Cholestatic liver diseases of genetic etiology: Advances and controversies

Abstract

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.

Protocols of Investigation of Neonatal Cholestasis—A Critical Appraisal

“…Extensive information useful for clinical-laboratory investigation can be found in Götze T, et al (2015). Table S1 includes further useful references [ 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 ] concerning the clinical investigation. The development of projects for decreasing the turnaround time of TGS to less than 7 days in the situation of ill-appearing babies with NC under intensive care unit could optimize diagnosis, treatment, and prognosis.…”

Genetics in Familial Intrahepatic Cholestasis: Clinical Patterns and Development of Liver and Biliary Cancers: A Review of the Literature

“…As matter of fact then, several genes involved in the development of inherited cholestasis are linked to the risk of HCC and CCA in pediatric and not pediatric populations: ABCB11 , ABCB4 , TJP2 , FXR , MYO5B , SLC51B , SLC25A13 , NOTCH2 , JAG1 , TGR5 and HNF1B [ 5 , 6 , 7 ].…”

Letter to the editor: The burgeoning field of progressive familial intrahepatic cholestasis

“…To the editor, Genetic cholestasis represents an incredibly evolving area open to new breakthroughs. [1] In the last issue of Hepatology we read, therefore, with interest the article by Ibrahim et al, [2] who provided a snapshot of the escalating number of adult and pediatric genetic cholestatic liver diseases and assessed what is new in the therapeutic pot. The authors must be commended for having succeeded in such a comprehensive systematization.…”

“…In the column "Disease" of the low/normal γ-glutamyltranspeptidase (GGT) conditions of their tab. 1, [2] the authors were seemingly correct by listing only five PFIC defects attributable to variants of genes coding ATPase phospholipid transporting 8B1 (PFIC1), ATP binding cassette subfamily B member 11 (PFIC2), tight junction protein 2 (TJP2; PFIC4), nuclear receptor subfamily 1 group H member 4 (farnesoid X receptor; PFIC5), and myosin VB (PFIC6). Instead, the list is incomplete/unavoidably outdated.…”