Biomarkers Associated With Future Severe Liver Disease in Children With Alpha-1-Antitrypsin Deficiency

Abstract

Background and AimsChildren 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 accumulation in hepatocytes of the mutant Z 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 (ChiLDReN) 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 ChiLDReN data and serum samples in 251 subjects from 2007-2015 for outcomes and Z polymer levels. 58 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=0.01). In infants without CEPH, higher polymer levels were associated with future CEPH later in childhood, but total AAT was not predictive. Higher 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 identifying subjects at high risk of future CEPH by combining clinical GGT and polymer levels (area under the curve (AUC) 0.83; 95% CI: 0.656 – 1.00, p = 0.019). Conclusions: High circulating Z polymer levels and high GGT early in life are associated with future CEPH in AATD, and use of predictive cutoffs may assist in future clinical trial design.