Noninvasive Evaluation of Liver Fibrosis and Portal Hypertension After Successful Portoenterostomy for Biliary Atresia

Abstract

We investigated noninvasive follow‐up markers for histologic liver fibrosis and portal hypertension (PH) in patients with biliary atresia after successful portoenterostomy (PE). Among children with bilirubin <20 µmol/L after PE (n = 39), Metavir fibrosis stage was evaluated at PE and in follow‐up protocol liver biopsies (n = 83). PH was defined as endoscopically confirmed esophageal varices or thrombocytopenia associated with splenomegaly. The accuracy of liver biochemistry and stiffness in detecting liver fibrosis and PH was analyzed by the area under the receiving operating characteristic curve (AUROC) and multiple regression models. During a median native liver survival of 8.3 years (interquartile range 2.5‐10.8 years), cirrhosis (Metavir F4) had developed in 51% of patients and PH in 54% of patients. Cirrhosis was equally common in all age tertiles of 1.2‐2.1 years (n = 10/27), 3.9‐5.8 years (n = 12/28), and 9.0‐14 years (n = 12/28). In the two oldest age tertiles, histologic liver fibrosis had progressed further in patients with PH than without PH (P < 0.001). PH was accurately predicted by the aspartate aminotransferase‐to‐platelet ratio index (APRI) (cutoff, 0.70; AUROC, 0.92), bile acids (cutoff, 49 µmol/L; AUROC, 0.91), and liver stiffness (cutoff, 16.9 kPa; AUROC, 0.89; P < 0.001 each) across all age tertiles. Liver stiffness was the most accurate predictor of cirrhosis overall (AUROC, 0.82; P < 0.001), whereas bilirubin was >11 µmol/L in the youngest tertile (AUROC, 0.91; P < 0.001), bile acids was >80 µmol/L in the middle tertile (AUROC, 0.81; P = 0.009), and liver stiffness was >24 kPa in the oldest age tertile (AUROC, 0.96; P = 0.002). Conclusion: After successful PE, development of PH associates with progression of liver fibrosis and can be accurately detected by APRI and stiffness. Liver stiffness most accurately identified cirrhosis in older children, whereas biochemical markers of cholestasis closely reflected histologic cirrhosis in younger children.

Evolving Up‐regulation of Biliary Fibrosis–Related Extracellular Matrix Molecules After Successful Portoenterostomy

“…(3) Recent studies have profiled histopathological and clinical aspects of post-SPE fibrosis. (4) The early neutrophil-dominated acute inflammation resolves within the first year, but a smaller lymphocyte infiltrate persists, and fibrosis progresses in most patients. (5) Increased numbers of mesenchymal extracellular matrix (ECM)-producing myofibroblasts and bile duct-forming cholangiocytes are evident in both PE and SPE samples.…”

60 Days in Biliary Atresia: A Historical Dogma Challenged

“…12 Superimposed upon the data are colored bands of ranges for normal values in older children (blue band, below) and findings of advanced liver disease (cirrhosis in pink and portal hypertension in yellow bands, respectively, above) described in children with BA who have undergone Kasai hepatoportoenterostomy. 13,14 review published posthumously in 1995, when he stated, "Our current goals when evaluating the infant with cholestasis are to exclude all other causes of hepatobiliary disease by 4 weeks to allow portoenterostomy to be performed by an expert surgeon when the infant is 5 to 6 weeks old." 15 Newborn screening programs for BA, including newborn conjugated bilirubin measurement and/or stool color cards, together with specific anticipatory guidance about prolonged neonatal jaundice, may be critical in efforts to meet these more modern targets.…”

“…4, blue band) and findings of advanced liver disease (cirrhosis in pink band and portal hypertension in yellow band, respectively) described in children with BA who have undergone Kasai hepatoportoenterostomy. 13,14 "Normal" stiffness was seen in infants only in the first 2 weeks of life, whereas values consistent with cirrhosis and portal hypertension were uniformly observed in infants older than 60 days. No clear target is identified in this analysis, but relentless progression from early infancy is apparent.…”

“…Superimposed on the data are colored bands of ranges for normal values in older children (Fig. , blue band) and findings of advanced liver disease (cirrhosis in pink band and portal hypertension in yellow band, respectively) described in children with BA who have undergone Kasai hepatoportoenterostomy …”

“…Transient elastography performed in infants prior to hepatoportoenterostomy at ages varying between 10 and 90 days of age (reproduced and modified with permission from the author and publisher) . Superimposed upon the data are colored bands of ranges for normal values in older children (blue band, below) and findings of advanced liver disease (cirrhosis in pink and portal hypertension in yellow bands, respectively, above) described in children with BA who have undergone Kasai hepatoportoenterostomy …”