Ductular Reaction Underlies Development of Portal Hypertension in Biliary Atresia

BACKGROUND & AIMS: As better understanding of pathophysiology and reliable predictors for portal hypertension (PH) are needed, we investigated how histological ductular reaction (DR) and liver fibrosis predict PH in biliary atresia (BA). METHODS: 60 BA patients treated between 1987 and 2024 at Helsinki University Hospital were enrolled. Patients underwent liver biopsies at Kasai portoenterostomy and 1 year postoperatively. PH was defined as endoscopic detection of oesophageal varices or thrombocytopenia (< 150*109) and splenomegaly. A neural network model was used to quantify proportional DR (DR%) relative to entire liver tissue, composed of cytokeratin-7-positive portal biliary epithelium (BE%) and parenchymal intermediate hepatocytes (PIH%). Fibrosis was measured by Metavir staging and computerized quantification of Sirius-Red-positive area (SRP%). Predictors of PH were studied with AUROC and survival analyses, and Cox regression models. RESULTS: After portoenterostomy, PH was detected in 70% (n = 42) of patients at median age 1.4 years (IQR 0.7-2.6). At portoenterostomy, DR% ≥ 6.9% (p = 0.016) and PIH% ≥ 1.6% (p < 0.001), but not liver fibrosis apart from cirrhosis (n = 5) predicted PH (p = 0.032). At 1 year, DR% ≥ 3.5% (p < 0.001), PIH% ≥ 0.7% (p < 0.001), BE% ≥ 3.2% (p = 0.006) as well as Metavir 3-4 vs. 1-2 (p = 0.037) and SRP% ≥ 28.4% (p = 0.006) predicted PH. Patients with PH showed progression of PIH% (p < 0.001) from portoenterostomy to follow-up biopsy, accompanied by more rapid progression of fibrosis. In univariable regression models, different DR components, but not fibrosis, were associated with PH both at portoenterostomy and follow-up also after successful portoenterostomy. CONCLUSION: DR predicted development of PH at and one year after portoenterostomy, associating with PH more consistently than fibrosis.