Autoimmune Biliary Diseases: From Fragmented Pathways to Precision Diagnosis
Source: PubMed Central Open Access, NCBI / U.S. National Library of Medicine
Background and significance Autoimmune biliary diseases, such as primary sclerosing cholangitis (PSC), Primary biliary cholangitis (PBC) and IgG4-related sclerosing cholangitis (IgG4-SC) are recognized as contributors to chronic cholestatic liver disease. Time-to-diagnosis remains prolonged, despite the presence of high resolution MRCP, expanded autoantibody panels and improved endoscopic tissue acquisition. This is due to the fragmented disease-specific pathways, variable marker sensitivity, overlap syndromes, malignant mimickers and in some cases early/small-duct imaging limitations. Objectives Critically evaluate and synthesize current diagnostic modalities and propose an integrated, precision-layered, phenotype-defined, and tissue-informed diagnostic pathway that standardizes evaluation across autoimmune and immune-mediated cholangiopathies. Methods Major society guidelines such as AASLD/EASL, key reviews and pivotal studies were used in order to extract evidence regarding autoimmune serologies, MRCP and advanced MRCP techniques, elastography/MRE for fibrosis staging and targeted endoscopic-tissue diagnostics, emphasizing on overlap phenotypes, intermediate strictures and malignancy exclusion. Results Seronegative/atypical PBC, limited sensitivity of MRCP in early or small-duct PSC, as well as frequent misclassification of IgG4-SC as PSC; are remarkable contributors of diagnostic delay. Iterative resolution, achieved through sequential escalation from serology to non-inva
Abstract
Background and significance Autoimmune biliary diseases, such as primary sclerosing cholangitis (PSC), Primary biliary cholangitis (PBC) and IgG4-related sclerosing cholangitis (IgG4-SC) are recognized as contributors to chronic cholestatic liver disease. Time-to-diagnosis remains prolonged, despite the presence of high resolution MRCP, expanded autoantibody panels and improved endoscopic tissue acquisition. This is due to the fragmented disease-specific pathways, variable marker sensitivity, overlap syndromes, malignant mimickers and in some cases early/small-duct imaging limitations. Objectives Critically evaluate and synthesize current diagnostic modalities and propose an integrated, precision-layered, phenotype-defined, and tissue-informed diagnostic pathway that standardizes evaluation across autoimmune and immune-mediated cholangiopathies. Methods Major society guidelines such as AASLD/EASL, key reviews and pivotal studies were used in order to extract evidence regarding autoimmune serologies, MRCP and advanced MRCP techniques, elastography/MRE for fibrosis staging and targeted endoscopic-tissue diagnostics, emphasizing on overlap phenotypes, intermediate strictures and malignancy exclusion. Results Seronegative/atypical PBC, limited sensitivity of MRCP in early or small-duct PSC, as well as frequent misclassification of IgG4-SC as PSC; are remarkable contributors of diagnostic delay. Iterative resolution, achieved through sequential escalation from serology to non-invasive ductal mapping, selective tissue clarification and investigational molecular and AI-assisted tools such as radiomics-enhanced MRCP, molecular cytology and liquid biopsy when conventional modalities fail, all aimed to improve discrimination of overlaps and support risk-stratified surveillance. Conclusion Diagnostic uncertainty and disease misclassification may be reduced by implementing a precision-layered, phenotype-defined, and tissue-informed diagnostic pathway. This will standardize evaluation across autoimmune biliary diseases. It is important to note that these emerging tools remain investigational and require prospective validation prior to routine clinical integration.