An alpha-1 antitrypsin deficiency genetic test identifies inherited variants in the SERPINA1 gene that can lower the amount or function of alpha-1 antitrypsin, often shortened to AAT. AAT is made mainly in the liver and protects lung tissue from enzymes released during inflammation. Some SERPINA1 variants reduce the protein reaching the bloodstream, leaving the lungs vulnerable to emphysema, while certain misfolded variants can accumulate inside liver cells and raise the risk of liver injury. Genetic testing is usually interpreted with a blood AAT level and sometimes protein phenotyping because no single measurement tells the whole story. Common results include MM, MZ, MS, SZ, and ZZ, but rare deficiency and null variants also occur. A confirmed result can explain unexplained COPD, bronchiectasis, or liver disease, guide family testing, and clarify whether lung-specific augmentation therapy may be considered. It cannot predict exactly who will develop disease or how quickly it will progress.
- SERPINA1 genotyping usually checks the common S and Z variants first, but sequencing may be needed when the AAT level and initial genotype do not match.
- A low AAT level supports deficiency but is not diagnostic by itself, because inflammation, pregnancy, estrogen use, and laboratory method can affect the concentration.
- ZZ is the classic severe genotype, with high lung risk and a meaningful risk of liver fibrosis, cirrhosis, and liver cancer.
- MZ usually causes an intermediate AAT level, with lung risk rising especially in smokers and liver risk increasing with other metabolic or toxic stressors.
- Smoking avoidance is the most important preventable step for anyone with a clinically significant deficiency genotype.
- Each first-degree relative should be offered testing after a confirmed diagnosis, using genotype-based testing rather than an AAT level alone.
Table of Contents
- Why SERPINA1 testing matters
- Who should be tested
- Common and rare SERPINA1 variants
- How testing is performed
- Interpreting genotypes and laboratory results
- Lung and liver risk after a positive result
- Family and reproductive implications
- Follow-up after results
Why SERPINA1 testing matters
AAT deficiency is both a protein deficiency disorder and, for some variants, a protein accumulation disorder. The lung and liver problems come from different mechanisms. In the lungs, too little functional AAT allows neutrophil elastase and related enzymes to damage alveolar walls. In the liver, the Z protein can misfold and become trapped inside liver cells, provoking inflammation, fibrosis, and sometimes cirrhosis or hepatocellular carcinoma.
That split mechanism explains why a serum level alone is incomplete. Two people can have similar AAT concentrations but different liver risks, and an acute inflammatory illness can temporarily raise the level into a range that hides an inherited deficiency. Genetic testing identifies the alleles responsible and helps distinguish common deficiency variants from rare variants that alter protein function or secretion.
The SERPINA1 gene is inherited in an autosomal codominant pattern. Both copies contribute to the laboratory phenotype. The usual M allele makes normally functioning AAT. The S allele causes a moderate reduction, while the Z allele causes a larger reduction and creates a polymer-forming protein that can collect in hepatocytes. A person’s result is written as two allele names, such as MZ or ZZ, because one allele is inherited from each biological parent.
Genotyping also prevents an important clinical error: assuming that every low AAT value means ZZ disease. Rare null alleles may produce almost no AAT but do not create the same polymer-related liver injury. Conversely, a dysfunctional allele may produce a near-normal quantity of protein that does not protect the lung normally. This is why a focused single-gene test may need sequencing rather than only a two-variant screen.
A genetic result does not diagnose COPD, emphysema, fibrosis, or cirrhosis. It identifies susceptibility and mechanism. Lung function testing, chest imaging, liver enzymes, platelet count, ultrasound or elastography, symptoms, age, smoking history, alcohol exposure, and metabolic health determine the person’s current disease status.
Who should be tested
Professional recommendations generally favor broad testing among people with conditions that can be caused or worsened by AAT deficiency. The disorder remains underdiagnosed because its symptoms resemble common smoking-related or metabolic diseases and because many affected people have no known family history.
Testing is appropriate for people with:
- COPD, regardless of age, ancestry, or smoking history
- Emphysema, especially when it begins early, affects the lower lungs, or occurs with little smoking exposure
- Unexplained bronchiectasis
- Asthma with persistent airflow obstruction that does not fully reverse
- Unexplained chronic liver disease, cirrhosis, or elevated liver enzymes
- Neonatal cholestasis or childhood liver disease without another clear cause
- Necrotizing panniculitis, a rare inflammatory skin condition
- Granulomatosis with polyangiitis in selected clinical settings
- A first-degree relative with AAT deficiency or a known SERPINA1 variant
Testing may also be offered when a person is considering augmentation therapy, because eligibility usually requires evidence of a severe deficiency genotype or another qualifying deficiency state plus obstructive lung disease. The exact treatment rules differ by country, product, payer, and guideline.
AAT deficiency should not be dismissed because a person is older, never smoked, has “ordinary” COPD, or comes from an ancestry group in which the condition is thought to be less common. S and Z allele frequencies vary across populations, and rare variants occur worldwide. Restricting testing to people of northern European ancestry misses cases.
Children of an affected person may be tested when the result can improve health protection, such as avoiding tobacco exposure and recognizing liver symptoms. Testing minors should include a discussion of psychosocial effects, privacy, and the difference between identifying a genotype and finding active disease. In a symptomatic infant with cholestasis, testing is diagnostic and time-sensitive rather than predictive.
A clinician may order a genetic screening test for relatives even when they feel well. For an adult with unexplained lung or liver disease, the same analysis functions as diagnostic testing. The laboratory method can be identical; the purpose and pretest probability are different.
Common and rare SERPINA1 variants
The historical “Pi” terminology comes from protein inhibitor phenotyping. Genotypes are often written as PiMM, PiMZ, PiSZ, or PiZZ, although reports may simply state MM, MZ, SZ, or ZZ. Modern reports may also list HGVS DNA and protein nomenclature.
The most familiar alleles are:
- M: normal production and function in most people
- S: moderate reduction in circulating AAT; usually less severe than Z
- Z: marked reduction in secretion, polymer accumulation in liver cells, and the strongest common association with severe deficiency
- Null: little or no AAT production; severe lung risk when two severe alleles are present, but no Z-polymer liver toxicity from the null allele itself
- Dysfunctional variants: protein may be present but function abnormally
More than a hundred SERPINA1 variants have been described, and not every rare change has a settled clinical meaning. Some laboratories use targeted genotyping that detects only S and Z. Others use an expanded panel covering several common and regional variants. Full sequence analysis examines the coding regions and nearby splice sites. Deletion and duplication testing may be added if sequencing does not explain a very low level.
A rare variant should not be labeled harmful solely because it is uncommon. Laboratories assess population frequency, predicted protein effect, published cases, functional studies, segregation in families, and whether the measured AAT level matches the proposed mechanism. The standard categories used in genetic variant classification include pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.
Some results require special caution. The F allele, for example, may produce a functionally impaired protein with a concentration that is not profoundly low. Rare M-like deficiency alleles may be missed by protein phenotyping because they migrate similarly to normal M protein. A null allele paired with M can also be mistaken for MM by a limited phenotype assay, even though the quantitative level may be lower than expected.
A complete report should state which variants were tested, whether sequencing was performed, whether copy-number analysis was included, and what residual risk remains after a negative result. “No S or Z variant detected” is not the same as “no clinically important SERPINA1 variant detected.”
How testing is performed
A thorough evaluation often uses three complementary components: serum AAT concentration, protein phenotype, and genotype. Not everyone needs all three at the first step, but discordant findings should trigger broader analysis.
Serum AAT concentration
The blood level estimates how much protein is circulating. Laboratories report results in mg/dL, g/L, or micromoles per liter, and reference intervals differ by assay. A commonly used severe-deficiency threshold is approximately 11 micromoles/L, often corresponding to about 50–80 mg/dL depending on the calibration method. The laboratory’s own method-specific range should be used rather than converting numbers casually.
AAT is an acute-phase reactant. Infection, inflammation, pregnancy, and estrogen therapy can raise the concentration. Measuring C-reactive protein at the same time can help identify an inflammatory state. A normal-looking level during pneumonia or another inflammatory illness may therefore need repeat testing when the person is well.
Protein phenotyping
Phenotyping separates AAT protein variants by how they move in an electric field. It can show patterns such as MM, MZ, SZ, or ZZ. It does not reliably identify every null or M-like allele, and recent infusion of purified AAT can complicate interpretation by adding donor M protein to the blood.
Genotyping and sequencing
Targeted genotyping usually identifies S and Z quickly from blood, saliva, or a dried blood spot. If the measured level is unexpectedly low, the phenotype and genotype conflict, or the clinical suspicion remains high, the laboratory may perform full SERPINA1 sequencing and deletion/duplication analysis.
| Finding | Possible explanation | Useful next step |
|---|---|---|
| Low level with MZ genotype | Expected MZ range, inflammation-free baseline, or a rare second variant | Review level, phenotype, and sequencing coverage |
| Very low level but no S or Z | Null or rare deficiency allele | Full sequencing and copy-number analysis |
| Normal level during illness | Acute-phase rise masking deficiency | Repeat when stable and add genotype |
| Phenotype appears MM but level is low | M-like rare allele, null allele, assay issue, or another cause | Genetic analysis and laboratory consultation |
Fasting is not required. Routine medicines usually do not alter DNA, but augmentation infusions can affect phenotype interpretation. A recent liver transplant changes the circulating AAT phenotype because the donor liver produces the protein. A stem-cell transplant does not replace liver production but can complicate DNA testing from blood; the laboratory should be told about any transplant history.
Interpreting genotypes and laboratory results
The genotype describes inherited risk, not a fixed outcome. Smoking, dust and fume exposure, respiratory infections, alcohol, obesity, diabetes, viral hepatitis, and other liver or lung conditions can change the likelihood and timing of disease.
| Result | Typical AAT status | General clinical interpretation |
|---|---|---|
| MM | Normal | Common genotype; classic inherited AAT deficiency is unlikely |
| MS | Mildly reduced or normal | Usually not severe deficiency; carrier information may matter for family planning |
| MZ | Intermediate | One Z allele; risk is modified strongly by smoking and liver stressors |
| SS | Moderately reduced | Usually lower risk than SZ or ZZ, but clinical context matters |
| SZ | Reduced, sometimes near severe threshold | Meaningful lung risk; liver risk is lower than ZZ but not absent |
| ZZ | Severely reduced | High risk for emphysema and clinically important liver disease |
| Null/null or Z/null | Very low or absent | Severe lung vulnerability; liver risk depends on whether a polymer-forming allele is present |
A negative S/Z genotype does not exclude AAT deficiency when the serum level is low. Conversely, one S or Z allele does not automatically explain every respiratory or liver symptom. A person with MZ and abnormal liver tests still needs evaluation for fatty liver disease, alcohol-related injury, medications, viral hepatitis, autoimmune disease, and other causes.
A variant of uncertain significance should not be treated as a confirmed deficiency allele without supporting evidence. The measured protein level, phenotype, family segregation, and functional data may help. Testing an affected relative can sometimes clarify whether the variant tracks with low AAT, but routine testing of healthy relatives for a VUS may not be informative.
Lung and liver risk after a positive result
Lung risk rises as functional AAT falls, but exposure history has enormous influence. Cigarette smoke both increases inflammatory enzyme release and can reduce AAT’s protective activity. People with severe deficiency who smoke may develop emphysema decades earlier than never-smokers. Vaping, cannabis smoke, occupational dusts, welding fumes, and repeated inhaled irritants also deserve discussion even though their risks are less precisely quantified.
Pulmonary assessment commonly includes spirometry, bronchodilator testing, oxygen saturation, symptom review, and sometimes full lung volumes or diffusing capacity. A baseline chest CT may be useful in selected symptomatic adults but is not repeated routinely without a clinical reason. Bronchiectasis can occur with or without classic emphysema.
Intravenous AAT augmentation therapy is intended for selected adults with severe deficiency and established airflow obstruction. It raises circulating AAT and can slow loss of lung density on CT in appropriate patients. It does not treat liver disease, because adding circulating protein does not remove the abnormal protein trapped in hepatocytes. It is also not a general treatment for MZ status without qualifying severe deficiency and lung disease.
Liver risk is not simply the mirror image of the blood level. ZZ disease produces the greatest common polymer burden. MZ can act as a disease modifier, particularly with obesity, metabolic dysfunction-associated steatotic liver disease, heavy alcohol use, or another chronic liver disorder. Children with ZZ may have neonatal jaundice or cholestasis, yet many improve; a smaller group develops progressive fibrosis or liver failure. Adults may develop fibrosis silently.
Liver follow-up may include AST, ALT, GGT, bilirubin, albumin, INR, platelet count, ultrasound, and elastography. Normal liver enzymes do not guarantee that fibrosis is absent. The exact surveillance schedule should be individualized by hepatology or another experienced clinician.
Urgent care is warranted for severe shortness of breath, blue lips, confusion, coughing blood, vomiting blood, black stools, rapidly increasing abdominal swelling, new jaundice, or signs of acute liver failure. A genetic result should never delay evaluation of an acute symptom.
Family and reproductive implications
First-degree relatives—parents, siblings, and children—should be offered testing after a clinically important SERPINA1 result. Genotyping is preferred over a serum level alone because relatives with intermediate levels can be missed during inflammation, and the exact familial allele provides clearer reproductive information.
Because both alleles contribute, reproductive risk depends on both partners. For example:
- An MZ parent and an MM parent have a 50% chance of an MZ child and a 50% chance of an MM child in each pregnancy.
- Two MZ parents have a 25% chance of MM, 50% chance of MZ, and 25% chance of ZZ in each pregnancy.
- An SZ parent and an MM parent can pass either S or Z, but the child is not expected to have ZZ unless the other parent also contributes Z.
- A person with a rare pathogenic allele needs partner testing that can detect more than S and Z if the familial variant is not included in standard panels.
These patterns are sometimes discussed under partner carrier-risk testing, although AAT deficiency is more accurately described as codominant because heterozygous states can have measurable biological and clinical effects.
Prenatal diagnosis and preimplantation genetic testing are technically possible when familial variants are known. Many families instead use the result for preparation and early health protection rather than embryo or fetal selection. Genetic counseling should present these options neutrally and explain the wide variability in expression.
A confirmed result also has immediate preventive value for relatives: avoiding smoking, limiting harmful occupational exposure, moderating alcohol, maintaining metabolic health, and obtaining prompt assessment for persistent respiratory or liver symptoms.
Follow-up after results
After testing, ask for the complete report rather than relying on a portal label such as “positive.” The report should identify both alleles, the testing method, the quantitative AAT result if performed, and any limitations. A pulmonologist, hepatologist, medical geneticist, or genetic counselor can reconcile discordant findings.
For a severe or clinically significant result, typical next steps include:
- Stop smoking and avoid secondhand smoke; offer evidence-based cessation treatment rather than advice alone.
- Assess lung symptoms and obtain baseline pulmonary function testing.
- Review liver history, examination, laboratory markers, and fibrosis assessment.
- Update influenza, pneumococcal, COVID-19, hepatitis A, and hepatitis B vaccination as clinically appropriate.
- Review occupational and home inhalation exposures.
- Test first-degree relatives with a method that detects the familial alleles.
- Discuss augmentation therapy only after genotype, level, lung function, and local criteria are confirmed.
- Revisit rare or uncertain variants if the phenotype and laboratory values remain unexplained.
For MZ or another intermediate result, the response should be proportionate. Many people never develop severe disease, but smoking and metabolic liver stress should be addressed early. Routine augmentation therapy is not supported simply because one Z allele is present. Follow-up should be based on symptoms, lung function, liver findings, and additional risk factors.
For a negative result with a persistently low AAT level, do not close the evaluation until rare variants, assay differences, protein loss, severe liver dysfunction, and other explanations have been considered. The most accurate diagnosis often comes from aligning the number, the phenotype pattern, and the DNA result rather than treating any one of them as final.
References
- Alpha-1 Antitrypsin Deficiency 2023 (Review)
- Recommendations for the diagnosis and treatment of alpha-1 antitrypsin deficiency 2024 (Guideline)
- Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review 2024 (Systematic Review)
- Alpha-1 antitrypsin deficiency 2024 (Review)
- Pediatric and Adult Liver Disease in Alpha-1 Antitrypsin Deficiency 2023 (Review)
- Diagnosis and augmentation therapy for alpha-1 antitrypsin deficiency: current knowledge and future strategies 2023 (Review)
Disclaimer
This article provides general education and does not interpret an individual AAT level, phenotype, or SERPINA1 result. Testing and treatment decisions should be reviewed with a qualified clinician, particularly when results are discordant, a rare variant is found, or lung or liver disease is present. Seek urgent medical care for severe breathing difficulty, coughing or vomiting blood, confusion, rapidly increasing abdominal swelling, or new jaundice.
