Alpha-1 antitrypsin deficiency: genetics, clinical manifestations, AI prognostics, and advanced imaging in liver disease

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder caused by mutations in the <i>SERPINA1</i> gene, resulting in reduced or dysfunctional alpha-1 antitrypsin (AAT) protein. This deficiency leads to progressive lung and liver diseases, including emphysema, chronic obstructive pulmonary disease, and cirrhosis. Despite its clinical significance, AATD remains underdiagnosed, delaying treatment. This review explores the molecular mechanisms of AATD, emphasizing Z-variant AAT protein accumulation in hepatocytes and excessive protease activity in the lungs. Advancements in imaging modalities - such as computed tomography, magnetic resonance imaging (MRI), dark-field radiography, and hyperpolarized MRI - enhance early diagnosis and disease monitoring. Novel therapies are reshaping AATD management, including small interfering RNA therapies (fazirsiran, belcesiran), gene-editing techniques (CRISPR-Cas9), regenerative approaches, autophagy-enhancing drugs, proteostasis regulators, aerosolized AAT, and artificial intelligence (AI) for real-time disease tracking via wearable devices. The integration of AI, advanced imaging, and emerging therapies represents a paradigm shift in AATD diagnosis and treatment. This review highlights the need for a multidisciplinary approach, early intervention, and personalized medicine to improve outcomes in both pulmonary and hepatic complications.