Biliary atresia, which affects between 1 in 3500 and 1

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1 GASTROENTEROLOGY 2010;139: CLINICAL LIVER, BILIARY TRACT Prognostic Value of Endoscopy in Children With Biliary Atresia at Risk for Early Development of Varices and Bleeding MATHIEU DUCHÉ,*, BÉATRICE DUCOT, ELODIE TOURNAY, MONIQUE FABRE, JOSEPH COHEN,* EMMANUEL JACQUEMIN,* and OLIVIER BERNARD* *Hépatologie Pédiatrique and Centre de Référence National de l Atrésie des Voies Biliaires and Anatomie Pathologique, Hôpital Bicêtre, AP-HP, and Université Paris- Sud, Le Kremlin-Bicêtre; Radiologie Pédiatrique and Santé Publique et Épidémiologie, Hôpital Bicêtre, AP-HP, Le Kremlin-Bicêtre; INSERM, CESP Centre for Research in Epidemiology and Population Health, U1018, Epidemiology of Reproduction and Children Development Team, and Université Paris-Sud 11, Le Kremlin Bicêtre; and Épidémiologie et Biostatistiques, Institut Gustave Roussy, Villejuif, France BACKGROUND & AIMS: Biliary atresia is the most common cause of childhood cirrhosis. We investigated prospectively the development of portal hypertension in 139 children with biliary atresia, the risk of gastrointestinal (GI) bleeding in the first years of life, and associations between endoscopic patterns of varices and risk. METHODS: Children with clinical or ultrasonographic signs of portal hypertension underwent upper GI endoscopy examinations (n 125, median age of 13 months). Information was recorded about esophageal varices and grade, red wale markings on the variceal wall, gastric varices along the cardia, and portal hypertensive gastropathy. A second endoscopy examination was performed in 64 children after a mean interval of 51 months to study their progression or regression. RESULTS: At the first endoscopy examination, 88 of 125 children had esophageal varices, including 74 who were younger than 2 years. Grade II and III varices, red markings, gastric varices, and signs of gastropathy were present in 29, 30, 24, and 27 children, respectively. At the second endoscopy examination, progression, stability, and regression of endoscopic signs were observed in 37, 18, and 9 of the 64 children, respectively. Twenty-eight children had GI bleeding at a median age of 17 months. Multivariate analysis showed that red markings, and most importantly gastric varices, were independent factors associated with bleeding. CONCLUSIONS: Children with biliary atresia have a high risk of portal hypertension in the first years of life. Spontaneous regression of varices is rare. Children with a combination of esophageal varices and red markings and/or gastric varices along the cardia should receive primary prophylaxis of bleeding. Keywords: Infants; Kasai Operation; Liver Transplantation. Biliary atresia, which affects between 1 in 3500 and 1 in 20,000 neonates, is the most frequent cause of cirrhosis in children and accounts for more than half the indications for liver transplantation in this age group. 1,2 Its treatment consists of the sequential use of one of the operations described by Kasai and of liver transplantation if this operation fails. 3,4 Early failure of a Kasai operation requires liver transplantation in the first months or years to prevent death, which otherwise occurs at a mean age of 18 months. 5 Because the intrahepatic bile ducts are involved in biliary atresia, ongoing cholestasis of various degrees is a constant feature in children whose Kasai operation has restored bile flow. 6,7 Therefore, in both short-term and long-term survivors of this operation, biliary cirrhosis is almost always present. 8,9 Consequently, virtually all children with biliary atresia are at risk for portal hypertension secondary to biliary cirrhosis, regardless of the result of the Kasai operation. Because gastrointestinal (GI) bleeding has been reported in very young children with biliary atresia, because in some cases this bleeding was lifethreatening, and because of the current controversy in pediatrics as to whether prophylactic treatment of a first GI bleeding episode is warranted, we report here our experience regarding the early development of portal hypertension in children with biliary atresia, the risk of GI bleeding in the first years of life, and the prognostic value of the endoscopic pattern of the varices relative to this risk. Patients and Methods From January 1, 1991, to December 12, 1996, 139 children were investigated prospectively for biliary atre- Abbreviations used in this paper: GI, gastrointestinal by the AGA Institute /$36.00 doi: /j.gastro

2 December 2010 PORTAL HYPERTENSION IN BILIARY ATRESIA 1953 sia, treated, and followed up in the Pediatric Hepatology Unit of the Bicêtre Hospital. Diagnosis of biliary atresia was proven in each case by histopathologic study of the biliary remnant. The remnant was taken from 130 children during a Kasai operation (including 104 who had undergone hepatic portoenterostomy and 26 who had undergone hepatic portocholecystostomy) and from the remaining 9 children at the time of liver transplantation because they had been seen at an age considered too old to undertake a Kasai operation with a reasonable chance of success. For the purpose of this study, the data concerning portal hypertension were recorded until July 2007, until an effective treatment was given, or until death (13 children who, except for one, died before 1997). The effective treatments comprised liver transplantation for 61 children at a mean age of 28 months (range, months), surgical portosystemic shunt for 3 at a mean age of 64 months (range, months), or endoscopic banding/sclerotherapy for 23 at a mean age of 29 months (range, months). One child, born in 1993, was lost to follow-up after 13 months. The mean age of the 139 children at the end of the period of study was 5 years (range, 5 months to 15 years). Data recorded included the degree of fibrosis on liver histology at the time of the Kasai operation, as previously described, 20 the presence or absence of the polysplenia syndrome, and, at each endoscopic examination, the following items: spleen size, total serum bilirubin concentration, prothrombin time, serum albumin concentration, and portal vein diameter as seen on abdominal ultrasonography. The first upper GI endoscopy was performed at a median age of 13 months (range, years) in 125 children who presented with a clinical sign of portal hypertension (splenomegaly or GI bleeding) and/or an ultrasonographic sign (increased thickness of the lesser omentum). No endoscopy was performed in 14 children; 4 children underwent emergency transplantation for acute liver failure, 1 child underwent a surgical portosystemic shunt elsewhere, 6 children died of acute liver failure with multiple organ failure (n 5) or polymalformation syndrome (n 1), and 3 are alive with no sign of portal hypertension at ages 7 to 14 years with a total serum bilirubin concentration less than 15 mol/l. Each endoscopy was performed by the same operator (M.D.) under general anesthesia or intrarectal midazolam sedation ( mg/kg), and the endoscopic findings were recorded and graded as follows: (1) esophageal varices: grade I when varices were flattened by insufflation, grade II when they were not flattened but separated by healthy mucosa, and grade III when varices were not flattened by insufflation and were confluent; (2) red wale markings on the mucosal wall: these were estimated as previously described 21 ; (3) gastric varices along the cardia, described as GOV by Sarin et al, 22 were recorded by direct examination and retroflexion; the presence of red markings on the gastric varices mucosa was also recorded as well as the presence of portal hypertensive gastropathy. Sixty-four children underwent 2 or more GI endoscopies, with a mean interval between the first and last of 51 months (range, 1 month to 13 years). The data recorded during the last and first endoscopies were compared, and progression of the endoscopic signs of portal hypertension was recorded when one or more of the following features were found: increase in the grade and/or number of esophageal varices, emergence of red markings, and emergence of gastric varices along the cardia. Stability of the endoscopic signs of portal hypertension was defined as the absence of change in the pattern of the last endoscopy relative to the first. Regression of these signs was recorded when one or more of the following features were found on comparison of the data for the first and last endoscopies: decrease in the grade and/or number of esophageal varices, complete regression of gastric varices, or complete regression of red markings. Informed consent of the parents was obtained before each endoscopic procedure. Statistical Methods Between-group percentages were compared using the 2 test, Fisher s exact test, or trend test. Means of serum bilirubin concentrations between first and last endoscopic examinations were compared with paired t test. To assess the risk of bleeding, survival analysis was performed in which start of follow-up was birth and end of follow-up was age at bleeding for children who had bled, age at liver transplantation, surgical portosystemic shunt, or endoscopic banding/sclerotherapy if one of these events had occurred, or age at last follow-up (or death) if no such event had occurred. Cumulative risk of bleeding was established using the Kaplan Meier method. The role of clinical, biochemical, and endoscopic variables in the risk of bleeding was assessed by univariate and multivariate Cox models. We introduced into the multivariate model variables related to bleeding, with P less than 20% in the univariate model. The endoscopic characteristics introduced into the Cox model were those of the first endoscopic examination. Endoscopic signs were grouped into a single variable with the following 4 values: (1) absence or presence of esophageal varices, absence of red markings, absence of gastric varices; (2) presence of esophageal varices, absence of red markings, presence of gastric varices; (3) presence of esophageal varices, presence of red markings, absence of gastric varices; and (4) presence of esophageal varices, presence of red markings, presence of gastric varices. Eight of the 27 children who bled and whose results for the first endoscopy were available had had this endoscopy at the time of bleeding; for the other 19, the interval between the first endoscopy and bleeding ranged from 0.4 month to 48 months (median, 14 months).

3 1954 DUCHÉ ET AL. GASTROENTEROLOGY Vol. 139, No. 6 Table 1. Upper GI Endoscopic Signs of Portal Hypertension at the Time of the First Endoscopy (Median Age, 13 Months) in 125 Children With Biliary Atresia Age at first endoscopy (y) No. of children examined Esophageal varices None Grade I Grade II Grade III Esophageal red Gastric red markings Gastric varices a signs Portal hypertensive gastropathy Younger than or older Total P value b a Varices along the cardia according to Sarin et al. 22 b Comparison between groups younger than 2 years and 2 years or older, Fisher s exact test. In a second study, designed to confirm the predictive value of the endoscopic signs for the risk of GI bleeding, further univariate and multivariate analyses were performed, based solely on the data recorded at the last endoscopy showing the presence of esophageal varices. These analyses concerned the presence or absence of bleeding. For the univariate analysis, the associations between the occurrence of bleeding and endoscopic signs in the children with esophageal varices were tested by the 2 test or Fisher s exact test, as appropriate. Multivariate analysis was performed using the logistic regression model. All tests were 2-sided, and P values less than.05 were considered significant. The predictors of an increased risk of bleeding were also identified using a classification tree based on classification and regression tree analysis. Statistical analyses were performed using Stata software (version 10; Stata Corp, College Station, TX), SAS software (V9.1; SAS Institute, Cary, NC), and R software (R Development Core Team, version 2.6.1). Results Early Natural History of Varices Of the 125 children who underwent at least one upper GI endoscopy at a median age of 13 months, 37 did not display any varices and 88 had esophageal varices (Table 1). Grade II and III esophageal varices were present in 27 of the 98 children (28%) who underwent the first endoscopy before the age of 2 years and in 2 of the 27 (7%) who underwent the first endoscopy after age 2 years. A similar trend toward the early emergence of red markings, gastric varices, and signs of portal hypertensive gastropathy was recorded. Fifteen children presented with a combination of grade II or III varices, gastric varices along the cardia, and red markings. The relationship between the total serum bilirubin concentration at the time of the first endoscopy and the endoscopic signs of portal hypertension is shown in Table 2. Esophageal red markings and signs of portal hypertensive gastropathy were significantly more frequent in children whose serum bilirubin concentration was greater than 20 mol/ L than in those with a concentration below this level. Sixty-four children underwent 2 or more upper GI endoscopies at a mean interval of 51 months (range, 1 month to 13 years) between the first and last procedures, all performed by the same operator. Progression, stability, and regression of the endoscopic signs of portal hypertension, as described in Patients and Methods, are summarized in Table 3. Eighteen children displayed no varices at the first endoscopy (at a mean age of 19 months) and had the last one after a mean follow-up of 71 months. Eight of the children displayed progression of endoscopic signs; these signs included grade I, II, and III esophageal varices (n 3, 4, and 1, respectively), as well as gastric varices along the cardia and/or red markings in 3 of the children with grade II or III varices. Thirty-one children presented with grade I varices at the first endoscopy (mean age, 20 months) and had the last one after a mean follow-up of 53 months; 7 of them regressed, including 3 who had no varices, 5 remained unchanged, and 19 displayed progression, 6 of them to an increased number of grade I varices, red markings, or gastric varices along the cardia, 8 to grade II varices Table 2. Relationship Between Total Serum Bilirubin Concentration and Endoscopic Signs of Portal Hypertension at Time of First Endoscopy (Median Age, 13 Months) in 125 Children With Biliary Atresia Total serum bilirubin concentration ( mol/l) No. of children Grade II III varices Esophageal red Gastric red markings Gastric varices a signs Portal hypertensive gastropathy P value b a Varices along the cardia according to Sarin et al. 22 b As established by the trend test for each endoscopic sign according to the total serum bilirubin concentration.

4 December 2010 PORTAL HYPERTENSION IN BILIARY ATRESIA 1955 Table 3. Evolution of Endoscopic Signs of Portal Hypertension in 64 Children With Biliary Atresia Who Underwent 2 or More Upper GI Endoscopies, According to the Grade of Esophageal Varices at the First Upper GI Endoscopy Performed at a Mean Age of 18 Months Initial grade of varices No. of children examined Progression Stability Regression Total 64 (100%) 37 (58%) 18 (28%) 9 (14%) NOTE. The last endoscopy was performed at a mean age of 69 months. For definitions of the grades of esophageal varices, see Patients and Methods. (including 5 with gastric varices along the cardia and/or red markings), and 5 to grade III varices (including 4 with gastric varices along the cardia and/or red markings). Thirteen children initially displayed grade II varices at a mean age of 14 months and had the last one after a mean follow-up of 24 months: 2 regressed to grade I varices, 2 remained unchanged, and 9 progressed, including 2 with red markings and/or gastric varices along the cardia, 3 with an increased number of grade II varices, and 4 with grade III varices. Of the 2 children with grade III varices aged 8 to 14 months, one remained unchanged for 7 months and the other progressed, with the appearance of gastric varices over a period of 6.5 months. Overall, the endoscopic signs of portal hypertension progressed in 37 (58%) of the 64 children, remained stable in 18 (28%), and regressed in 9 (14%). Table 4 indicates the total serum bilirubin concentrations at the time of the first and last endoscopies in the 64 children. There was a general trend toward an increase in serum bilirubin concentration with time. The mean increase in serum bilirubin concentration was higher in children who displayed progression of endoscopic signs of portal hypertension. However, it is worth noting that the progression of endoscopic signs, even to grade III varices, was observed in some of the children who maintained a normal total serum bilirubin concentration throughout the period of study. In the overall population of 125 children, taking into account the results of the last endoscopy, 17 displayed grade III varices at a mean age of 3.9 years (range, 5.5 months to 15 years), 28 displayed grade II varices at a mean age of 4.3 years (range, 7 months to 15 years), 48 displayed grade I varices at a mean age of 2.3 years (range, 3 months to 11 years), and 32 had no varices at a mean age of 5 years (range, 2 months to 14 years). Risk of GI Bleeding GI bleeding (21 cases of hematemesis and 7 cases of melena) occurred in 28 of the 139 children investigated. The mean decrease in blood hemoglobin concentration was 3.7 g/dl, and 18 children required blood transfusion. Median age at the first bleed was 17 months (range, 4 months to 5 years and 10 months). Eight children bled before 1 year of age, 13 between 1 and 2.5 years, and the remaining 7 at ages ranging from 4 years to 5 years and 10 months; thus, three-fourths of children who bled did so before years of age. Using the univariate Cox model, there were no significant differences between the risk of bleeding according to the type of Kasai operation performed and the degree of fibrosis on liver histology at the time of the operation. There was, however, a relationship between the risk of bleeding and the presence or absence of ascites, total serum bilirubin concentration, prothrombin time, and portal vein diameter. In this study, the actuarial Table 4. Relationship Between Total Serum Bilirubin Concentration and Progression, Stability, or Regression of Endoscopic Signs of Portal Hypertension in 64 Children With Biliary Atresia Who Underwent at Least 2 Upper GI Endoscopies at a Mean Interval of 51 Months, According to the Grade of Esophageal Varices at Time of First Endoscopy Mean total serum bilirubin concentration ( mol/l) (range) Stability/regression Progression Initial grade of esophageal varices First endoscopy Last endoscopy First endoscopy Last endoscopy 19 (3 100) 43 (4 259) 95 (4 294) 149 (6 491) 0 (n 10) (n 8) 97 (4 376) 118 (6 445) 115 (3 357) 168 (4 538) I (n 12) (n 19) 189 ( ) 198 ( ) 101 (7 277) 203 (10 878) II (n 4) (n 9) III (2 children) 1 child: child: Total a 91 (n 27) (n 37) 169 P value b a All grades of esophageal varices and patients with no varices at the time of the first endoscopy. b Comparison between first and last endoscopy.

5 1956 DUCHÉ ET AL. GASTROENTEROLOGY Vol. 139, No. 6 Figure 1. Cumulative risk of GI bleeding in 125 children with biliary atresia according to the results of the first upper GI endoscopy, performed at a median age of 13 months. (A) Grade of esophageal varices (Ev): Ev 0, no varices; Ev 1, grade 1 varices; Ev 2, grade 2 varices; Ev 3, grade 3 varices. (B) Presence or absence of red markings (Rs) on the esophageal (Es) mucosa on the varices. Es Rs 0, no red markings; Es Rs, presence of red markings. (C) Presence or absence of gastric varices along the cardia (GV). GV 0, no gastric varices along the cardia; GV, presence of gastric varices along the cardia. (D) Presence or absence of portal hypertensive gastropathy (PHG). PHG 0, no portal hypertensive gastropathy; PHG, presence of portal hypertensive gastropathy. risk of bleeding (see Patients and Methods) was estimated according to the results of the first upper GI endoscopy, performed in 125 children at a median age of 13 months (Figure 1). One of the 28 children who bled had not undergone endoscopy. The data, therefore, include 27 children who bled and underwent upper GI endoscopy. All children who initially had grade III varices bled before the age of 29 months, except for one who underwent liver transplantation at 17 months. The initial presence of grade II varices, the presence of grade I varices, and the absence of visible varices were respectively associated with 5-year actuarial risks of bleeding of 59%, 17%, and 12%; the risk of bleeding was multiplied by 6.9 (95% confidence interval, ; P.0001) by the presence of grade II or III varices compared with children with no varices. The initial presence of esophageal red markings at the first endoscopy was associated with a 76% 5-year actuarial risk of bleeding versus 17% if no such markings were present and multiplied the risk of bleeding by 8 ( ; P.0001) compared with children without red markings. The initial presence of gastric varices along the cardia was associated with an 80% 5-year actuarial risk of bleeding versus 15% if no gastric varices were present and multiplied by 9.3 ( ; P.0001) the risk of bleeding compared with children with no gastric varices; the presence of red markings over gastric varices did not significantly increase the risk of bleeding. Initial signs of portal hypertensive gastropathy were associated with a 5-year actuarial risk of bleeding of 69% versus 20% if no portal hypertensive gastropathy was present and multiplied the risk of bleeding by 4.8 ( ; P.0001) compared with children with no such signs. The relationship between endoscopic variables and the risk of bleeding, calculated according to the univariate Cox model, is shown in Table 5. Using the multivariate Cox model, we found that the risk of bleeding was related to the presence of ascites, prothrombin time, and endoscopic characteristics but above all to the presence of gastric varices along the cardia (Table 5). In our second study, we used the data recorded at the last endoscopy showing esophageal varices, performed for 91 children at a mean age of 38 months. The data include 26 of the 28 children who bled; as already mentioned, one child did not undergo endoscopy, and an-

6 December 2010 PORTAL HYPERTENSION IN BILIARY ATRESIA 1957 Table 5. Study of Factors Possibly Associated With GI Bleeding in 125 Children With Biliary Atresia Who Underwent at Least One GI Endoscopy (Survival Analysis With the Cox Model) Univariate analysis Multivariate analysis HR HR 95% CI P value HR HR 95% CI P value Ascites No Yes Spleen Normal 1.69 Enlarged Polysplenia syndrome Cholangitis episodes a Serum albumin concentration (g/l) Serum bilirubin concentration ( mol/l) Prothrombin time (%) Portal vein diameter (mm) Esophageal varices b Varices or not, no red markings No gastric varices 1 1 Red markings, no gastric varices No red markings, gastric varices Red markings, gastric varices Portal hypertensive gastropathy b No Yes HR, hazard ratio; CI, confidence interval. a Among children who underwent hepatic portoenterostomy. b Data are based on the results of the first endoscopy. One of the children who bled did not undergo endoscopy and was therefore not included. other actually bled from varices of the intestinal en-roux loop without esophageal varices. In 20 of the 26 children, endoscopy was performed at a median of 6 days after bleeding. Thirteen of the 17 children (76%) with grade III varices experienced GI bleeding, as opposed to 10 of the 26 (38%) with grade II varices and 3 of the 48 (6%) with grade I varices (P.001); we noted with interest that 2 of the 3 latter children had gastric varices along the cardia. Twenty-one of the 36 children (58%) with esophageal red markings presented with bleeding as opposed to 5 of the 55 (9%) without these red markings (P.001). Twentyfive of the 36 children (69%) with gastric varices along the cardia presented with GI bleeding as opposed to 1 of the 55 (2%) without (P.001). Twelve of the 34 children (38%) with portal hypertensive gastropathy presented with GI bleeding as opposed to 14 of the 57 (22%) who bled without hypertensive gastropathy (P.29). The multivariate analysis showed that only the presence of red markings on esophageal varices (P.01) and the presence of gastric varices along the cardia (P.001) were independently associated with the occurrence of bleeding. In the optimal classification tree in Figure 2, 2 factors were used to classify the children into high- medium- and low-risk bleeding groups: the presence of gastric varices along the cardia and the presence of red markings on esophageal varices. Children with no gastric varices were classified in the low risk of bleeding group (because only 2% of them bled), those who had gastric varices but no esophageal red signs in the medium risk of bleeding group (36% of them bled), and those with gastric varices and red esophageal signs in the high risk of bleeding group (84% of them bled).

7 1958 DUCHÉ ET AL. GASTROENTEROLOGY Vol. 139, No. 6 Figure 2. Importance of the presence of gastric varices along the cardia (GOV according to Sarin et al 22 ) with or without associated esophageal red markings, for prediction of the risk of GI bleeding, as observed in 93 children with biliary atresia who underwent upper GI endoscopy showing esophageal varices at a mean age of 38 months. In 20 of the 26 children who bled, endoscopy was performed a median of 6 days after bleeding. Discussion The results of this prospective study of children with biliary atresia provide 5 indications that seem to us of interest: severe endoscopic signs of portal hypertension can appear early in life, these signs carry a risk of bleeding as early as the first year of life, they progress with time in most cases, severe endoscopic signs of portal hypertension are mostly seen in children with ongoing cholestatic jaundice but also observed in jaundice-free children, 23 and an endoscopic pattern of varices is predictive of the risk of GI bleeding. Compared with other causes of cirrhosis in children, the risk of portal hypertension is an unusually early and severe one in those with biliary atresia. This may be due to the severe cholestatic fibrosis that is already present in many infants at the time of the Kasai operation, that is, in the very first months of life. 20 Such fibrosis progresses to cirrhosis, whether or not the operation fails or succeeds in suppressing jaundice, probably because of the associated lesions of the intrahepatic bile ducts. 8,9 However, the precocity, frequency, and severity of portal hypertension in children with biliary atresia is striking, especially compared with that seen in children with Alagille syndrome, another severe cholestatic disease that starts at birth; thus, of the 139 children reported here, 28 (20%) presented with GI bleeding, as opposed to 5 (3%) of 132 children with Alagille syndrome. 24 The early occurrence of GI bleeding due to portal hypertension in children with biliary atresia is reminiscent of what is observed in children with portal vein obstruction, who also present with bleeding in the first years of life. 25 Obstructive lesions of the intrahepatic portal branches have indeed been reported in children with biliary atresia. 26,27 Such lesions may combine with cirrhosis to quicken the development of portal hypertension. Because of the early appearance of esophageal varices and the early risk of bleeding, the question arises as to whether it is possible to identify children at risk before bleeding occurs and therefore to institute preventive treatment of the first bleeding episode. Primary prophylaxis of GI bleeding has been used in adults with cirrhosis for 20 years and is recommended for patients with large varices and esophageal red markings as detected on systematic upper GI endoscopy. 28 These signs are considered to be associated with a high risk of bleeding. However, no such data exist for children, let alone infants with biliary atresia, and the principle of primary prophylaxis of GI bleeding is still being debated for this age group The results reported for the present homogeneous population of children with biliary cirrhosis secondary to biliary atresia provide information that could probably allow decisions to be made for several reasons. Firstly, the upper GI endoscopy performed at a median age of about 1 year allows fairly reliable prediction of subsequent bleeding on the basis of the following signs: the presence of grade II or III esophageal varices, red markings on the esophageal mucosa, gastric varices along the cardia, and portal hypertensive gastropathy at this early age. All these signs are strongly associated with a risk of bleeding in the years ahead. Secondly, because of the trend toward progression of the endoscopic signs of portal hypertension with age in a number of children, the absence of esophageal varices and of other signs, or the presence of grade I esophageal varices only at 1 year of age, do not preclude bleeding. This justifies repeat endoscopies at regular intervals to detect the emergence of grade II and III esophageal varices and of esophageal red markings, associated in this population of children with biliary atresia, with a high risk of GI bleeding, as long since described in adults. 21 However, regardless of the grade of esophageal varices and the presence of esophageal red markings, the presence of gastric varices along the cardia emerges, in this study, as the most significant independent endoscopic sign associated with the risk of bleeding. Gastric varices, in the fundus or below the cardia, have been mentioned in adults with portal hypertension and bleeding. 22,29 31 A few pediatric reports also mention the presence of cardial gastric varices along with other endoscopic signs of portal hypertension in children and infants with biliary atresia who underwent primary or secondary prophylaxis Nevertheless, as far as we know, this is the first time that gastric varices along the cardia have been iden-

8 December 2010 PORTAL HYPERTENSION IN BILIARY ATRESIA 1959 tified as the most significant predictor of bleeding in a prospective study, in the long-term, and in a large homogeneous population of patients examined by the same endoscopist. A search for gastric varices along the cardia should therefore be undertaken in infants and young children with biliary atresia who undergo upper GI endoscopy, and the presence of such varices should be taken into consideration when deciding on preventive treatment. In adults, either medical treatment with betablocking agents or endoscopic banding of varices is used for primary prophylaxis. 28 In children, convincing data concerning the efficacy and tolerance of pharmacologic treatment are not available. 19 In a few studies, primary prophylaxis with endoscopic sclerotherapy or banding was reported to have been used with some success in children, 32,34,36,37 but so far there has not been any report defining the type of endoscopic pattern justifying its use as preventive treatment in children with portal hypertension. The data reported here do provide such a definition and could perhaps be extrapolated to other causes of portal hypertension in children to justify primary prophylaxis of GI bleeding in children, as advocated for adults. We suggest that primary prophylaxis is warranted in the following cases: grade III esophageal varices, grade II esophageal varices with red markings, grade II esophageal varices with gastric varices along the cardia, grade II esophageal varices with red markings and gastric varices along the cardia, and grade I esophageal varices with gastric varices along the cardia. Because of the continuity between esophageal and gastric varices along the cardia, we suggest that endoscopic banding or sclerosis of esophageal varices could also be used to treat associated cardial gastric varices and that the specific treatment with endoscopic histoacryl injection of gastric varices along the cardia with products designed to treat fundal varices is only necessary in the rare cases of isolated gastric varices or of gastric varices combined with grade I esophageal varices. 35,38 In conclusion, children with biliary atresia are at high risk for developing signs of portal hypertension at an early age, regardless of the success or failure of the Kasai operation. Seventy-five percent of these children present with esophageal varices before the age of 2 years; spontaneous regression of these varices is rare and is only observed for small varices, as the general rule is either stability or progression of the endoscopic signs of portal hypertension with time. Fifteen percent of children with biliary atresia present with GI bleeding before the age of years. The risk of such bleeding can be foreseen by the presence of grade III varices, esophageal red markings, and above all the presence of gastric varices along the cardia. Primary prophylaxis of bleeding is justified when these signs are present. References 1. Chardot C, Carton M, Spire-Bendelac N, et al. Epidemiology of biliary atresia in France: a national study J Hepatol 1999;31: Fouquet V, Alves A, Branchereau S, et al. Long-term outcome of pediatric liver transplantation for biliary atresia: a ten-year follow-up in a single center. Liver Transplant 2005;11: Kasai M. Treatment of biliary atresia with special reference to hepatic porto-enterostomy and its modifications. Prog Pediatr Surg 1974;6: Kelly D, Davenport M. Current management of biliary atresia. Arch Dis Child 2007;92: Hays DM, Snyder WH. Life-span in untreated biliary atresia. Surgery 1963;54: Chiba T, Kasai M, Sasano N. Histopathological studies on intrahepatic bile ducts in the vicinity of porta hepatis in biliary atresia. Tohoku J Exp Med 1976;118: Kimura K, Hashimoto S, Nishijima E, et al. Percutaneous transhepatic cholangiodrainage after hepatic portoenterostomy for biliary atresia. J Pediatr Surg 1980;15: Gautier M, Valayer J, Odièvre M, et al. Histological liver evaluation 5 years after surgery for extrahepatic biliary atresia: a study of 20 cases. J Pediatr Surg 1984;19: Lykavieris P, Chardot C, Sokhn M, et al. Outcome in adulthood of biliary atresia: a study of 63 patients who survived for over 20 years with their native liver. Hepatology 2005;41: Lilly JR, Stellin G. Variceal hemorrhage in biliary atresia. J Pediatr Surg 1984;19: 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: Cao S, Monge H, Semba C, et al. 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9 1960 DUCHÉ ET AL. GASTROENTEROLOGY Vol. 139, No Lykavieris P, Hadchouel M, Chardot C, et al. Outcome of liver disease in children with Alagille syndrome: a study of 163 patients. Gut 2001;49: Alvarez F, Bernard O, Brunelle F, et al. Portal obstruction in children. I. Clinical investigation and hemorrhage risk. J Pediatr 1983;103: Kasai M, Okamoto A, Ohi R, et al. Changes of portal vein pressure and intrahepatic blood vessels after surgery for biliary atresia. J Pediatr Surg 1981;16: Bernard O, Alvarez F, Brunelle F, et al. Portal hypertension in children. Clin Gastroenterol 1985;14: Boyer TD. Primary prophylaxis for variceal bleeding: are we there yet? Gastroenterology 2005;128: Zoli M, Merkel C, Magalotti D, et al. Evaluation of a new endoscopic index to predict first bleeding from the upper gastrointestinal tract in patients with cirrhosis. Hepatology 1996;24: Kleber G, Sauerbruch T, Ansari H, et al. Prediction of variceal hemorrhage in cirrhosis: a prospective follow-up study. Gastroenterology 1991;100: Kim T, Shijo H, Kokawa H, et al. Risk factors for hemorrhage from gastric fundal varices. Hepatology 1997;25: Sasaki T, Hasegawa T, Nakajima K, et al. Endoscopic variceal ligation in the management of gastroesophageal varices in postoperative biliary atresia. J Pediatr Surg 1998;33: Ohnuma N, Takahashi H, Tanabe M, et al. Endoscopic variceal ligation using a clipping apparatus in children with portal hypertension. Endoscopy 1997;29: Duché M, Habès D, Roulleau P, et al. Prophylactic endoscopic sclerotherapy of large esophagogastric varices in infants with biliary atresia. Gastrointest Endosc 2008;67: Horigome H, Nomura T, Saso K, et al. Endoscopic injection sclerotherapy for esophagogastric variceal bleeding in children with biliary atresia. Hepatogastroenterology 1999;46: 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: Celinska-Cedro D, Teisseyre M, Woynarowski M, et al. Endoscopic ligation of esophageal varices for prophylaxis of first bleeding in children and adolescents with portal hypertension: preliminary results of a prospective study. J Pediatr Surg 2003; 38: Rivet C, Robles-Medranda C, Dumortier J, et al. Endoscopic treatment of gastroesophageal varices in young infants with cyanoacrylate glue: a pilot study. Gastrointest Endosc 2009;69: Received March 30, Accepted July 2, Reprint requests Address requests for reprints to: Olivier Bernard, Hépatologie Pédiatrique, Hôpital Bicêtre, Le Kremlin-Bicêtre, France. olivier.bernard@bct.aphp.fr; fax: (33) Acknowledgments The authors thank Mathilde Dreyfus for English language editing, for which funding was provided by the Fondation Rumsey-Cartier. This report is dedicated to the memory of Professor Daniel Alagille, who founded the Pediatric Hepatology Service of Bicêtre Hospital more than 40 years ago and who created the conditions that made this study possible. Conflicts of interest The authors disclose no conflicts.