Fromme et al. summarize both the pathophysiology of this disorder arising from the retention of mutated AAT in hepatocytes as well as the hepatic consequences of the major AATD genotypes. While the homozygous Pi*Z mutation (Pi*ZZ genotype) is seen in 1:2,000 individuals of European descent and confers a strong susceptibility to both paediatric and adult liver disease, the heterozygous Pi*Z mutation (Pi*MZ) occurs in 1:30 Caucasians and presents a disease modifier rather than a causative factor. The authors explain the factors promoting AATD-associated liver disease, as well as new diagnostic and thera-peutic approaches in the field.
The progress in understanding of the disease led to a phase 2 clinical trial that was lead by ERN Rare Liver In-vestigators. They could show that treatment with the siRNA fazirsiran markedly suppresses AAT production and improves liver-related parameters thereby giving a hope to subjects with the currently untreatable disorder.