Alpha-1 Antitrypsin Deficiency (AATD) is a disorder resulting from the body’s inability to produce sufficient levels of a protective protein called alpha-1 antitrypsin (AAT). This protein deficiency is recognized as one of the most common serious genetic disorders affecting adults and children. Despite the inflammatory consequences of the condition, AATD is not classified as an autoimmune disease. Its origin lies in a specific error within a single gene, making it an inherited genetic disorder.
Understanding Autoimmune Versus Inherited Disease
The mechanisms behind autoimmune diseases and inherited genetic disorders are fundamentally different. An autoimmune disease occurs when the adaptive immune system malfunctions, mistakenly identifying healthy body tissues as foreign invaders. The immune system then mounts a direct, sustained attack against these self-antigens, leading to chronic inflammation and tissue destruction. These conditions are typically considered multifactorial, arising from a complex interplay of genetic predisposition and environmental triggers.
Inherited diseases, in contrast, are caused by errors or mutations in an individual’s DNA that are passed down through generations. These genetic errors lead to the production of non-functional proteins or an insufficient quantity of a normal protein. The resulting health issue is a direct consequence of this protein failure, not an attack by the immune system on healthy cells.
AATD is explicitly an inherited disorder because it results from mutations in the SERPINA1 gene. The damage seen in AATD is a consequence of a lack of protection, whereas in an autoimmune disorder, the damage is a result of an aggressive, misdirected attack.
The Function of Alpha-1 Antitrypsin Protein
The AAT protein is a member of the serine protease inhibitor family, known as a serpin, and is primarily synthesized in the liver. Its main function is to act as a potent inhibitor of certain enzymes released by inflammatory cells, particularly neutrophil elastase. Neutrophil elastase is a powerful enzyme released by white blood cells to break down damaged tissue and bacteria during infection or inflammation. If left unchecked, this enzyme can indiscriminately destroy healthy tissue, especially the delicate structure of the lungs.
In healthy individuals, the AAT protein circulates in the bloodstream and neutralizes neutrophil elastase after it has served its purpose, acting as a protective shield. The most common mutation (Z allele) causes the newly synthesized AAT protein to misfold into an abnormal shape. These misfolded proteins are unable to be properly secreted into the bloodstream and instead accumulate within the hepatocytes, the liver cells where they are produced. This entrapment prevents the protective AAT from reaching the lungs in sufficient quantities.
Mechanisms of Organ Damage in AATD
The organ damage in AATD stems from two distinct pathological processes affecting the lungs and the liver. In the lungs, the lack of circulating AAT protein leaves the tissue defenses severely compromised. When inflammation or infection occurs, neutrophils release elastase, which goes uninhibited without AAT to neutralize it. This unblocked elastase degrades the elastin and structural components of the lung tissue, destroying the walls of the small air sacs (alveoli). This constant breakdown leads to the development of panacinar emphysema.
The second mechanism of damage occurs within the liver, the site of AAT production. The misfolded AAT proteins (Z polymers) aggregate into large, insoluble chains inside the liver cells. This accumulation creates cellular stress and activates inflammatory pathways within the hepatocytes. The resulting chronic inflammation and cellular injury can lead to fibrosis, cirrhosis, or liver failure in some patients.
Identifying and Treating Alpha-1 Antitrypsin Deficiency
Diagnosis of AATD typically involves simple blood tests to determine the level of AAT protein circulating in the blood. Abnormally low levels signal the possibility of a deficiency, prompting further investigation. Genetic testing is then performed to confirm the diagnosis by identifying the specific mutations present in the SERPINA1 gene, such as the common Z allele.
The standard treatment for the lung component of AATD is AAT augmentation therapy. This involves intravenously infusing purified AAT protein harvested from the plasma of healthy donors. The goal is to raise the concentration of AAT in the bloodstream and lungs, restoring the protective shield against neutrophil elastase. This treatment helps to slow the progression of lung damage and preserve lung function.
For liver involvement, treatment is focused on managing symptoms and complications. In severe cases where liver function declines significantly, a liver transplant may be required to remove the source of the misfolded protein. Lifestyle modifications, such as avoiding smoking and excessive alcohol consumption, are also crucial components of the treatment plan.