α-1 Antitrypsin deficiency-associated liver disease (AATD-LD) remains underrecognized despite its significant contribution to morbidity and mortality in adults with the PiZZ genotype. Lack of standardized definitions, diagnostic criteria, and staging impedes timely diagnosis and therapeutic development. To address these gaps, a multi-disciplinary expert panel convened under the auspices of the American Gastroenterological Association in collaboration with the American Association for the Study of Liver Diseases, European Association for the Study of the Liver, and Alpha-1 Foundation to develop consensus recommendations for nomenclature, diagnosis, staging, and clinical trial endpoints in AATD-LD.

Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes.

Alpha-antitrypsin (AAT) deficiency results from carriage of a homozygous “Z” mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency.

Liver disease in homozygous ZZ alpha-1 antitrypsin (AAT) deficiency occurs due to the accumulation of large quantities of AAT mutant Z protein polymers in the liver. The mutant Z protein folds improperly during biogenesis and is retained within the hepatocytes rather than appropriately secreted. These intracellular polymers trigger an injury cascade, which leads to liver injury. However, the clinical liver disease is highly variable and not all patients with this same homozygous ZZ genotype develop liver disease. Evidence suggests that genetic determinants of intracellular protein processing, among other unidentified genetic and environmental factors, likely play a role in liver disease susceptibility. Advancements made in development of new treatment strategies using siRNA technology, and other novel approaches, are promising, and multiple human liver disease trials are underway.

The clinical presentation of liver disease is highly variable in homozygous ZZ alpha-1 antitrypsin (AAT) deficiency, and not all patients with the homozygous ZZ genotype develop liver disease. Although not fully identified, there is likely a strong influence of genetic and environmental modifiers of the intracellular injury cascade and fibrotic response. Most ZZ children are well and remain undiagnosed. Of those who come to medical attention, the most common pediatric presentation is neonatal cholestatic hepatitis, sometimes referred to as “neonatal hepatitis syndrome”. The gold standard for diagnosis of AAT deficiency is analysis of the AAT protein phenotype in the patient serum or the genotype of their DNA genome. Careful follow up of all diagnosed children is important. Heterozygotes for S and Z alleles of AAT (SZ) may develop progressive liver disease similar to ZZ patients and also require close monitoring. There is no specific treatment for AAT deficiency induced liver disease and current therapy remains supportive with management of complications. Rarely, patients require liver transplant and typically the patient outcomes are excellent. With improved understanding of liver injury mechanisms, new strategies for treatment are now being explored, including siRNA technology, molecules to modulate secretion, and enhancers of proteolysis.