ModifiedEmblemHealthPolicy AHS-M2068

Testing for Alpha-1 Antitrypsin Deficiency - Lab Benefit Program (LBM)

This reimbursement policy governs coverage criteria for laboratory testing for alpha-1 antitrypsin deficiency (AATD) under EmblemHealth's Lab Benefit Program and applies to providers requesting testing for members; applicability depends on individual benefit coverage.

Policy Summary

PayerEmblemHealth

PolicyTesting for Alpha-1 Antitrypsin Deficiency - Lab Benefit Program (LBM)

Policy CodePolicy AHS-M2068

Change TypeCoverage consolidation + frequency limit added

Effective DateMar 1, 2023

Next Review DateN/A

Key ActionOrder serum AAT quantification and AAT phenotyping/proteotyping (or isoelectric focusing when indicated) — these tests meet coverage criteria once per lifetime for specified clinical indications.

SourceLink

POLICY UPDATE CHANGES

Addition of 'once per lifetime' to Coverage Criteria 1 making serum quantification and phenotyping/prototyping covered once per lifetime in specified situations.

Combined serum quantification, phenotyping, prototyping, and genotyping into a single criterion with conditions from Coverage Criteria 1 remaining.

Lab Benefit Program (LBM) expanded to include EmblemHealth HMO/PPO (Non-City) Commercial, Medicare and Medicaid plans effective 10/1/2024.

Deleted former Note listing the ATS recommendations on diagnosis (moved to Guidelines section).

once per lifetimeAAT testing allowed in specified situations

18+age threshold for several covered indications

quant/phenotype/genotype

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

laboratory strategies described

1 in 2,000–5,000estimated prevalence of AATD

4referenced procedure codes

Coverage Criteria for AATD Testing

inv-01: Coverage criteria — Coverage criteria for laboratory testing to evaluate suspected AAT deficiency.

Covered when ALL of the following are met:

ALL of the following

Serum quantification of alpha-1 antitrypsin (AAT) protein AND AAT phenotyping or AAT proteotyping (see Note 1)
AND the individual meets ONE of the following clinical indications:
- Symptomatic individual ≥18 years with emphysema, COPD, or asthma
- Individual with unexplained liver disease (e.g., chronic hepatitis with or without cirrhosis, chronically elevated aminotransferase levels, portal hypertension, primary liver cancer)
- Individual with persistent obstruction on pulmonary function testing without identifiable risk factors (e.g., cigarette smoking, occupational exposure)
- Individual ≥18 years with necrotizing panniculitis
- Sibling of an individual with known AAT deficiency
- Individual with anti-proteinase-3 (C-ANCA)–positive vasculitis
- Individual with bronchiectasis without evident etiology
- Individual with neonatal cholestasis

ALL of the following

If genotype testing for common variants is negative OR there is discordance between serum AAT levels and proteotype BUT clinical suspicion remains, isoelectric focusing/phenotyping MEETS COVERAGE CRITERIA

ALL of the following

Testing for AAT deficiency in all other situations not described above DOES NOT MEET COVERAGE CRITERIA

ALL of the following

AAT phenotyping should be performed using isoelectric focusing; AAT proteotyping for Z and S alleles should be performed using liquid chromatography–tandem mass spectrometry (Note 1)
Coverage Criteria consolidated to combine serum quantification, phenotyping/proteotyping, and genotyping into a single criterion; refer to Coverage Criteria 1 and the once-per-lifetime frequency limit

inv-02: Indications and testing approach — Guideline-based indications and recommended testing strategies for AATD.

Guideline-based indications and recommended testing strategies for AATD.

ALL of the following

Quantitative determination of AAT levels in blood is the initial crucial test to identify AATD
Qualitative tests (phenotyping/proteotyping or genotyping) are required to identify the genetic mutation(s) causing AATD
Genotyping allows rapid identification/exclusion of S and Z alleles; gene sequencing is indicated when null or other deficient variants are suspected

Situations with strong/Type A guideline recommendations

Symptomatic adults with emphysema, COPD, or asthma with incompletely reversible airflow obstruction

inv-03: Coverage Criteria 1 (consolidated) — Consolidated criterion combining serum quantification and phenotyping/prototyping/genotyping with conditions.

Consolidated coverage criterion combining serum quantification with phenotyping/proteotyping/genotyping and operational frequency limit.

ALL of the following

Serum quantification of AAT protein AND AAT phenotyping or proteotyping (and genotyping as part of the consolidated testing strategy) MEET COVERAGE CRITERIA once per lifetime
The test(s) meet criteria only when the individual satisfies one or more of the specified clinical indications in Coverage Criteria 1 (eg symptomatic adults with emphysema/COPD/asthma, unexplained liver disease, persistent obstruction without risk factors, necrotizing panniculitis, siblings of known AATD, C-ANCA–positive vasculitis, bronchiectasis without evident etiology, neonatal cholestasis)
If genotype for common variants is negative or there is discordance between serum level and proteotype but clinical suspicion remains, isoelectric focusing/phenotyping meets coverage criteria as part of the consolidated approach

ALL of the following

Procedure Codes and Test Types

Procedure/test types referencedmixed

AAT quantification	Serum quantification of AAT protein (eg, immune turbidimetry, nephelometry)
AAT phenotyping	Isoelectric focusing protein phenotyping (IEF)
AAT proteotyping	Proteotyping (Pi-typing) by LC-MS/MS
Genotyping	Targeted genotyping for common SERPINA1 alleles (eg, S and Z) and full gene sequencing when indicated

Recommended testsmixed

Serum AAT quantification	Initial quantitative testing of AAT levels (eg, nephelometry, turbidimetry); labs often reflex to phenotyping at <100 mg/dL
Isoelectric focusing phenotyping (IEF)	Protein phenotyping by isoelectric focusing recommended as qualitative confirmatory testing
Proteotyping (LC-MS/MS)	Proteotype/Pi-typing for Z and S alleles using liquid chromatography–tandem mass spectrometry
Genotyping for S and Z alleles	Targeted molecular genotyping for common SERPINA1 variants; sequencing for rare/null variants

Referenced procedure codesCPT | HCPCS | mixed

82103	Alpha-1-antitrypsin; total
82104	Alpha-1-antitrypsin; phenotype
82542	Column chromatography, includes mass spectrometry, if performed (eg, HPLC, LC, LC/MS, LC/MS-MS, GC, GC/MS-MS, GC/MS, HPLC/MS), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen
83789	Mass spectrometry and tandem mass spectrometry (eg, MS, MS/MS, MALDI, MS-TOF, QTOF), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen

AAT low level thresholds and reflex testing triggers

Example low thresholdSerum AAT < 11 micromol/L (≈57 mg/dL) is generally considered low; many laboratories reflex to phenotyping for AAT when serum AAT is <100 mg/dL (≈18.4 micromol/L).

Laboratory reflex practiceBecause reference ranges vary by method, most labs perform isoelectric focusing phenotyping for individuals with AAT levels <100 mg/dL (18.4 micromol/L).

Borderline/qualitative testing guidanceAmerican Thoracic Society suggests qualitative testing for borderline serum levels (12–35 micromoles or 90–140 mg/dL).

Frequency limit

Frequency limitSerum quantification and AAT phenotyping/proteotyping (and genotyping per the consolidated criterion) MEET COVERAGE CRITERIA once per lifetime when Coverage Criteria 1 conditions are met.

Prior Authorization and Testing Workflow

Prior Authorization

Prior authorization / coverage guidance for AAT testing

Serum AAT quantification and AAT phenotyping/proteotyping (or isoelectric focusing phenotyping when indicated) MEETS COVERAGE CRITERIA once per lifetime for individuals suspected of having AAT deficiency when they meet one of the specified indications (symptomatic adults ≥18 years with emphysema/COPD/asthma; unexplained liver disease; persistent obstruction without identifiable risk factors; adults ≥18 years with necrotizing panniculitis; siblings of a known AATD individual; C‑ANCA–positive vasculitis; bronchiectasis without evident etiology; neonatal cholestasis).

Coverage is limited to the listed clinical situations; testing for AAT deficiency in all other situations DOES NOT MEET COVERAGE CRITERIA.
Frequency limit: once per lifetime for Coverage Criteria 1.

Documentation Required

Testing recommendations and methods (guideline-based)

Follow guideline-derived indications and testing approaches: begin with serum quantitative AAT determination; use protein phenotyping (isoelectric focusing) or proteotyping (LC‑MS/MS) to characterize variants; perform targeted genotyping for common S and Z alleles, and reserve gene sequencing when a null or rare deficient variant is suspected. Test relatives after appropriate counseling per guideline recommendations.

Key Terms and Test Methods

AAT / A1AT

DefinitionAlpha-1 antitrypsin (AAT; also listed as A1AT) — a protease inhibitor protein; deficiency (AATD) is an inherited disorder affecting lung and liver function.

AbbreviationsA1AT = Alpha-1 antitrypsin; AATD = Alpha 1-antitrypsin deficiency.

Clinical relevanceTesting strategies for suspected AATD include serum quantification, protein phenotyping, proteotyping, targeted genotyping, and sequencing as indicated.

AAT phenotyping (isoelectric focusing)

Test methodIsoelectric focusing (IEF) phenotyping uses differences in migration rates of AAT protein variants under isoelectric focusing; it is a protein-based (not genetic) test.

Role in diagnosisRecommended as the traditional 'gold standard' by ATS/ERS when performed by a reliable laboratory to identify AAT protein variants (eg M, Z, F migrations).

Policy Summary

PayerEmblemHealth

PolicyTesting for Alpha-1 Antitrypsin Deficiency - Lab Benefit Program (LBM)

Policy CodePolicy AHS-M2068

Change TypeCoverage consolidation + frequency limit added

Effective DateMar 1, 2023

Next Review DateN/A

SourceLink

On This Page

Individuals with unexplained liver disease (neonates, children, adults)

Asymptomatic individuals with persistent obstruction on pulmonary function testing without identifiable risk factors (eg, cigarette smoking, occupational exposure)

Adults with necrotizing panniculitis

Siblings of an individual with known AAT deficiency

Additional recommended indications (Type B/C)

Adults with bronchiectasis without evident etiology
Adolescents with persistent airflow obstruction
Asymptomatic individuals with persistent airflow obstruction and no risk factors
Adults with C-ANCA (anti-proteinase 3)-positive vasculitis
Individuals with family history of COPD or liver disease where AATD is possible; relatives of individuals with known AAT deficiency (offspring, parents, distant relatives)

ALL of the following

Start with serum AAT quantification; reflex to phenotyping (isoelectric focusing) or proteotyping (LC-MS/MS) per laboratory practice
Use genotyping for at least S and Z alleles for primary diagnosis; consider gene sequencing for suspected null or rare variants
Phenotyping by isoelectric focusing is an accepted 'gold standard' for diagnosing AAT deficiency when performed by a reliable laboratory

ALL of the following

Genetic testing should be performed after informed consent in accordance with guidelines and legislation; family testing should include appropriate counseling

Once-per-lifetime frequency limit applies to Coverage Criteria 1 where tests meet the clinical indications described

Scope of lifetime limitApplies to the consolidated Coverage Criteria 1 which combines serum quantification and phenotyping/proteotyping/genotyping modalities.

Operational effective date notedRevision documented adding 'once per lifetime' to Coverage Criteria 1 (see revision history).

ATS/ERS and ERS recommend quantitative AAT testing as the first step and protein phenotyping by isoelectric focusing as an accepted diagnostic standard.
Genotyping for S and Z alleles provides rapid, specific identification; sequencing is recommended when non‑S/non‑Z or null variants are suspected.
Alpha‑1 Foundation recommends genotyping for at least S and Z for diagnostic testing and family testing with counseling.

Prior Authorization

Consolidation of coverage criteria — refer to Coverage Criteria 1

Serum quantification, phenotyping/proteotyping, and genotyping have been consolidated into a single coverage criterion (Coverage Criteria 1); refer to Coverage Criteria 1 for the clinical conditions that must be met and the once‑per‑lifetime frequency limit.

This consolidation combines prior separate criteria so that quantification, phenotyping/proteotyping (or IEF), and genotyping are considered under one authorized pathway.
See Coverage Criteria 1 for the list of covered indications and the lifetime frequency limitation.

When usedOften performed as reflex testing when quantitative serum AAT is low or borderline, and may be used when genotype and level results are discordant.

AAT proteotyping

Method descriptionProteotyping (Pi-typing) for Z and S alleles is performed using liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Clinical performanceLC-MS/MS proteotype-based algorithms have been shown to reduce reflex IEF phenotyping substantially while maintaining high sensitivity (eg 99.9% in a retrospective application).

Role in testing workflowProteotyping can serve as a primary qualitative approach to identify deficiency-associated phenotypes and reduce need for reflex IEF in many cases.

AAT genotyping / sequencing

Common methodsGenotyping for common SERPINA1 variants typically uses PCR or RFLP techniques to detect S and Z alleles; full gene sequencing is used when rare or null variants are suspected.

When to use sequencingGene sequencing is indicated for cases with suspected rare/null variants or when targeted genotyping does not explain discordant clinical/biochemical findings.

Guideline positionERS and Alpha-1 Foundation recommend genotyping for at least the S and Z alleles as part of diagnostic evaluation; sequencing as needed for unresolved cases.

IEF phenotyping

Technique overviewPhenotyping by isoelectric focusing (IEF) separates AAT protein variants by migration rate on a gel; e.g., M variant migrates to the middle, Z migrates slowest, F migrates toward the anode.

Clinical roleConsidered the accepted 'gold standard' by ATS/ERS for diagnosing AAT deficiency when performed by a reliable laboratory.

LimitationsIEF is a protein-based test (not genetic); results can be inconclusive or discordant with quantitative testing, sometimes necessitating genotype testing.

Genotyping (S and Z)

Targets (S and Z)Genotyping for the S and Z alleles provides rapid and precise identification/exclusion of the most common SERPINA1 variants and is recommended as part of diagnostic testing.

Sensitivity/specificityGenotyping for S and Z alleles is reported by guideline and expert groups to be highly sensitive and specific (>99% when both alleles assessed).

Use in family testingGuidelines recommend genotyping for relatives after an affected proband and advise genetic counseling prior to genetic testing.

Proteotype algorithm (LC-MS/MS)

Algorithm performanceProteotype (LC-MS/MS) algorithms demonstrated high sensitivity (99.9% in a retrospective application) and greatly reduced the need for reflex IEF phenotyping in published cohorts.

Impact on workflowIn one study LC-MS/MS reduced IEF phenotyping by 97% and limited reflex IEF to ~3% of cases, with only 0.2% additional phenotype findings from those reflexes.

Clinical implicationProteotyping is presented as a sensitive, cost-effective approach for diagnosing clinical AAT deficiency and may streamline laboratory workflows.

LDTs and FDA-approved AATD tests

LDTs vs FDA-approved testsLaboratory-developed tests (LDTs) are high-complexity tests regulated under CLIA '88 by CMS and are not FDA-approved; FDA approval/clearance is not required for clinical use but some SERPINA1 tests have received FDA approval/clearance.

When to considerProprietary and FDA-approved genotyping assays may be used for screening/detection; LDTs remain common and must be validated and performed in-house per CLIA requirements.