Alpha-1 antitrypsin deficiency (AATD) is a rare, underdiagnosed genetic disorder characterized by deficient or dysfunctional alpha-1 antitrypsin (AAT), leading to unopposed neutrophil protease activity. This can often lead to progressive lung and liver damage, and in rare cases panniculitis, which can be potentially lethal. Current diagnostic strategies rely on a stepwise approach beginning with serum AAT measurement, followed by phenotyping and genotyping to confirm pathogenic variants. Despite recommendations from major respiratory societies to test all patients with chronic obstructive pulmonary disease (COPD), unexplained liver disease, panniculitis, and vasculitis, delayed recognition persists because of clinical overlap with asthma, COPD, and alcohol- and non-alcohol-related liver disease. Management emphasizes lifestyle modification, avoidance of risk factors, and pharmacological support. Currently, intravenous augmentation therapy is the only disease-modifying option approved for pulmonary disease. Augmentation is expensive and variably available, or reimbursed worldwide. Surgical and interventional approaches, including lung volume reduction techniques and transplantation, provide options for advanced disease, although outcomes vary. Emerging therapies, such as inhaled AAT formulations, recombinant fusion proteins, RNA-editing platforms, and DNA editing using CRISPR-based strategies, aim to correct the protease-antiprotease imbalance and restore endogenous AAT production. The therapeutic landscape is rapidly evolving, but significant challenges remain in improving early detection, broadening access to effective treatments, and optimizing individualized care. Future advances will likely depend on integrating newer therapies with early intervention strategies to preserve organ function and improve long-term prognosis.
Mawani et al. (Thu,) studied this question.