Mathias Ruiz1,2, Florence Lacaille3, Julien Berthiller4, Philippe Joly5,6, Jérôme Dumortier7, Madeleine Aumar8, Laure Bridoux-Henno9, Emmanuel Jacquemin10,11, Thierry Lamireau12, Pierre Broué13, Christine Rivet1, Abdelouahed Belmalih1, Lioara Restier1, Colette Chapuis-Cellier2,14, Marion Bouchecareilh15, Alain Lachaux1,2. 1. Hépatologie, Gastroentérologie et Nutrition pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Lyon, France. 2. Faculté de Médecine Lyon-Est, Université Claude Bernard Lyon 1, Lyon, France. 3. Gastroentérologie, Hépatologie et Nutrition pédiatriques, Hôpital Universitaire Necker-Enfants Malades, Paris, France. 4. Unité de support méthodologique du groupement Est, Pôle Information Médicale Evaluation Recherche, Hospices Civils de Lyon, Lyon, France. 5. Inter-university Laboratory of Human Movement Science, University Lyon - University Claude Bernard Lyon 1, Villeurbanne, France. 6. Laboratoire de Biochimie et biologie moléculaire Grand-Est, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. 7. Hépatologie, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France. 8. Gastroentérologie, Hépatologie et Nutrition pédiatrique, Centre d'investigation clinique CHU Lille, University of Lille, Lille, France. 9. Gastroentérologie, Hépatologie et Nutrition pédiatriques, CHU Rennes, Rennes, France. 10. Pediatric Hepatology and Pediatric Liver Transplantation Unit and National Reference Centre for Rare Pediatric Liver Diseases, Hepatinov, Bicêtre Universitary Hospital, University of Paris-Sud, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France. 11. Inserm, UMR-S1174, University of Paris-Sud, Orsay, France. 12. Gastroentérologie, Hépatologie et Nutrition pédiatriques, Bordeaux, France. 13. Gastroentérologie, Hépatologie, Nutrition, Diabétologie pédiatriques, Maladies héréditaires du métabolisme, CHU Toulouse, Toulouse, France. 14. Laboratoire d'Immunologie, Centre de Biologie Sud, Hospices Civils de Lyon, Lyon, France. 15. INSERM, UMR1053 Bordeaux Research In Translational Oncology, University Bordeaux, BaRITOn, Bordeaux, France.
Abstract
BACKGROUND & AIMS: To identify prognostic factors for liver disease in children with alpha-1 antitrypsin deficiency, irrespective of phenotype, using the DEFI-ALPHA cohort. METHODS: Retrospective, then prospective from 2010, multicentre study including children known to have alpha-1 antitrypsin blood concentration below 0.8 g/L, born in France since 1989. Clinical and biological data were collected. Liver disease was classified as "severe" (portal hypertension, liver failure, liver transplantation or death); "moderate" (persistent abnormal liver biology without portal hypertension); and "mild/none" (normal or almost normal liver biology and native liver). Prognostic factors for severe liver disease were evaluated using a Cox semiparametric model. RESULTS: In January 2017, 153 patients from 19 centres had been included; genotypes were PIZZ in 81.9%, PISZ in 8.1%, other in 10.0%. Mean ± SD follow-up was 4.7 ± 2.1 years. Half of patients had moderate liver disease. Twenty-eight children (18.3%) had severe liver disease (mean age 2.5 years, range: 0-11.6): diagnosis of alpha-1 antitrypsin deficiency was made before two months of age in 65.4%, genotypes were PIZZ in 25 (89.3%), PISZ in 2, PIMlike Z in 1, 15 children underwent liver transplantation, 1 child died at 3 years of age. Neonatal cholestasis was significantly associated with severe liver disease (P = 0.007). CONCLUSION: Alpha-1 antitrypsin-deficient patients presenting with neonatal cholestasis were likely to develop severe liver disease. Some patients with non-homozygous ZZ genotype can develop severe liver disease, such as PISZ and M variants, when associated with predisposing factors. Further genetic studies will help to identify other factors involved in the development of liver complications.
BACKGROUND & AIMS: To identify prognostic factors for liver disease in children with alpha-1 antitrypsindeficiency, irrespective of phenotype, using the DEFI-ALPHA cohort. METHODS: Retrospective, then prospective from 2010, multicentre study including children known to have alpha-1 antitrypsin blood concentration below 0.8 g/L, born in France since 1989. Clinical and biological data were collected. Liver disease was classified as "severe" (portal hypertension, liver failure, liver transplantation or death); "moderate" (persistent abnormal liver biology without portal hypertension); and "mild/none" (normal or almost normal liver biology and native liver). Prognostic factors for severe liver disease were evaluated using a Cox semiparametric model. RESULTS: In January 2017, 153 patients from 19 centres had been included; genotypes were PIZZ in 81.9%, PISZ in 8.1%, other in 10.0%. Mean ± SD follow-up was 4.7 ± 2.1 years. Half of patients had moderate liver disease. Twenty-eight children (18.3%) had severe liver disease (mean age 2.5 years, range: 0-11.6): diagnosis of alpha-1 antitrypsindeficiency was made before two months of age in 65.4%, genotypes were PIZZ in 25 (89.3%), PISZ in 2, PIMlike Z in 1, 15 children underwent liver transplantation, 1 childdied at 3 years of age. Neonatal cholestasis was significantly associated with severe liver disease (P = 0.007). CONCLUSION:Alpha-1 antitrypsin-deficient patients presenting with neonatal cholestasis were likely to develop severe liver disease. Some patients with non-homozygous ZZ genotype can develop severe liver disease, such as PISZ and M variants, when associated with predisposing factors. Further genetic studies will help to identify other factors involved in the development of liver complications.
Authors: Benjamin L Shneider; Nathan P Goodrich; Wen Ye; Cindy Sawyers; Jean P Molleston; Robert M Merion; Daniel H Leung; Saul J Karpen; Binita M Kamath; Laurel Cavallo; Kasper Wang; Jeffrey H Teckman; James E Squires; Shikha S Sundaram; Philip Rosenthal; Rene Romero; Karen F Murray; Kathleen M Loomes; M Kyle Jensen; Jorge A Bezerra; Lee M Bass; Ronald J Sokol; John C Magee Journal: Hepatol Commun Date: 2020-08-05