“For many years we have known that most kids with ZZ Alpha-1 do fine, but a few get very sick and are even at risk of needing a life saving liver transplant. Previously, we did not have a way to predict which kids might be at high risk of severe disease. Now, for the first time, thanks to the Alpha-1 Foundation’s support of the nationwide Childhood Liver Disease Research Network, we have developed the first tool to predict kids at high risk of severe disease. The work continues and a second generation, even more powerful tool, is now under development. Thanks to the Foundation, the patients and families who participated in the study and the US National Institutes of Health (NIH) for enabling this first if its kind discovery.” – Jeffrey Teckman MD, Pediatric Gastroenterology
Background and Aims
Children with alpha-1-antitrypsin deficiency (AATD) exhibit a wide range of liver disease outcomes from portal hypertension and transplant to asymptomatic without fibrosis. Individual outcomes cannot be predicted. Liver injury in AATD is caused by the accumulation in hepatocytes of the mutant Z alpha-1-antitrypsin (AAT) protein, especially the toxic, intracellular polymerized conformation. AATD patients have trace Z polymer detectable in serum with unknown significance.
Methods
The Childhood Liver Disease Research Network is an NIH consortium for the study of pediatric liver diseases, including AATD. We obtained data and samples with the aim of identifying biomarkers predictive of severe AATD liver disease.
Results
We analyzed prospective AATD Childhood Liver Disease Research Network data and serum samples in 251 subjects from 2007 to 2015 for outcomes and Z polymer levels. Fifty-eight of 251 had clinically evident portal hypertension (CEPH) at enrollment, and 10 developed CEPH during follow-up. Higher Z AAT polymer levels were associated with existing CEPH (P = .01). In infants without CEPH, higher polymer levels were associated with future CEPH later in childhood, but total AAT was not predictive. Higher gamma-glutamyl transferase (GGT) in the first few months of life was also significantly associated with future CEPH, and risk-threshold GGT levels can be identified. A model was constructed to identify subjects at high risk of future CEPH by combining clinical GGT and polymer levels (area under the curve of 0.83; 95% confidence interval: 0.656–1.00, P = .019).
Conclusion
High circulating Z polymer levels and high GGT early in life are associated with future CEPH in AATD, and the use of predictive cutoffs may assist in future clinical trial design.
Click here to read the full scientific article in Gastro Hep Advances, Vol. 3, Issue 6.
