Ductular Reaction Underlies Development of Portal Hypertension in Biliary Atresia

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).

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.

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.

DR predicted development of PH at and one year after portoenterostomy, associating with PH more consistently than fibrosis.