Alpha-1 antitrypsin deficiency (AATD) is a congenital disorder that primarily affects the lungs and liver. It is characterized by low levels of the protein alpha-1 antitrypsin (AAT) in the blood. The deficiency is caused by mutations on the SERPINA1 gene and is inherited by autosomal co-dominant transmission. Over 150 mutations in the SERPINA1 gene have been identified and are associated with variable presentations of disease. Many of these mutations cause so-called "toxic loss of function" resulting in lack of destruction of elastase and other proteases, while others cause "toxic gain of function" leading to intracellular accumulation of abnormally polymerized AAT. The normal phenotype is PiMM; common abnormal phenotypes include PiZZ and PiMZ.

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.

Symptoms and complications vary. Patients may have increased risk for chronic kidney disease, diabetes, metabolic alterations, ANCA-associated vasculitis, gallstone disease, emphysema, chronic obstructive pulmonary disease (COPD) (especially current and former smokers), cystic fibrosis–associated liver disease with portal hypertension, nonalcoholic fatty liver disease cirrhosis, and advanced liver fibrosis.

Patients presenting within the first four decades of life are more commonly at risk of suffering complications due to liver dysfunction. 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. Studies show that as many as 40% of AATD patients with mutations causing "toxic gain of function" accumulation of AAT in hepatocytes demonstrate histologically significant liver injury and cirrhosis at time of death. 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 (72% and 10%, respectively).