Currentmedical mutual - ohioPolicy AHS - M2068 - Testing for Alpha-1 Antitrypsin Deficiency, 1 = Initial Presentation

Testing for Alpha-1 Antitrypsin Deficiency

Coverage policy for laboratory testing to diagnose alpha-1 antitrypsin deficiency (AATD), specifying which tests and clinical indications meet or do not meet coverage for Medical Mutual - Ohio members.

Policy Summary

Payermedical mutual - ohio

PolicyTesting for Alpha-1 Antitrypsin Deficiency

Policy CodePolicy AHS - M2068 - Testing for Alpha-1 Antitrypsin Deficiency, 1 = Initial Presentation

Change TypeReviewed and Updated (non-material)

Effective Date02/01/2026

Next Review Date

Key ActionObtain a serum AAT quantification as the initial test and document the clinical indication; perform reflex phenotyping or genotyping as indicated.

SourceLink

POLICY UPDATE CHANGES

Reviewed and Updated: Updated the background, guidelines and recommendations, and evidence-based scientific references.

once per lifetimeAAT testing frequency covered

1 in 2,000–5,000Estimated prevalence

up to 100,000Severe cases (US est.)

14SERPINA1 alleles reported

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CPT/HCPCS codes listed

Coverage Criteria

inv-01: Covered Indications (Initial testing)

Serum AAT quantification and AAT phenotyping/proteotyping meet coverage criteria once per lifetime when ANY of the following are present:

Covered indications: a) Symptomatic individuals 18 years or older with emphysema, COPD, or asthma; b) Individuals with unexplained liver disease (e.g., chronic hepatitis with or without cirrhosis, chronically elevated aminotransferase levels, portal hypertension, primary liver cancer); c) Individuals with persistent obstruction on pulmonary function tests without identifiable risk factors (e.g., cigarette smoking, occupational exposure); d) Individuals 18 years or older with necrotizing panniculitis; e) Siblings of an individual with known alpha-1 antitrypsin (AAT) deficiency; f) Individuals with anti-proteinase three-positive vasculitis (C-ANCA-positive vasculitis); g) Individuals with bronchiectasis without evident etiology; h) Individuals with neonatal cholestasis.once per lifetime

Phenotyping should use isoelectric focusing; proteotyping for Z and S alleles via LC-MS/MS.

inv-02: Secondary/reflex testing

Reflex/secondary coverage:

Reflex phenotyping: For individuals with negative genotype results for common variants or discordant results between AAT serum levels and proteotype, but for whom clinical suspicion of AAT deficiency remains, isoelectric focusing/phenotyping meets coverage criteria.as needed

Phenotyping should be performed using isoelectric focusing; proteotyping for Z and S alleles via LC-MS/MS (see Note 1).

inv-03: Type A - Recommended testing

Testing recommended (Type A) when ALL of the listed clinical scenarios apply to the patient (per ATS/ERS / specialty organizations):

Type A diagnostic testing indications: 1. Symptomatic adults with emphysema, COPD, or asthma with airflow obstruction that is not completely reversible with aggressive bronchodilator therapy; 2. Individuals with unexplained liver disease (neonates, children, and adults); 3. Asymptomatic individuals with persistent obstruction on pulmonary function tests with identifiable risk factors (e.g., cigarette smoking, occupational exposure); 4. Adults with necrotizing panniculitis; 5. Siblings of an individual with known AAT deficiency.

ATS/ERS and specialty organization (ACG, Alpha-1 Foundation) Type A recommendations; quantitative AAT level recommended as initial test with follow-up phenotyping/genotyping as indicated.

inv-04: Type B - Testing should be discussed

Testing should be discussed (Type B) in the following scenarios:

Type B diagnostic testing indications: 1. Adults with bronchiectasis without evident etiology; 2. Adolescents with persistent airflow obstruction; 3. Asymptomatic individuals with persistent airflow obstruction and no risk factors; 4. Adults with C-ANCA (anti-proteinase-3)-positive vasculitis; 5. Individuals with a family history of COPD or liver disease not known to be attributed to AAT deficiency; 6. Distant relatives of an individual who is homozygous for AAT deficiency; 7. Offspring or parents of an individual with homozygous AAT deficiency; 8. Siblings, offspring, parents, or distant relatives of an individual who is heterozygous for AAT deficiency; 9. Individuals at high risk of having AAT deficiency-related diseases; 10. Partners of individuals who are homozygous or heterozygous for AAT deficiency.

ATS/ERS Type B recommendations; consider counseling and informed consent for genetic testing.

inv-05: Type C/D - Not recommended or discouraged

Testing not recommended (Type C) or discouraged (Type D) in these scenarios:

Type C - Not recommended: 1. Adults with asthma in whom airflow obstruction is completely reversible; 2. Predispositional testing; 3. Population screening of smokers with normal spirometry.

ATS/ERS Type C

Type D - Recommend against: 1. Predispositional fetal testing; 2. Population screening of neonates, adolescents, or adults (population screening is not recommended currently, with a possible country‑specific exception described in guideline text).

ATS/ERS Type D

inv-06: Algorithm and family testing

Testing algorithm and interpretation guidance per guideline statements:

Initial testing: Quantitative determination of AAT levels in blood is the crucial first test to identify AAT deficiency; abnormal or low results should be followed by qualitative testing (phenotyping by isoelectric focusing) and genotyping for common alleles (S and Z); gene sequencing is recommended when null or rare deficient variants are suspected.

ERS/ATS and Alpha-1 Foundation guidance

Family testing should include genotyping and counseling rather than AAT level testing alone; testing of relatives should be offered after identification of a proband and after appropriate counseling and informed consent.

Alpha-1 Foundation guidance

Testing for alpha-1 antitrypsin (AAT) deficiency for any situations not explicitly listed in the policy's covered indications does not meet coverage criteria. The policy states that when clinical circumstances fall outside the specified covered indications, the test is considered not supported by published evidence and may be denied.

The European Respiratory Society (ERS) guideline notes that there is no evidence to support efficacy of AAT augmentation therapy in PiSZ, PiMZ, or current smokers of any phenotype. This statement provides context for restricting testing and treatment decisions in these specific genotypes and in active smokers.

The British Columbia guideline observes that routine testing for A1AT deficiency is frequently low yield, expensive, and often duplicated, and may not meaningfully alter management. As a result, BC recommends referring patients with high pre-test probability to a specialist rather than performing broad routine screening.

Any AAT testing requested for indications outside those explicitly listed in the covered indications section is considered not meeting coverage criteria. Such testing lacks sufficient published evidence of clinical benefit per the policy and is therefore subject to denial.

Population screening of neonates, adolescents, or adults is not recommended by guideline classifications (Type D) and, absent a defined high-prevalence exception or specific clinical indication, such screening would generally be considered not medically necessary and not covered.

Covered Indications (Specific Clinical Scenarios)

inv-34: Symptomatic adults and listed conditions

Quantification and phenotyping/proteotyping meet coverage once per lifetime for these indications:

Covered symptomatic and listed conditions: Symptomatic adults with emphysema/COPD/asthma; unexplained liver disease; persistent unexplained pulmonary obstruction; necrotizing panniculitis; siblings of known AAT deficiency probands; C-ANCA (anti-proteinase-3)-positive vasculitis; bronchiectasis without evident etiology; neonatal cholestasis.once per lifetime

Phenotyping should be performed using isoelectric focusing; proteotyping for Z and S alleles via LC-MS/MS (Note 1).

inv-35: Guideline-recommended scenarios

Guideline-recommended scenarios — testing for AATD is supported in these clinical contexts:

Guideline-recommended scenarios: Symptomatic COPD/emphysema with incompletely reversible airflow obstruction; unexplained liver disease across age groups; necrotizing panniculitis; unexplained bronchiectasis; and testing of family members of affected probands.

Frequency Limits and Testing Frequency

inv-37: AAT quantification and AAT phenotyping/proteotyping — Once per lifetime.

ScopeSerum AAT quantification and AAT phenotyping/proteotyping meet coverage criteria once per lifetime for indicated individuals.

Frequency limitOnce per lifetime.

Covered actionsIncludes both quantitative AAT measurement and confirmatory phenotyping or proteotyping as specified in covered indications.

inv-38: Quantitative AAT level — One-time screening (recommended once for COPD/adolescents with asthma per WHO/ERS guidance).

Screening recommendationQuantitative AAT level measurement recommended as a one-time screening in patients with COPD or adolescents with asthma (per ATS/ERS guidance).

Initial testQuantitative determination of AAT levels in blood is the crucial first test to identify AATD.

Coding and Procedure Codes

Applicable CPT/HCPCS Procedure CodesCPT

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.

inv-13: Low AAT serum level threshold — thresholds and lab reflex values described.

Low AAT threshold (primary)Serum AAT level below 11 micromol/L (less than 57 mg/dL) is generally considered low.

Laboratory reflex thresholdMany laboratories reflex to isoelectric phenotyping for serum AAT levels <100 mg/dL (≈18.4 micromol/L).

ATS borderline rangeATS describes borderline serum levels as 12–35 micromoles (≈90–140 mg/dL) and recommends qualitative testing for borderline values.

Provider Actions and Documentation

Prior Authorization

Prior Authorization and Benefit Verification

Prior authorization and benefit verification: Verify the member’s coverage and whether prior authorization is required before ordering alpha-1 antitrypsin (AAT) testing. Coverage determinations are benefit-dependent; testing that meets the policy criteria is covered once per lifetime for indicated individuals. Follow the payer’s prior authorization processes and the member’s specific benefit rules prior to performing tests.

Coverage: AAT testing that meets the policy’s listed indications is covered once per lifetime.
Prior authorization: Subject to the member’s benefit plan and payer rules—confirm prior authorization requirements and submit required documentation when applicable.
Documentation to support coverage: clinical indication matching covered indications (e.g., emphysema/COPD/asthma in adults, unexplained liver disease, persistent unexplained pulmonary obstruction, necrotizing panniculitis, siblings of known AATD).

Documentation Required

Recommended Testing Sequence and Documentation

Ordering Requirements and Consent

Prior Authorization

Verify member benefits and document indication before ordering

Verify member benefits at the time of the request and document the clinical indication in the record; benefit coverage determines whether the test application meets coverage criteria.

Application of coverage criteria is dependent upon an individual's benefit coverage at the time of the request.

Documentation Required

Obtain informed consent and genetic counseling for genetic testing

Obtain informed consent and provide appropriate genetic counseling before performing genotyping; offer family testing only after the proband has been identified and counseling completed.

ERS/Alpha‑1 Foundation: genetic testing should be carried out only after informed consent.
Family testing should be considered after appropriate counseling and after a proband is identified.

Not Covered / Exclusions

Testing for AAT deficiency when the indication is not among those specified in the policy’s covered list (for example, general population screening or unspecified clinical uses) is not covered. The policy explicitly identifies all other situations as not meeting coverage criteria.

Population screening of general groups — including neonates, adolescents, or adults — is not recommended by guideline statements and therefore is not covered unless a specific, high-risk clinical indication exists that meets the covered criteria.

British Columbia guidance discourages routine broad testing in low pre-test probability populations because it is often expensive and low yield and may duplicate testing without changing management; such routine broad screening is therefore considered not covered under the policy.

Background and Epidemiology

Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder caused by pathogenic variants in the SERPINA1 gene that result in deficient or dysfunctional AAT protein. Clinically, AATD is underrecognized and can lead to early-onset emphysema/COPD, liver disease (including neonatal cholestasis and adult chronic liver disease), and less commonly necrotizing panniculitis. Professional guidelines recommend a stepwise laboratory approach: quantitative AAT measurement as the initial screening test, followed by qualitative phenotyping (isoelectric focusing) and genotyping or sequencing as indicated to identify S, Z, null, and other variants. Family testing is advised after appropriate counseling, and testing should be performed with informed consent. Guidelines also note limited therapeutic benefit of augmentation in certain genotypes and emphasize selective testing based on clinical indications rather than population screening.

Definitions

inv-27: A1AT / AAT — Alpha-1 antitrypsin (A1AT, AAT).

DefinitionAlpha-1 antitrypsin (A1AT, AAT).

AbbreviationA1AT is used interchangeably with AAT in this policy.

Clinical relevanceAAT is the protein measured and characterized when evaluating for alpha-1 antitrypsin deficiency.

inv-28: COPD — Chronic obstructive pulmonary disorder.

DefinitionCOPD = Chronic obstructive pulmonary disorder.

Testing indicationAll subjects with COPD or asthma characterized by incompletely reversible airflow obstruction should be tested once for quantitative AAT determination.

Clinical note

Revision History

09/04/2025review_updateLatest

Policy reviewed and updated: background, guidelines/recommendations, and evidence-based references were updated after literature review; no modifications to coverage criteria were required.

02/01/2026effective_date

Policy effective date recorded for this version of the document.

Policy Summary

Payermedical mutual - ohio

PolicyTesting for Alpha-1 Antitrypsin Deficiency

Policy CodePolicy AHS - M2068 - Testing for Alpha-1 Antitrypsin Deficiency, 1 = Initial Presentation

Change TypeReviewed and Updated (non-material)

Effective Date02/01/2026

Next Review Date

Key ActionObtain a serum AAT quantification as the initial test and document the clinical indication; perform reflex phenotyping or genotyping as indicated.

SourceLink

On This Page

Recommendations reflect ATS/ERS, ACG, and Alpha-1 Foundation guidance; quantitative AAT measurement first, followed by phenotyping/genotyping as indicated.

inv-36: Specialty-guided evaluation

Evaluation for suspected AATD in contexts guided by specialty recommendations and when testing will inform management:

Specialty-guided evaluation: Testing for suspected alpha-1 antitrypsin deficiency when recommended by specialty guidelines (e.g., symptomatic COPD, unexplained liver disease, family history) and when results will affect clinical management; refer patients with high pre-test probability to specialists as advised by some regional guidelines.

Includes guidance that labs performing LDTs must validate tests under CLIA; FDA‑cleared genotyping assays exist for screening and diagnostic use.

Reflex testingAbnormal quantitative results should be followed by qualitative testing (phenotyping) and genotyping as indicated.

Recommended and suggested testing sequence: Start with quantitative serum AAT level measurement as the initial test. If levels are low, borderline, or discordant with clinical suspicion, proceed to qualitative testing (phenotyping/proteotyping by isoelectric focusing or mass spectrometry) and/or targeted genotyping for common S and Z alleles. Use full gene sequencing when rare or null variants are suspected. Document the stepwise rationale and each test result in the medical record.

Initial test: Serum AAT quantification (e.g., nephelometry/turbidimetry).
Reflex testing: Phenotyping (isoelectric focusing) or proteotyping (LC-MS/MS) for abnormal, borderline, or discordant quantitative results.
Genotyping: Targeted assays for common S and Z alleles when phenotyping is inconclusive or to confirm genotype; consider expanded genotyping or full gene sequencing for rare/null variants.
Documentation: Record clinical indication, quantitative result, reason for reflex testing, and informed consent for genetic testing where applicable.

Note

Stepwise Diagnostic Testing and Specialist Referral

Stepwise diagnostic testing and specialist referral: Follow a stepwise diagnostic approach—quantitative AAT level first, qualitative phenotyping/proteotyping and genotyping as indicated; refer patients with high pre-test probability to a specialist rather than broad initial testing.

Stepwise approach: 1) Measure AAT serum level; 2) If low or borderline, perform phenotyping/proteotyping; 3) If inconclusive or discordant, perform genotyping for common alleles; 4) Use gene sequencing for suspected rare/null variants.
Specialist referral: Refer patients with high pre-test probability (per clinical judgment or guideline recommendations) to pulmonary or genetic specialists for evaluation and testing management.
Consent and counseling: Ensure informed consent for genetic testing and provide genetic counseling for family testing when appropriate.

Billing Rule

Procedure Codes Referenced

Procedure codes referenced: Use listed CPT/HCPCS codes for ordering and billing; follow payer coding and billing rules and verify whether specific codes require prior authorization.

82103 — Alpha-1-antitrypsin; total.
82104 — Alpha-1-antitrypsin; phenotype.
82542 — Column chromatography, includes mass spectrometry, if performed; qualitative or quantitative, each specimen.
83789 — Mass spectrometry and tandem mass spectrometry; non-drug analyte(s), qualitative or quantitative, each specimen.
Note: Procedure codes in this policy are for reference and may not be all-inclusive; confirm coding requirements with the payer prior to billing.

Prior Authorization

Verify Government Coverage

Verify government coverage: When applicable, confirm that Medicare, Medicaid, or other government/local coverage determinations (NCDs or LCDs) do not conflict with this policy. If a government policy applies, it supersedes this policy for affected members.

Check Medicare LCD/NCD and state Medicaid policies prior to testing for members covered under those programs.
If a conflict exists between this policy and an applicable government coverage determination, follow the government determination.
Resources: Medicare Coverage Database (http://www.cms.gov/medicarecoverage-database/search.aspx) and relevant state Medicaid websites.

Billing Rule

Confirm LDT validation (CLIA) and verify government coverage

Ensure laboratory‑developed tests (LDTs) are validated under CLIA (high‑complexity) and verify coverage against Medicare/Medicaid/LCD/NCD rules prior to ordering.

LDTs are regulated by CMS as high‑complexity tests under CLIA '88 and must be validated and performed in‑house.
Verify applicable Medicare and state Medicaid policies when coverage may be affected.

Early-onset or emphysema without recognized risk factors are listed clinical factors to prompt AAT testing.

inv-29: Quantitative AAT testing — Measurement of serum alpha-1 antitrypsin concentration used as the initial screening test.

DefinitionMeasurement of serum alpha-1 antitrypsin concentration used as the initial screening test for suspected AAT deficiency.

MethodsPerformed by immune turbidimetry, nephelometry, or other quantitative assays; levels vary by methodology.

Role in algorithmQuantitative test is the crucial first test; abnormal levels prompt phenotyping/genotyping per guidelines.

inv-30: Phenotyping (isoelectric focusing, IEF) — Protein phenotyping to identify AAT variants; historical gold standard.

DefinitionProtein phenotyping by isoelectric focusing (IEF) identifies AAT protein variants present in the sample and has been considered the accepted 'gold standard' by guidelines.

Use casePerformed when quantitative levels are low, borderline, or when further characterization of protein variants is needed.

LimitationsPhenotype is not a genetic test; results can be inconclusive or discordant with quantitative testing, requiring genotype testing.

inv-31: Genotyping / sequencing — Molecular methods to detect common alleles (S and Z) and sequencing for rare/null variants.

DefinitionMolecular methods (targeted genotyping for common S and Z alleles) and sequencing for rare or null SERPINA1 variants.

Guideline notesGenotyping allows rapid, precise identification/exclusion of S and Z alleles; sequencing is necessary when null or rare variants are suspected.

ConsentGenetic testing should be carried out only after informed consent and appropriate counseling.

inv-32: LDT (Laboratory-developed test) — LDT definition and CLIA regulation context.

DefinitionLaboratory-developed tests (LDTs) are lab-specific assays validated and performed in-house and are regulated by CMS under CLIA as high-complexity tests (CLIA '88).

Regulatory noteLDTs are not approved or cleared by the FDA; FDA clearance/approval is not required for clinical use under current practice described in this policy.

Laboratory responsibilityLabs performing LDTs must validate tests internally under CLIA requirements.

inv-33: FDA-approved SERPINA1 tests — AlphaID and SERPINA1 Variant Detection System references.

ExamplesFDA-approved SERPINA1 tests include Grifols' SERPINA1 Variant Detection System and AlphaID™ (FDA approvals cited 2017 and 2019).

23andMeThe FDA-approved 23andMe PGS Genetic Health Risk Report for AATD (approved April 6, 2017) detects PI*Z and PI*S variants via SNP testing.

ScopeGrifols' assays detect a broad panel of prevalent mutations and can be used for screening/genotyping as described in the policy.