Etiology and clinical characteristics of infantile cholestasis: a single-center retrospective study of 326 cases

Objective To retrospectively investigate the clinical characteristics and etiological spectrum of infantile cholestasis, with an emphasis on evolving diagnostic approaches. Methods Clinical data of 326 infants diagnosed with infantile cholestasis at the Children's Hospital Affiliated to Shandong University from January 2020 to December 2025 were retrospectively analyzed. Etiological distribution was systematically examined. Serum bile acid profiling was performed for suspected bile acid synthesis defects, and genetic sequencing for unexplained or suspected genetic cholestasis. Results Among 326 infants with infantile cholestasis, 56.7% presented with light- or clay-colored stools, 62.9% had hepatomegaly, and 8.3% had comorbidities. The etiological spectrum included biliary tract anomalies [50.6%, including 161 biliary atresia (BA)], genetic metabolic liver diseases (9.8%, n = 32), infectious causes (7.4%), drug-related causes (3.4%), idiopathic cholestasis (6.7%), other rare causes (0.9%), and undetermined etiology (21.2%). No significant differences in sex or age were observed between the genetic metabolic group ( n = 32) and BA group ( n = 161) (both P > 0.05). After excluding 165 surgical cases, genetic testing was performed in 55 of 161 remaining infants (34.2%), with pathogenic or likely pathogenic variants identified in 33 (60.0% detection rate) across 14 genes (e.g., JAG1 , SLC25A13 , ABCC2 ). In an exploratory subgroup analysis (genetic metabolic, n = 16; BA, n = 20), the BA subgroup showed significantly higher levels of matrix metalloproteinase-7 (MMP-7), direct bilirubin, and GGT ( P = 0.002 for GGT), with no other significant differences between the two subgroups. Conclusion The etiology of infantile cholestasis is complex and highly heterogeneous. Genetic testing improves the diagnostic yield of inherited metabolic liver diseases. Serum bile acid profiling provides metabolomic signatures for etiological differentiation. Conventional liver function tests combined with serum MMP-7 represent a simple, reliable, noninvasive approach for early differentiation of biliary atresia.