Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by low levels or decreased activity of the protein alpha-1 antitrypsin (AAT).

AATD is caused by mutations on the SERPINA1 gene and is inherited in an autosomal co-dominant manner. Over 150 mutations in the SERPINA1 gene have been identified and are associated with variable presentations of disease. In terms of severity, alleles are named MM (normal), MS, MZ, SZ, and ZZ (most severe). Abnormal alleles lead to intracellular accumulation of abnormally polymerized AAT and lower than normal plasma concentration of AAT. Sequestration of AAT produced in the liver in hepatocytes is thought to be responsible for liver disease. Reduced protease (eg, neutrophil elastase) inhibition by AAT in the circulation and consequent abnormal pulmonary elastic breakdown is thought to contribute to chronic obstructive pulmonary disease (COPD).

Prevalence varies considerably globally; however, it is estimated that approximately 3 million people worldwide are genotypically severely AAT deficient, and nearly 100 000 of those individuals are in the United States. The ZZ genotype is the rarest, affecting 1/2000-4000 individuals, while the MS and MZ genotypes are more common, accounting for 1/10 and 1/25 of the general population.

Disease manifestations and complications vary. Liver disease and lung disease are the most frequent manifestations seen. Patients are typically not diagnosed until after development of early COPD in their 40s or 50s or in the setting of early-onset liver disease. Earlier presentations, such as neonatal hepatitis, can develop in 10% of patients. Recurrent panniculitis, while rare, is typically the initial notable cutaneous manifestation.

Patients may also have increased risk for chronic kidney disease, diabetes, metabolic alterations, ANCA-associated vasculitis, gallstone disease, emphysema, nonalcoholic fatty liver disease, cirrhosis, and advanced liver fibrosis.

Cigarette smoking is one of the strongest drivers of rate of decline in lung function and consequently increases risk of death due to respiratory failure. Male sex and obesity may convey an increased risk of progression of liver injury to progressive hepatic failure over other traditional liver risk factors, such as alcohol use disorder and viral hepatitis. Respiratory failure and liver disease are major causes of mortality in severely deficient patients.