Alpha-1 Antitrypsin (AAT) is a protein produced primarily by the liver that circulates throughout the body, acting as a powerful protective agent. The AAT test is a simple blood measure used to determine the concentration of this protein in the bloodstream. Low levels are the primary indicator of Alpha-1 Antitrypsin Deficiency (AATD), a genetic condition that significantly increases the risk for certain lung and liver diseases. This test is often the first step in identifying individuals at risk for these inherited conditions.
The Essential Function of Alpha-1 Antitrypsin
AAT’s main biological job is to act as a protease inhibitor, a type of molecule that stops certain enzymes from causing tissue damage. It is a serine protease inhibitor, or serpin, and its principal target is an enzyme called neutrophil elastase (NE). Neutrophils are white blood cells that rush to sites of inflammation or infection, and they release NE to break down harmful bacteria and damaged tissue.
While neutrophil elastase is a necessary part of the immune response, it can also destroy healthy tissue if left unchecked. This is where AAT steps in, essentially acting as the “off switch” for NE. AAT binds to the elastase enzyme, neutralizing its destructive capability.
This function is particularly important in the lungs, where inflammation from environmental irritants (like smoke or pollution) leads to a continuous release of neutrophil elastase. Without sufficient AAT, the enzyme breaks down the delicate elastin fibers that form the alveoli. This unopposed breakdown ultimately causes emphysema and other forms of chronic obstructive pulmonary disease (COPD).
AAT is synthesized mainly in the liver, from where it is secreted into the bloodstream to travel to the lungs and other tissues. In cases of genetic deficiency, the AAT protein is either produced in insufficient quantity or is structurally abnormal, preventing it from reaching the lungs effectively. This creates a damaging protease-antiprotease imbalance, leaving the lungs vulnerable to proteolytic attack and subsequent deterioration.
Defining the Test and Normal Reference Range
The Alpha-1 Antitrypsin test is performed on a blood sample, usually drawn from a vein in the arm. The test quantifies the amount of AAT protein circulating in the plasma. Results are typically reported in one of two main units: milligrams per deciliter (mg/dL) or micromoles per liter (\(\mu\)mol/L).
The established normal reference range for Alpha-1 Antitrypsin in healthy adults with the common normal genotype (PiMM) generally falls between 100 and 300 mg/dL. When expressed in molar concentration, this range is approximately 20 to 53 \(\mu\)mol/L. These ranges can vary based on the specific analytical method used by the testing laboratory.
A level is considered deficient and an indicator for further evaluation if it falls below 100 mg/dL (approximately 18.4 \(\mu\)mol/L). Clinicians commonly use a lower threshold of 11 \(\mu\)mol/L (about 57 mg/dL) as the protective level, below which the risk of developing emphysema becomes significantly higher. These cutoffs help determine the severity of a potential deficiency and guide subsequent diagnostic steps.
The normal range reflects the concentration required to maintain a protective antiprotease shield within the lungs. Individuals with the common normal genotype, PiMM, produce fully functional AAT in adequate amounts. A result falling within this range suggests the patient is protected from the proteolytic damage associated with AAT deficiency.
What Abnormal Alpha-1 Antitrypsin Levels Indicate
Levels outside the normal reference range can point to different underlying physiological states. A significantly low AAT result suggests Alpha-1 Antitrypsin Deficiency (AATD), an inherited disorder. The most severe form of AATD, associated with the PiZZ genotype, typically results in very low serum levels, often only 10% to 20% of the normal range.
These low levels result in a severe lack of protection in the lungs, predisposing individuals to early-onset emphysema and COPD, particularly if they smoke. Low AAT concentrations also increase the risk of liver disease, as the abnormal protein builds up in the liver cells, leading to scarring and potential cirrhosis. The risk of lung disease becomes especially high when AAT levels drop below the protective threshold of 11 \(\mu\)mol/L.
Conversely, an AAT test result that is higher than the normal range does not typically indicate a genetic deficiency. Alpha-1 Antitrypsin is classified as an acute phase reactant, meaning its concentration in the blood naturally increases in response to inflammation, infection, or trauma. Therefore, elevated levels are often a temporary finding caused by conditions like pneumonia, bronchitis, or even pregnancy.
Certain medications, such as oral contraceptives, can also cause a temporary increase in AAT levels. In these cases, the high reading is a sign of the body’s general inflammatory response or hormonal status, not a disease process. High AAT levels are generally not a cause for concern unless they suggest an underlying inflammatory condition requiring attention.
Follow-Up Testing and Management Overview
When an initial quantitative AAT test returns a low or borderline result, confirmatory testing is necessary to establish a definitive diagnosis of AATD. The next step involves determining the specific genetic variants, or alleles, responsible for the low levels. This is accomplished through phenotyping or genotyping, which identifies the specific form of the SERPINA1 gene the individual possesses.
Phenotyping uses isoelectric focusing to identify different protein variants, while genotyping identifies specific DNA mutations, such as the common deficient PiZ or PiS alleles. These tests are crucial because the severity of the deficiency and the associated disease risk depend on the specific combination of alleles. For instance, the PiZZ genotype faces a much higher risk of lung and liver disease compared to the PiMZ genotype.
Management for diagnosed AATD focuses on preventing or slowing the progression of lung damage. Supportive care includes avoiding all tobacco smoke, receiving appropriate vaccinations, and using standard medications for COPD symptoms, like bronchodilators. For those with established lung disease and low AAT levels, a specific treatment called augmentation therapy may be recommended.
Augmentation therapy involves the regular intravenous infusion of purified, healthy AAT protein derived from human plasma donors. This treatment aims to raise the circulating AAT level above the protective threshold, providing the lungs with the necessary antiprotease shield. While augmentation therapy is not recommended for isolated liver disease, liver transplantation remains an option for individuals with advanced liver failure due to AATD.