Longitudinal Outcomes in Young Patients with Alpha-1-Antitrypsin Deficiency with Native Liver Reveal that Neonatal Cholestasis is a Poor Predictor of Future Portal Hypertension

J Pediatr. 2020 Dec;227:81-86.e4. doi: 10.1016/j.jpeds.2020.07.031. Epub 2020 Jul 11.


Objectives: To identify predictors of portal hypertension, liver transplantation, and death in North American youth with alpha-1-antitrypsin (AAT) deficiency, and compare with patients with AAT deficiency elsewhere.

Study design: The Childhood Liver Disease Research Network Longitudinal Observational Study of Genetic Causes of Intrahepatic Cholestasis is a prospective, cohort study of pediatric cholestatic liver diseases, including AAT deficiency, enrolling PIZZ and PISZ subjects 0-25 years of age seen since November 2007 at 17 tertiary care centers in the US and Canada. Data from standard-of-care baseline and annual follow-up visits were recorded from medical records, history, physical examination, and laboratory studies. Participants with portal hypertension were identified based on data collected.

Results: We enrolled 350 participants (60% male) with a native liver; 278 (79%) entered the cohort without portal hypertension and 18 developed portal hypertension during follow-up. Thirty participants required liver transplantation; 2 patients died during 1077 person-years of follow-up. There was no difference in participants with or without preceding neonatal cholestasis progressing to transplantation or death during the study (12% vs 7%; P = .09), or in experiencing portal hypertension (28% vs 21%; P = .16); the hazard ratio for neonatal cholestasis leading to portal hypertension was P = .04. Development of portal hypertension was associated with a reduced height Z-score.

Conclusions: Portal hypertension in youth with AAT deficiency impacts growth measures. Progression to liver transplantation is slow and death is rare, but the risk of complications and severe liver disease progression persists throughout childhood. A history of neonatal cholestasis is a weak predictor of severe disease.

Keywords: cirrhosis; jaundice; liver enzymes; liver transplant; metabolic liver disease.

Publication types

  • Multicenter Study
  • Observational Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cholestasis, Intrahepatic / complications*
  • Disease Progression
  • Female
  • Humans
  • Hypertension, Portal / etiology*
  • Hypertension, Portal / surgery
  • Infant
  • Infant, Newborn
  • Liver Transplantation
  • Longitudinal Studies
  • Male
  • Young Adult
  • alpha 1-Antitrypsin Deficiency / blood
  • alpha 1-Antitrypsin Deficiency / complications*

Grant support