Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency

Author:

Ruiz Mathias1,Lacaille Florence2,Schrader Christina3,Pons Monica45,Socha Piotr6,Krag Aleksander7,Sturm Ekkehard8,Bouchecareilh Marion9,Strnad Pavel3

Affiliation:

1. Hépatologie, Gastroentérologie et Nutrition Pédiatriques, Hôpital Femme Mère Enfant, Hospices civils de Lyon, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Lyon, France

2. Service de Gastroentérologie-Nutrition Pédiatriques et Unité d'Hépatologie Pédiatrique Hôpital Universitaire Necker-Enfants Malades, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Paris, France

3. Medical Clinic III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Aachen, Germany

4. Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autonoma de Barcelona, Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Barcelona, Spain

5. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain

6. The Children's Memorial Health Institute, Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, Al. Dzieci Polskich, Warszawa, Poland

7. Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark

8. Pediatric Gastroenterology and Hepatology, University Children's Hospital Tübingen, Member Center of the European Reference Network on Rare Liver Disorders (ERN RARE LIVER), Tübingen, Germany

9. University of Bordeaux, CNRS, INSERM, BRIC, U1312, Bordeaux, France

Abstract

Alpha-1 antitrypsin deficiency (AATD) arises due to inherited variants in SERPINA1, the AAT gene that impairs the production or secretion of this hepatocellular protein and leads to a gain-of-function liver proteotoxicity. Homozygous Pi*Z pathogenic variant (Pi*ZZ genotype) is the leading cause of severe AATD. It manifests in 2 to 10% of carriers as neonatal cholestasis and 20 to 35% of adults as significant liver fibrosis. Both children and adults may develop an end-stage liver disease requiring liver transplantation. Heterozygous Pi*Z pathogenic variant (Pi*MZ genotype) constitutes an established disease modifier. Our review summarizes the natural history and management of subjects with both pediatric and adult AATD-associated liver disease. Current findings from a phase 2 clinical trial indicate that RNA silencing may constitute a viable therapeutic approach for adult AATD. In conclusion, AATD is an increasingly appreciated pediatric and adult liver disorder that is becoming an attractive target for modern pharmacologic strategies.

Funder

Deutsche Forschungsgemeinschaft

Publisher

Georg Thieme Verlag KG

Subject

Hepatology

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