Genetic and clinical spectrum of progressive familial intrahepatic cholestasis type 1: novel ATP8B1 variants and genotype-phenotype correlations.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is a rare genetic disorder caused by variants in ATP8B1. The aim of this study was to characterize the clinical and genetic spectrum of PFIC1 and to investigate genotype-phenotype correlations in affected individuals. Clinical manifestations and laboratory findings from 15 newly identified individuals with PFIC1, together with data from 70 previously reported cases retrieved from the PubMed and CNKI databases, were collected and analyzed. A total of 10 novel pathogenic or likely pathogenic ATP8B1 variants were identified. Clinical manifestations included cholestatic jaundice, pruritus, hepatomegaly, diarrhea, deafness, and pancreatitis, accompanied by elevated serum transaminase, total/direct bilirubin, and total bile acid levels, with normal or low gamma-glutamyl transpeptidase (GGT) levels. Most patients with PFIC1 (71.2%, 42/59) showed an insufficient response to oral ursodeoxycholic acid (UDCA). Among patients who underwent liver transplantation (LT), severe postoperative complications, including hepatic steatosis (93.3%, 14/15) and intractable diarrhea (86.7%, 13/15), were common. In contrast, LT combined with surgical biliary diversion (SBD) reduced the incidence of these complications to 44.4% (4/9) for both outcomes. At the last follow-up, unfavorable clinical outcomes were observed in 64.7% (44/68) of cases. Compared with individuals carrying non-biallelic null ATP8B1 variants, those with biallelic null variants had an earlier age at onset, a lower response rate to UDCA, and reduced LT-free survival. Conclusion: This study described 15 new cases of PFIC1 carrying 10 novel ATP8B1 variants. PFIC1 involved multisystem manifestations, with normal-GGT cholestatic hepatitis representing a characteristic feature. The therapeutic efficacy of UDCA remained limited, and LT alone was associated with substantial postoperative complications, whereas combined LT and SBD appeared to reduce complication rates. Individuals with biallelic null ATP8B1 variants demonstrated earlier disease onset and poorer therapeutic and clinical outcomes.