Alpha-1 Antitrypsin Deficiency (AATD) is a hereditary disorder that limits the body’s ability to produce a protective protein called alpha-1 antitrypsin (AAT). This condition is rooted in genetic mutations that compromise the normal function or circulation of AAT, leading to low levels in the bloodstream. The resulting protein deficiency leaves certain tissues, primarily the lungs, vulnerable to damage from the body’s own defense mechanisms. AATD requires specialized medical attention to mitigate the progression of organ damage over time.
The Role of Alpha-1 Antitrypsin
The alpha-1 antitrypsin protein is a type of serpin, or serine protease inhibitor, that is primarily synthesized in the liver and then circulated throughout the body. Its main physiological function is to act as an “off switch” for specific destructive enzymes, most notably neutrophil elastase. Neutrophil elastase is a powerful enzyme released by immune cells called neutrophils to break down damaged tissue and fight infection in the lungs.
Under normal circumstances, AAT travels to the lungs and rapidly neutralizes any excess neutrophil elastase after it has completed its defensive task. This interaction maintains a delicate protease/antiprotease balance within the lung tissue, preventing indiscriminate destruction of the delicate air sacs and connective tissue. When AAT levels are severely low due to deficiency, this critical balance is lost, allowing the elastase to continue its breakdown activity unchecked. This leads directly to the gradual and permanent destruction of the lung’s elastic structures.
How AATD Affects the Body
AATD primarily involves the lungs and the liver, though the mechanism of damage differs between the two organs. In the lungs, the unchecked activity of neutrophil elastase leads to the breakdown of elastin, resulting in emphysema, a form of chronic obstructive pulmonary disease (COPD). This emphysema often presents earlier in life, typically between 30 and 50 years of age, and is characterized by shortness of breath, wheezing, and chronic cough.
The liver is affected because certain mutated forms of the AAT protein cannot be properly released from the liver cells where they are produced. Instead, the misfolded protein accumulates within the hepatocytes, triggering a toxic reaction that can lead to inflammation, scarring, and ultimately cirrhosis. Liver disease can manifest in infancy as neonatal hepatitis and jaundice, or it can progress silently to liver failure in adulthood.
AATD can also affect other systems. A rare manifestation includes necrotizing panniculitis, which involves inflammation and damage to the fat layer just beneath the skin. The severity of organ involvement can vary widely. Smoking greatly accelerates the development and severity of lung disease in individuals with AATD.
Genetic Inheritance and Risk
Alpha-1 Antitrypsin Deficiency is inherited in an autosomal co-dominant pattern, meaning the disorder is passed down through genes located on non-sex chromosomes, and the effects of both inherited genes are expressed. The condition is caused by variations in the SERPINA1 gene, which provides the instructions for making the AAT protein. Over 120 different gene variants, or alleles, have been identified, but the most common are the normal M allele (PiM) and the deficiency alleles, S (PiS) and Z (PiZ).
The combination of alleles an individual inherits determines their phenotype, which directly correlates with the amount of AAT protein in their blood. The PiMM phenotype represents two normal alleles and results in 100% of the normal AAT level. The PiZZ phenotype, resulting from two Z alleles, is the most common cause of severe deficiency, leading to AAT levels as low as 10 to 15% of normal.
Individuals who inherit one normal M allele and one Z allele (PiMZ) are considered heterozygous carriers. PiMZ carriers have reduced AAT levels—around 55% of normal—and are generally not classified as having severe deficiency. However, these carriers may still face an increased risk of developing lung disease, particularly if they smoke or are exposed to other environmental irritants.
Diagnosis and Management
The process for identifying AATD typically begins with a blood test that measures the total circulating level of the AAT protein. If the level is low, a second, more specific test called phenotyping or genotyping is performed to confirm the diagnosis and identify the exact combination of alleles. This genetic testing determines the severity of the deficiency and helps guide clinical management.
The specific medical treatment for AATD-related lung disease is Augmentation Therapy, which involves the intravenous infusion of purified AAT protein derived from healthy human donors. This therapy aims to increase the concentration of functional AAT in the blood and lungs, restoring the anti-elastase capacity. Augmentation therapy is recommended for non-smokers with established airflow limitation to slow the progressive destruction of lung tissue.
In addition to this targeted treatment, supportive care is essential for both lung and liver disease. Smoking cessation is the single most impactful action an individual can take to prevent or slow the progression of lung damage. Supportive measures for lung disease include bronchodilators and inhaled corticosteroids, similar to those used for COPD. For severe liver disease, careful monitoring is necessary, and a liver transplant may be required in cases of end-stage liver failure.