Print Genetic Testing for Alpha-1 Antitrypsin Deficiency

Genetic Testing for Alpha-1 Antitrypsin Deficiency






Alpha-1 antitrypsin deficiency (AATD) is an autosomal recessive genetic disorder that decreases production of the alpha-1 antitrypsin (AAT) protein or production of abnormal types of the protein that are functionally deficient. Individuals with AATD, especially smokers, have an increased risk of lung and liver disease. Available tests measure serum AAT levels and phenotype AAT protein variants. Genetic testing is also available to detect the most common mutations associated with AATD. Data from screening studies have found the prevalence of AATD in the United States to be between 1 in 2,857 and 1 in 5,097 individuals.

AAT is an acute phase glycoprotein, primarily synthesized in the liver and secreted into the bloodstream. One of the primary functions of the AAT protein is to protect the lungs from damage by the enzyme elastase. Elastase, part of the normal response to injury and inflammation, breaks down proteins and can damage lung tissue if its action is not regulated by AAT. Individuals with AAT deficiency thus have an increased risk of lung disease.

Respiratory disease tends to be more severe and occur sooner (i.e., between ages 40 and 50) in individuals with AAT deficiency who smoke cigarettes and/or are exposed to occupational dust or fumes. In non-smokers and individuals without environmental exposure, onset of respiratory disease occurs more commonly in the sixth decade. Childhood-onset lung disease is rare with AATD. AATD is also associated with an increased risk of liver disease, thought to occur due to aggregation of damaged AAT in the liver cells, where the protein is produced. The most common manifestation of liver disease in childhood is jaundice. Adults with AATD-associated liver disease generally present with cirrhosis and fibrosis. Panniculitis is a rare, but well-recognized complication of AAT deficiency. This dermatologic condition is characterized by inflammatory and necrotizing lesions of the skin and subcutaneous tissue.

The primary interventions to prevent or treat symptoms in individuals with AATD involve behavioral change, especially avoiding or quitting cigarette smoking. Smoking is the most important risk factor for the development of emphysema in AATD in individuals who are homozygous for the most severe AAT mutations. In addition, individuals with AATD are advised to avoid other substances that can irritate the lungs (e.g., cigarette smoke, dust and workplace chemicals), as well as substances that can cause liver damage (eg, alcohol). There are also general recommendations to exercise, avoid stress, and have a nutritious diet. Furthermore, patients with AATD may be recommended to have earlier or more aggressive treatments for conditions such as asthma outbreaks or acute exacerbations of chronic obstructive pulmonary disease (COPD). One treatment option that is specific to AATD is alpha-1 antitrypsin augmentation. There are commercially available intravenous AAT augmentation products; patients generally receive injections of plasma every 3 to 4 weeks for life. Inhaled AAT augmentation therapy is under development. There is no consensus on the efficacy of augmentation treatment. Product labels state that the effect of augmentation therapy on emphysema progression and pulmonary exacerbations has not been demonstrated in randomized controlled trials.

Diagnostic Testing for AAT

Several types of tests are available for patients who are suspected of having AATD. A blood test is available that quantifies the total amount of alpha-1 antitrypsin in the blood, detecting decreases in AAT protein levels, but not distinguishing among abnormal protein types. AAT is an acute phase reactant, and levels will be elevated in acute and chronic inflammatory conditions, infections and some cancers, which may cause levels to appear normal in individuals with mild to moderate AAT deficiency. In general, a serum AAT concentration less than 15-20% of the normal value is highly suggestive of a homozygous alpha-1 antitrypsin mutation.

The alpha-1 phenotype test identifies the type of circulating AAT protein in the blood by isoelectric focusing of the various AAT protein types. Patterns of protein migration in an electric field are evaluated and compared with normal patterns to determine if and what type of abnormal AAT protein may be present.

Genetic testing is also available. Production of AAT is encoded by the SERPINA1 gene, which is co-dominant (each gene copy is responsible for producing half of the AAT). Although there are more than 75 sequence variants of the SERPINA1 gene (i.e., 75 possible alleles), only a few are common in North America. Approximately 95% of individuals have 2 copies of the normal M allele sequence (MM) and have mean serum AAT concentrations ranging from 20-53 µmol/L. The most common abnormal forms are the Z allele and the S allele. Individuals with 2 copies of the Z allele (ZZ) tend to be most severely affected, with mean serum AAT concentrations of 2.5 to 7 µmol/L and a high risk of COPD. Individuals with genotype SS and heterozygous individuals with genotype MZ have low risk of COPD and moderately lower levels of AAT. Individuals with rarer mutations of the SERPINA1 gene or null alleles may not produce any AAT and are also at high risk.

Genetic testing for AATD can be done with the alpha-1 genotype test. This test uses Polymerase chain reaction analysis or nucleic acid-based analysis, to identify abnormal alleles of AAT DNA. Currently available genotype tests are only designed to detect the most common mutations (i.e. the S and Z alleles).

There are several testing approaches to detect AATD. One is to initially perform serum quantitation and then, if the AAT level is found to be low, a follow-up phenotype or genotype test is ordered. Another approach is to perform serum protein quantification, followed by genotype testing in subjects with clinical suspicion of AATD. If these tests are discordant, phenotype testing is then performed.

In 2007, the phenotyping test Hydragel 18 Alpha-1 Antitrypsin Isofocusing kit (Sebia, GA) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process for the qualitative detection and identification of the phenotypes of AAT protein.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. Molecular diagnostic laboratories may also be accredited by the College of American Pathologists Laboratory Accreditation Program. To date, FDA has chosen not to require any regulatory review of this test.



Genetic testing for alpha-1 antitrypsin deficiency may be considered medically necessary when both of the following conditions are met: 
  1. Patient is suspected of having alpha-1 antitrypsin deficiency because of clinical factors and/or because the patient may be at high risk of having alpha-1 antitrypsin deficiency due to a first-degree relative with AAT deficiency (see Policy Guidelines); AND
  2. Patient has a serum alpha-1 antitrypsin level in the range of severe deficiency (see Policy Guidelines).

Genetic testing for alpha-1 antitrypsin deficiency is considered investigational in all other situations.






The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

According to the 2003 joint statement on diagnosis and management of alpha-1 antitrypsin deficiency by the American Thoracic Society and European Respiratory Society, the following features should prompt suspicion by physicians that their patient may be more likely to have AAT deficiency:

Clinical Factors

  • Early-onset emphysema (age of 45 years or less)
  • Emphysema in the absence of a recognized risk factor (smoking, occupational dust exposure, etc.)
  • Emphysema with prominent basilar hyperlucency
  • Otherwise unexplained liver disease
  • Necrotizing panniculitis
  • Anti-proteinase 3-positive vasculitis (C-ANCA [anti-neutrophil cytoplasmic antibody]-positive vasculitis)
  • Bronchiectasis without evident etiology

Family History

  • A first-degree relative is defined as a parent, child, or sibling.

AAT deficiency occurs largely in Caucasians. For example, the prevalence in Sweden is approximately 1 in 1,575 and the estimated prevalence in the United States is between 1 in 2,857 and 1 in 5,097.

The following table shows the range of serum levels of alpha-1 antitrypsin by common phenotypes according to the commercial standard milligram per deciliter (mg/dL) and the purified standard micromole (uM). A level of less than 11 μmol is generally considered to be associated with an increased risk of clinical disease, but this cut-off may vary by the specific test used:


























Genetic Counseling

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.



07/19/2012: Approved by Medical Policy Advisory Committee.

08/07/2013: Policy reviewed; no changes.

07/03/2014: Policy reviewed; descripton updated. Policy statement unchanged.

08/26/2015: Medical policy revised to add ICD-10 codes.

09/11/2015: Policy reviewed; policy statements unchanged. Added medically necessary and investigative definitions in the Policy Guidelines section.

03/08/2016: Policy description updated regarding laboratory-developed tests. Policy statements unchanged. Policy guidelines updated to add genetic counseling information.

06/06/2016: Policy number A.2.04.79 added.

01/30/2017: Policy description updated. Policy statements unchanged.



Blue Cross Blue Shield Association policy # 2.04.79 



This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Code Number




SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (eg, alpha-1-antitrypsin deficiency), gene analysis, common variants (eg, *S and *Z)



ICD-9 Procedure

ICD-10 Procedure




ICD-9 Diagnosis

ICD-10 Diagnosis


Alpha-1-antitrypsin deficiency


Alpha-1-antitrypsin deficiency


Genetic disease carrier


Family history of carrier of genetic disease


Testing for genetic disease carrier status


Encounter of female for testing for genetic disease carrier status for procreative management


Testing of male for genetic disease carrier status


Encounter of male for testing for genetic disease carrier status for procreative management


Screening for genetic disease carrier status


Encounter for nonprocreative screening for genetic disease carrier status

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