Cholestasis associated to inborn errors in bile acid synthesis

Author:

Espinosa-Escudero Ricardo1ORCID,Herraez Elisa2ORCID,Sanchez-Martin Anabel1ORCID,Sanchon-Sanchez Paula2ORCID,Marin Jose J. G.2ORCID,Monte Maria J.2ORCID

Affiliation:

1. Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain

2. Experimental Hepatology and Drug Targeting (HEVEPHARM), University of Salamanca, Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain; Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain

Abstract

Several metabolic pathways are involved in the biotransformation of C27 neutral cholesterol to C24 primary bile acids (BAs), mainly cholic acid (CA) and chenodeoxycholic acid (CDCA), which are then conjugated with glycine or taurine. This process can start with the modification of the steroid ring or the shortening of the side chain and involves enzymes present in different subcellular compartments. Inborn errors affecting the biogenesis of organelles, such as peroxisomes, or the expression or function of specific enzymes of these convergent routes result in: i) the lack of mature C24-BAs, with the subsequent impairment in digestion and absorption of dietary fat and liposoluble vitamins, such as vitamin K, which may account for a deficient hepatic synthesis of several coagulation factors; ii) the accumulation of intermediate metabolites, which may affect hepatocyte physiology, causing cholestasis as a commonly shared alteration besides other deleterious hepatic events; and iii) extrahepatic clinical manifestations due to accumulation of toxic metabolites in other territories, such as the nervous system, causing neurological disorders. In general, diseases whose primary alteration is a genetic defect in BA synthesis are diagnosed in children or young individuals with a very low incidence. The symptomatology can markedly vary among individuals, ranging from mild to severe conditions. Oral therapy, based on the enrichment of the BA pool with natural C24-BAs, such as CA, CDCA, glyco-CA, or ursodeoxycholic acid (UDCA), depending on the exact deficiency causing the disease, may be beneficial in preventing life-threatening situations. In contrast, in other cases, a liver transplant is the only option for these patients. This review describes the updated information on the genetic and molecular bases of these diseases and the current approaches to achieve a selective diagnosis and specific treatment.

Publisher

Open Exploration Publishing

Subject

General Economics, Econometrics and Finance,General Social Sciences,Health, Toxicology and Mutagenesis,Public Health, Environmental and Occupational Health,Multidisciplinary,General Chemical Engineering,Law,Surfaces, Coatings and Films,General Energy,Mechanical Engineering,Industrial and Manufacturing Engineering,Strategy and Management,Computer Science Applications,Industrial relations,Management Information Systems,Marketing,General Engineering,Developmental and Educational Psychology,Education,Engineering (miscellaneous),Instrumentation

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