Alpha-1 antitrypsin deficiency (AATD) is diagnosed through a combination of a blood test measuring protein levels and genetic testing to identify the specific gene variant involved. The process typically starts with a simple blood draw and, if levels come back low, moves to genetic confirmation. Most people who have the condition don’t know it, and the average person with AATD goes undiagnosed for years because symptoms overlap with common lung and liver diseases.
Who Should Be Tested
Not everyone needs screening for AATD, but certain patterns should raise suspicion. The major red flags include emphysema developing at age 45 or younger, emphysema in someone who has never smoked or had significant dust exposure, and unexplained liver disease at any age. A family history of emphysema, bronchiectasis, liver disease, or a skin condition called panniculitis also warrants testing.
If you have COPD and your doctor hasn’t mentioned AATD testing, it’s worth asking about. Guidelines from the American Thoracic Society and European Respiratory Society recommend testing for anyone with COPD, particularly when the usual risk factors don’t fully explain the disease. The condition is genetic, so if one family member is diagnosed, first-degree relatives (parents, siblings, children) should also be tested.
Step 1: Measuring AAT Levels in Blood
The first step is a blood test that measures how much alpha-1 antitrypsin protein is circulating in your bloodstream. This protein normally protects your lungs from damage caused by your own immune system. When levels are too low, the lungs lose that protection, and tissue breakdown accelerates.
The key number here is 11 micromoles per liter (roughly 57 mg/dL), often called the “protective threshold.” Below that level, your lungs don’t have enough protein to defend against ongoing damage. Normal levels for someone without the condition typically fall around 20 to 53 micromoles per liter (100 to 220 mg/dL, depending on the lab).
There’s one important catch with this blood test: AAT is what’s known as an acute phase reactant. That means your levels naturally rise when your body is fighting an infection, dealing with inflammation, or responding to injury. Estrogen levels (such as during pregnancy or while taking oral contraceptives) can also push AAT readings higher. In a large screening study, roughly a quarter of people carrying one copy of the Z gene variant had inflammation that artificially elevated their AAT levels into a range that looked less concerning. For example, people with the MZ genotype had median levels of 104 mg/dL during inflammation but only 85 mg/dL without it. This difference is enough to mask a diagnosis. If your doctor suspects AATD but the initial level comes back borderline, retesting when you’re not acutely ill gives a more accurate picture.
Step 2: Genetic Testing for Confirmation
A low AAT blood level alone doesn’t complete the diagnosis. Genetic testing identifies which specific gene variants you carry, and this matters because different variants cause different levels of risk. Two types of genetic tests are commonly used:
- Genotype testing looks directly at your DNA for the most common mutations known to cause AATD, particularly the Z and S variants.
- Phenotype testing examines the AAT protein itself to see if its structure has been altered in a way that prevents it from working properly.
If neither of these tests finds a clear answer but AAT levels remain below 60 mg/dL, the next step is full gene sequencing of the SERPINA1 gene (the gene responsible for making AAT). This catches rarer variants that standard genotype panels miss. Full sequencing is also used when only one variant is found but levels are still unexpectedly low, suggesting a second, less common mutation on the other gene copy.
What the Genotype Results Mean
Everyone inherits two copies of the SERPINA1 gene, one from each parent. The normal version is called M, so a person with two normal copies is PiMM. The variants that cause the most trouble are Z and S. Your specific combination determines both your AAT levels and your risk profile.
PiZZ is the most common severe deficiency genotype. People with two Z copies produce very little functional AAT because most of the protein gets stuck inside liver cells instead of reaching the bloodstream. This is the combination most strongly linked to early-onset emphysema and COPD, and it also carries the highest risk of liver disease because the trapped protein damages liver tissue over time.
PiSZ produces AAT levels in the range of 45 to 80 mg/dL. About 11% of people with this genotype fall below the 11 micromolar protective threshold. The lung disease risk is roughly three times higher than someone with normal genes, though it tends to be milder than PiZZ and is particularly tied to smoking or occupational exposures. Liver disease risk exists but is proportionally lower than PiZZ, since less protein gets trapped in the liver.
PiMZ means you carry one normal copy and one Z copy. AAT levels typically range from 66 to 120 mg/dL. This genotype raises the risk of emphysema compared to PiMM, especially in smokers and former smokers. It also acts as a modifier for liver disease, meaning it can worsen the course of conditions like alcoholic cirrhosis or non-alcoholic fatty liver disease. Many MZ carriers live without symptoms, but the combination of this genotype with smoking or heavy alcohol use significantly changes the outlook.
Why Inflammation Can Mask the Diagnosis
The acute phase response deserves extra attention because it’s one of the main reasons AATD gets missed. When your body is inflamed (from a cold, a COPD flare-up, surgery, or even chronic conditions like rheumatoid arthritis), your liver ramps up production of AAT. In people with the normal M gene, this response is strong, and levels can jump by 20 mg/dL or more. People with the Z variant, however, show a weaker inflammatory response because their liver cells are already struggling to secrete the protein.
This creates a diagnostic gray zone. A PiMZ individual tested during a respiratory infection might show an AAT level of 104 mg/dL, which looks borderline but not alarming. Tested when healthy, that same person’s level drops to 85 mg/dL, a reading that more clearly points toward deficiency. Checking inflammatory markers like C-reactive protein (CRP) at the same time as the AAT blood draw helps your doctor judge whether inflammation is skewing the result. A CRP of 5 mg/L or higher suggests the AAT reading may be artificially elevated.
Testing Family Members
Because AATD is inherited in a straightforward pattern (one gene copy from each parent), a confirmed diagnosis in one person has direct implications for relatives. If you’re diagnosed with PiZZ, both of your parents carry at least one Z allele, and each of your siblings has a 25% chance of also being PiZZ. Your children will inherit at least one Z copy from you, and their risk of severe deficiency depends on what your partner carries.
Family screening, sometimes called cascade testing, is the most efficient way to find undiagnosed cases. Siblings of a PiZZ individual have the highest yield for testing. For relatives, the process is the same: an AAT blood level followed by genotyping if levels are low or borderline. Identifying the condition before symptoms develop allows for practical steps like avoiding smoking, reducing occupational dust exposure, and monitoring lung and liver function over time.