, Liang HL, Lai KH, Chang CF, Hwu JH, Chen SM, Lin CK, Chiang HT. The impact of endoscopic variceal ligation on the pressure of the portal venous system. J Hepatol 1996;24:74 – 80. 4. Lo GH, Lai KH, Cheng JS, Chen MH, Huang HC, Hsu PI, Lin CK. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000;32:461– 465. 5. North Italian Endoscopic Club for the study and treatment of esophageal varices. Prediction of first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1988;319:983–989. 6. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001;345:669 – 681. 7. Conn HO, Grace ND, Bosch J, Groszmann RJ, Rodes J, Wright SC, Maltoff DS, Garcia-Tsao G, Fisher RL, Navasa M, Drewniak SJ, Atterbury CE, Bodas JM, Lerner E, Bramante C. Propranolol in the prevention of the first hemorrhage from esophagogastric varices: a multicenter, randomized clinical trial. Hepatology 1991;13: 902–912. 8. Lo GH, Chen WC, Chen MH, Lin CP, Lo CC, Hsu PI, Cheng JS, Lai KH. Endoscopic ligation versus nadolol in the prophylaxis of first variceal bleeding in cirrhosis. Gastrointest Endosc 2004;59: 333–338. 9. Lo GH, Lai KH, Cheng JS, Lin CK, Hsu PI, Chiang HT. Prophylactic banding ligation of high-risk esophageal varices in patients with cirrhosis: a prospective, randomized trial. J Hepatol 1999;31: 451– 456. 10. Colman JC, Jennings GL, McLean AJ, Mignot PR, Dudley FJ. Propranolol in decompensated alcoholic cirrhosis. Lancet 1982; 2:1040 –1041. 11. Van Vlierberghe H, De Vos M, Hautekeete M, Elewaut A. Severe bleeding following endoscopic variceal ligation: should EVL be avoided in Child C patients? Acta Gastroenterol Belg 1999;62: 175–177. doi:10.1053/j.gastro.2004.04.030
GASTROENTEROLOGY Vol. 127, No. 5
Reply. I am glad my review article interested Drs. Lo and Lai. Concerning the points they raise: (1) Effect of endoscopic treatments on portal pressure: very little data exist on the effect of variceal sclerotherapy and band ligation on portal pressure. The available studies1,2 show that both an increase and a decrease may occur after variceal eradication by sclerotherapy or band ligation, although an increase is observed in about two thirds of patients. Concerning band ligation, statistical analysis of the data by Drs. Lo and Lai2 shows that the differences observed are not statistically significant, both when all patients are analyzed together and when separate analyses are made for the patients in whom the pressure increased and for those in whom it decreased. Thus, the conclusion remains that band ligation does not influence significantly portal pressure. At any rate, the meaning of my sentence was that endoscopic methods are not intended to prevent bleeding by influencing portal pressure. (2) Concerning the statement that -blockers may not be effective in Child–Pugh C patients, this is contrary to the conclusion of a meta-analysis carried out on individual patients data by Poynard et al.3, which showed that the efficacy of -blockers is independent of the degree of liver decompensation. The statement that “no study has ever been carried out to investigate which therapy is suitable for preventing the first variceal bleeding in patients with a high Child– Pugh score” is incorrect: indeed, we have carried out a trial comparing nadolol and Isosorbide-5 mononitrate in patients with decompensated cirrhosis,4 and have shown that nadolol is effective in these patients. In addition, Child–Pugh class C patients were included in all studies of prophylactic band ligation, although no trial of primary prophylaxis with this form of treatment has been carried out specifically in decompensated patients. We all agree that patients with severe liver decompensation should be considered for transplantation; however, the clinical vignette that formed the basis for the review was about a patient in whom varices were incidentally discovered. The overwhelming majority of such patients has a well-preserved liver function, and thus are not candidates for transplantation. ROBERTO DE FRANCHIS University of Milano Department of Internal Medicine Milano, Italy 1. Korula J, Ralls P. The effects of chronic endoscopic variceal sclerotherapy on portal pressure in cirrhotics. Gastroenterology 1991; 101:800 – 805. 2. Lo GH, Liang HL, Lai KH, Chang CF, Hwu JH, Chen SM, Lin CK, Chiang HT. The impact of endoscopic variceal ligation on the pressure of the portal venous system. J Hepatol 1996;24:74 – 80. 3. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, Lebrec D. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group. N Engl J Med 1991;324:1532–1538. 4. Borroni G, Salerno F, Cazzaniga M, Bissoli F, Lorenzano E, Maggi A, et al. Nadolol is superior to isosorbide mononitrate for the prevention of the first variceal bleeding in cirrhotic patients with ascites. J Hepatol 2002;37:315–321. doi:10.1053/j.gastro.2004.09.067
CORRESPONDENCE Readers are encouraged to write letters to the editor concerning articles that have been published in GASTROENTEROLOGY. Short, general comments are also considered, but use of the Correspondence section for publication of original data in preliminary form is not encouraged. Letters should be typewritten and submitted electronically to www.gastro-central.org. Please be sure to send 2 hard copies of any figures to the editorial office.
Primary Biliary Cirrhosis in Genetically Identical Twins Dear Sir: The study by Selmi et al.1 further confirms the critical importance of inherited factors in primary biliary cirrhosis (PBC) by showing high concordance rates in their monozygotic twin pairs. A similar concordant occurrence of this chronic liver disease was recorded in twin sisters with PBC that were HLA-identical over a decade ago.2 This earlier report of genetically identical twins from Canada documented their life-long clinical course including a transient episode of childhood jaundice (both, age 10 years), possibly due to an infectious agent or shared environmental factor, followed by a long asymptomatic phase (for both, almost 40 years) in largely different geographic locales. Eventually, both became symptomatic with their liver disease, presenting independently only months apart to university teaching hospitals in different provinces (both, age 51 years). Subsequently, both died with progressive liver failure in the same year (both, age 56 years) after liver transplantations were declined for religious reasons. Although their suggestion that an international study employing inheritance by descent methodology might be useful for further definition of the genetic basis of PBC, this also may represent a unique opportunity to define the life-long clinical courses of their genetically well-documented twin pairs with PBC. This may permit comparison of possible differences in the natural clinical histories of either monozygotic or dizygotic twins with this intriguing chronic liver disease. HUGH J. FREEMAN Professor of Medicine (Gastroenterology) University of British Columbia Vancouver, British Columbia, Canada 1. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, Gordon SC, Wright HI, Zweiban B, Podda M, Gershwin ME. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004;127:485– 492. 2. Freeman HJ, Bailey RJ. Primary biliary cirrhosis in HLA-identical twin sisters. Can J Gastroenterol 1994;8:88 –91. doi:10.1053/j.gastro.2004.08.044
Reply. We are grateful to Dr. Freeman for bringing to our attention his 1994 report of an additional HLA-identical twin set that was concordant for PBC, particularly since his manuscript/ data could not be found on PubMed. Even though Dr. Freeman’s conclusion agrees with ours, we should note that his definition of zygosity was based solely on HLA, while we used more extensive molecular methods for zygosity determination in our recent paper.1 Importantly, however, the observation by Dr. Freeman prompts us to renew our belief that a worldwide effort in collecting larger numbers of twins would allow a better estimation of concordance rates in such unique patients and of epigenetic influ-
ence on disease susceptibility. Lastly, since acceptance of our manuscript we became aware of one additional dizygotic twin set that was as expected discordant for PBC. CARLO SELMI, MD, PhD M. ERIC GERSHWIN, MD Division of Rheumatology Allergy and Clinical Immunology University of California Davis, California Division of Internal Medicine Department of Medicine, Surgery, and Dentistry San Paolo School of Medicine University of Milan Milan, Italy 1. Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish RG, Gordon SC, Wright HI, Zweiban B, Podda M, Gershwin ME. Primary biliary cirrhosis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology 2004;127:485– 492. doi:10.1053/j.gastro.2004.08.044
The Treatment of Incidental Esophageal Varices Dear Sir: We read with interest the review article by De Franchis that was published in the June 2004 issue of GASTROENTEROLOGY.1 This review article has updated recent advances in the prophylaxis of esophageal varices that have never bled. We would like to address some comments on this issue. Dr. De Franchis listed the mechanisms of action of treatments for portal hypertension in Table 3 and concluded that endoscopic treatments aimed at obliterating the varices without influencing portal pressure. Actually, an increase of portal pressure has been noted in approximately 70% of patients receiving chronic endoscopic sclerotherapy or banding ligation to prevent rebleeding.2–3 This is the rationale underlying the combination of banding ligation with -blockers to prevent variceal rebleeding.4 Although the portal pressure was measured in patients who have bled from esophageal varices, we believe that similar impact on the portal pressure may occur after endoscopic therapy for prophylaxis of first bleed from esophageal varices. It is well accepted that high-risk esophageal varices should receive prophylactic therapy to prevent first variceal bleed. De Franchis suggested to start with -blockers if there are no contraindications. If the patient has a contraindication to -blockers or cannot tolerate side effects or is unwilling to embark in a lifelong treatment, banding ligation would be offered. Currently, this approach is very reasonable and acceptable by both the patients and gastroenterologists. However, not all patients with high-risk esophageal varices should receive either -blockers or banding ligation to prevent first variceal bleed. As we all know, patients of Child–Pugh’s C class are predisposed to a high risk of variceal bleeding5 and hepatic failure. Decompensated cir-
1646
CORRESPONDENCE
rhotic patients should be evaluated for the possibility of liver transplantation.6 Most studies that evaluate risk of first variceal bleeding generally excluded those patients with high Child–Pugh’s scores.7–9 No study has ever been carried out to investigate which therapy is suitable for preventing first variceal bleeding in patients with a high Child–Pugh’s score. Hemodynamic studies have suggested that propranolol has little effect in patients with advanced cirrhosis.10 Also, the safety of banding ligation in Child class C patients has been questioned.11 Thus, cirrhotic patients associated with high-risk esophageal varices and signs of impending hepatic failure, such as hepatorenal syndrome, deep jaundice, refractory ascites, severe hepatic encephalopathy, or advanced hepatocellular carcinoma with main portal vein thrombosis, the safety and effectiveness of employing either -blockers or banding ligation should be seriously considered. GIN-HO LO, MD KWOK-HUNG LAI, MD Division of Gastroenterology Department of Medicine Kaohsiung Veterans General Hospital National Yang-Ming University Kaohsiung, Taiwan 1. De Franchis R. Incidental esophageal varices. Gastroenterology 2004;126:1860 –1867. 2. Korula J, Ralls P. The effects of chronic endoscopic variceal sclerotherapy on portal pressure in cirrhotics. Gastroenterology 1991;101:800 – 805. 3. Lo GH, Liang HL, Lai KH, Chang CF, Hwu JH, Chen SM, Lin CK, Chiang HT. The impact of endoscopic variceal ligation on the pressure of the portal venous system. J Hepatol 1996;24:74 – 80. 4. Lo GH, Lai KH, Cheng JS, Chen MH, Huang HC, Hsu PI, Lin CK. Endoscopic variceal ligation plus nadolol and sucralfate compared with ligation alone for the prevention of variceal rebleeding: a prospective, randomized trial. Hepatology 2000;32:461– 465. 5. North Italian Endoscopic Club for the study and treatment of esophageal varices. Prediction of first variceal hemorrhage in patients with cirrhosis of the liver and esophageal varices. N Engl J Med 1988;319:983–989. 6. Sharara AI, Rockey DC. Gastroesophageal variceal hemorrhage. N Engl J Med 2001;345:669 – 681. 7. Conn HO, Grace ND, Bosch J, Groszmann RJ, Rodes J, Wright SC, Maltoff DS, Garcia-Tsao G, Fisher RL, Navasa M, Drewniak SJ, Atterbury CE, Bodas JM, Lerner E, Bramante C. Propranolol in the prevention of the first hemorrhage from esophagogastric varices: a multicenter, randomized clinical trial. Hepatology 1991;13: 902–912. 8. Lo GH, Chen WC, Chen MH, Lin CP, Lo CC, Hsu PI, Cheng JS, Lai KH. Endoscopic ligation versus nadolol in the prophylaxis of first variceal bleeding in cirrhosis. Gastrointest Endosc 2004;59: 333–338. 9. Lo GH, Lai KH, Cheng JS, Lin CK, Hsu PI, Chiang HT. Prophylactic banding ligation of high-risk esophageal varices in patients with cirrhosis: a prospective, randomized trial. J Hepatol 1999;31: 451– 456. 10. Colman JC, Jennings GL, McLean AJ, Mignot PR, Dudley FJ. Propranolol in decompensated alcoholic cirrhosis. Lancet 1982; 2:1040 –1041. 11. Van Vlierberghe H, De Vos M, Hautekeete M, Elewaut A. Severe bleeding following endoscopic variceal ligation: should EVL be avoided in Child C patients? Acta Gastroenterol Belg 1999;62: 175–177. doi:10.1053/j.gastro.2004.04.030
GASTROENTEROLOGY Vol. 127, No. 5
Reply. I am glad my review article interested Drs. Lo and Lai. Concerning the points they raise: (1) Effect of endoscopic treatments on portal pressure: very little data exist on the effect of variceal sclerotherapy and band ligation on portal pressure. The available studies1,2 show that both an increase and a decrease may occur after variceal eradication by sclerotherapy or band ligation, although an increase is observed in about two thirds of patients. Concerning band ligation, statistical analysis of the data by Drs. Lo and Lai2 shows that the differences observed are not statistically significant, both when all patients are analyzed together and when separate analyses are made for the patients in whom the pressure increased and for those in whom it decreased. Thus, the conclusion remains that band ligation does not influence significantly portal pressure. At any rate, the meaning of my sentence was that endoscopic methods are not intended to prevent bleeding by influencing portal pressure. (2) Concerning the statement that -blockers may not be effective in Child–Pugh C patients, this is contrary to the conclusion of a meta-analysis carried out on individual patients data by Poynard et al.3, which showed that the efficacy of -blockers is independent of the degree of liver decompensation. The statement that “no study has ever been carried out to investigate which therapy is suitable for preventing the first variceal bleeding in patients with a high Child– Pugh score” is incorrect: indeed, we have carried out a trial comparing nadolol and Isosorbide-5 mononitrate in patients with decompensated cirrhosis,4 and have shown that nadolol is effective in these patients. In addition, Child–Pugh class C patients were included in all studies of prophylactic band ligation, although no trial of primary prophylaxis with this form of treatment has been carried out specifically in decompensated patients. We all agree that patients with severe liver decompensation should be considered for transplantation; however, the clinical vignette that formed the basis for the review was about a patient in whom varices were incidentally discovered. The overwhelming majority of such patients has a well-preserved liver function, and thus are not candidates for transplantation. ROBERTO DE FRANCHIS University of Milano Department of Internal Medicine Milano, Italy 1. Korula J, Ralls P. The effects of chronic endoscopic variceal sclerotherapy on portal pressure in cirrhotics. Gastroenterology 1991; 101:800 – 805. 2. Lo GH, Liang HL, Lai KH, Chang CF, Hwu JH, Chen SM, Lin CK, Chiang HT. The impact of endoscopic variceal ligation on the pressure of the portal venous system. J Hepatol 1996;24:74 – 80. 3. Poynard T, Cales P, Pasta L, Ideo G, Pascal JP, Pagliaro L, Lebrec D. Beta-adrenergic-antagonist drugs in the prevention of gastrointestinal bleeding in patients with cirrhosis and esophageal varices. An analysis of data and prognostic factors in 589 patients from four randomized clinical trials. Franco-Italian Multicenter Study Group. N Engl J Med 1991;324:1532–1538. 4. Borroni G, Salerno F, Cazzaniga M, Bissoli F, Lorenzano E, Maggi A, et al. Nadolol is superior to isosorbide mononitrate for the prevention of the first variceal bleeding in cirrhotic patients with ascites. J Hepatol 2002;37:315–321. doi:10.1053/j.gastro.2004.09.067