ModifiedOscar HealthPolicy N/A

RTM Testing for Alpha-1 Antitrypsin Deficiency

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This policy governs coverage of serum alpha-1 antitrypsin quantification, AAT phenotyping or proteotyping, isoelectric focusing, and related testing for individuals suspected of having alpha-1 antitrypsin deficiency. Coverage is subject to the member's benefit plan, state of residence, authorization requirements, and medical-necessity criteria.

Policy Summary

PayerOscar Health

PolicyRTM Testing for Alpha-1 Antitrypsin Deficiency

Policy CodePolicy N/A

Change TypeModified

Effective DateJan 1, 2027

Last ReviewSep 28, 2026

Next Review DateN/A

Key ActionFor suspected AAT deficiency, submit serum AAT protein quantification with AAT phenotyping or proteotyping when a qualifying clinical or family-history indication is present.

SourceLink

POLICY UPDATE CHANGES

CPT codes 82542 and 83789 were removed from the Applicable CPT/HCPCS Procedure Codes section.

The policy background, guidelines and recommendations, and evidence-based scientific references were updated during the 09/28/2026 policy review.

Once/lifetimeCoverage frequency for qualifying initial testing

8Listed clinical or family-history indications

5Recommended Type A testing situations

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ModifiedOscar HealthPolicy N/A

RTM Testing for Alpha-1 Antitrypsin Deficiency

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Policy Summary

PayerOscar Health

PolicyRTM Testing for Alpha-1 Antitrypsin Deficiency

Policy CodePolicy N/A

Change TypeModified

Effective DateJan 1, 2027

Last ReviewSep 28, 2026

Next Review DateN/A

Key ActionFor suspected AAT deficiency, submit serum AAT protein quantification with AAT phenotyping or proteotyping when a qualifying clinical or family-history indication is present.

SourceLink

POLICY UPDATE CHANGES

CPT codes 82542 and 83789 were removed from the Applicable CPT/HCPCS Procedure Codes section.

The policy background, guidelines and recommendations, and evidence-based scientific references were updated during the 09/28/2026 policy review.

Once/lifetimeCoverage frequency for qualifying initial testing

8Listed clinical or family-history indications

5Recommended Type A testing situations

11 µmol/LLow serum AAT threshold

2Applicable procedure codes

Coverage Criteria

Initial AAT quantification and phenotype or proteotype testing

Covered once per lifetime when suspected AAT deficiency and at least one qualifying clinical or family-history indication is present.

Initial qualifying testing

Qualifying indication
- Symptomatic adult pulmonary disease: The individual is 18 years or older and symptomatic with emphysema, COPD, or asthma.
- Unexplained liver disease: The individual has unexplained liver disease, including chronic hepatitis with or without cirrhosis, chronically elevated aminotransferase levels, portal hypertension, or primary liver cancer.
- Persistent pulmonary obstruction: The individual has persistent obstruction on pulmonary function tests without identifiable risk factors such as cigarette smoking or occupational exposure.
- Necrotizing panniculitis: The individual is 18 years or older and has necrotizing panniculitis.
- Affected sibling: The individual is a sibling of a person with known AAT deficiency.
- C-ANCA-positive vasculitis: The individual has anti-proteinase 3-positive, C-ANCA-positive vasculitis.
- Unexplained bronchiectasis: The individual has bronchiectasis without evident etiology.
- Neonatal cholestasis: The individual has neonatal cholestasis.

Follow-up isoelectric focusing or phenotyping

Covered when clinical suspicion remains after initial molecular or protein testing and a qualifying prior-result condition is present.

Follow-up phenotyping

Prior-result condition
- Negative common-variant genotype: Genotype results for common variants are negative.
- Discordant results: AAT serum levels and proteotype results are discordant.

Not medically necessary or not meeting criteria

Testing does not meet criteria when the request is outside the policy’s covered indications.

Unlisted situation: The request is for AAT deficiency testing in a situation not described in the qualifying clinical or family-history indications.

The policy states that available published scientific literature does not confirm that testing in these situations is required and beneficial for diagnosis and treatment.

Type A recommended diagnostic testing

Genetic testing is recommended in any one of the following Type A situations.

Type A indication

Symptomatic obstructive lung disease: An adult has emphysema, COPD, or asthma with airflow obstruction that is not completely reversible with aggressive bronchodilator treatment.
Unexplained liver disease: The individual has unexplained liver disease, including a neonate, child, or adult.
Persistent obstruction with risk factors: An asymptomatic individual has persistent obstruction on pulmonary function tests and an identifiable risk factor such as cigarette smoking or occupational exposure.
Necrotizing panniculitis: An adult has necrotizing panniculitis.

Type B testing to discuss

Genetic testing should be discussed and may be accepted or declined in any one of the following Type B situations.

Type B indication

Unexplained bronchiectasis: An adult has bronchiectasis without evidence of etiology.
Adolescent obstruction: An adolescent has persistent airflow obstruction.
Obstruction without risk factors: An asymptomatic individual has persistent airflow obstruction and no risk factors.
C-ANCA-positive vasculitis: An adult has C-ANCA-positive, anti-proteinase 3-positive vasculitis.

Type C testing not recommended

Genetic testing is not recommended and should not be encouraged in any one of the following Type C situations.

Type C situation

Completely reversible asthma obstruction: An adult has asthma in which airflow obstruction is completely reversible.
Predispositional testing: Testing is requested solely for predisposition without a qualifying clinical indication.
Smoker screening: Testing is requested as population screening of smokers with normal spirometry.

Type D testing to discourage

Genetic testing should be discouraged in any one of the following Type D situations.

Type D situation

Fetal predispositional testing: Testing is requested for fetal predisposition without a qualifying clinical indication.
Population screening: Testing is requested as population screening of neonates, adolescents, or adults.

Clinical findings supporting AATD testing

Evaluate for AAT deficiency when one or more of the following clinical findings creates reasonable suspicion.

Supporting clinical finding

Early-onset emphysema: The individual has emphysema at age 45 years or less.Age <= 45 years
Unexplained emphysema: The individual has emphysema without a recognized risk factor such as smoking or occupational dust exposure.
Basilar emphysema: The individual has emphysema with prominent basilar hyperlucency.
Unexplained liver disease: The individual has otherwise unexplained liver disease or cirrhosis without a known etiology.

Testing for alpha-1 antitrypsin (AAT) deficiency does not meet criteria when the request concerns a situation that is not included among the policy’s qualifying clinical or family-history indications. For qualifying initial testing, serum AAT quantification with phenotyping or proteotyping is limited to once per lifetime.

Testing solely for predisposition, predispositional fetal testing, or population screening is not recommended or should be discouraged. This includes screening smokers with normal spirometry and population screening of neonates, adolescents, or adults.

Genetic testing is not recommended for adults with asthma when the associated airflow obstruction is completely reversible with aggressive bronchodilator treatment.

Testing requested outside the listed clinical and family-history indications does not meet criteria because published scientific literature confirming that the testing is required and beneficial for diagnosis and treatment is lacking.

AAT deficiency testing performed solely for population screening or predisposition assessment lacks a recommended clinical indication under the cited recommendations. Such testing is classified as not recommended or as testing that should be discouraged, including fetal predispositional testing and screening of neonates, adolescents, or adults.

Covered Clinical and Family-History Indications

Qualifying indications and initial AATD testing pathway

For a person suspected of AAT deficiency, the following pathway is covered when at least one qualifying indication is present.

Qualifying suspicion and indication

Covered indication
- Pulmonary disease: The individual is an adult with emphysema, COPD, or asthma; or has persistent pulmonary obstruction without identifiable risk factors.
- Hepatic disease: The individual has unexplained liver disease or neonatal cholestasis.
- Dermatologic or vascular disease: The individual is an adult with necrotizing panniculitis or has C-ANCA-positive vasculitis.

Eligibility Requirements

Eligibility is based on a qualifying clinical finding or family history. Covered situations include symptomatic adults with emphysema, COPD, or asthma; unexplained liver disease; persistent pulmonary obstruction with identifiable risk factors; necrotizing panniculitis; C-ANCA-positive vasculitis; unexplained bronchiectasis; neonatal cholestasis; and a sibling or other relative of an individual with known AAT deficiency or an abnormal AAT gene. Family testing should not rely on AAT level testing alone; relatives should receive appropriate genetic counseling and be offered testing.

Follow-up isoelectric focusing or phenotyping meets criteria when clinical suspicion of AAT deficiency remains and either common-variant genotype results are negative or the AAT serum level and proteotype are discordant. Quantitative AAT testing should be followed by qualitative testing when deficiency is suspected; abnormal quantitative results should undergo PI typing. When a rare or null variant is suspected, gene sequencing may be needed. For family testing, AAT level testing alone is not sufficient to fully characterize disease risk.

Coding and Laboratory Thresholds

Applicable CPT/HCPCS Procedure CodesCPT

82103	Alpha-1-antitrypsin; total
82104	Alpha-1-antitrypsin; phenotype

Coding thresholds

Generally low serum AAT levelBelow 11 micromol/L (less than 57 mg/dL using nephelometry)

Coding thresholds

Common laboratory trigger for isoelectric phenotypingSerum AAT level less than 100 mg/dL (18.4 micromol/L)

Coding thresholds

Borderline serum AAT level12-35 micromoles or 90-140 mg/dL

Provider Actions and Documentation

Documentation Required

Order Quantification With Phenotype or Proteotype

For suspected alpha-1 antitrypsin (AAT) deficiency, order serum quantitative AAT protein testing together with AAT phenotyping or AAT proteotyping. Perform phenotyping by isoelectric focusing; perform Pi-typing/protease-inhibitor typing for Z and S alleles by liquid chromatography–tandem mass spectrometry.

The combination meets criteria once per lifetime when a qualifying indication is present.

Documentation Required

Follow Up Discordant or Negative Results

When common-variant genotype results are negative, or serum AAT levels and proteotype results are discordant, perform isoelectric focusing/phenotyping if clinical suspicion remains. This follow-up testing meets criteria.

Use a reliable laboratory for serum phenotyping by isoelectric focusing.
Document the persistent clinical suspicion and the discordant or negative result prompting follow-up.

Background

Alpha-1 antitrypsin deficiency (AATD) is an inherited genetic disorder caused by deficient or defective AAT protein. It can affect the lungs, liver, and, rarely, the skin, predisposing individuals to early-onset emphysema and liver disease. Associated findings may include asthma, bronchiectasis, spontaneous pneumothorax, cirrhosis, cholestasis, hepatomegaly, and necrotizing panniculitis. AAT is encoded by the SERPINA1 gene; evaluation generally uses serum or plasma AAT quantification, protein phenotyping, proteotyping, and genotyping.

Definitions and Abbreviations

Definitions

AATAlpha-1 antitrypsin

Definitions

AATDAlpha-1 antitrypsin deficiency

Definitions

COPDChronic obstructive pulmonary disorder

Definitions

C-ANCAC-anti-neutrophil cytoplasmic antibody

Not Covered Services and Situations

The following situations are not covered under the policy: testing for AAT deficiency when no qualifying clinical or family-history indication is present; predispositional fetal testing; predispositional testing without a clinical indication; population screening of neonates, adolescents, or adults; and screening smokers with normal spirometry. Testing is also not recommended for adults with asthma whose airflow obstruction is completely reversible.

Policy Summary

PayerOscar Health

PolicyRTM Testing for Alpha-1 Antitrypsin Deficiency

Policy CodePolicy N/A

Change TypeModified

Effective DateJan 1, 2027

Last ReviewSep 28, 2026

Next Review DateN/A

Key ActionFor suspected AAT deficiency, submit serum AAT protein quantification with AAT phenotyping or proteotyping when a qualifying clinical or family-history indication is present.

SourceLink

On This Page

Affected sibling: The individual is a sibling of a person with known AAT deficiency.

Unattributed family history: The individual has a family history of COPD or liver disease not known to be attributed to AAT deficiency.

Distant relative of homozygote: The individual is a distant relative of a person homozygous for AAT deficiency.

Immediate relative of homozygote: The individual is an offspring or parent of a person homozygous for AAT deficiency.

Relative of heterozygote: The individual is a sibling, offspring, parent, or distant relative of a person heterozygous for AAT deficiency.

High-risk individual: The individual is at high risk of AATD-related disease.

Partner testing: The individual is not personally at risk of AATD but is the partner of a person homozygous or heterozygous for AAT deficiency.

Associated disorders: The individual has necrotizing panniculitis, C-ANCA-positive vasculitis, or bronchiectasis without an evident etiology.

Persistent liver enzyme elevation: The individual has persistently elevated AST or ALT, or hepatocellular injury with disproportionate AST and ALT elevation compared with alkaline phosphatase.

Bronchiectasis: The individual has bronchiectasis without evident etiology.

Family history: The individual is a sibling of a person with known AAT deficiency.

Testing pathway: Initial serum AAT quantification is performed with AAT phenotyping or proteotyping.Once per lifetime

Phenotyping should use isoelectric focusing; proteotyping for Z and S alleles should use liquid chromatography-tandem mass spectrometry.

Symptomatic adults with emphysema, COPD, or asthma

Genetic testing is recommended for symptomatic adults with qualifying obstructive lung disease.

Type A pulmonary indication: The individual is an adult with emphysema, COPD, or asthma and airflow obstruction that is not completely reversible with aggressive bronchodilator treatment.

ATS/ERS Type A recommendation.

Unexplained liver disease or persistent AST/ALT elevation

Testing is covered or recommended when liver disease or persistent aminotransferase elevation is unexplained.

Hepatic indication

Unexplained liver disease: The individual has unexplained liver disease, including chronic hepatitis with or without cirrhosis, portal hypertension, primary liver cancer, hepatosplenomegaly, ascites, esophageal varices, chronic hepatitis, cirrhosis, or hepatic failure.
Persistent AST or ALT elevation: The individual has persistently elevated AST or ALT.
Hepatocellular injury: The individual has hepatocellular injury with disproportionate AST and ALT elevation compared with alkaline phosphatase.
Age range: The individual may be a neonate, child, adolescent, or adult.

Asymptomatic persistent pulmonary obstruction with risk factors

Genetic testing is recommended for asymptomatic individuals with persistent obstruction and identifiable risk factors.

Type A pulmonary-function indication

Identifiable risk factor
- Cigarette smoking: The individual has a history of cigarette smoking.
- Occupational exposure: The individual has an occupational exposure, such as occupational dust exposure.

Necrotizing panniculitis, C-ANCA-positive vasculitis, or unexplained bronchiectasis

Testing is supported for these adult clinical presentations; bronchiectasis is a Type B recommendation but is included as an AATD testing indication by the Alpha-1 Foundation.

Covered adult indication

Necrotizing panniculitis: The adult has necrotizing panniculitis.
C-ANCA-positive vasculitis: The adult has C-ANCA-positive, anti-proteinase 3-positive vasculitis.
Unexplained bronchiectasis: The adult has bronchiectasis without evidence of etiology.

Siblings and other relatives of individuals with known AAT deficiency or an abnormal AAT gene

Family testing is covered or recommended for relatives of individuals with known AAT deficiency or an abnormal AAT gene.

Family-history indication

Qualifying relationship
- Sibling of affected individual: The individual is a sibling of a person with known AAT deficiency.
- Relative of homozygote: The individual is a distant relative, offspring, or parent of a person homozygous for AAT deficiency.
- Relative of heterozygote: The individual is a sibling, offspring, parent, or distant relative of a person heterozygous for AAT deficiency.
- Family member with abnormal gene: The individual is a parent, sibling, child, or extended family member of a person identified with an abnormal AAT gene.
Testing method: Testing uses more than AAT level testing alone because AAT level testing does not fully characterize disease risk.
Appropriate testing may include genotyping for at least the S and Z alleles, with Pi-typing, AAT level testing, and/or expanded genotyping as advanced or confirmatory testing.

Documentation Required

Document the Clinical Indication

Document the clinical indication supporting the performed AAT test and submit accurate coding and service documentation. Coverage is subject to the member’s benefit, authorization and medical-necessity requirements, and state of residence.

Record the relevant symptoms, diagnosis, pulmonary-function findings, liver findings, dermatologic or vasculitic condition, bronchiectasis, neonatal cholestasis, or qualifying family history.
Identify the exact AAT service performed, including quantitative testing, phenotyping, proteotyping, or follow-up testing.

Documentation Required

Document Reflex or Follow-Up Testing

After a negative genotype for common variants or discordance between serum AAT levels and proteotype, document the result and the continuing clinical suspicion of AAT deficiency before ordering isoelectric focusing/phenotyping.

State which result was negative or discordant.
Explain why additional phenotyping is clinically necessary.

Unsupported block type: documentation

Documentation Required

Confirm a Qualifying Clinical Indication

Evaluate testing in patients with qualifying pulmonary, hepatic, dermatologic, vasculitic, bronchiectatic, neonatal, or family-history indications. Examples include symptomatic adults with emphysema, COPD or asthma; unexplained liver disease; persistent unexplained airflow obstruction; necrotizing panniculitis; anti-proteinase 3-positive vasculitis; bronchiectasis without an evident cause; neonatal cholestasis; and siblings of an individual with known AAT deficiency.

Look for early-onset emphysema, emphysema without recognized risk factors, or prominent basilar hyperlucency.
Consider unexplained chronic liver disease, cirrhosis, or persistently elevated aminotransferases.
Consider relevant family history and evaluate relatives with appropriate counseling.

Denial Risk

Unlisted Indications May Be Denied

Testing for AAT deficiency in situations not described as qualifying does not meet criteria and may be denied for lack of evidence that the testing is required and beneficial for diagnosis or treatment.

Do not submit testing without a documented qualifying indication.

Billing Rule

Once-Per-Lifetime Frequency Limit

Serum AAT quantification with phenotyping or proteotyping is covered once per lifetime for individuals with a qualifying indication.

Do not repeat the qualifying serum quantification/phenotyping or proteotyping combination without documenting a coverage-supported reason.

Denial Risk

Inaccurate Coding or Documentation Risks Denial

Submit accurate documentation and code the services according to applicable industry standards, including CPT, HCPCS, ICD-10-CM/PCS, NCCI and other CMS or billing guidance. Failure to follow coding, billing or documentation requirements may result in claim denial and/or recoupment of payment.

Ensure the diagnosis supports the documented indication.
Ensure the billed service matches the service actually performed.
Retain documentation supporting medical necessity and the testing sequence.

Denial Risk

Avoid Predisposition Testing and Population Screening

Do not use AAT testing solely for predisposition or routine population screening. Predispositional testing is not recommended, predispositional fetal testing should be discouraged, and population screening of smokers with normal spirometry or of neonates, adolescents or adults should not be encouraged.

Testing partners or relatives should be considered only in the appropriate clinical and counseling context.
Do not represent screening or predisposition testing as diagnostic testing for a qualifying illness.

Note

Completely Reversible Asthma Obstruction

Do not encourage AAT genetic testing for adults with asthma when airflow obstruction is completely reversible with aggressive bronchodilator treatment. Testing recommendations apply to asthma characterized by incompletely reversible airflow obstruction or another qualifying indication.

Document pulmonary-function findings and treatment response when asthma is the indication.

Documentation Required

Provider Actions for Consent and Relatives

Before genetic testing, obtain informed consent and provide appropriate counseling. When an individual with AAT deficiency is identified, consider testing relatives after counseling and document the consent, counseling and clinical rationale.

Explain the purpose and potential implications of genetic testing.
Offer appropriately counseled relative testing when clinically indicated.

Note

Engage the Appropriate Clinicians and Specialists

Clinicians evaluating relevant indications may include primary-care physicians and specialists involved in pulmonary, hepatic, dermatologic, rheumatologic or neonatal care. Coordinate evaluation for unexplained emphysema or airflow obstruction, liver disease, necrotizing panniculitis, anti-proteinase 3-positive vasculitis, bronchiectasis, neonatal cholestasis and relevant family history.

Pulmonology or respiratory clinicians should assess emphysema, COPD, asthma and persistent airflow obstruction.
Hepatology, gastroenterology or pediatric clinicians should assess unexplained liver disease and neonatal cholestasis.
Dermatology and rheumatology clinicians should assess necrotizing panniculitis and anti-proteinase 3-positive vasculitis.
Coordinate genetic counseling and family evaluation when AAT deficiency is identified.

Definitions

SERPINA1Serine protease inhibitor gene encoding AAT

Definitions

PiProtease inhibitor; the allele nomenclature used for AAT variants

Definitions

LC-MS/MSLiquid chromatography-tandem mass spectrometry

Definitions

PCRPolymerase chain reaction

Definitions

RFLPRestriction fragment length polymorphism

Recommendation classifications

Type A recommendationA classification in which genetic testing is recommended for the specified clinical or family-history situation.

Recommendation classifications

Type B recommendationA classification in which genetic testing should be discussed and may be accepted or declined.

Recommendation classifications

Type C recommendationA classification in which genetic testing is not recommended and should not be encouraged.

Recommendation classifications

Type D recommendationA classification in which genetic testing should be discouraged.

Definitions

Laboratory-developed testA laboratory-developed test validated and performed in-house; such tests are regulated by CMS as high-complexity tests under CLIA '88.

Definitions

Laboratory-developed test (LDT)Laboratory-developed tests are tests developed and validated by laboratories for in-house performance; they are regulated by CMS as high-complexity tests under CLIA '88 and are not FDA-approved or cleared, although FDA clearance or approval is not currently required for clinical use.