Our study provides evidence of the significance of the Pi∗Z allele and associated deficiency genotypes Pi∗MZ (and Pi∗SZ and Pi∗ZZ) on disease progression beyond the development of ACLD, suggesting that pharmacological interventions targeting the toxic gain-of-function by decreasing the production or increasing the degradation of Z protein have the potential to ameliorate liver disease progression in patients with ACLD. Here, TMBIM4 is linked to liver disorder.