Secondary prophylaxis of variceal hemorrhage in biliary atresia—Analysis of prospective multicenter studies

Gastroesophageal variceal hemorrhage (VH) can lead to morbidity and occasionally mortality in biliary atresia (BA), including decompensation in hepatic function and accelerated listing for liver transplantation.1-4 We have previously reported that the 5-year incidence of VH in BA is 8%–10%.5 Guidelines, based upon expert opinion for treatment of pediatric portal hypertension (PHT), recommend secondary prophylaxis of esophageal varices following a bleeding episode to prevent further bleeding episodes and decompensation.6 Guidelines for adults recommend secondary prophylaxis by variceal ligation (EVL) and/or propranolol/carvedilol.7 There are few studies that systematically and prospectively evaluated the management and outcome after VH in BA. The Childhood Liver Disease Research Network (ChiLDReN), funded by the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK)/National Institute of Health, conducts the Prospective Database of Infants with Cholestasis (PROBE; Clinical Trials.gov: NCT00061828) and the Biliary Atresia Study in Infants and Children (BASIC; Clinical Trials.gov: NCT00345553). These are incident and prevalent cohorts, respectively, designed to prospectively acquire clinical data, allowing for analysis of the natural history and interventional approaches after VH in BA. Research was conducted in accordance with both the Declaration of Helsinki and the Istanbul Declaration. All participating ChiLDReN centers had institutional and central review boards and/or research ethics approval. Written informed consent was obtained from parents and/or guardians, and assent was obtained from children aged 7 years or older. Data from PROBE participants enrolled beginning June 2004, with follow-up to July 2023 and BASIC participants enrolled beginning July 2006, with follow-up to March 2023 were analyzed. PROBE participants were dichotomized according to functioning post-hepatoportoenterostomy (HPE) bile drainage as determined by achievement of total bilirubin <2 mg/dL within 3 months of HPE (TB < 2 vs TB > 2).8 The study population consisted of children with BA who met definite or possible clinically evident portal hypertension criteria (dpCEPH)9 and subsequently had gastrointestinal hemorrhage (GIH). The index GIH (GIHi) was defined as the first GIH after a study visit with dpCEPH, presumed to be due to VH. Clinical, laboratory, and endoscopic data were collected at baseline as well as prospectively following GIHi. Additional GIH and/or endoscopic interventions reported within 7 days of GIHi were treated as a single bleeding episode. Risk factors of interest included demographic variables, medical history, and laboratory measurements (collected during routine care). Summary statistics were calculated to describe the study population. Kruskal–Wallis or chi-squared tests were used to compare characteristics between groups. Kaplan–Meier curves were used to estimate the time to transplant/death after GIHi. The log-rank test was used to test the difference in time to transplant/death between those who received banding/sclerotherapy and those who did not. 180 participants with BA and native liver who had GIHi were included (PROBE-96, BASIC-84; Table S1). Thirty-three (38%) PROBE participants had TB < 2. The median age at GIHi was 11 and 77 months in PROBE and BASIC, respectively (Table S1). The median (Q1, Q3) time-to-bleed after the first visit with dpCEPH was 5 months (2, 18) for PROBE and 9 months (2, 34) for BASIC participants. Figure 1A,B demonstrates cumulative incidence curves for each group. Time to GIHi was significantly shorter in TB > 2 PROBE participants at 4 months (2, 15) compared to TB < 2 at 11 months4, 5 (p = 0.01). At GIHi, 110 (61%) participants underwent endoscopy; 96 (87%) had esophageal varices. Fifty had varices that were considered large or did not flatten with insufflation (Table S1), while 45 had varices that were graded as small to medium or flattened with insufflation. At GIHi and in follow-up, endoscopic interventions were performed in 78 participants overall (74 had either EVL or endoscopic sclerotherapy [EST] and 4 had both), while 32 had no intervention. At GIHi, the median platelet count was 102 × 103/mL (64,158 × 103/mL). The frequency of platelet count >150 × 103/mL was greater for subjects <36 months of age at GIHi (<36 months to 22/58 [37.9%] vs. >36 months 3/37 [8.1%], p = 0.0016). Of the 25 participants with platelet count >150 × 103/mL, 18 had endoscopy, and varices were documented in all cases. After GIHi, the use of beta-blockers (n = 5), portosystemic shunting (n = 0), and transjugular intrahepatic portosystemic shunting (n = 1) was limited. Participants not undergoing endoscopy were younger, more likely to be listed for transplant, and had a TB > 2 with an elevated bilirubin at GIHi (Table 1). Among those undergoing endoscopy, those with large varices were more likely to have EVL and/or EST performed. PELD score either at listing or at transplant, and platelet count at GIHi were similar between the groups. The clinical course after GIHi is demonstrated in swimmer plots (Figure S1A–E). The figures illustrate the timing of all endoscopies, endoscopic interventions, bleeding episodes, liver transplantation, and mortality. In BASIC, 43% had no primary intervention (2% rebled within 6 months), 43% a single intervention (2% rebled within 6 months), and 14% underwent >2 endoscopic interventions (none rebled within 6 months) (Figure S1A,B). Among PROBE participants with a TB < 2, 33% had no primary intervention (3% rebled within 6 months), 49% had one intervention (18% rebled within 6 months), and 18% had >2 interventions (6% rebled within 6 months) (Figure S1C). In the PROBE cohort with TB > 2, 40% had no primary intervention, with the majority undergoing transplant within 6 months, 44% had one intervention at presentation (14% rebled within 6 months), and 16% had repeated endoscopic interventions (7% rebled within 6 months) (Figure S1D). Active secondary prophylaxis, defined as >2 endoscopic interventions within 3 months of GIHi, was performed in only 17 participants overall (9.4%) (Figure S1A–D). When GIHi occurred before 12 months of age, transplant was very common (62%) within 6 months of GIHi (Figure S1E). Transplant-free survival following the index GIH is shown in Figure 1C for the overall study population. Survival curves were similar independent of endoscopic intervention but were shorter in TB > 2 PROBE participants (Figure 1D–F). Forty-four participants (30%) underwent liver transplant within 3 months of GIHi. Thirty-one (70%) of these were listed for liver transplant before GIHi. At the time of GIHi, median total bilirubin was 14.6 mg/dL, albumin 3.0 g/dL, platelet count 95 × 103, and international normalized ratio 1.6. The median actual PELD score at transplant was 24. This is a real-world prospective observational study of treatment and outcome of GIH in the setting of CEPH across a diverse group of pediatric liver transplant centers in North America. The existing recommendation for pediatric patients with PHT and esophageal VH is to conduct secondary prophylaxis to completely eradicate the esophageal varices, therefore decreasing or delaying the risk of a second VH and potentially enhancing native liver survival.6 This recommendation stems from studies published nearly 40 years ago demonstrating a survival benefit of secondary prophylaxis compared to controls in adults with cirrhosis of many causes, which are not representative of pediatrics, including alcohol, viral, or primary biliary cholangitis.10, 11 Similar data supporting secondary prophylaxis in pediatrics do not exist. Our study shows that management across multiple pediatric transplant centers does not consistently follow these recommendations. Only a minority of participants with BA complete secondary prophylaxis, and many have only a solitary endoscopic intervention. A substantial portion (39%) of the cohort did not have endoscopic evaluation after GIH in the setting of existing PHT. Variceal bleeding in children is an uncommon event with low mortality. The explanations for and implications of these findings are nuanced. Many patients with variceal bleeding, especially infants with poorly functioning HPE, went directly to transplant, implying that the perception of risk-benefit ratio favored expedited liver transplantation. Interestingly, the platelet criteria for CEPH (i.e., <150 × 103/mL) may not hold up as well in younger children as recently reported in a large experience from France.9, 12 The concept that secondary prophylaxis with a goal of variceal eradication is clearly indicated and beneficial, as is the case in adults, is not apparently universally accepted in pediatrics. Assessment of variceal grading after VH as an indication for the need for secondary prophylaxis may be at play, although this approach is not proven for this clinical decision-making. The value of a single endoscopic intervention is unclear. It is of interest that survival with native liver was similar with or without endoscopic intervention. This may reflect excellent clinical decision-making or suggest there is no benefit to secondary prophylaxis. Identification of those patients likely to have recurrent bleeding and who will most benefit from secondary prophylaxis would be useful. Prospective longitudinal data may provide evidence to influence practical aspects of secondary prophylaxis of variceal hemorrhage in children. Secondary prophylaxis of VH in BA is often not the “classical” repeated procedures to obliteration of varices. Instead, a more nuanced approach is undertaken, seemingly based upon transplant candidacy and assessment of risk of recurrent VH. Lee M. Bass MD (Northwestern University School of Medicine, Lurie Children's Hospital); Kieran Hawthorne MSc (Arbor Research Collaborative for Health); John C. Magee MD (Arbor Research Collaborative for Health; University of Michigan); Simon P. Horslen MB, ChB (Department of Pediatrics, University of Pittsburgh School of Medicine); Wen Ye PhD (Arbor Research Collaborative for Health); Jean P. Molleston MD (Indiana University School of Medicine/Riley Hospital for Children); Lisa Henn PhD (Arbor Research Collaborative for Health); Daniel H. Leung MD (Baylor College of Medicine and Texas Children's Hospital); Ronald J. Sokol MD (University of Colorado School of Medicine, Department of Pediatrics and Children's Hospital Colorado); Saul J. Karpen MD, PhD (Virginia Commonwealth University); Philip Rosenthal MD (University of California, San Francisco Benioff Children's Hospital); Kathleen M. Loomes MD (Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia); Rohit Kohli MBBS (Children's Hospital Los Angeles); Pamela L. Valentino MD (University of Washington School of Medicine, Department of Pediatrics); Alexander Miethke MD (Cincinnati Children's Hospital Medical Center); Vicky L. Ng MD (University of Toronto School of Medicine, Hospital for Sick Kids); M. Kyle Jensen MD (Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Primary Children's Hospital, University of Utah); Benjamin L. Shneider MD (Baylor College of Medicine and Texas Children's Hospital). This study was supported by the National Institutes of Health (NIH) grants as follows: Lee M. Bass, DK062436; Simon P. Horslen, DK062466; Jean P. Molleston, DK084536; Ronald J. Sokol, DK062453 and TR004399; Saul J. Karpen, DK062470; Philip Rosenthal, DK062500; Kathleen M. Loomes, DK062481; Rohit Kohli, DK084538; Pamela L. Valentino, DK084575; Alexander Miethke, DK062497; M. Kyle Jensen, DK103140; John C. Magee, DK062456; and Benjamin L. Shneider, DK103149. The authors declare no conflicts of interest. Figure S1. Swimmer Plot of Events From the Time of the Index Bleeding Event 1A. BASIC participants with < 6 months follow-up. 1E PROBE participants who had index bleed before 12 months of age. Swimmer plots are shown for individual participants with the time of events as noted in the figure legend from the index bleed (filled black circle - bleed noted on endoscopy form with endoscopic intervention, open black circle - bleed noted on endoscopy form without endoscopic intervention, closed green square - bleed noted on interval history form with endoscopic intervention, open green square - bleed noted on interval history form with endoscopic intervention, filled green circle - prophylactic endoscopic intervention, open green circle - follow up endoscopy without endoscopic intervention (i.e. surveillance), triangle - liver transplant, filled black square – death, diamond – last study visit with native liver, plus sign – time of data cut-off with survival with native liver. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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