Description
Alpha 1-antitrypsin deficiency (AATD) is a genetic disease that causes deficient or defective production of the alpha-1 antitrypsin (AAT) protease inhibitor that can affect the lungs, liver, and skin (J. Stoller, 2020b). AAT deficiency results in unbalanced rapid breakdown of proteins, especially in the supporting elastic tissue of the lungs (NORD, 2022).

Policy 
Serum Testing

1. Serum quantification of alpha-1 antitrypsin (A1AT) protein and/or A1AT phenotyping by isoelectric focusing or A1AT proteotyping (Pi-typing or protease inhibitor typing) for Z and S alleles by liquid chromatography-tandem mass spectrometry is considered MEDICALLY NECESSARY in the following situations:
   1. Symptomatic adults with emphysema, COPD, or asthma 
   2. Individuals with unexplained liver disease
   3. Individuals with persistent obstruction on pulmonary function tests without identifiable risk factors (e.g., cigarette smoking, occupational exposure)
   4. Adults with necrotizing panniculitis
   5. Siblings of an individual with known alpha-1 antitrypsin (AAT) deficiency
   6. Individuals with anti-proteinase three-positive vasculitis (C-ANCA [anti-neutrophil cytoplasmic antibody]-positive vasculitis)
   7. Individuals with bronchiectasis without evident etiology
2. In individuals with negative genotype testing for common variants or discordant results between A1AT serum levels and proteotype, isoelectric focusing/phenotyping is considered MEDICALLY NECESSARY when there is strong suspicion of the disease based on laboratory testing and symptoms.

Genetic testing

3. Genetic testing for alpha-1 antitrypsin deficiency is considered MEDICALLY NECESSARY in the following situations:
   1. Patient is suspected of having alpha-1 antitrypsin deficiency because of the following clinical factors
      1. Early-onset emphysema (age of 45 years or less); OR
      2. Emphysema in the absence of a recognized risk factor (smoking, occupational dust exposure, etc.); OR
      3. Emphysema with prominent basilar hyperlucency; OR
      4. Otherwise unexplained liver disease; OR
      5. Necrotizing panniculitis; OR
      6. Anti-proteinase three-positive vasculitis (C-ANCA [anti-neutrophil cytoplasmic antibody]-positive vasculitis); OR 
      7. Bronchiectasis without evident etiology
   2. Patient has discordant results between serum levels and proteotype testing for Z and S alleles by mass spectrometry
4. Genetic testing for alpha-1 antitrypsin deficiency is considered MEDICALLY NECESSARY for at risk individuals with a first-degree relative with AAT deficiency. 
5. When there is strong suspicion of the disease based on laboratory testing and symptoms in an individual with negative genotype testing for common variants or discordant results between A1AT serum levels and proteotype or phenotype, full SERPINA1 gene sequencing is considered MEDICALLY NECESSARY. 

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

6. Testing for alpha-1 antitrypsin deficiency is considered NOT MEDICALLY NECESSARY in all other situations.

Note:

In 2003, the American Thoracic Society published recommendations on the diagnosis and management of individuals with AAT deficiency.
Recommendations were classified as follows:

Type A: Genetic testing is recommended
Type B: Genetic testing should be discussed and could be accepted or declined
Type C: Genetic testing is not recommended, i.e., should not be encouraged
Type D: Recommend against genetic testing, i.e., should be discouraged

Type A recommendations for diagnostic testing in the following situations:

1. Symptomatic adults with emphysema, COPD or asthma with airflow obstruction that is not completely reversible with aggressive treatment with bronchodilators

2. Individuals with unexplained liver disease

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 alpha-1 antitrypsin (AAT) deficiency

Type B recommendations for diagnostic testing in the following situations:

1. Adults with bronchiectasis without evidence etiology

2. Adolescents with persistent airflow obstruction

3. Asymptomatic individuals with persistent airflow obstruction and no risk factors

4. Adults with C-ANCA positive (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. Individuals who are not at risk themselves of having AAT deficiency but who are partners of individuals who are homozygous or heterozygous for AAT deficiency

Type C recommendations for diagnostic testing in the following situations　

1. Adults with asthma in whom airflow obstruction is completely reversible

2. Predispositional testing

3. Population screening of smokers with normal spirometry

Type D recommendations for diagnostic testing in the following situations:

1. Predispositional fetal testing

2. Population screening of either neonates, adolescents or adults*

* Population screening is not recommended currently. However, a possible exception (type B recommendation) may apply in countries satisfying all three of the following conditions: (1) the prevalence of AAT deficiency is high (about 1/1,500, or more); (2) smoking is prevalent; and (3) adequate counseling services are available.

According to the 2003 joint statement on diagnosis and management of alpha-1 antitrypsin deficiency by the American Thoracic Society/European Respiratory Society:¹

The following features should prompt suspicion by physicians that their patient may be more likely to have AAT deficiency:

Clinical Factors

1. Early-onset emphysema (age of 45 years or less)

2. Emphysema in the absence of a recognized risk factor (smoking, occupational dust exposure, etc.)

3. Emphysema with prominent basilar hyperlucency

4. Otherwise unexplained liver disease

5. Necrotizing panniculitis

6. Anti-proteinase three-positive vasculitis (C-ANCA [anti-neutrophil cytoplasmic antibody]-positive vasculitis)

7. Bronchiectasis without evident etiology

Rationale 
Alpha-1 antitrypsin (AAT) deficiency is an underrecognized genetic condition that affects approximately 1 in 2,000 to 1 in 5,000 individuals and predisposes to liver disease and early-onset emphysema (J. K. Stoller & Aboussouan, 2012). It is estimated (Campos, Wanner, Zhang, & Sandhaus, 2005) that up to 80,000 to 100,000 people in the United States have the severe form of the disease (homozygous in null or abnormal alleles). There is much variation in the disease prevalence in other nations (de Serres, Blanco, & Fernandez-Bustillo, 2007), but most current estimates are that 3 million people worldwide have severe AATD (J. Stoller, 2020a).

Alpha-1 Antitrypsin deficiency (AATD) is a result of abnormal alpha-1 antitrypsin (AAT) protein inherited in an autosomal recessive pattern with codominant expression in which both genes inherited can be active and contribute to the genetic trait they control. AAT is a member of the serine protease inhibitor (Pi) family, referred to as “serpins”, and it inhibits the proteolytic enzymes elastase, trypsin, chymotrypsin, and thrombin. AAT is encoded by the gene SERPINA1 (J. Stoller, 2020a).

The AAT protein is produced in the liver and has a role in protecting lungs from injury by neutrophil elastase, which is secreted by white blood cells as a response to inflammation or infection. If the enzyme remains unchecked by AAT protein, damage to alveoli resulting in chronic obstructive pulmonary disease can occur. This includes emphysema, asthma, bronchiectasis, and spontaneous pneumothorax. Smoking and other environmental exposure can cause further damage (J. Stoller, 2020a, 2020b). 

Abnormal molecules of AAT protein caused by this illness can also cause liver dysfunction. Pathologic polymerization of the variant AAT can occur, resulting in intrahepatocyte accumulation of AAT molecules, leading to cirrhosis, fibrosis, cholestasis, or hepatomegaly. Liver disease is more common in individuals with certain allele combinations. Male gender and obesity may be risk factors for progression to advanced liver disease in adulthood among patients with severe AAT deficiency. In contrast, alcohol use and viral hepatitis do not appear to increase the risk of progressive hepatic failure (J. Stoller, 2020b). AATD is a common genetic cause of liver disease in children (de Serres, Blanco, & Fernandez-Bustillo, 2003).

Skin manifestations of AATD are also recognized. The most associated skin condition is necrotizing panniculitis. In this condition, inflammatory skin lesions are thought to be a consequence of the AAT protein loss of function and subsequent unchecked proteolysis enzyme activity in the skin and subcutaneous tissue. Associations between alpha-1 antitrypsin (AAT) and vascular disease, inflammatory bowel disease, glomerulonephritis, and vasculitis have been proposed but not definitively established (J. Stoller, 2020b).

Due to the numerous alleles associated with AAT, each allele has been given a letter code based on the “electrophoretic mobility of the protein produced”. The normal allele is the “M” allele, and the most common mutation is the “Z” allele. This system applies for each individual allele; for example, a homozygous Z genotype would be denoted as “ZZ.” Similarly, a wildtype (or “normal”) genotype would be “MM”. Besides the normal phenotype, the three other categories of AAT include “deficient” in which insufficient AAT is produced; “null” in which no AAT is produced at all; and “dysfunctional” in which a typical amount of AAT is produced, but the AAT protein does not function correctly (J. Stoller, 2020a).

Proprietary Testing
Initial testing often begins with serum quantification of AAT protein. This can be done through several methods, including immune turbidimetry and nephelometry (J. Stoller, 2020a). A low level is generally represented by a serum level below 11 micromol/L (less than 57 mg/dl using nephelometry). Due to the variation of reference ranges in different testing methodologies, most labs will complete isoelectric phenotyping on any individual with a serum AAT levels of < 100 mg/dL (18.4 micromol/L). In fact, the American Thoracic Society suggests persons with borderline serum levels (defined as 12-35 micromoles or 90 to 140 mg/dL) have qualitative testing (ATS/ERS, 2003).

Isoelectric immunophenotype testing uses the difference in migration rates of allele variants under isoelectric focusing. For example, the M variant will migrate to the middle of the gel, Z will migrate the slowest, and F migrates quickly to the side closest to the anode. This is not a genetic test. On occasion the results can be inconclusive or discordant with quantitative testing, requiring genotype testing of the most-common variants (J. Stoller, 2020a).

Genotype testing for the most common allele variants can be utilized where isoelectric immunophenotype testing is inconclusive. Usually polymerase chain reaction (PCR) or restriction fragment length polymorphism (RFLP) techniques are utilized to determine if the most common alleles are present. When dealing with the possibility of a rare variant or null allele, full gene sequencing can be utilized as a final diagnostic measure (J. Stoller, 2020a). 

In 2017, Grifols won FDA approval for AAT Deficiency Test, which is capable of simultaneously analyzing 99% of the most prevalent known mutations causing alpha-1 antitrypsin deficiency. The molecular test analyzes simultaneously 192 samples per kit, and in a single reaction, identifies 14 of the most prevalent known mutations in the SERPINA1 gene, responsible for this genetic disorder.

Using Progenika’s FDA-cleared A1AT Genotyping Test, Matrix Clinical Labs released the proprietary Alpha ID screening test, a comprehensive targeted genetic test assessing 14 common and rare alleles in the SERPINA1 gene. “The Alpha ID screening test utilizes an easy-to-use saliva collection swab and does not require a blood draw or finger stick. If a positive result is found using this test, a follow-up test, Alpha ID Confirm, uses a finger stick and a blood spot card to asses A1AT protein levels as well a potential reflex to next-generation sequencing (NGS) to help physicians achieve an accurate diagnosis of Alpha-1 antitrypsin deficiency (A1ATD)” (Matrix Clinical Labs & 2022).

Clinical Utility and Validity 
The literature on the analytic and clinical validity of genetic testing for AATD is limited. In addition, few randomized controlled trials (RCTs) have evaluated the impact of AATD testing on patient outcomes. Current evidence-based guidelines (Vogelmeier et al., 2017) for diagnosis and management of AATD recommend specific interventions for patients with emphysema and AATD. AAT augmentation therapy is often prescribed for patients with AATD and chronic obstructive pulmonary disorder (COPD). In addition, several studies have documented that the disease is under-recognized with delay in diagnosis of between 5 to 8 years (Barrecheguren et al., 2016; J. K. Stoller et al., 2005). 

Snyder et al. (2006) evaluated the laboratory methods of assessing AATD. Samples from 512 individuals were analyzed, and “A1AT concentrations were measured by nephelometry. Phenotype analysis was performed by isoelectric focusing electrophoresis. The genotype assay detected the S and Z deficiency alleles by a melting curve analysis.” Of these 512 samples, 10 (2%) were discordant between genotype and phenotype. Of these 10 results, 7 were attributed to phenotyping errors. 4% of the samples submitted to genotype and quantitative analysis were “reflexed” to phenotyping, where phenotyping confirmed the genotype result 85% of the time. The investigators concluded, “The combination of genotyping and quantification, with a reflex to phenotyping, is the optimal strategy for the laboratory evaluation of A1AT deficiency” (Snyder et al., 2006).

Sorroche et al. (2015) examined a cohort of COPD patients and the prevalence of severe AATD. 1002 patients were evaluated, and 785 (78.34%) had normal AAT levels. The remaining 217 patients had low AAT levels, but only 15 patients had a genotype associated with severe AATD. Of these 15 patients, 12 were ZZ and 3 were SZ. Of the 202 other patients, 29 were a Z heterozygote, 25 were an S heterozygote, and 4 were an SS homozygote. 144 patients could not be definitively diagnosed (Sorroche et al., 2015).

Corda et al. (2011) examined the prevalence of AATD in a supposed “high-risk” area. 817 residents participated, and 67 had low AAT serum levels. 118 residents carried AATD-related alleles, 114 of which were heterozygotes “(46 Z, 52 S, 9 P(brescia), 4 M(wurzburg), 2 I, 1 P(lowell).” The authors concluded, “the large number of mostly asymptomatic individuals with AATD identified suggests that in high-risk areas adult population screening programs employing the latest genetic methods are feasible” (Corda et al., 2011).

Soriano et al. (2018) evaluated the prevalence of AATD testing in COPD patients. The patient sample came from “550 UK Optimum Patient Care Research Database general practices.” Out of 107,024 COPD patients, only 2.2% had any record of being tested for AATD. Of those tested, 23.7% were diagnosed with AATD. The investigators also noted that between 1994 and 2013, the incidence of AATD diagnosis increased. The authors concluded “that AATD remains markedly underdiagnosed in COPD patients” (Soriano et al., 2018).

Greulich et al. (2016) evaluated the results of a large, targeted screening program for AATD. The samples were distributed by a German AAT laboratory over a period of 12 years, and 18,638 testing kits were obtained. Of this sample, 6919 carried at least one mutation, and 1835 patients were considered to have severe AATD. 194 of these patients had “rare” genotypes. The authors concluded that “among clinical characteristics, a history of COPD, emphysema, and bronchiectasis were significant predictors for Pi*ZZ, whereas a history of asthma, cough and phlegm were predictors of not carrying the genotype Pi*ZZ” (Greulich et al., 2016).

Mattman et al. (2020) compared the comprehensiveness and efficiency of pathogenic variant (PV) detection of four different protocols from 2011 to 2018 in laboratories across Canada. From 5399 index patients, 396 ZZ genotypes were identified. The protocol for serum A1AT concentration/DNA sequencing in the Ontario center (ON-CD) yielded the highest PV detection — “genotypes with at least one PV, other than S, Z, or F, were identified at 0.67/ZZ as compared to < 0.2/ZZ (all others).” However, it also had the highest rates of undefined molecular variants (UMV) (0.16/ZZ vs <0.12/ZZ) or likely benign variants (LBV) compared to all others (0.08/ZZ vs < 0.06/ZZ). The authors concluded the “strategies with readily detect variants across the full coding sequence of SERPINA1 detect more PV as well as more UMV and LBV” (Mattman et al., 2020). 

Hamesch et al. (2019) evaluated the clinical landscape of liver symptoms in patients with AATD, specifically the Pi*ZZ genotype. 554 patients (403 exploratory cohort, 151 confirmatory cohort) were included and were compared to 234 controls without pre-existing liver disease. The authors found significantly higher levels of serum liver enzymes in the Pi*ZZ carriers compared to controls, further noting that “significant’ fibrosis was suspected in 20% – 36% of Pi*ZZ carriers. Signs of advanced fibrosis were 9 to 20 times more common in carriers compared to non-carriers. Controlled attenuation parameter of ≥ 280 dB/m, which suggests “severe” steatosis was detected in 39% of carriers compared to 31% of controls. Finally, Pi*ZZ carriers were found to have lower serum concentrations of triglyceride, low, and very-low density lipoprotein cholesterol compared to controls, which the authors suggested to represent impaired hepatic secretion of liquid. Overall, the authors concluded that they identified evidence of liver steatosis, impaired liver secretion, liver fibrosis, and that their data could assist in hepatologic management of Pi*ZZ carriers (Hamesch et al., 2019).

Strnad et al. (2019) investigated the impact of the Pi*Z and Pi*S genotypes on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. Separate cohorts of 1184 with NAFLD and 2462 with chronic alcohol abuse were included. The authors found Pi*Z genotypes in 13.8% of patients with cirrhotic NAFLD but only 2.4% of patients without liver fibrosis. From there, the increased risk of NAFLD subjects to develop cirrhosis was found to be 7.3 times higher in Pi*Z carriers. The Pi*Z variant was also found in 6.2% of alcohol abusers but only 2.2% of alcohol abusers without significant liver injury. The increased risk was found to be 5.2 times higher in Pi*Z carriers. The Pi*S variant was not associated with NAFLD-related cirrhosis and only mildly with alcohol-related cirrhosis (increased risk = 1.47 times). The authors concluded that the Pi*Z variant was the strongest “single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers” and remarked that this finding should be considered in future genetic counseling of affected individuals (Strnad et al., 2019).

Carreto et al. (2020) examined the utility of routine screening for AATD among patients with bronchiectasis, due to the contradiction in guidelines from the British Thoracic Society, which recommend screening for bronchiectasis among patients with AATD, but not vice versa. After screening 1600 patients with bronchiectasis from two centers in the UK from 2012-2016, they found only eight patients with AATD. They concluded that because of the low prevalence of AATD as an etiology for disease presentation among patients with bronchiectasis, routine screening for AATD would not significantly impact clinical management through augmentation therapy, smoking cessation, and genetic counselling, among other methods. Despite this, the researchers did note that higher rates of detection may be found in other geographical regions in the UK or in other countries (Carreto et al., 2020).

(Bellemare et al., 2021) studied the clinical utility of determining the allelic background of mutations causing alpha-1 antitrypsin deficiency. SERPINA1 was DNA sequenced to identify rare variants that could confer the risk of developing emphysema. Seven carriers of a rare variant, Leu353Phe_fsTer24, known to lead to undetectable serum levels of AAT, were studied using an allele-specific DNA sequencing method that they developed. Results demonstrated that Leu353Phe_fsTer24 variant was transmitted on the same allele as the M3 variant in all the patients and two of the seven patients had either a S or Z allele. The lowest AAT serum levels were observed in compound heterozygotes for the S or Z allele, suggesting higher risk of developing emphysema. This study showed that understanding the clinical significance of genetic variants found in SERPINA1 can lead to better clinical outcomes (Bellemare et al., 2021).

American Thoracic Society/European Respiratory Society 
The ATS/ERS released joint guidelines on the “Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency.” These recommendations are as follows (ATS/ERS, 2003):

Policy Guidelines

Recommendations were classified as follows:

Type A: Genetic testing is recommended

Type B: Genetic testing should be discussed and could be accepted or declined

Type C: Genetic testing is not recommended, i.e., should not be encouraged

Type D: Recommend against genetic testing, i.e., should be discouraged

Type A recommendations for diagnostic testing in the following situations:

1. Symptomatic adults with emphysema, COPD or asthma with airflow obstruction that is not completely reversible with aggressive treatment with bronchodilators
2. Individuals with unexplained liver disease
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 alpha-1 antitrypsin (AAT) deficiency

Type B recommendations for diagnostic testing in the following situations:

1. Adults with bronchiectasis without evidence etiology
2. Adolescents with persistent airflow obstruction
3. Asymptomatic individuals with persistent airflow obstruction and no risk factors
4. Adults with C-ANCA positive (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. Individuals who are not at risk themselves of having AAT deficiency but who are partners of individuals who are homozygous or heterozygous for AAT deficiency

Type C recommendations for diagnostic testing in the following situations　

• Adults with asthma in whom airflow obstruction is completely reversible
• Predispositional testing
• Population screening of smokers with normal spirometry

Type D recommendations for diagnostic testing in the following situations:

• Predispositional fetal testing
• Population screening of either neonates, adolescents or adults*

* Population screening is not recommended currently. However, a possible exception (type B recommendation) may apply in countries satisfying all three of the following conditions: (1) the prevalence of AAT deficiency is high (about 1/1,500, or more); (2) smoking is prevalent; and (3) adequate counseling services are available.

The following features should prompt suspicion by physicians that their patient may be more likely to have AAT deficiency:

Clinical Factors

• Early-onset emphysema (age of 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 [anti-neutrophil cytoplasmic antibody]-positive vasculitis)
• Bronchiectasis without evident etiology

The ATS/ERS also made statements on serum testing for AATD. “Serum phenotyping by isoelectric focusing performed by a reliable laboratory is the accepted “gold standard” for diagnosing AAT deficiency.” The guidelines recommend “that all subjects with COPD or asthma characterized by incompletely reversible airflow obstruction should be tested once for quantitative AAT determination. Also, individuals with evidence of cirrhosis of the liver with no known etiology should be tested for candidate phenotypes (e.g., PI*ZZ, PI*MZ, PI*Mmalton) and testing should be considered in individuals with the syndrome of Wegener's granulomatosis (antiproteinase-3 vasculitis)” (ATS/ERS, 2003).

American College of Gastroenterology (ACG) 
The ACG recommends the following for AATD:

• “Patients with persistently elevated aspartate aminotransferase (AST) or alanine aminotransferase (ALT) should undergo screening for alpha-1 antitrypsin (A1AT) deficiency with alpha-1 anti-trypsin phenotype.”
• Evaluation of hepatocellular injury (defined by the guidelines as “disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels") includes testing for A1AT deficiency (Kwo, Cohen, & Lim, 2017)."

World Health Organization (WHO)
The WHO released a memorandum on AATD regarding AATD’s association with conditions such as COPD and asthma. Their recommendation is as follows: “It is therefore recommended that all patients with COPD and adults and adolescents with asthma be screened once for AAT deficiency using a quantitative test. Those with abnormal results on screening should undergo PI typing” (WHO, 1997).

European Respiratory Society (ERS) 
The ERS (Miravitlles et al., 2017) published updated guidelines which recommend:

• “The quantitative determination of AAT levels in blood is a crucial first test to identify AATD. Quantitative deficiency must be supported by qualitative tests to identify the genetic mutation(s) causing AATD.”
• “Protein phenotyping by isoelectric focusing identifies variants where AAT is present in the sample including the rarer variants F, I and P etc.”
• “Genotyping allows a rapid and precise identification/exclusion of S and Z alleles and other variants, where specific primers are available.”
• “Gene sequencing remains necessary for those cases where a null variant or a deficient variant other than Z or S is suspected.”
• “Testing of relatives of identified patients should be considered after appropriate counselling.
• “Genetic testing should be carried out only after informed consent is given and in accordance with the relevant guidelines and legislation.”

The ERS has also noted that “there is no evidence to support efficacy of AAT augmentation therapy in PiSZ, PiMZ or current smokers of any protein phenotype” (Miravitlles et al., 2017).

Alpha-1 Foundation
The Alpha-1 Foundation (Sandhaus et al., 2016) sponsored a medical and scientific advisory committee of experts to examine all relevant, recent literature in order to provide concise recommendations for the diagnosis and management of individuals with AATD.

• “For family testing after a proband is identified, AAT level testing alone is not recommended because it does not fully characterize disease risk from AATD.”
• “For diagnostic testing of symptomatic individuals, they recommend genotyping for at least the S and Z alleles. Advanced or confirmatory testing should include Pi-typing, AAT level testing, and/or expanded genotyping.”
• “All patients with COPD, unexplained chronic liver disease, necrotizing panniculitis, granulomatosis with polyangiitis, or unexplained bronchiectasis should be tested for AATD.”
• “Parents, siblings, and children, as well as extended family of individuals identified with an abnormal gene for AAT, should be provided genetic counseling and offered testing for AATD (see guideline document for special considerations about testing minors).”

The Foundation also noted the following (these statements were not labeled recommendations):

• “For primary diagnosis of AATD the most sensitive and specific method of diagnosis is direct identification of the Z allele by genotyping. By also including the S allele, genotyping for the S and Z allele is greater than 99% specific and sensitive."
• “AAT levels are insufficient to identify at risk individuals because the AAT level changes with inflammation, pregnancy, and in children."
• “The range of serum AAT levels among individuals with specific genotypes is sufficiently broad that there is overlap between different genotypes. Thus, serum AAT levels cannot discriminate between different genotypes and additional AAT testing is needed.”

Global Initiative for Chronic Obstructive Lung Disease (GOLD)
GOLD notes that genes such as MMP-12 may contribute to a decline in lung function. However, they acknowledge that “it remains uncertain whether these are genes are directly responsible for COPD or are merely markers of causal genes” (GOLD, 2021). 

On alpha-1-antitrypsin deficiency, GOLD also stated “Although the classical patient is young (< 45 years) with panlobular basal emphysema, it has become recognized that delay in diagnosis has led to identification of some AATD patients when they are older and have a more typical distribution of emphysema (centrilobular apical). A low concentration (< 20% normal) is highly suggestive of homozygous deficiency. Family members should be screened and, together with the patient, referred to specialist centers for advice and management” (GOLD, 2021). 

Canadian Thoracic Society (CTS)
The CTS released guidelines on genetic testing for AATD, which are as follows:

• “We suggest targeted testing for A1AT deficiency be considered in individuals with COPD diagnosed before 65 years of age or with a smoking history of < 20 pack years. (Grade of recommendation: 2C)”
• “We suggest targeted testing for A1AT deficiency not be undertaken in individuals with bronchiectasis or asthma. (Grade of recommendation: 2C) (Marciniuk et al., 2012)”

National Institute Health and Care Excellence (NICE)
NICE published a guideline discussing chronic obstructive pulmonary disease (COPD) in 2019. In it, they note that measurement of serum alpha-1 antitrypsin has a role in identifying deficiencies if the condition is “early onset, [of] minimal smoking history, or [has] family history.”

Table of Terminology

References 

1. ATS/ERS. (2003). American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med, 168(7), 818-900. doi:10.1164/rccm.168.7.818
2. Barrecheguren, M., Monteagudo, M., Simonet, P., Llor, C., Rodriguez, E., Ferrer, J., . . . Miravitlles, M. (2016). Diagnosis of alpha-1 antitrypsin deficiency: a population-based study. Int J Chron Obstruct Pulmon Dis, 11, 999-1004. doi:10.2147/copd.s108505
3. Bellemare, J., Gaudreault, N., Valette, K., Belmonte, I., Nuñez, A., Miravitlles, M., . . . Bossé, Y. (2021). The Clinical Utility of Determining the Allelic Background of Mutations Causing Alpha-1 Antitrypsin Deficiency: The Case with the Null Variant Q0(Mattawa)/Q0(Ourém). Chronic Obstr Pulm Dis, 8(1), 31-40. doi:10.15326/jcopdf.8.1.2020.0168
4. Campos, M. A., Wanner, A., Zhang, G., & Sandhaus, R. A. (2005). Trends in the diagnosis of symptomatic patients with alpha1-antitrypsin deficiency between 1968 and 2003. Chest, 128(3), 1179-1186. doi:10.1378/chest.128.3.1179
5. Carreto, L., Morrison, M., Donovan, J., Finch, S., Tan, G. L., Fardon, T., . . . Chalmers, J. D. (2020). Utility of routine screening for alpha-1 antitrypsin deficiency in patients with bronchiectasis. Thorax, 75(7), 592-593. doi:10.1136/thoraxjnl-2019-214195
6. Corda, L., Medicina, D., La Piana, G. E., Bertella, E., Moretti, G., Bianchi, L., . . . Balbi, B. (2011). Population genetic screening for alpha1-antitrypsin deficiency in a high-prevalence area. Respiration, 82(5), 418-425. doi:10.1159/000325067
7. de Serres, F. J., Blanco, I., & Fernandez-Bustillo, E. (2003). Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America. Clin Genet, 64(5), 382-397. 
8. de Serres, F. J., Blanco, I., & Fernandez-Bustillo, E. (2007). PI S and PI Z alpha-1 antitrypsin deficiency worldwide. A review of existing genetic epidemiological data. Monaldi Arch Chest Dis, 67(4), 184-208. doi:10.4081/monaldi.2007.476
9. FDA. (2017). Decision Summary for 23andMe PGS Genetic Health Risk Report. U.S. Food and Drug Administration Retrieved from https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN160026.pdf
10. GOLD. (2021). Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Retrieved from https://goldcopd.org/wp-content/uploads/2020/11/GOLD-REPORT-2021-v1.1-25Nov20_WMV.pdf
11. Greulich, T., Nell, C., Herr, C., Vogelmeier, C., Kotke, V., Wiedmann, S., . . . Koczulla, A. R. (2016). Results from a large targeted screening program for alpha-1-antitrypsin deficiency: 2003 - 2015. Orphanet J Rare Dis, 11(1), 75. doi:10.1186/s13023-016-0453-8
12. Grifols. (2017). FDA approval of genetic test for alpha-1 deficiency and EMA approval of fibrin sealant. Retrieved from http://www.grifols.com/en/web/international/view-news/-/new/fda-approval-of-genetic-test-for-alpha-1-deficiency-and-ema-approval-of-fibrin-sealant
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Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.  

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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