With the application of modern investigative technologies, cholestatic
liver diseases of genetic etiology are increasingly identified as the root cause of previously designated "idiopathic" adult and pediatric
liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic
liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a "sequencing first" approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary
liver transplantation versus medical
therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved
therapies for hepatologists has real potential to help many of our patients with genetic causes of
cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted
biomarkers of
disease progression and
pruritus. We discuss strategies to overcome the challenges of genotype-phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future
therapies, real-world evaluations of individual and combined
therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.