New Insights in Genetic Cholestasis: From Molecular Mechanisms to Clinical Implications

Author:

Sticova Eva12ORCID,Jirsa Milan3,Pawłowska Joanna4

Affiliation:

1. Clinical and Transplant Pathology Centre, Institute for Clinical and Experimental Medicine, Prague 4, 140 21, Czech Republic

2. Department of Pathology, Third Faculty of Medicine, Charles University, Prague 10, 100 00, Czech Republic

3. Laboratory of Experimental Hepatology, Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague 4, 140 21, Czech Republic

4. Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute (CMHI), Warsaw 04-730, Poland

Abstract

Cholestasis is characterised by impaired bile secretion and accumulation of bile salts in the organism. Hereditary cholestasis is a heterogeneous group of rare autosomal recessive liver disorders, which are characterised by intrahepatic cholestasis, pruritus, and jaundice and caused by defects in genes related to the secretion and transport of bile salts and lipids. Phenotypic manifestation is highly variable, ranging from progressive familial intrahepatic cholestasis (PFIC)—with onset in early infancy and progression to end-stage liver disease—to a milder intermittent mostly nonprogressive form known as benign recurrent intrahepatic cholestasis (BRIC). Cases have been reported of initially benign episodic cholestasis that subsequently transitions to a persistent progressive form of the disease. Therefore, BRIC and PFIC seem to represent two extremes of a continuous spectrum of phenotypes that comprise one disease. Thus far, five representatives of PFIC (named PFIC1-5) caused by pathogenic mutations present in both alleles ofATP8B1,ABCB11,ABCB4,TJP2,andNR1H4have been described. In addition to familial intrahepatic cholestasis, partial defects inATP8B1,ABCB11,andABCB4predispose patients to drug-induced cholestasis and intrahepatic cholestasis in pregnancy. This review summarises the current knowledge of the clinical manifestations, genetics, and molecular mechanisms of these diseases and briefly outlines the therapeutic options, both conservative and invasive, with an outlook for future personalised therapeutic strategies.

Funder

Institute for Clinical and Experimental Medicine

Publisher

Hindawi Limited

Subject

Gastroenterology,Hepatology,General Medicine

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