Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance

Jeffrey Teckman; Philip Rosenthal; Rosalinda V Ignacio; Cathie Spino; Lee M Bass; Simon Horslen; Kasper Wang; John C Magee; Saul Karpen; Akihiro Asai; Jean P Molleston; Robert H Squires; Binita M Kamath; Stephen L Guthery; Kathleen M Loomes; Benjamin L Shneider; Ronald J Sokol; ChiLDReN (Childhood Liver Disease Research Network)

doi:10.1097/HC9.0000000000000345

Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance

Hepatol Commun. 2023 Dec 7;7(12):e0345. doi: 10.1097/HC9.0000000000000345. eCollection 2023 Dec 1.

Authors

Jeffrey Teckman¹, Philip Rosenthal², Rosalinda V Ignacio³, Cathie Spino³, Lee M Bass⁴, Simon Horslen⁵, Kasper Wang⁶, John C Magee⁷, Saul Karpen⁸, Akihiro Asai⁹, Jean P Molleston¹⁰, Robert H Squires¹¹, Binita M Kamath¹², Stephen L Guthery¹³, Kathleen M Loomes¹⁴, Benjamin L Shneider¹⁵, Ronald J Sokol¹⁶; ChiLDReN (Childhood Liver Disease Research Network)

Affiliations

¹ Department of Pediatrics and Biochemistry, Saint Louis University, Cardinal Glennon Children's Hospital, Saint Louis, Missouri, USA.
² Department of Pediatrics and Surgery, University of California San Francisco, San Francisco, California, USA.
³ Department of Biostatistics, University of Michigan, Ann Arbor, Michigan, USA.
⁴ Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
⁵ Department of Pediatric Gastroenterology and Hepatology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, Washington, USA.
⁶ Department of Pediatric Gastroenterology, Children's Hospital Los Angeles, Los Angeles, California, USA.
⁷ Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
⁸ Department of Pediatrics, Emory University, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.
⁹ Department of Gastroenterology, and Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
¹⁰ Department of Pediatric Gastroenterology, Hepatology and Nutrition, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana, USA.
¹¹ Department of Pediatrics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹² Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology and Nutrition, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
¹³ Department of Pediatrics, University of Utah College of Medicine and Intermountain Primary Children's Hospital, Salt Lake City, Utah, USA.
¹⁴ Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology and Nutrition, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
¹⁵ Department of Pediatric Gastroenterology, Hepatology and Nutrition, Baylor College of Medicine, Texas Children's Hospital, Houston, Texas, USA.
¹⁶ Department of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.

Abstract

Background: Our objective was to better understand the natural history and disease modifiers of Alpha-1-antitrypsin deficiency (AATD), a common genetic liver disease causing hepatitis and cirrhosis in adults and children. The clinical course is highly variable. Some infants present with neonatal cholestasis, which can resolve spontaneously or progress to cirrhosis; others are well in infancy, only to develop portal hypertension later in childhood.

Methods: The Childhood Liver Disease Research Network has been enrolling AATD participants into longitudinal, observational studies at North American tertiary centers since 2004. We examined the clinical courses of 2 subgroups of participants from the several hundred enrolled; first, those presenting with neonatal cholestasis captured by a unique study, enrolled because of neonatal cholestasis but before specific diagnosis, then followed longitudinally (n=46); second, separately, all participants who progressed to liver transplant (n=119).

Results: We found male predominance for neonatal cholestasis in AATD (65% male, p=0.04), an association of neonatal gamma-glutamyl transpeptidase elevation to more severe disease, and a higher rate of neonatal cholestasis progression to portal hypertension than previously reported (41%) occurring at median age of 5 months. Participants with and without preceding neonatal cholestasis were at risk of progression to transplant. Participants who progressed to liver transplant following neonatal cholestasis were significantly younger at transplant than those without neonatal cholestasis (4.1 vs. 7.8 years, p=0.04, overall range 0.3-17 years). Neonatal cholestasis had a negative impact on growth parameters. Coagulopathy and varices were common before transplant, but gastrointestinal bleeding was not.

Conclusions: Patients with AATD and neonatal cholestasis are at risk of early progression to severe liver disease, but the risk of severe disease extends throughout childhood. Careful attention to nutrition and growth is needed.

Trial registration: ClinicalTrials.gov NCT00061828 NCT00571272.

MeSH terms

Child
Cholestasis* / genetics
Female
Humans
Hypertension, Portal* / etiology
Infant
Infant, Newborn
Liver Cirrhosis / diagnosis
Liver Cirrhosis / epidemiology
Liver Cirrhosis / etiology
Male
Phenotype
alpha 1-Antitrypsin / metabolism
alpha 1-Antitrypsin Deficiency* / complications
alpha 1-Antitrypsin Deficiency* / diagnosis
alpha 1-Antitrypsin Deficiency* / epidemiology

Neonatal cholestasis in children with Alpha-1-AT deficiency is a risk for earlier severe liver disease with male predominance

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