Adult Summary Report Secondary Findings in Adult Subjects Non-diagnostic, excludes newborn screening & prenatal testing/screening A Current Version Rule-Out Dashboard Release History Status (Adult): Passed (Consensus scoring is Complete) Curation Status (Adult): Released 1.2.2

Condition: Alpha-1 Antitrypsin Deficiency
Mode(s) of Inheritance: Autosomal Recessive
Actionability Assertion
Gene Condition Pairs(s)
Final Assertion
SERPINA10013282 (alpha 1-antitrypsin deficiency)
Assertion Pending
Actionability Rationale
This topic was initially scored prior to development of the process for making actionability assertions. The Actionability Working Group decided to defer making an assertion until after the topic could be reviewed through the update process.
Final Consensus Scoresa
Outcome / Intervention Pair
Nature of the
Gene Condition Pairs: SERPINA1 0013282 (OMIM:613490)
COPD / Smoking cessation
Liver disease / Limit alcohol consumption
Emphysema / A1AT augmentation therapy

Narrative Description of Evidence
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Condition
Alpha-1 Antitrypsin (A1AT) deficiency (defined by A1AT level) occurs in approximately 1 in 5000 to 7000 individuals in North America and in 1 in 1500 to 3000 in Scandinavia. Severe A1AT deficiency is most commonly found in Whites, followed by Hispanics and African Americans with the lowest prevalence among Mexican Americans and none among Asians. Less severe A1AT deficiency genotypes occur more frequently in Mexican American or Hispanic American populations but remain rare among African Americans and absent among Asian Americans.
1 2 3
Clinical Features
(Signs / symptoms)
A1AT deficiency is characterized by an increased risk for chronic obstructive pulmonary disease (COPD; defined as emphysema, persistent airflow obstruction, and/or chronic bronchitis) in adults; liver disease in children and adults; panniculitis (inflammation of subcutaneous adipose tissue); and c-ANCA-positive vasculitis (microscopic polyangiitis, Churg-Strauss syndrome, or granulomatosis with polyangiitis). The frequency of A1AT-associated COPD cases is about 1-2% of overall COPD patients.
A1AT deficiency in the lung results in reduced inhibition of neutrophil elastase (increased in smokers) and excessive destruction of alveolar wall elastin. In hepatocytes, protein products of pathogenic alleles accumulate and polymerize causing liver disease.
1 3
Natural History
(Important subgroups & survival / recovery)
Severity of disease depends on genotype as well as environmental factors (see section on Prevalence of Genetic Mutations for an overview of genotype designations for A1AT deficiency).
Liver abnormalities develop in only a portion of children with AATD. The overall risk that individuals of PI*ZZ genotype, the most common and severe deficiency genotype, will develop severe liver disease in childhood is low, about 2%. Up to 20% of adults of the same genotype develop liver disease (primarily cirrhosis and fibrosis) by age 50 years; risk may be higher for males and peak in the 6th decade. Prevalence of liver disease may be highest in individuals who have never smoked and do not have COPD (as high as 40% in older individuals, based on autopsy studies). The risk for hepatocellular carcinoma in PI*ZZ individuals is elevated compared to those with liver cirrhosis but no A1AT deficiency. Individuals of PI*SZ genotype, the next most severe, are not at high risk for liver disease.
Emphysema is the dominant pulmonary lesion in A1AT deficiency and the most common manifestation of the disease. Patients with severe (serum A1AT levels ≤ 11 uM or PI*ZZ) A1AT deficiency are at high risk and those with intermediate (A1AT levels 11-20 uM or PI*MZ, *SS, or *SZ) deficiency are mostly at low risk of lung disease. However, the 20% of PI*SZ individuals with low A1AT levels are known to be at increased risk. A1AT deficiency-related emphysema changes are typically more pronounced in the bases of the lungs, in contrast to the usual pattern of upper lobe involvement. Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Active smoking is the most important additional risk factor for the development and course of lung function deficits and COPD. Onset of respiratory disease is usually between ages 40 and 50 years in smokers. Individuals with A1AT deficiency, who have never smoked, rarely develop respiratory symptoms before the 5th decade and detectable impairment by lung function tests does not occur before the 6th or 7th decade. For non-smokers, some never develop COPD and may have a normal lifespan. Other environmental and genetic modifiers may also be independent risk factors.
Chronic bronchitis may occur in 20 to 34% of A1AT deficiency cases overall, but in up to 59% of those who smoke. Bronchial hyper-responsiveness is common among A1AT-deficient individuals, with asthma reported at a frequency of 4 to 34%.
Among patients enrolled in the NHLBI Alpha-1-Antitrypsin Deficiency Registry (severe A1AT deficiency, mean age 46 years) who had not been treated with A1AT augmentation therapy and had been followed for at least 6 months and up to 5 years, 5-year mortality was approximately 33% for those with FEV1<50% at enrollment (n=122) and 3% for those with FEV1≥50% at enrollment (n=204).
1 4 5 6
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with A1AT deficiency, evaluations of lung (pulmonary function tests, chest CT), liver (including biopsy when clinically indicated), skin (assessment for panniculitis), and vasculature are recommended. (Tier 3)
Patients identified as having A1AT deficiency should be offered a referral to a specialist center for clinical management of this condition. (Tier 2)
Recommendations on the use of A1AT augmentation therapy in patients with A1AT deficiency are conflicting. While guidelines based on evidence do not recommend augmentation therapy. (Tier 1)
7 8
Other guidelines that include expert consensus indicate that augmentation therapy may be considered. (Tier 2)
9 10 11 12
Most of these latter recommendations provide specific criteria for treatment such as age (aged 18 or older), severity of A1AT deficiency (A1AT concentration ≤50 mg/dl), smoking status (ex- or former smokers), documented COPD due to emphysema (e.g., FEV1 25-80% of predicted value), and genotype (PI*ZZ or PI*null cases). Studies on the effectiveness of augmentation therapy are conflicting. Nonrandomized registry data studies have reported non-significant improvements in loss of lung density based on CT scans and decline in FEV1. One study of registry data indicated improved survival (relative risk = 0.64, 95% CI: 0.43-0.94). However, these studies may be biased, as subjects were not randomized and decisions about treatment were made by the clinician. Randomized controlled trials published to date are small and report no significant benefit of augmentation therapy. No studies to date have shown improvements in quality of life or exacerbations.
Vaccination against hepatitis A and B is recommended. (Tier 3)
Patients with severe A1AT deficiency should undergo pulmonary function tests (including spirometry with bronchodilators and diffusing capacity measurements) every six to 12 months. (Tier 3)
All individuals with the PI*ZZ genotype (including those who did not manifest liver disease in childhood) should undergo periodic evaluation of liver function and screening tests to detect the presence of severe fibrosis or cirrhosis. (Tier 3)
Circumstances to Avoid
Alcohol consumption should be minimized. (Tier 3)
Smoking, both active and passive, should be avoided. Smoking cessation should be encouraged for all individuals who smoke. (Tier 4)
Although evidence on the relationship between awareness of AAT deficiency and smoking cessation is limited, information about genetic predisposition to lung cancer has been shown to increase quit attempts. There is evidence that adolescents aware of AAT deficiency status are less likely to start smoking than their peers. (Tier 3)
Reduction of total personal exposure to occupational dusts, fumes, and gases and to indoor and outdoor air pollutants may be more difficult but should be attempted. (Tier 4)
The Lung Health Study, which was not specific for A1AT deficiency, evaluated the effects on symptoms of chronic cough, chronic phlegm production, wheezing and shortness of breath. The prevalence of each of the four symptoms in the two intervention groups was significantly less than in the usual care group (p<0.0001). Smokers with early COPD who were assigned to a smoking cessation intervention had fewer respiratory symptoms after 5 years of follow-up. (Tier 3)
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
Prevalence of Genetic Variants
A1AT deficiency results from the presence of one or two deficiency alleles for the SERPINA1 gene. The protein product of this gene, sometimes referred to as protease inhibitor (PI), can be characterized in the clinical laboratory to determine an individual's A1AT phenotype. The PI*M phenotype is normal, while PI*Z is the most common deficiency phenotype followed by PI*S. PI*ZZ reflects a genotype of 2 deficiency alleles and is associated with serum levels of A1AT at 10-20% of normal. PI*ZZ is the genotype of 95% of affected individuals with clinical manifestations of A1AT deficiency. The remaining are linked to PI*SZ and many other rare null (level of A1AT is 0) or other genotypes. Individuals of PI*MM, *MS, *MZ, and *SS genotypes are considered to be at background risk for disease manifestations. (Tier 4)
Estimated prevalence (1/x):
Asian 0 0
Black 153,000 17,500
Hispanic 12,000 1,100
Mexican 0 0
White 4,500 1,100 (Tier 5)
1 2
(Include any high risk racial or ethnic subgroups)
Risk of emphysema:
PI*ZZ: 80-100%
PI*SZ: 20-50%
PI*SS: Background
Null-Null: 100% (Tier 3)
Risk of cirrhosis:
PI*ZZ and age >50: 15-19%
PI*SZ: Not found
PI*SS: Not found
Null-Null: 0% (Tier 3)
1 14
Risk of hepatocellular carcinoma:
PI*ZZ: 1.5% (Tier 3)
Relative Risk
(Include any high risk racial or ethnic subgroups)
No relative risk estimates were found.
Phenotypic expression varies within and between families. Smoking or occupational exposures can accelerate lung disease, but do not account for all variation in disease expression. Genetic modifiers that remain poorly understood likely account for some variability. (Tier 3)
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions consist of avoidance of smoking and environmental irritants, vaccines to prevent lung and liver infection, non-invasive lung function tests, imaging procedures, and invasive liver biopsy if clinically indicated.
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
A poll of 304 individuals diagnosed to have severe A1AT deficiency found an average delay of 7.2 years between the first onset of symptoms and the initial diagnosis of the condition; 43% of respondents reported seeing at least three physicians and 12% reported seeing 6-10 physicians before the correct diagnosis was made. (Tier 3)
A1AT deficiency is significantly underdiagnosed with as many as 90% of cases going undetected. (Tier 3)
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Gene Condition Associations
Condition Associations
OMIM Identifier
Primary MONDO Identifier
Additional MONDO Identifiers
Reference List
1. Alpha-1 Antitrypsin Deficiency. In: Stoller JK, Lacbawan FL, and Aboussouan LS, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from:
2. de Serres FJ, Blanco I, Fernandez-Bustillo E. Ethnic differences in alpha-1 antitrypsin deficiency in the United States of America. Ther Adv Respir Dis. (2010) 4(2):63-70.
3. Janciauskiene S, Ferrarotti I, Laenger F, Jonigk D, Luisetti M. Clinical utility gene card for: alpha-1-antitrypsin deficiency. Eur J Hum Genet. (2011) 19(5).
4. Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med. (1998) 158(1):49-59.
5. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health Organ. Bulletin of the World Health Organization. (1997) 75(5):397-415.
6. Senn O, Russi EW, Imboden M, Probst-Hensch NM. alpha1-Antitrypsin deficiency and lung disease: risk modification by occupational and environmental inhalants. Eur Respir J. (2005) 26(5):909-17.
7. Chronic obstructive pulmonary disease: Management of chronic obstructive pulmonary disease in adults in primary and secondary care. NICE guideline. Publisher: National Clinical Guideline Centre. (2010) Website:
8. Gotzsche PC, Johansen HK. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Cochrane Database Syst Rev. (2010)
9. Casas F, Blanco I, Martinez MT, Bustamante A, Miravitlles M, Cadenas S, Hernandez JM, Lazaro L, Rodriguez E, Rodriguez-Frias F, Torres M, Lara B. Indications for active case searches and intravenous alpha-1 antitrypsin treatment for patients with alpha-1 antitrypsin deficiency chronic pulmonary obstructive disease: an update. Arch Bronconeumol. (2015) 51(4):185-92.
10. Global Initiative for Chronic Obstructive Lung Disease. Global Strategy for the Diagnosis, Management, and Prevention of COPD. Publisher: Global Initiative for Chronic Obstructive Lung Disease (GOLD). (2016) Accessed: 2016-02-09. Website:
11. Koblizek V, Chlumsky J, Zindr V, Neumannova K, Zatloukal J, Zak J, Sedlak V, Kocianova J, Zatloukal J, Hejduk K, Pracharova S. Chronic Obstructive Pulmonary Disease: official diagnosis and treatment guidelines of the Czech Pneumological and Phthisiological Society; a novel phenotypic approach to COPD with patient-oriented care. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. (2013) 157(2):189-201.
12. Marciniuk DD, Hernandez P, Balter M, Bourbeau J, Chapman KR, Ford GT, Lauzon JL, Maltais F, O'Donnell DE, Goodridge D, Strange C, Cave AJ, Curren K, Muthuri S. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J. (2012) 19(2):109-16.
13. VA/DoD Clinical Practice Guideline for the Management of Chronic Obstructive Pulmonary Disease. (2014) Website:
14. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. ALPHA-1-ANTITRYPSIN DEFICIENCY; A1ATD. MIM: 613490: 2016 Aug 04. World Wide Web URL:
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