Choledochal cysts (CDCs), also referred to as congenital bile duct dilatation, are rare congenital anomalies affecting the intrahepatic and extrahepatic bile ducts in pediatric populations, with an incidence of approximately 1 in 13,000 among Asian individuals (1). With advancements in prenatal diagnosis and care, up to 70% of CDC cases are identified during the fetal stage (1). Infants diagnosed prenatally with CDCs represent a distinct cohort, as they are at risk for early-onset liver fibrosis, necessitating prompt evaluation and surgical intervention. Previous studies had indicated that the prevalence of liver fibrosis in these infants ranges from 33% to 100%, with advanced fibrosis observed in 20% to 44% of cases (2–4).

Liver biopsy is currently the gold standard for evaluating liver fibrosis. However, it is invasive and associated with risks such as hemorrhage and sampling variability. Growing interest has emerged in non-invasive approaches for predicting liver fibrosis. The aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) index are widely used for non-invasive liver fibrosis assessment in both adults and children with viral hepatitis and biliary atresia (5–7). However, their validation in infants with prenatally diagnosed CDCs remains limited.

The optimal surgical timing and prognostic implications of liver fibrosis progression in infants with prenatally diagnosed CDCs remain controversial. This study aims to identify risk factors associated with significant liver fibrosis in pediatric cases and to evaluate the use of APRI and FIB-4 in assessing fibrosis severity.

Hepatic histopathological changes are common in pediatric CDC patients. While gross liver morphology often appears normal, subclinical hepatic injury persists, characterized by biliary ductal hyperplasia, cholestasis, inflammatory infiltration, and periportal fibrosis, with severe cases progressing rapidly to cirrhosis (9). Age-stratified analyses demonstrate increasing fibrosis severity with advancing age, particularly in neonates and infants (9–11). Our cohort showed no significant difference in surgical age between moderate and mild fibrosis subgroups, potentially reflecting population-specific characteristics. Prospective data from Diao et al. suggested accelerated fibrogenesis in early-gestation diagnoses compared to late-gestation cases, implying intrauterine progression of hepatic pathology (2). However, our data showed a non-significant trend toward elevated fibrosis burden in late-gestation diagnoses, leaving the relationship between gestational age at prenatal diagnosis and severe liver fibrosis risk inconclusive. Pathological mechanisms underlying hepatic fibrogenesis in CDCs involve multifactorial processes, including distal biliary obstruction, pancreatobiliary reflux, cholangitis, and biliary hypoplasia (10, 12). In our study, patients with significant liver fibrosis exhibited a higher prevalence of clinical symptoms, particularly jaundice and pale stools. These findings underscore the need for heightened clinical vigilance in prenatally diagnosed CDC neonates presenting with persistent obstructive jaundice, as this may indicate progressive fibrotic changes requiring timely intervention.

Contemporary liver fibrosis staging systems (Scheuer, METAVIR, Ishak, Batts-Ludwig) share a core histological consensus, prioritizing fibrous septa formation as the primary determinant of disease progression (13). Clinically, significant fibrosis (SF) is defined as ≥S2 (Scheuer/METAVIR) or ≥S3 (Ishak), while advanced fibrosis (AF) is classified as ≥S3 (Scheuer/METAVIR) or ≥S4 (Ishak) (14). The Batts-Ludwig system, an optimized iteration of Scheuer's criteria, enhances reproducibility through standardized visual references, making it the gold standard for pediatric hepatic fibrosis assessment (15, 16). In our cohort, 80% of participants exhibited histological fibrosis. The SF rate (32%) and AF rate (10%) were significantly lower than previously reported CDC series (p < 0.05), suggesting a relatively mild fibrosis burden in our prenatally diagnosed CDC patients.

This study identifies Type IV CDCs and elevated GGT as independent predictors of significant liver fibrosis in prenatally diagnosed infants, consistent with prior evidence (10, 17). Type IV CDC demonstrates accelerated fibrogenesis due to its unique pathoanatomy, combined intrahepatic/extrahepatic biliary dilatation. The pathophysiology primarily involves mechanical obstruction from protein plugs, biliary sludge, and inflammatory strictures rather than pancreaticobiliary maljunction (17). We speculate that type IV CDCs encompass both intrahepatic and distal bile duct obstructions, driven by protein plugs, bile sludge, inflammatory edema, and congenital strictures. These combined factors accelerate the progression and severity of liver fibrosis in type IV CDCs. Elevated GGT is a biochemical marker of cholestatic injury severity, reflecting obstruction-induced biliary hypertension. Serum GGT level was an independent predictive factor of CDCs perforation (18, 19). Our data support the hypothesis that bile duct obstruction is a key driver of rapid fibrosis progression in infants with prenatal CDC diagnosis.

Developing an accurate, non-invasive diagnostic model for CDC-related liver fibrosis holds significant value for the early diagnosis and treatment of fibrosis in CDC patients. While Tang et al. demonstrated exceptional diagnostic performance of the APRI in pediatric CDC cases (AUROC 0.97, cutoff 0.57, specificity 100%, sensitivity 86.7%) for moderate-to-severe fibrosis (Metavir F3-4), their findings may be constrained by limited sample size, potentially introducing sampling bias (7). Chen et al. proposed a sequential application of Aspartate Aminotransferase-to-Platelet Ratio (APAR) and APRI to optimize diagnostic accuracy, achieving an AUROC of 0.791 with 81.42% sensitivity and 67.65% specificity in progressive fibrosis detection (16). Our cohort analysis reveals that APRI maintains robust predictive value for significant fibrosis in prenatally diagnosed CDC infants. Notably, while liver biochemical markers alone may not comprehensively assess fibrosis extent, GGT levels exceeding 327 U/L exhibit promising discriminative capacity, suggesting its potential integration into multimodal diagnostic algorithms.

The optimal surgical timing for prenatally diagnosed CDCs remains contentious. Current guidelines advocate neonatal intervention for symptomatic cases with jaundice, acholic stools, infection, hepatic dysfunction, or cyst progression (20, 21). However, we believe that in most cases of prenatally diagnosed CDC, the degree of liver fibrosis at birth is not severe. Infants without clinical symptoms can be closely monitored after birth, and surgery may not be necessary during the neonatal period. Conversely, Type IV CDC cases exhibiting biochemical derangements (GGT > 327 U/L) during surveillance warrant expedited intervention due to rapid fibrogenesis risk. It was previously believed that once liver fibrosis develops, it is irreversible; however, increasing evidence shows that fibrosis formation is a dynamic process. Chronic injury leads to both fibrosis deposition and degradation (22). Serial liver biopsies in CDC patients undergoing staged surgical management demonstrated histologic fibrosis regression in 73% (8/11) of cases post-definitive cyst excision (23). Even cirrhotic remodeling shows potential reversibility following timely etiological correction (22). Therefore, once the underlying cause of liver damage is addressed, the majority of CDC patients experience reversible liver tissue pathology, which does not affect their long-term prognosis.

This study has several limitations. Firstly, the small sample size might restrict the robustness of the results, thereby requiring validation with a larger cohort. Secondly, the study was conducted at a tertiary maternal and child health center where the incidence of significant liver fibrosis is relatively high, potentially leading to selection bias. Therefore, multicenter and community-based studies are necessary for further verification. Thirdly, although the current liver fibrosis staging system is widely employed, the definition of stages 2 and 3 remains somewhat subjective. Future research should incorporate artificial intelligence or additional immunohistochemical markers to offer more objective and precise evaluations.

In conclusion, our cohort observed liver fibrosis predominantly in the early stages (Batts-Ludwig S0∼S1) in 80% of prenatally diagnosed CDC cases. Mechanical bile duct obstruction emerged as the primary pathophysiological driver of accelerated fibrogenesis. The APRI and GGT levels demonstrated strong predictive value for significant fibrosis (AUROC 0.76∼0.86), with GGT > 327 U/L showing 88% specificity. Notably, Type IV CDC cases exhibiting GGT levels exceeding 327 U/L showed an increased risk of significant liver fibrosis, necessitating early surgical intervention. After addressing the underlying cause of liver damage, liver fibrosis in the majority of CDC patients is reversible, and the long-term prognosis is favorable.