Genetic Testing for Alpha-1 Antitrypsin Deficiency

POLICY NUMBER

A.2.04.79

DESCRIPTION

Alpha₁-antitrypsin deficiency (AATD) is an autosomal recessive genetic disorder that results in decreased production of functional 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 pathogenic variants 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.

Alpha₁-Antitrypsin Deficiency Genetics

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 to 53 µmol/L. The most common abnormal forms are the Z and the S alleles. 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 chronic obstructive pulmonary disease. Individuals with genotype SS and heterozygous individuals with genotype MZ have a low-risk of chronic obstructive pulmonary disease and moderately lower levels of AAT. Individuals with rarer pathogenic variants of the SERPINA1 gene or null alleles may not produce any AAT and are also at high-risk.

Clinical Presentation

AATD is a multisystem disease, primarily affecting the lungs and liver, and less commonly, the skin. It may present differently at different ages.

Pulmonary Manifestations

Respiratory disease tends to be more severe and occur sooner (i.e., between ages 40 and 50 years) in individuals with AATD who smoke cigarettes and/or are exposed to occupational dust or fumes. In non-smokers and individuals without environmental exposure, the onset of respiratory disease occurs more commonly in the sixth decade. Childhood-onset lung disease is rare with AATD.

Liver Manifestations

Adults with AATD-associated liver disease generally present with cirrhosis and fibrosis. In contrast, newborns with AATD can present with cholestasis or (less frequently) hepatomegaly and elevated aminotransferase levels. The AATD-associated cholestasis is typically associated with PI*Z homozygotes or PI*SZ heterozygotes, which tend to have less severe lung disease in adulthood. AATD-associated-cholestatic jaundice can progress to require a liver transplant in newborns. In a large series (1976) of 127 newborns with AATD found by screening, the prevalence of liver damage was 11%, severe in about two-thirds of cases.

Skin Manifestations

Panniculitis is a rare, but well-recognized complication of AATD. This dermatologic condition is characterized by inflammatory and necrotizing lesions of the skin and subcutaneous tissue.

Clinical Management

The primary interventions to prevent or treat lung-related symptoms in adults 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 pathogenic variants. In addition, individuals with AATD are advised to avoid other substances that can irritate the lungs (e.g., cigarette smoke, dust, 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. 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.

Other aspects of AATD management involve monitoring for and screening for comorbidities, including liver disease.

Diagnostic Testing for Alpha₁-Antitrypsin

Several types of tests are available for patients 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 AATD. In general, a serum AAT concentration less than 15% to 20% of the normal value is highly suggestive of a homozygous alpha-1 antitrypsin pathogenic variant.

The alpha₁ 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 for AATD can be done with the alpha₁ 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 pathogenic variants (i.e. 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 A1AT 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. In 2022, the SPIFE A1AT phenotyping kit (Helena Laboratories) was approved by the FDA by the 510(k) process for the same indication. In 2017, the A1AT Genotyping Test (Grifols) was approved by the FDA as an aid to diagnosis of individuals with AATD. FDA product code: OBZ, PZH.

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 the CLIA for high-complexity testing. To date, the Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Genetic testing for alpha₁-antitrypsin deficiency may be considered medically necessary when either of the following conditions are met: 

1. Individual is suspected of having alpha₁-antitrypsin deficiency because of clinical factors and/or because the individual may be at high risk of having alpha₁-antitrypsin deficiency due to a first-degree relative with AAT deficiency (see Policy Guidelines); OR

2. Individual has a serum alpha₁-antitrypsin level in the range of severe deficiency (see Policy Guidelines).

Genetic testing for alpha₁-antitrypsin deficiency is considered investigational in all other situations.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

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

Clinical factors relevant for suspicion of alpha₁-antitrypsin deficiency based on 2016 Alpha-1 Foundation clinical practice guidelines are:

• Individuals with chronic obstructive pulmonary disease (COPD);

• Individuals with asthma and airflow obstruction not completely reversible with bronchodilators;

• Individuals with otherwise unexplained liver disease;

• Individuals with necrotizing panniculitis;

• Individuals with anti-proteinase 3-positive vasculitis (cytoplasmic anti-neutrophil cytoplasmic antibody-positive vasculitis);

• Individuals with bronchiectasis without evident etiology.

Family history relevant for suspicion of alpha₁-antitrypsin deficiency:

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

Table 1 shows the range of serum levels of alpha₁-antitrypsin by common phenotypes according to the commercial standard milligram per deciliter and the purified standard micromole. A level less than 11 mmol is generally considered to be associated with an increased risk of clinical disease, but this cutoff may vary by the specific test used (American Thoracic Society & European Respiratory Society, 2003; Global Initiative for Chronic Obstructive Lung Disease, 2024).

Table 1. Range of Alpha₁-Antitrypsin Serum Levels by Common Phenotypes

Genetics Nomenclature Update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 2). The Society’s nomenclature is recommended by the Human Variome Project, the HUman Genome Organization, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 3 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 2. Nomenclature to Report on Variants Found in DNA

Table 3. ACMG-AMP Standards and Guidelines for Variant Classification

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 Mental Health Disorders, 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 medical necessity, “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.

POLICY HISTORY

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

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

07/03/2014: Policy reviewed; description 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.

02/07/2018: Policy description updated regarding liver manifestations. Policy statements unchanged. Policy Guidelines updated regarding genetics nomenclature.

02/25/2019: Policy reviewed; no changes.

11/15/2019: Policy reviewed. Medically necessary policy statement revised to state that genetic testing for alpha-1 antitrypsin deficiency may be considered medically necessary when either of the conditions are met. Previously, both conditions were required.

02/10/2020: Policy reviewed; no changes.

03/30/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

02/11/2022: Policy reviewed; no changes.

02/15/2023: Policy description updated regarding tests. Policy statements and Policy Guidelines updated to change "patient" to "individual."

09/22/2023: Policy reviewed. Policy statements unchanged. Policy Guidelines updated regarding clinical factors relevant for suspicion of alpha1-antitrypsin deficiency.

02/19/2024: Policy reviewed. Policy statements unchanged. Policy Guidelines updated.

03/12/2025: Policy reviewed. Policy statements unchanged. Policy Guidelines updated.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.79 

CODE REFERENCE

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

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