Liver disease related to alpha1‐antitrypsin deficiency in French children: The DEFI‐ALPHA cohort

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 See Editorial on page 1019 | 1137 RUIZ et al.

DEFI‐ALFA: The French key to the alpha1 mystery?

“…Notably, individuals diagnosed with a neonatal cholestasis were more likely to develop a severe liver disease, a finding, that is supported by several, but not all previous publications . Finally, >50% of the subjects, that progressed to a severe liver disease, ended up with a liver transplantation . This likely reflects the fact that liver transplantation constitutes an excellent treatment option for AATD patients, but also the finding that a subset of individuals with advanced liver disease may improve spontaneously .…”

“…To solve this mystery, a systematic clinical evaluation of AATD children is urgently needed. In that respect, the article from Ruiz et al, describing a large, multi‐centre French cohort of pediatric AATD cases, represents an important and badly needed step in the right direction …”

“…The presented paper from Ruiz et al confirms and further exceeds the observations made by others. Notably, 80% of the analysed individuals carry the classic Pi*ZZ genotype, despite the fact that Pi*SZ and Pi*MZ genotypes are much more prevalent in France . While this observation might be in part because of a relatively low cut‐off for AAT levels that was used as the study inclusion criteria, that likely led to exclusion of some Pi*MZ and Pi*SZ individuals, the composition of the cohort strongly suggests that Pi*ZZ subjects are considerably more likely to develop a clinically significant liver disease than carriers of other genotypes.…”

Alpha 1-Antitrypsin Deficiency: A Disorder of Proteostasis-Mediated Protein Folding and Trafficking Pathways

“…Moreover, the main classic environmental factors such as alcohol associated with liver injury cannot be advanced during childhood. Thus, the presence of modifier genes in the onset of severe pediatric AATD liver disease is now well recognized but still remains to be identified [9,33,54]. Among all the potential candidates, several publications suggest that genetic factors affecting the efficiency of the disposal pathways (UPS and/or autophagy) might act as potential modifiers of AATD liver disease outcome.…”

“…In homozygous patients, the protein is not only inefficiently exported from the ER, but also accumulates as Z-AAT protein aggregates-the main cause of liver disease. The severity of the liver damage ranges from transient neonatal cholestasis to cirrhosis, leading to hepatic transplantation in childhood (mean age 2.5 years old) [9]. Currently, it is impossible to predict which patients with AATD may develop lung or liver issues.…”