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Biomarkers Associated With Future Severe Liver Disease in Children With Alpha-1-Antitrypsin Deficiency
Jeffrey H Teckman1, Paula Buchanan2, Keith Steven Blomenkamp1
1Department of Pediatrics and Biochemistry and Molecular Biology, St. Louis University School of Medicine, Cardinal Glennon Children's Hospital, St. Louis, Missouri.
Insights
High Z polymer levels and gamma-glutamyl transferase (GGT) in early childhood predict severe liver disease in alpha-1-antitrypsin deficiency (AATD). This finding aids in identifying at-risk children for clinical trials.
Area of Science:
- Pediatric Hepatology
- Genetic Liver Diseases
- Biomarker Discovery
Background:
- Alpha-1-antitrypsin deficiency (AATD) causes variable liver disease in children, from asymptomatic to severe portal hypertension.
- Liver injury in AATD is linked to mutant Z alpha-1-antitrypsin (AAT) protein accumulation and polymerization within hepatocytes.
- The significance of circulating Z polymer in AATD patients remains unclear.
Purpose of the Study:
- To identify predictive biomarkers for severe liver disease in pediatric AATD.
- To analyze the relationship between Z polymer levels and clinical outcomes in children with AATD.
Main Methods:
- Analysis of prospective data and serum samples from 251 pediatric AATD subjects (2007-2015).
- Assessment of Z AAT polymer levels, total AAT, and gamma-glutamyl transferase (GGT) in relation to liver disease outcomes.
- Development of a predictive model for clinically evident portal hypertension (CEPH).
Main Results:
- Higher Z AAT polymer levels correlated with existing CEPH (P = .01).
- In infants, elevated polymer levels predicted future CEPH, while total AAT levels did not.
- High early-life GGT was significantly associated with future CEPH.
- A predictive model combining GGT and polymer levels achieved an AUC of 0.83 (P = .019).
Conclusions:
- Elevated circulating Z polymer and early-life GGT are associated with future severe liver disease (CEPH) in pediatric AATD.
- Predictive cutoffs for these biomarkers can aid in designing future clinical trials for AATD.
- This research offers valuable insights into early risk stratification for AATD-related liver complications.
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.
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