Maria Hukkinen1, Anna Kerola1, Jouko Lohi2, Päivi Heikkilä2, Laura Merras-Salmio3, Timo Jahnukainen4, Antti Koivusalo1, Hannu Jalanko4, Mikko P Pakarinen5. 1. Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Hospital, Helsinki, Finland; Section of Pediatric Surgery, Children's Hospital, Helsinki University Hospital, Helsinki, Finland. 2. Department of Pathology, HUSLAB, Helsinki University Hospital, Helsinki, Finland. 3. Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Hospital, Helsinki, Finland; Department of Pediatric Gastroenterology, Children's Hospital, Helsinki University Hospital, Helsinki, Finland. 4. Department of Pediatric Nephrology and Transplantation, Children's Hospital, Helsinki University Hospital, Helsinki, Finland. 5. Pediatric Liver and Gut Research Group, Children's Hospital, Helsinki University Hospital, Helsinki, Finland; Section of Pediatric Surgery, Children's Hospital, Helsinki University Hospital, Helsinki, Finland. Electronic address: mikko.pakarinen@hus.fi.
Abstract
BACKGROUND: Different treatment policies can influence biliary atresia outcomes, but the pathophysiology of expanding fibrosis occurring even after successful portoenterostomy remains unclear. STUDY DESIGN: Clearance of jaundice (COJ) (bilirubin <20 μmol/L), native liver survival, and overall survival rates of biliary atresia patients were analyzed before and after national centralization of management, as well as in relation to native liver histopathology of protocol biopsies. RESULTS: Of the 59 patients, 35 were managed after centralization and received standardized postoperative adjuvant therapy, including corticosteroids. After centralization, age at portoenterostomy decreased from 73 days to 54 days (p = 0.014) and COJ rate increased from 42% to 80% (p = 0.005), 5-year native liver survival increased from 38% to 70% (p = 0.014), and 5-year overall survival increased from 68% to 94% (p = 0.007). High-grade portal inflammation at portoenterostomy predicted COJ (odds ratio 3.66; p = 0.011) and slower fibrosis progression (β = -0.74; p = 0.005). Native liver survival was extended in patients with high-grade portal inflammation (p = 0.002) and in patients whose bilirubin normalized within 3 months (p < 0.001). Portal inflammation and cholestasis reduced only after COJ (p < 0.001), and persisting ductal reaction, reflected by cytokeratin 7-positive proliferating bile ductules and periportal hepatocytes, correlated with follow-up fibrosis (r = 0.454 to 0.763; p < 0.001 to 0.003). Cytokeratin 7 immunopositivity of periportal hepatocytes increased after COJ (p = 0.015) and was the only predictor of follow-up liver fibrosis (β = 0.36; p = 0.002) in multiple regression. CONCLUSIONS: Biliary atresia outcomes improved significantly after centralization and standardized management. Resolution of cholestasis and reduction of high-grade portal inflammation postoperatively predict slower fibrosis progression and improved native liver survival, and persisting ductal reaction parallels progressive native liver fibrosis despite COJ.
BACKGROUND: Different treatment policies can influence biliary atresia outcomes, but the pathophysiology of expanding fibrosis occurring even after successful portoenterostomy remains unclear. STUDY DESIGN: Clearance of jaundice (COJ) (bilirubin <20 μmol/L), native liver survival, and overall survival rates of biliary atresiapatients were analyzed before and after national centralization of management, as well as in relation to native liver histopathology of protocol biopsies. RESULTS: Of the 59 patients, 35 were managed after centralization and received standardized postoperative adjuvant therapy, including corticosteroids. After centralization, age at portoenterostomy decreased from 73 days to 54 days (p = 0.014) and COJ rate increased from 42% to 80% (p = 0.005), 5-year native liver survival increased from 38% to 70% (p = 0.014), and 5-year overall survival increased from 68% to 94% (p = 0.007). High-grade portal inflammation at portoenterostomy predicted COJ (odds ratio 3.66; p = 0.011) and slower fibrosis progression (β = -0.74; p = 0.005). Native liver survival was extended in patients with high-grade portal inflammation (p = 0.002) and in patients whose bilirubin normalized within 3 months (p < 0.001). Portal inflammation and cholestasis reduced only after COJ (p < 0.001), and persisting ductal reaction, reflected by cytokeratin 7-positive proliferating bile ductules and periportal hepatocytes, correlated with follow-up fibrosis (r = 0.454 to 0.763; p < 0.001 to 0.003). Cytokeratin 7 immunopositivity of periportal hepatocytes increased after COJ (p = 0.015) and was the only predictor of follow-up liver fibrosis (β = 0.36; p = 0.002) in multiple regression. CONCLUSIONS:Biliary atresia outcomes improved significantly after centralization and standardized management. Resolution of cholestasis and reduction of high-grade portal inflammation postoperatively predict slower fibrosis progression and improved native liver survival, and persisting ductal reaction parallels progressive native liver fibrosis despite COJ.
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Authors: Nimish Godbole; Iiris Nyholm; Maria Hukkinen; Joseph R Davidson; Athanasios Tyraskis; Jouko Lohi; Päivi Heikkilä; Katja Eloranta; Marjut Pihlajoki; Mark Davenport; Markku Heikinheimo; Antti Kyrönlahti; Mikko P Pakarinen Journal: Sci Rep Date: 2022-05-04 Impact factor: 4.996