Currentblue cross blue shield - tennesseePolicy N/A

Testing For Alpha-1 Antitrypsin Deficiency

Defines clinical indications, limitations, and recommended testing methods (serum quantification, phenotyping, genotyping, and SERPINA1 sequencing) for diagnosing AATD and describes guideline alignment and scientific background. Applies to commercial coverage determinations; Medicare/Medicaid specifications referenced in Section VII.

Policy Summary

Payerblue cross blue shield - tennessee

PolicyTesting For Alpha-1 Antitrypsin Deficiency

Policy CodePolicy N/A

Change TypeAdopted Avalon recommendation

Effective Date7/1/2023

Next Review DateN/A

Key ActionOrder A1AT serum quantification, phenotyping, genotyping, or SERPINA1 sequencing only when patient meets one of the listed covered clinical indications (symptoms, family history, discordant/negative genotyping with high suspicion).

SourceLink

POLICY UPDATE CHANGES

Policy adopted Avalon policy recommendation (effective 7/1/2023).

7Covered serum indications

4Genetic testing scenarios

1Not-covered category

MultipleReferences

Effective date entries

Coverage Summary

Scope: This policy covers diagnostic testing for Alpha-1 Antitrypsin Deficiency (AATD), defining clinical indications, limitations, and recommended laboratory methods including serum A1AT quantification, phenotyping (isoelectric focusing/Pi-typing), targeted genotyping for common S and Z alleles, and full SERPINA1 sequencing when indicated. Coverage stance is mixed — specific situations and clinical indications are listed as covered while testing outside those indications is not covered.

Subject and status: The subject is testing for AATD; policy status is CURRENT and applies to commercial coverage determinations with Medicare/Medicaid specifications referenced.

High-level testing strategy: The preferred laboratory approach is a combination of quantification and genotyping with reflex to phenotyping (isoelectric focusing or proteotyping) when discordant or when genotype is negative but clinical suspicion remains; full SERPINA1 gene sequencing is reserved for cases with strong suspicion or discordant/negative targeted genotype results to detect rare or null variants.

Prevalence/evidence: AATD is underrecognized, estimated at approximately 1 in 2,000 to 1 in 5,000 individuals with up to 80,000–100,000 people in the U.S. having severe disease. Guideline and evidence support come from multiple sources (ATS/ERS, ERS, WHO, ACG, Alpha-1 Foundation, GOLD, CTS, NICE, and peer-reviewed studies) and analytical studies (e.g., Snyder et al.) that favor the combined testing algorithm.

Effective adoption date: Policy adopted per Avalon recommendation effective 7/1/2023.

Key thresholds & quick facts

Serum AAT low level thresholdBelow 11 micromol/L (<57 mg/dL); many labs reflex to phenotyping at <100 mg/dL (18.4 micromol/L); ATS suggests qualitative testing for borderline 12–35 micromoles (90–140 mg/dL)

Prevalence estimateApproximately 1 in 2,000–1 in 5,000; up to 80,000–100,000 in US with severe disease

Covered serum testing clinical indications (count)7 listed indications for serum testing

Covered genetic testing scenarios (count)4 covered genetic testing scenarios

Medical Necessity / Covered Indications

Serum testing - Covered situations

Serum quantification of A1AT protein and/or A1AT phenotyping by isoelectric focusing or A1AT proteotyping (Pi‑typing) or proteomics MEETS COVERAGE CRITERIA in the following situations:

ALL of the following

Symptomatic adults with emphysema, COPD, or asthma
Individuals with unexplained liver disease
Individuals with persistent obstruction on pulmonary function tests without identifiable risk factors (e.g., cigarette smoking, occupational exposure)
Adults with necrotizing panniculitis

Provider Actions & Billing

Documentation Required

Apply clinical criteria for testing

Order A1AT serum quantification, phenotyping, targeted genotyping, or SERPINA1 sequencing only when the patient meets one of the policy's listed covered clinical indications (symptoms, family history, or discordant/negative genotyping with high clinical suspicion). Document which covered indication applies when ordering to support coverage.

Apply testing only for covered indications (e.g., symptomatic emphysema/COPD/asthma, unexplained liver disease, persistent unexplained obstruction, necrotizing panniculitis, siblings/first-degree relatives of affected individuals, bronchiectasis without evident etiology, C-ANCA–positive vasculitis).
Record discordant laboratory results or strong clinical suspicion when ordering advanced testing (phenotyping or full sequencing).

Documentation Required

Use reflex testing strategy

Recommended laboratory approach: perform quantitative A1AT testing and targeted genotyping for common S and Z alleles together, with reflex to phenotyping (isoelectric focusing or proteotyping) when results are discordant or genotype is negative but suspicion remains. Reserve full SERPINA1 gene sequencing (or expanded genotyping) when reflex testing and clinical/laboratory data suggest rare or null variants.

Coding

No procedure or billing codes listed in Part 1mixed

No codes listed

Background & Evidence

Background: Alpha-1 antitrypsin deficiency (AATD) is an underrecognized autosomal condition (codominant expression) that predisposes to early-onset emphysema, COPD, liver disease, and skin manifestations such as necrotizing panniculitis. Estimates place prevalence at about 1 in 2,000 to 1 in 5,000 individuals and up to 80,000–100,000 people in the U.S. with severe disease.

Clinical manifestations and rationale for testing: AAT protects the lung from neutrophil elastase; deficient or dysfunctional AAT leads to emphysema (often early-onset), bronchiectasis, and variable liver disease from intracellular polymerization of abnormal AAT. Guidelines recommend testing patients with compatible clinical features (e.g., early-onset emphysema, unexplained liver disease, necrotizing panniculitis, bronchiectasis of unknown cause, or family members of affected individuals).

Recommended testing strategy (exact methods): Initial evaluation commonly begins with serum A1AT quantification (methods include nephelometry or turbidimetry) with laboratory thresholds noted as low: <11 micromol/L (<57 mg/dL) and many labs reflexing to phenotyping at <100 mg/dL (18.4 micromol/L); ATS suggests qualitative testing for borderline levels 12–35 micromoles (90–140 mg/dL).

Follow-up and confirmatory testing: Phenotyping by isoelectric focusing (Pi-typing) is an accepted qualitative standard to identify protein variants and is used when quantification is low or discordant. Targeted genotyping (S and Z alleles) provides rapid identification of the most common pathogenic variants. When genotype testing for common variants is negative but clinical/laboratory suspicion remains, or when discordant results occur, full SERPINA1 gene sequencing is indicated to detect rare or null alleles.

Optimal laboratory algorithm and evidence: Multiple guidelines and analytic studies support a combined approach of quantification plus genotyping with reflex to phenotyping; Snyder et al. and ERS guidance specifically endorse this algorithm as the optimal laboratory evaluation strategy.

Definitions

Term	Definition
{"text":"A1AT","status":""},{"text":"Alpha-1 antitrypsin","status":"neutral"}
{"text":"AATD","status":""},{"text":"Alpha 1-antitrypsin deficiency","status":"neutral"}
{"text":"SERPINA1","status":""},{"text":"Gene encoding alpha-1 antitrypsin","status":"neutral"}
{"text":"Pi-typing","status":""},{"text":"Protease inhibitor phenotyping (isoelectric focusing)","status":"neutral"}

Revision History

7/1/2023policy_adoptionLatest

Policy adopted Avalon policy recommendation

Policy Summary

Payerblue cross blue shield - tennessee

PolicyTesting For Alpha-1 Antitrypsin Deficiency

Policy CodePolicy N/A

Change TypeAdopted Avalon recommendation

Effective Date7/1/2023

Next Review DateN/A

SourceLink

On This Page

Siblings of an individual with known alpha-1 antitrypsin (AAT) deficiency

Individuals with anti-proteinase three-positive vasculitis (C-ANCA-positive vasculitis)

Individuals with bronchiectasis without evident etiology

Phenotyping when genotype discordant or negative - Covered

Isoelectric focusing/phenotyping MEETS COVERAGE CRITERIA when:

ANY of the following

Individual has negative genotype testing for common variants but strong clinical/lab suspicion of disease
Discordant results between A1AT serum levels and proteotype

Genetic testing - Covered situations

Genetic testing for AATD MEETS COVERAGE CRITERIA in the following situations:

ANY of the following

Clinical factors prompting testing (any one of):
- Early-onset emphysema (age 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 three-positive vasculitis (C-ANCA-positive vasculitis)
- Bronchiectasis without evident etiology
Patient has discordant results between serum levels and proteotype testing for Z and S alleles by mass spectrometry
At-risk individuals with a first-degree relative with AAT deficiency

SERPINA1 full gene sequencing - Covered situations

Full SERPINA1 gene sequencing MEETS COVERAGE CRITERIA when:

ANY of the following

There is strong suspicion of disease based on laboratory testing and symptoms in an individual with negative genotype testing for common variants
There are discordant results between A1AT serum levels and proteotype or phenotype

Not covered

Testing that does not meet criteria:

ALL of the following

Testing for alpha-1 antitrypsin deficiency DOES NOT MEET COVERAGE CRITERIA in all other situations (i.e., not meeting the specific covered indications above)

Coverage criteria (overall)

Referenced clinical guidance and evidence support testing; specific clinical criteria were in part 1 (not provided here).

Testing and reimbursement decisions follow clinical guidelines and literature cited in the policy

See references list for supporting guidance (e.g., ATS/ERS statement, GOLD, UpToDate, WHO).

Combination of genotyping and quantification with reflex to phenotyping is the optimal laboratory strategy (Snyder et al., 2006).
Genotyping rapidly identifies S and Z alleles; sequencing is necessary when null or non‑S/Z deficient variants are suspected (ERS/ERS statements).
Phenotyping identifies variants present in the sample and is used for discordant or inconclusive cases.

Documentation Required

Consider guideline alignment

Follow established specialty guideline recommendations referenced in the policy (e.g., ATS/ERS, ERS, WHO, ACG, Alpha‑1 Foundation, GOLD, CTS, NICE) for who to screen and which tests to perform. Align testing decisions and documentation with those guideline criteria to ensure appropriate clinical justification.

ATS/ERS and ERS provide diagnostic recommendations and clinical features that should prompt testing (early-onset emphysema, unexplained liver disease, necrotizing panniculitis, bronchiectasis, C-ANCA vasculitis).
WHO and ACG recommend quantitative screening in COPD/asthma/liver enzyme abnormalities and reflex qualitative testing as indicated.

Documentation Required

Follow referenced clinical guidance

When ordering and documenting AATD testing, follow the diagnostic algorithms and management recommendations cited in the policy (quantification, genotyping, phenotyping, sequencing) and record the guideline-identified indication and test rationale in the medical record to support reimbursement.

Document the specific guideline‑based indication for testing (e.g., ATS/ERS Type A/B criteria) in the chart.
Include laboratory result interpretation (quantitative level, genotype/phenotype results, and reason for reflex sequencing if performed) to substantiate medical necessity for payers.

Billing Rule

Policy effective date adoption

Policy adopted Avalon recommendation effective 2023-07-01. Billing and reimbursement should follow this policy as of that effective date.

Effective date: 7/1/2023 — Adopted Avalon policy recommendation.

Evidence and guidance

Prevalence estimateApproximately 1 in 2,000–1 in 5,000 individuals; up to 80,000–100,000 US with severe disease

Analytic/clinical validityCombination of genotyping and quantification with reflex to phenotyping considered optimal (Snyder et al. 2006); limited RCTs and variable analytic literature

Key guidelineEuropean Respiratory Society statement: diagnosis and treatment of pulmonary disease in AATD (Eur Respir J, 2017)

Supporting guidanceGOLD, WHO, ATS/ERS, ACG, Alpha-1 Foundation and other guideline documents cited