Diagnosis and Testing
The World Health Organization, the American Thoracic Society, the European Respiratory Society and Alpha-1 Canada recommend that everyone with COPD be tested for Alpha-1 Antitrypsin Deficiency.
A1AD is suspected in individuals with evidence of:
- pulmonary disease (i.e., emphysema, asthma, persistent airflow obstruction, and/or chronic bronchitis)
- evidence of liver disease at any age, including obstructive jaundice in infancy
- individuals with bronchiectasis
- A1AD is also observed rarely in individuals with Wegener granulomatosis and necrotizing pannicultis
The diagnosis of A1AD relies on the following:
- demonstration of low plasma concentration of Alpha-1 Antitrypsin (AAT)
- observation of a deficient variant of the protein AAT by protease inhibitor (PI) typing
- detection by molecular genetic testing of mutations in both copies of SERPINA1, the gene encoding AAT
Measurement of AAT level is the first step
The diagnosis of A1AD relies on demonstration of low plasma concentration of AAT, followed by (when low) either observation of a deficient variant of the protein AAT by protease inhibitor (PI) typing or detection of mutations in both copies of the gene SERPINA1, which encodes AAT. PI*Z is the most common deficiency allele. Ninety-five percent of A1AD results from the presence of two Z alleles. Genetic testing is clinically available.
Measurement of AAT is done inexpensively in many labs in all provinces. Some routinely refer low results to one of four Canadian labs that perform PI typing or directly to a DNA diagnostic laboratory for genotyping of SERPINA1, the gene responsible for A1AD. The exception is Alberta. In Southern Alberta, testing is requested through Calgary Laboratory Services. In Northern Alberta, testing is requested through DynaLIFEDx.
In some provinces, AAT serum level and phenotyping or genotyping can be ordered on a single requisition. On a laboratory requisition you may order “Alpha-1 Antitrypsin level” and specify “Phenotype if <1.5g/L” this will authorize total assay and pre-authorize phenotyping if appropriate and if available through that laboratory.
In other provinces, phenotyping (PI typing, Protease Inhibitor typing or genotyping) can be ordered separately, however, is usually done only when previously measured AAT is 1.5 g/L or less (or below the normal mean for the testing laboratory), OR the patient is a first-degree relative/spouse of a known AAT deficient subject. Your request for PI typing or genotyping when ordered separately should specify the previous result or the subject’s name and relationship for phenotyping to proceed.
If a low serum level is found it does not establish a diagnosis of clinically important severe deficiency. In fact, the majority of abnormal results are mildly reduced values found in carriers at low risk of having clinical disease, confirmatory phenotyping or genotyping is needed.
Interpretation of results
The normal plasma concentration of AAT is 80% to 20% of normal. Mean is 1.3 g/L (range: 1.06 g/L to 1.58 g/L).
For adults with the PI ZZ genotype the concentration is usually 13% to 23% of normal (mean: 18%±5% of normal).
For children with the PI ZZ genotype and liver disease the plasma concentration can be as high as 40% of normal.
If a low serum level is found it does NOT establish a diagnosis of clinically important severe deficiency. In fact, the majority of abnormal results are mildly reduced values found in carriers at low risk of having clinical disease, confirmatory phenotyping or genotyping is needed.
Typically, a requisition specific for the laboratory doing the testing is needed. (Please note that genotyping requires a blood sample collected in an EDTA tube).
Protease Inhibitor (PI) Types
Plasma concentration of AAT approximately 18% of normal (0.23 g/L)
Not usually associated with a high risk for liver or lung disease; higher risk of developing COPD among smokers
Slightly increased risk for decreased lung function
Observed in normal individuals with normal plasma concentration of AAT
For more information on having your patients tested contact Alpha-1 Canada at 1-888-669-4583 or visit our web site at www.alpha1canada.ca.
The Alpha-1 Canadian Registry provides information on research and testing, you can visit their website at www.alpha1canadianregistry.com or call 1-800-352-8186.
A1AD affects all racial groups worldwide. It is most common among Caucasians and least common in Asian and black populations, among whom rare deficiency variants other than PI ZZ also occur.
The prevalence of A1AD in the white population of North America ranges between one in 5,000 and one in 7,000.
Intravenous augmentation therapy (regular infusion of purified human AAT to augment deficient ATT serum concentrations) is widely prescribed in the United States and other countries and has been recommended by the Canadian Thoracic Society for affected individuals whose FEV1 is 25% to 80% of predicted and have never smoked or have quit smoking yet continue to show rapid decline in FEV1 despite optimal medical therapy; however, definitive controlled trials have not been carried out.
Intravenous augmentation therapy is not useful for A1AD liver disease.
It is recommended that patients:
- contact Alpha-1 Canada
- avoid smoking
- avoid an occupation with exposure to environmental pollutants
- avoid exposure to mineral dust, gas and fumes
Patients diagnosed with Alpha-1 Antitrypsin Deficiency should be referred to the following resources:
If you or anyone in your family is interested in a confidential Alpha-1 Antitrypsin Deficiency test, the Alpha-1 Coded Testing (ACT) Study is a free test that is performed at home. An Alpha-1 test kit will be mailed out after signing an electronic consent and filling out the online questionnaire to be a participant in a research study. The questionnaire, which is the research study, is facilitated by the Medical University of South Carolina (MUSC) in collaboration with Alpha-1 Foundation.
Once the online questionnaire is completed the MUSC lab will send out a blood test kit to your home, that contains instructions for obtaining drops of blood. Test kits are then returned by paid mailer to MUSC and MUSC will then provide your genotype and your estimated Alpha-1 level in a result letter which will arrive in the mail to your home within 6-8 weeks.
Those whose results are deficient or carriers will receive a brochure with their results inviting them to join a Research Registry. It is for those who want to participate in studies to help find a cure for Alpha-1. This list is also totally confidential.
Please note that each participant 18 years of age and older must sign their own consent and respond to their own questionnaire. Parents and guardians must fill out consents and questionnaires for each of their minor children. Spouses must fill out their own forms as well.
For further information and to access the study questionnaire, please visit: https://redcap.musc.edu/surveys/index.php?hash=621bf66ddb7c962aa0d22ac97d69b793