Systematic review shows high rates of fibrosis and cirrhosis in children with Pi*ZZ alpha-1 antitrypsin deficiency1 in 4 children with A1AT deficiency develop cirrhosis

BACKGROUND: Pediatric Pi*ZZ alpha-1 antitrypsin deficiency (A1ATD) can cause hepatocyte A1AT polymer retention and progressive liver injury, but estimates of childhood liver morbidity vary across studies and remain poorly defined. AIM: To quantify liver-specific outcomes in pediatric Pi*ZZ A1ATD. METHODS: We systematically reviewed studies reporting liver-specific outcomes in children with confirmed Pi*ZZ/ZZ A1ATD (PROSPERO CRD42022335666). We extracted prevalence of fibrosis and cirrhosis, elevated liver enzymes, and liver transplantation. Random-effects meta-analysis pooled logit-transformed proportions (with sensitivity analyses assessing robustness to model assumptions). RESULTS: Thirteen studies including 398 children met inclusion criteria. Pooled prevalence was 41.3% (95% CI 29.6-54.0) for fibrosis and 17.3% (7.2-35.9) for cirrhosis, with substantial heterogeneity for cirrhosis (I 78.6%). Liver transplantation prevalence was 10.7% (6.3-13.0). Elevated liver enzymes occurred in 43.0% (19.2-70.5) with high heterogeneity (I 89.4%). Across cohorts, the proportion with elevated liver enzymes declined with increasing mean age, despite ongoing liver disease in reported histology-based outcomes. CONCLUSIONS: Clinically important liver disease occurs in a substantial subset of children with Pi*ZZ A1ATD. Declining rates of elevated liver enzymes with age should not be interpreted as disease resolution. Standardized registries are needed for longitudinal surveillance, to identify disease modifiers, and to guide early intervention in this high-risk population.