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.
| Original language | English (US) |
|---|---|
| Article number | e0345 |
| Journal | Hepatology Communications |
| Volume | 7 |
| Issue number | 12 |
| DOIs | |
| State | Published - Dec 2023 |
Funding
Jeffrey Teckman consults and received grants from BioMarin, KorroBio, NeuBase, Takeda, Vertex, and UniQure. He consults for Arrowhead and Intellia. Philip Rosenthal consults and received grants from Albireo. He consults for Audentes, BioMarin, Dicerna, Encoded, and MedinCell and received grants from AbbVie and Gilead. Lee Bass consults and is on the speakers’ bureau for Mirum. He consults for AstraZeneca and Albireo and is on the speakers’ bureau for Mead Johnson Nutrition. Simon Horslen consults and received grants from Albireo. He consults for iECURE and Alexion and received grants from Mirum. Saul Karpen consults for Albireo/Ipsen, Mirum, Hemoshear and Intercept. Binita Kamath consults and received grants from Mirum and Albireo. She consults for Audentes. Kathleen Loomes consults and received grants from Mirum and Albireo. She consults for Travere. Ronald Sokol advises Mirum, Albireo, and Astellas. Jean Molleston received grants from Cf Foundation, Mirum, Albireo, AbbVie, and Gilead. The remaining authors have no conflicts to report. This work was supported by funding from the Alpha-1 Foundation (University of Colorado Denver and Saint Louis University School of Medicine) and by U01 grants from the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) and UL1 grants from the National Center for Advancing Translational Sciences (NCATS): DK062445 (Mt. Sinai School of Medicine), DK062497 and UL1 TR000077 (Cincinnati Children's Hospital Medical Center, University of Cincinnati), DK103149 (Baylor College of Medicine), DK062470 (Children's Healthcare of Atlanta, Emory University), DK062481 and UL1 TR000003 (The Children's Hospital of Philadelphia, University of Pennsylvania), DK062456 (University of Michigan), DK084536 and UL1 TR000006 (Riley Hospital for Children, Indiana University), DK084575 and UL1 TR000423 (Seattle Children's Hospital, University of Washington), DK062500 and UL1 TR000004 (UCSF Children's Hospital, University of California San Francisco), DK062503 and UL1 TR000424 (Johns Hopkins School of Medicine), DK062466 and UL1 TR000005 (Children's Hospital of Pittsburgh, University of Pittsburgh), DK062453 and UL1 TR002535 (University of Colorado Denver, Children's Hospital Colorado), DK062452 and UL1 TR000448 (Washington University School of Medicine, St. Louis, St. Louis Children's Hospital), DK084538 and UL1 TR000130 (Children's Hospital Los Angeles, University of Southern California), DK062436 and UL1 TR000150 (Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University), DK103140 (University of Utah), DK103135 (Hospital for Sick Children, Toronto). This work was supported by funding from the Alpha-1 Foundation (University of Colorado Denver and Saint Louis University School of Medicine) and by U01 grants from the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK) and UL1 grants from the National Center for Advancing Translational Sciences (NCATS): DK062445 (Mt. Sinai School of Medicine), DK062497 and UL1 TR000077 (Cincinnati Children’s Hospital Medical Center, University of Cincinnati), DK103149 (Baylor College of Medicine), DK062470 (Children’s Healthcare of Atlanta, Emory University), DK062481 and UL1 TR000003 (The Children’s Hospital of Philadelphia, University of Pennsylvania), DK062456 (University of Michigan), DK084536 and UL1 TR000006 (Riley Hospital for Children, Indiana University), DK084575 and UL1 TR000423 (Seattle Children’s Hospital, University of Washington), DK062500 and UL1 TR000004 (UCSF Children’s Hospital, University of California San Francisco), DK062503 and UL1 TR000424 (Johns Hopkins School of Medicine), DK062466 and UL1 TR000005 (Children’s Hospital of Pittsburgh, University of Pittsburgh), DK062453 and UL1 TR002535 (University of Colorado Denver, Children’s Hospital Colorado), DK062452 and UL1 TR000448 (Washington University School of Medicine, St. Louis, St. Louis Children’s Hospital), DK084538 and UL1
ASJC Scopus subject areas
- Hepatology
