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

Liver Int. 2019 Jun;39(6):1136-1146. doi: 10.1111/liv.14035. Epub 2019 Feb 1.


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.

Trial registration: NCT01862211.

Keywords: cirrhosis; liver enzyme; liver transplantation; metabolic liver disease.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Child, Preschool
  • Cholestasis / blood
  • Cholestasis / etiology
  • Cholestasis / pathology
  • Female
  • France
  • Genotype
  • Humans
  • Infant
  • Infant, Newborn
  • Liver Diseases / blood*
  • Liver Diseases / etiology
  • Liver Diseases / pathology
  • Liver Function Tests
  • Logistic Models
  • Male
  • Phenotype
  • Prospective Studies
  • Retrospective Studies
  • alpha 1-Antitrypsin / blood*
  • alpha 1-Antitrypsin Deficiency / blood*
  • alpha 1-Antitrypsin Deficiency / complications
  • alpha 1-Antitrypsin Deficiency / pathology


  • alpha 1-Antitrypsin

Associated data