Severe deficiency of alpha-1 antitrypsin (AAT) is associated with early onset pulmonary emphysema and with several forms of liver disease, including cirrhosis, neonatal hepatitis, and hepatocellular carcinoma. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency" and "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency".)
The discovery of the structure and function of the AAT protein, and its subsequent isolation and purification, have allowed replacement therapy (so-called "augmentation therapy") aimed at preventing progression of the associated lung disease [1,2]. Isolation of the gene and advances in gene therapy further broadened the potential for specific therapy.
The normal plasma levels of AAT are 20 to 53 µmol/L (100 to 220 mg/dL by nephelometry). Population studies suggest a minimum plasma threshold of 11 µmol/L (corresponding to 80 mg/dL in some assays and ~57 mg/dL by nephelometry), below which there is insufficient AAT to protect the lung, leading to a risk of developing emphysema. Most patients below this threshold level have the PI*ZZ (protease inhibitor Z) phenotype (table 1). For other phenotypes that describe a range of plasma levels that straddle the 11µmol/L "protective threshold," the plasma levels should be used as a guide for considering augmentation therapy. A review of the different AAT alleles is discussed elsewhere. (See "Clinical manifestations, diagnosis, and natural history of alpha-1 antitrypsin deficiency".)
The current goal in the treatment of AAT deficiency is to raise the plasma AAT level (and therefore the concentration of AAT in the lung interstitium) above the protective threshold. Three major approaches have been considered to achieve this goal:
- Intravenous or aerosolized augmentation therapy
- Enhancement of endogenous alpha-1 antitrypsin production
- Gene therapy