Resources for Physicians - Diagnosis and Testing

Updated June 30, 2009

Clinical Diagnosis

A1AD is suspected in individuals with evidence of:

• pulmonary disease (i.e., emphysema, asthma, persistent airflow obstruction, and/or chronic bronchitis) and/or
• 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 panniculitis

The diagnosis of A1AD relies on the following:

• demonstration of low plasma concentration of alpha-1 antitrypsin (AAT)

AND

• observation of a deficient variant of the protein AAT by protease inhibitor (PI) typing

OR

• 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 in many laboratories. Many that do not perform the test will send samples to a lab that does. Some routinely refer low results to a PI typing laboratory (e.g. University of Alberta).

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.

Phenotyping (PI typing, Protease Inhibitor typing) 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 when ordered separately should specify the previous result or the subject’s name and relationship for phenotyping to proceed.

Interpretation of Results

The normal plasma concentration of AAT is 80% to 120% 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.

Protease Inhibitor (PI) Types

• PI ZZ: Plasma concentration of AAT approximately 18% of normal (0.23 g/L)
• PI SZ: Not usually associated with a high risk for liver or lung disease; higher risk of developing COPD among smokers
• PI MZ: Slightly increased risk for decreased lung function
• PI MM: Observed in normal individuals with normal plasma concentration of AAT

For more information about testing contact Alpha-1 Canada at 1-888-669-4583 or jim.mundy@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.

Prevalence

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.