- Email: [email protected]
Preventing Variceal Bleeding in Infants and Children: Is Less More?
Editorial 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54
Preventing Variceal Bleeding in Infants and Children: Is Less More? See “Experience with endoscopic management of high-risk gastroesophageal varices with and without bleeding in children with biliary atresia,” by Duche M, Ducot B, Ackermann O, et al, on page 000.
I
n this issue of GASTROENTEROLOGY, Duche et al1 report their retrospective experience with endoscopic management of esophageal varices in 66 young children (mean age, <2 years old) with biliary atresia and portal hypertension: 36 who had never bled undergoing preventative endoscopic management (primary prophylaxis), and 30 who had a prior variceal bleed and were undergoing endoscopic secondary prophylaxis. After 4–5 sessions of endoscopic variceal band ligation (EVL; or sclerotherapy early in the study and in children < w8 kg), none of the children receiving primary prophylaxis bled after eradication of varices and only 10% of the secondary prophylaxis group had breakthrough bleeding. Varices could not be eradicated in about 25% of both groups. Early bleeding during treatment occurred in 6% of the primary prophylaxis group and 17% of the secondary prophylaxis group. Of the primary prophylaxis group, 58% underwent liver transplantation, whereas 76% of the secondary prophylaxis group was transplanted. Varices reappeared in about 40% in both groups. Based on these data, the authors recommend screening endoscopy and primary prophylaxis with endoscopic therapy in children with high-risk varices (Figure 1). Adult guidelines for the management of esophageal varices in patients with cirrhosis are clear and are predicated on reducing the morbidity and mortality of variceal bleeding.2 Screening endoscopy for varices is recommended upon diagnosis of cirrhosis. In the patient who has never bled, if small varices are present, along with bleeding risk factors such as Child’s class B/C or red wale marks on varices, nonselective b-blocker prophylaxis is recommended. When large varices are seen, b-blockers or EVL are recommended for those with bleeding risk factors, whereas b-blockers are preferred for those without risk factors. b-Blockers are titrated to the maximum tolerated dose. In the adult patient who has already had an esophageal variceal hemorrhage, secondary prophylaxis with combination therapy—a b-blocker and EVL—is recommended, with close endoscopic follow-up. Transjugular intrahepatic portosystemic shunting (or even surgical shunting) is recommended in Child’s A/B patients who continue bleeding despite prophylaxis. Large, randomized, controlled trials and meta-analyses have studied these issues. For example, a 1999
meta-analysis including 1189 patients showed a bleeding rate of 30% among patients who did not receive primary prophylaxis and 14% in patients who received b-blockers.3 A 2005 meta-analysis including 600 adult cirrhotics who had never bled demonstrated a lower bleeding rate when treated with EVL instead of propranolol, with fewer adverse events but similar mortality.4 In a more recent meta-analysis evaluating randomized, controlled trials including 1860 adult cirrhotics with a history of variceal bleeding, combination therapy with a b-blocker and band ligation was superior to band ligation alone in preventing rebleeding.5 Pediatric data on management of varices (especially primary prophylaxis), in contrast, are limited. The diseases that cause cirrhosis in children differ from those that cause it in adults; more than half of childhood cirrhotics have biliary atresia, developing cirrhosis and portal hypertension in the first years of life, often but not always after the Kasai operation fails to achieve adequate bile flow. Evolving investigations have identified “prediction rules” using platelets, spleen size, and albumin that are fairly accurate in predicting the presence or absence of varices.6–8 Recent studies have also provided initial descriptions of variceal appearance and subsequent risk of hemorrhage in children.9,10 Although it is clear that endoscopic primary prophylaxis of varices in children is feasible, screening endoscopy is not universally recommended or implemented in children.11 Limited data indicate that as many as 70%–90% of children with biliary atresia, often in the first years of life, do have varices when endoscopy is performed.9,10 Twenty to thirty percent (or more) of children with biliary atresia have variceal bleeding, often early in their lives9,10,12,13; some of these children have ascites and other evidence of end-stage liver disease, whereas others have preserved synthetic function and normal bilirubin. Experienced pediatric hepatologists acknowledge that death from first variceal bleeding in children is rare; in several small published series, death from uncontrolled bleeding is 2%–5%, with additional mortality owing to underlying liver disease in more children.10,14–17 To date, information on prophylaxis of gastrointestinal bleeding in children is scarce. In contrast with the experience in adults, studies of propranolol prophylaxis are extremely limited, uncontrolled, and not convincingly effective.18 Appropriate pediatric dosing of propranolol and its effects on hemodynamics in children are unknown. The pediatric literature on primary endoscopic prophylaxis includes sclerotherapy and EVL, including 1 randomized, controlled trial (100 children), which demonstrated the possibility of achieving a lower rate of bleeding in those undergoing sclerotherapy compared with controls.18,19 No GASTROENTEROLOGY 2013;-:1–4
EDI 5.2.0 DTD YGAST58621_proof 22 August 2013 6:20 pm ce
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108
109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163
print & web 4C=FPO
Editorial, continued
Figure 1. Outcome of primary and secondary prophylaxis of variceal bleeding in 66 children with portal hypertension.
effect on mortality could be shown in that study. A number of small case series of children who have already undergone a variceal bleed report a low rate of rebleeding after EVL.20 A randomized, controlled trial in 49 children comparing sclerotherapy to EVL showed rebleeding in 25% versus 4%.21 Esophageal perforation, ulceration, and stricture formation have been reported after endoscopic treatment of varices in children.10,22 Notably, general anesthesia is usually required in children, and smaller children (<2 years old) have required sclerotherapy with its attendant morbidity. Although data are limited, most pediatric hepatologists would agree that secondary prophylaxis of the child who has had a variceal hemorrhage is reasonable, given the historically high rebleeding rate and the excellent adult data in support of it. Primary prophylaxis in children deserves more debate, however. The findings reported in this issue of GASTROENTEROLOGY’s young (but heterogeneous) group of biliary atresia infants may not be generalizable to other cirrhotic conditions of childhood (or to extrahepatic portal vein obstruction, which is not addressed in this editorial). These children had a mean bilirubin of >10 mg/dL, and 20% had ascites; these parameters would be expected to be associated with a greater risk of bleeding and perhaps greater mortality.12,23–25 A very experienced endoscopist performed the procedures while administering octreotide during an average of four 3-day hospitalizations. Two of the children bled during the process of eliminating the varices,
possibly from ulcers induced by the procedure. Serious complications of EVL were not reported in this group. Within an average of 14 months, more than half of both groups of children undergoing primary prophylaxis and secondary prophylaxis were transplanted. Varices could not be eradicated in one quarter of the children. The recurrence of varices after eradication was very high at 37%. From this perspective, several factors must be considered in evaluating the merits of primary prophylaxis of variceal bleeding in children. Foremost, the risk of mortality of children with a first variceal bleed is low (see references above), partly because underlying liver disease may be well-compensated at onset of bleeding and because comorbidities typically seen in adults are often absent. The risks of endoscopic treatment in children may exceed those in adults; these uncommonly performed procedures in small patients require general anesthesia, multiple procedures, and sometimes sclerotherapy, not to mention a 3-day hospital admission in the present report. We need to weigh the risks and benefits of multiple procedures in a nonbleeding child who may not bleed for years, when varices have a high chance of recurring and transplant is frequently imminent.13,24 Because mortality from gastrointestinal bleeding in children is quite low (zero in this small study), we may need to consider a “wait and watch” approach, taking other issues such as other features of advancing liver disease, failure to thrive, neurodevelopmental impact, and fat-soluble vitamin deficiencies into consideration when weighing primary prophylaxis of variceal bleeding versus more aggressive transplantation. For example, if a failed Kasai operation is an indication for transplantation, the issue of primary prophylaxis may become moot. These considerations argue against a recommendation of routine screening endoscopy and/or primary endoscopic prophylactic therapy for children with biliary atresia, cirrhosis, and portal hypertension. After a first variceal bleed, secondary endoscopic prophylaxis can be initiated, with prompt listing for liver transplantation for those children in whom hepatic decompensation is present or imminent (eg, in the setting of a failed Kasai procedure). This study highlights the need for future research in pediatric liver disease. Liver diseases in childhood are often mechanistically different from those in adulthood; pathophysiologic mechanisms of fibrosis and angiogenesis may differ.26 Unanswered questions include: (1) Which children are at most risk for bleeding and for worse outcomes after bleeding? Ideally, those children who will bleed would be identified noninvasively and parameters such as bilirubin and ascites can indicate increased morbidity of bleeding.12,27 (2) Is EVL effective in preventing first bleeding in children and more importantly what is the impact of this on long-term outcome? A randomized, controlled trial would be ideal, but the
2 EDI 5.2.0 DTD YGAST58621_proof 22 August 2013 6:20 pm ce
164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218
Editorial, continued 219 220 221 222 223 224 225 226 227 228 229 230 231 Q1 232 233 234 235 236 237 238 239 240 241 242 Q3 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 Q2 261 262 263 264 265 266 267 268 269 270 271 272 273
numerous obstacles to such a solution include the rarity of the condition, lack of standardization as to EVL schedule, and difficulties in recruitment.18 We need to determine whether the risk/benefit ratio truly favors proceeding with EVL in these children who have never experienced a variceal hemorrhage. It will also be important to study whether gastric and ectopic varices then become problematic in children who have had eradication of esophageal varices. (3) Which children would be better served by undergoing liver transplantation, avoiding an expensive and risky series of endoscopies? The trite adage is that children are not just small adults; indeed, we need to know how to manage portal hypertension in children. Given the limitations in pediatric research, creative trial designs are necessary to address this important question. Even multicenter research networks like the Cholestatic Liver Diseases Research and Education Network (ChiLDREN), following >1000 children with biliary atresia, face enormous obstacles to studying portal hypertension and its management. And yet, this kind of collaboration is the only way to determine if therapies so clearly effective when studied in hundreds of adults can be safely applied to helping children.
JEAN PAPPAS MOLLESTON Department of Clinical Pediatrics Pediatric Gastroenterology, Hepatology and Nutrition Indiana University School of Medicine Riley Hospital for Children Indianapolis, Indiana BENJAMIN L. SHNEIDER Department of Pediatrics, Pediatric Hepatology University of Pittsburgh of UPMC Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20. 21.
References 1. Duche M, Ducot B, Ackermann O, et al. Experience with endoscopic management of high-risk gastroesophageal varices with and without bleeding in children with biliary atresia. Gastroenterology 2013;145: 000–000. 2. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922–938. 3. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999; 19:475–505. 4. Khuroo MS, Khuroo NS, Farahat KL, et al. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding. Aliment Pharmacol Ther 2005;21:347–361. 5. Gonzalez R, Zamora J, Gomez-Camarero J, et al. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109–1022. 6. Fagundes ED, Ferreira AR, Roquete ML, et al. Clinical and laboratory predictors of esophageal varices in children and adolescents with
22.
23.
24.
25.
26.
portal hypertension syndrome. J Pediatr Gastroenterol Nutr 2008; 46:178–183. Gana JC, Turner D, Mieli-Vergani G, et al. A clinical prediction rule and platelet count predict esophageal varices in children. Gastroenterology 2011;141:2009–2016. Adami MR, Ferreira CT, Kieling CO, et al. Noninvasive methods for prediction of esophageal varices in pediatric patients with portal hypertension. World J Gastroenterol 2013;19:2053–2059. Duche M, Ducot B, Tournay E, et al. Prognostic value of endoscopy in children with biliary atresia at risk for early development of varices and bleeding. Gastroenterology 2010;139:1952–1960. Wanty C, Helleputte T, Smets F, et al. Assessment of risk of bleeding from esophageal varices during management of biliary atresia in children. J Pediatr Gastroenterol Nutr 2013;56:537–543. Shneider BL, Bosch J, de Franchis R, et al. Portal hypertension in children: expert pediatric opinion on the report of the Baveno v Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension. Pediatr Transplant 2012;16:426–437. Miga D, Sokol RJ, Mackenzie T, et al. Survival after first esophageal variceal hemorrhage in patients with biliary atresia. J Pediatr 2001; 139:291–296. Shneider BL, Abel B, Haber B, et al. Portal hypertension in children and young adults with biliary atresia. J Pediatr Gastroenterol Nutr 2012;55:567–573. Eroglu Y, Emerick KM, Whitingon PF, et al. Octreotide therapy for control of acute gastrointestinal bleeding in children. J Pediatr Gastroenterol Nutr 2004;38:41–47. Stringer MD, Howard ER, Mowat AP. Endoscopic sclerotherapy in the management of esophageal varices in 61 children with biliary atresia. J Pediatr Surg 1989;24:438–442. Howard ER, Stringer MD, Mowat AP. Assessment of injection sclerotherapy in the management of 152 children with oesophageal varices. Br J Surg 1988;75:404–408. Miloh T, Kratimenos P, Shneider B, et al. Acute variceal bleeding in children: single center experience [abstract]. Hepatology 2010; 52:260A. Ling SC, Walters T, McKiernan PJ, et al. Primary prophylaxis of variceal hemorrhage in children with portal hypertension: a framework for future research. J Pediatr Gastroenterol Nutr 2011;52:254–261. Goncalves ME, Cardoso SR, Maksoud JG. Prophylactic sclerotherapy in children with esophageal varices: long-term results of a controlled prospective randomized trial. J Pediatr Surg 2000;35:401–405. Molleston JP. Variceal bleeding in children. J Pediatr Gastroenterol Nutr 2003;37:538–545. Zargar SA, Javid G, Khan BA, et al. Endoscopic ligation compared with sclerotherapy for bleeding esophageal varices in children with extrahepatic portal venous obstruction. Hepatology 2002;36: 666–672. Poddar U, Thapa BR, Singh K. Endoscopic sclerotherapy in children: experience with 257 cases of extrahepatic portal venous obstruction. Gastrointest Endosc 2003;57:683–686. Lampela H, Kosola S, Koivusalo A, et al. Endoscopic surveillance and primary prophylaxis sclerotherapy of esophageal varices in biliary atresia. J Pediatr Gastroenterol Nutr 2012;55:574–579. Shneider BL, Brown MB, Haber B, et al. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr 2006;148:467–474. Shneider B, Magee J, Karpen S, et al. Prospective multicenter analysis of post-operative total bilirubin as a biomarker for shortterm outcome after hepatoportoenterostomy for biliary atresia [abstract]. Hepatology 2011;54:114A. Fernandez M, Mejias M, Garcia-Pras E, et al. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology 2007;46:1208–1217. 3
EDI 5.2.0 DTD YGAST58621_proof 22 August 2013 6:20 pm ce
274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328
Editorial, continued 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383
27. Gana JC, Turner D, Avitzur Y, et al. Prediction of esophageal variceal bleeding in children [abstract]. Gastroenterology 2009;136:A825.
Hospital for Children, 705 Riley Hospital Drive – ROC 4210, Indianapolis, Indiana 46202. e-mail: [email protected].
Reprint requests Address requests for reprints to: Jean Pappas Molleston, MD, Professor of Clinical Pediatrics, Director, Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Riley
Conflicts of interest The author discloses no conflicts. © 2013 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2013.08.026
4 EDI 5.2.0 DTD YGAST58621_proof 22 August 2013 6:20 pm ce
384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438
Preventing Variceal Bleeding in Infants and Children: Is Less More? See “Experience with endoscopic management of high-risk gastroesophageal varices with and without bleeding in children with biliary atresia,” by Duche M, Ducot B, Ackermann O, et al, on page 000.
I
n this issue of GASTROENTEROLOGY, Duche et al1 report their retrospective experience with endoscopic management of esophageal varices in 66 young children (mean age, <2 years old) with biliary atresia and portal hypertension: 36 who had never bled undergoing preventative endoscopic management (primary prophylaxis), and 30 who had a prior variceal bleed and were undergoing endoscopic secondary prophylaxis. After 4–5 sessions of endoscopic variceal band ligation (EVL; or sclerotherapy early in the study and in children < w8 kg), none of the children receiving primary prophylaxis bled after eradication of varices and only 10% of the secondary prophylaxis group had breakthrough bleeding. Varices could not be eradicated in about 25% of both groups. Early bleeding during treatment occurred in 6% of the primary prophylaxis group and 17% of the secondary prophylaxis group. Of the primary prophylaxis group, 58% underwent liver transplantation, whereas 76% of the secondary prophylaxis group was transplanted. Varices reappeared in about 40% in both groups. Based on these data, the authors recommend screening endoscopy and primary prophylaxis with endoscopic therapy in children with high-risk varices (Figure 1). Adult guidelines for the management of esophageal varices in patients with cirrhosis are clear and are predicated on reducing the morbidity and mortality of variceal bleeding.2 Screening endoscopy for varices is recommended upon diagnosis of cirrhosis. In the patient who has never bled, if small varices are present, along with bleeding risk factors such as Child’s class B/C or red wale marks on varices, nonselective b-blocker prophylaxis is recommended. When large varices are seen, b-blockers or EVL are recommended for those with bleeding risk factors, whereas b-blockers are preferred for those without risk factors. b-Blockers are titrated to the maximum tolerated dose. In the adult patient who has already had an esophageal variceal hemorrhage, secondary prophylaxis with combination therapy—a b-blocker and EVL—is recommended, with close endoscopic follow-up. Transjugular intrahepatic portosystemic shunting (or even surgical shunting) is recommended in Child’s A/B patients who continue bleeding despite prophylaxis. Large, randomized, controlled trials and meta-analyses have studied these issues. For example, a 1999
meta-analysis including 1189 patients showed a bleeding rate of 30% among patients who did not receive primary prophylaxis and 14% in patients who received b-blockers.3 A 2005 meta-analysis including 600 adult cirrhotics who had never bled demonstrated a lower bleeding rate when treated with EVL instead of propranolol, with fewer adverse events but similar mortality.4 In a more recent meta-analysis evaluating randomized, controlled trials including 1860 adult cirrhotics with a history of variceal bleeding, combination therapy with a b-blocker and band ligation was superior to band ligation alone in preventing rebleeding.5 Pediatric data on management of varices (especially primary prophylaxis), in contrast, are limited. The diseases that cause cirrhosis in children differ from those that cause it in adults; more than half of childhood cirrhotics have biliary atresia, developing cirrhosis and portal hypertension in the first years of life, often but not always after the Kasai operation fails to achieve adequate bile flow. Evolving investigations have identified “prediction rules” using platelets, spleen size, and albumin that are fairly accurate in predicting the presence or absence of varices.6–8 Recent studies have also provided initial descriptions of variceal appearance and subsequent risk of hemorrhage in children.9,10 Although it is clear that endoscopic primary prophylaxis of varices in children is feasible, screening endoscopy is not universally recommended or implemented in children.11 Limited data indicate that as many as 70%–90% of children with biliary atresia, often in the first years of life, do have varices when endoscopy is performed.9,10 Twenty to thirty percent (or more) of children with biliary atresia have variceal bleeding, often early in their lives9,10,12,13; some of these children have ascites and other evidence of end-stage liver disease, whereas others have preserved synthetic function and normal bilirubin. Experienced pediatric hepatologists acknowledge that death from first variceal bleeding in children is rare; in several small published series, death from uncontrolled bleeding is 2%–5%, with additional mortality owing to underlying liver disease in more children.10,14–17 To date, information on prophylaxis of gastrointestinal bleeding in children is scarce. In contrast with the experience in adults, studies of propranolol prophylaxis are extremely limited, uncontrolled, and not convincingly effective.18 Appropriate pediatric dosing of propranolol and its effects on hemodynamics in children are unknown. The pediatric literature on primary endoscopic prophylaxis includes sclerotherapy and EVL, including 1 randomized, controlled trial (100 children), which demonstrated the possibility of achieving a lower rate of bleeding in those undergoing sclerotherapy compared with controls.18,19 No GASTROENTEROLOGY 2013;-:1–4
EDI 5.2.0 DTD YGAST58621_proof 22 August 2013 6:20 pm ce
55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108
109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163
print & web 4C=FPO
Editorial, continued
Figure 1. Outcome of primary and secondary prophylaxis of variceal bleeding in 66 children with portal hypertension.
effect on mortality could be shown in that study. A number of small case series of children who have already undergone a variceal bleed report a low rate of rebleeding after EVL.20 A randomized, controlled trial in 49 children comparing sclerotherapy to EVL showed rebleeding in 25% versus 4%.21 Esophageal perforation, ulceration, and stricture formation have been reported after endoscopic treatment of varices in children.10,22 Notably, general anesthesia is usually required in children, and smaller children (<2 years old) have required sclerotherapy with its attendant morbidity. Although data are limited, most pediatric hepatologists would agree that secondary prophylaxis of the child who has had a variceal hemorrhage is reasonable, given the historically high rebleeding rate and the excellent adult data in support of it. Primary prophylaxis in children deserves more debate, however. The findings reported in this issue of GASTROENTEROLOGY’s young (but heterogeneous) group of biliary atresia infants may not be generalizable to other cirrhotic conditions of childhood (or to extrahepatic portal vein obstruction, which is not addressed in this editorial). These children had a mean bilirubin of >10 mg/dL, and 20% had ascites; these parameters would be expected to be associated with a greater risk of bleeding and perhaps greater mortality.12,23–25 A very experienced endoscopist performed the procedures while administering octreotide during an average of four 3-day hospitalizations. Two of the children bled during the process of eliminating the varices,
possibly from ulcers induced by the procedure. Serious complications of EVL were not reported in this group. Within an average of 14 months, more than half of both groups of children undergoing primary prophylaxis and secondary prophylaxis were transplanted. Varices could not be eradicated in one quarter of the children. The recurrence of varices after eradication was very high at 37%. From this perspective, several factors must be considered in evaluating the merits of primary prophylaxis of variceal bleeding in children. Foremost, the risk of mortality of children with a first variceal bleed is low (see references above), partly because underlying liver disease may be well-compensated at onset of bleeding and because comorbidities typically seen in adults are often absent. The risks of endoscopic treatment in children may exceed those in adults; these uncommonly performed procedures in small patients require general anesthesia, multiple procedures, and sometimes sclerotherapy, not to mention a 3-day hospital admission in the present report. We need to weigh the risks and benefits of multiple procedures in a nonbleeding child who may not bleed for years, when varices have a high chance of recurring and transplant is frequently imminent.13,24 Because mortality from gastrointestinal bleeding in children is quite low (zero in this small study), we may need to consider a “wait and watch” approach, taking other issues such as other features of advancing liver disease, failure to thrive, neurodevelopmental impact, and fat-soluble vitamin deficiencies into consideration when weighing primary prophylaxis of variceal bleeding versus more aggressive transplantation. For example, if a failed Kasai operation is an indication for transplantation, the issue of primary prophylaxis may become moot. These considerations argue against a recommendation of routine screening endoscopy and/or primary endoscopic prophylactic therapy for children with biliary atresia, cirrhosis, and portal hypertension. After a first variceal bleed, secondary endoscopic prophylaxis can be initiated, with prompt listing for liver transplantation for those children in whom hepatic decompensation is present or imminent (eg, in the setting of a failed Kasai procedure). This study highlights the need for future research in pediatric liver disease. Liver diseases in childhood are often mechanistically different from those in adulthood; pathophysiologic mechanisms of fibrosis and angiogenesis may differ.26 Unanswered questions include: (1) Which children are at most risk for bleeding and for worse outcomes after bleeding? Ideally, those children who will bleed would be identified noninvasively and parameters such as bilirubin and ascites can indicate increased morbidity of bleeding.12,27 (2) Is EVL effective in preventing first bleeding in children and more importantly what is the impact of this on long-term outcome? A randomized, controlled trial would be ideal, but the
2 EDI 5.2.0 DTD YGAST58621_proof 22 August 2013 6:20 pm ce
164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218
Editorial, continued 219 220 221 222 223 224 225 226 227 228 229 230 231 Q1 232 233 234 235 236 237 238 239 240 241 242 Q3 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 Q2 261 262 263 264 265 266 267 268 269 270 271 272 273
numerous obstacles to such a solution include the rarity of the condition, lack of standardization as to EVL schedule, and difficulties in recruitment.18 We need to determine whether the risk/benefit ratio truly favors proceeding with EVL in these children who have never experienced a variceal hemorrhage. It will also be important to study whether gastric and ectopic varices then become problematic in children who have had eradication of esophageal varices. (3) Which children would be better served by undergoing liver transplantation, avoiding an expensive and risky series of endoscopies? The trite adage is that children are not just small adults; indeed, we need to know how to manage portal hypertension in children. Given the limitations in pediatric research, creative trial designs are necessary to address this important question. Even multicenter research networks like the Cholestatic Liver Diseases Research and Education Network (ChiLDREN), following >1000 children with biliary atresia, face enormous obstacles to studying portal hypertension and its management. And yet, this kind of collaboration is the only way to determine if therapies so clearly effective when studied in hundreds of adults can be safely applied to helping children.
JEAN PAPPAS MOLLESTON Department of Clinical Pediatrics Pediatric Gastroenterology, Hepatology and Nutrition Indiana University School of Medicine Riley Hospital for Children Indianapolis, Indiana BENJAMIN L. SHNEIDER Department of Pediatrics, Pediatric Hepatology University of Pittsburgh of UPMC Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20. 21.
References 1. Duche M, Ducot B, Ackermann O, et al. Experience with endoscopic management of high-risk gastroesophageal varices with and without bleeding in children with biliary atresia. Gastroenterology 2013;145: 000–000. 2. Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007;46:922–938. 3. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin Liver Dis 1999; 19:475–505. 4. Khuroo MS, Khuroo NS, Farahat KL, et al. Meta-analysis: endoscopic variceal ligation for primary prophylaxis of oesophageal variceal bleeding. Aliment Pharmacol Ther 2005;21:347–361. 5. Gonzalez R, Zamora J, Gomez-Camarero J, et al. Meta-analysis: combination endoscopic and drug therapy to prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109–1022. 6. Fagundes ED, Ferreira AR, Roquete ML, et al. Clinical and laboratory predictors of esophageal varices in children and adolescents with
22.
23.
24.
25.
26.
portal hypertension syndrome. J Pediatr Gastroenterol Nutr 2008; 46:178–183. Gana JC, Turner D, Mieli-Vergani G, et al. A clinical prediction rule and platelet count predict esophageal varices in children. Gastroenterology 2011;141:2009–2016. Adami MR, Ferreira CT, Kieling CO, et al. Noninvasive methods for prediction of esophageal varices in pediatric patients with portal hypertension. World J Gastroenterol 2013;19:2053–2059. Duche M, Ducot B, Tournay E, et al. Prognostic value of endoscopy in children with biliary atresia at risk for early development of varices and bleeding. Gastroenterology 2010;139:1952–1960. Wanty C, Helleputte T, Smets F, et al. Assessment of risk of bleeding from esophageal varices during management of biliary atresia in children. J Pediatr Gastroenterol Nutr 2013;56:537–543. Shneider BL, Bosch J, de Franchis R, et al. Portal hypertension in children: expert pediatric opinion on the report of the Baveno v Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension. Pediatr Transplant 2012;16:426–437. Miga D, Sokol RJ, Mackenzie T, et al. Survival after first esophageal variceal hemorrhage in patients with biliary atresia. J Pediatr 2001; 139:291–296. Shneider BL, Abel B, Haber B, et al. Portal hypertension in children and young adults with biliary atresia. J Pediatr Gastroenterol Nutr 2012;55:567–573. Eroglu Y, Emerick KM, Whitingon PF, et al. Octreotide therapy for control of acute gastrointestinal bleeding in children. J Pediatr Gastroenterol Nutr 2004;38:41–47. Stringer MD, Howard ER, Mowat AP. Endoscopic sclerotherapy in the management of esophageal varices in 61 children with biliary atresia. J Pediatr Surg 1989;24:438–442. Howard ER, Stringer MD, Mowat AP. Assessment of injection sclerotherapy in the management of 152 children with oesophageal varices. Br J Surg 1988;75:404–408. Miloh T, Kratimenos P, Shneider B, et al. Acute variceal bleeding in children: single center experience [abstract]. Hepatology 2010; 52:260A. Ling SC, Walters T, McKiernan PJ, et al. Primary prophylaxis of variceal hemorrhage in children with portal hypertension: a framework for future research. J Pediatr Gastroenterol Nutr 2011;52:254–261. Goncalves ME, Cardoso SR, Maksoud JG. Prophylactic sclerotherapy in children with esophageal varices: long-term results of a controlled prospective randomized trial. J Pediatr Surg 2000;35:401–405. Molleston JP. Variceal bleeding in children. J Pediatr Gastroenterol Nutr 2003;37:538–545. Zargar SA, Javid G, Khan BA, et al. Endoscopic ligation compared with sclerotherapy for bleeding esophageal varices in children with extrahepatic portal venous obstruction. Hepatology 2002;36: 666–672. Poddar U, Thapa BR, Singh K. Endoscopic sclerotherapy in children: experience with 257 cases of extrahepatic portal venous obstruction. Gastrointest Endosc 2003;57:683–686. Lampela H, Kosola S, Koivusalo A, et al. Endoscopic surveillance and primary prophylaxis sclerotherapy of esophageal varices in biliary atresia. J Pediatr Gastroenterol Nutr 2012;55:574–579. Shneider BL, Brown MB, Haber B, et al. A multicenter study of the outcome of biliary atresia in the United States, 1997 to 2000. J Pediatr 2006;148:467–474. Shneider B, Magee J, Karpen S, et al. Prospective multicenter analysis of post-operative total bilirubin as a biomarker for shortterm outcome after hepatoportoenterostomy for biliary atresia [abstract]. Hepatology 2011;54:114A. Fernandez M, Mejias M, Garcia-Pras E, et al. Reversal of portal hypertension and hyperdynamic splanchnic circulation by combined vascular endothelial growth factor and platelet-derived growth factor blockade in rats. Hepatology 2007;46:1208–1217. 3
EDI 5.2.0 DTD YGAST58621_proof 22 August 2013 6:20 pm ce
274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328
Editorial, continued 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383
27. Gana JC, Turner D, Avitzur Y, et al. Prediction of esophageal variceal bleeding in children [abstract]. Gastroenterology 2009;136:A825.
Hospital for Children, 705 Riley Hospital Drive – ROC 4210, Indianapolis, Indiana 46202. e-mail: [email protected].
Reprint requests Address requests for reprints to: Jean Pappas Molleston, MD, Professor of Clinical Pediatrics, Director, Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Riley
Conflicts of interest The author discloses no conflicts. © 2013 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2013.08.026
4 EDI 5.2.0 DTD YGAST58621_proof 22 August 2013 6:20 pm ce
384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438