Beyond cirrhosis: Major adverse liver outcomes across homozygous and heterozygous Alpha-1 antitrypsin deficiency associated liver disease.

AATD-associated liver disease (AATD-LD) is defined by elevation of AST, ALT or GGT, which may be episodic, and/or liver fibrosis >=F2, in adults with AATD, particularly but not exclusively those with the PiZZ genotype. Include a serum alpha-1 antitrypsin level in the diagnostic evaluation of chronic liver disease, and confirm a low level with genotyping. Stage fibrosis with noninvasive elastography (vibration-controlled transient elastography or magnetic resonance elastography) as the preferred method; liver biopsy is not routinely required and is reserved for cases where competing etiologies must be excluded. Follow patients with a tiered longitudinal algorithm of serial noninvasive testing, with timely referral for liver transplantation evaluation. There is no approved AATD-specific therapy for the liver disease: manage cirrhosis and its complications per standard of care, perform HCC surveillance with ultrasound +/- AFP every 6 months once cirrhotic, screen for varices per standard cirrhosis practice, and refer early for transplant evaluation in decompensated disease (ascites, variceal bleeding, or hepatic encephalopathy). Intravenous augmentation therapy is explicitly NOT recommended as treatment for AATD liver disease (Alpha-1 Foundation 2016, Rec 3j, strong recommendation); its role is pulmonary, where it is strongly recommended for FEV1 30-65% predicted, also recommended (weak, low-quality evidence) for FEV1 <30%, a matter for individualized benefit-versus-cost discussion above 65%, and not recommended for the MZ genotype with COPD or for those who continue to smoke. Tobacco exposure prevention and cessation is a strong, high-quality-evidence recommendation. Adult siblings of an affected individual should be offered genetic counseling and testing (strong, moderate quality); parents, children and extended family should also be offered counseling and testing (weak, low quality). For trial design, phase 3 should enroll F2-F4; F1 may suit phase 1-2 safety studies; cirrhotics may be excluded depending on therapeutic class; preserved pulmonary function is not required for trials of DNA/RNA-editing therapies that raise AAT levels; the consensus primary efficacy endpoint is a >=1-stage improvement in fibrosis.